Chapter 15 –understanding expensive drugs

“We shall find the answer when we examine the problem.  The problem is never apart from the answer.  The problem is the answer.”  Bruce Lee.

1. SETTING THE PRICE

“The cost of a thing is the amount of what I will call life which is required to be exchanged for it, immediately or in the long run.”
― Henry David Thoreau, Walden

To appreciate how and when Pharma learned it can charge as much as it thinks it can get away with, it helps to scrutinize the price trajectory of Gleevec.  The first of many drugs that attacked cancer in a new manner, its cost was high and kept rising.  No one seemed to care and the other pharmaceutical manufacturers noticed. 

Malignancies start when a newly born single celldoesn’t die when it’s supposed to.  It reproduces relatively rapidly; its offspring learn how to escape detection by the body’s immune system; it spreads; and it takes root in distant parts of the body.¹⁵    

When I entered medical school in 1958, aside from nitrogen mustard derivatives, cancer altering chemicals were virtually non-existent. In the subsequent decades a number of drugs that attacked rapidly growing cells, malignant or otherwise, were developed.  In the 1960s doctors started using combinations of several of these medications to cure some lymphomas and leukemias.  The chemicals also commonly eradicated a few uncommon malignancies—like some metastatic testicular cancers and choriocarcinoma.   

Our medications were toxic and often caused major side effects, but when they were given to people with widespread cancers, tumors would shrink and some lives were extended. 

They were later used to destroy “probable” metastases. We knew that malignant cells from some surgically removed cancers had already seeded parts of the body. The “seeds” were not visible, not detectable; but we could identify the cancers that were at risk, the tumors that would statistically benefit from chemotherapy. 

Gleevec (Imatinib), a “small molecule”, was the first of many drugs that attacked cancer in different way. Conceived and fully developed over many years in the labs of big Pharma, it changed the way the industry valued the drugs we use to treat certain malignancies.  At $26,000 a year (in 2001), the medication’s introductory cost was deemed “high but fair” by the Chairman and CEO of Novartis. Then the company started increasing the price in parallel with “the purchasing power of money.”  After 2005 yearly boosts started exceeding inflation by 5 percent, and the government did not significantly object.  By 2007 Gleevec was costing consumers “$3,757 a month ($45,000 a year).”  Again there were no substantial objections. The cost of the drug took off in 2009.  Its price point passed $60,000 in 2010, and it exceeded the $100,000 a year mark in 2013.¹

 The approach helped lead to a new valuation model.  Certain classes of medications fresh out of the gate had exorbitant “list prices” and their cost was “adjusted” annually—often in an upward direction.

The product of decades of research at the Ciba-Geigy labs in Basel Switzerland, Gleevec was discovered by a research team chasing a dream, a theory, a hypothesis.  Alex Matter, a Swiss M.D. advocated looking for a small molecule that would get inside cancer cells and stop them from growing.

“Inspired by the likes of Louis Pasteur and Marie Curie”,  Matter was 12 years old when he began dreaming that he would one day be involved in the discovery of important new medicines.”  I don’t know if he ever practiced medicine, there’s not much written about his private life, but in 1983 he became a Ciba researcher in Basel,  a centuries old city that straddles both shores of a bend in the Rhine River.  

At the time he was apparently wondering what happens when the offspring of a normal cell turns out to be cancerous.  Could it be that one of its numerous tyrosine kinase enzymes, proteins that “function as an “on” or “off” switches, gets stuck in the “on” position, and causes the cell to grow and grow”?

Each part of the body is made up of cells.  Within each of these small units, traffic is directed down various metabolic pathways by enzymes called kinases.¹⁶ These enzymes control the functions of cells.  At the appropriate time they cause them to “grow, shrink, and die.”  Malignant tumors are sometimes created when one of the kinases gets stuck in the pro-growth position.  The cells don’t die when they are supposed to, and the collection of abnormal cells gets bigger and spreads.

What if we could block a corrupting kinase without harming a cell’s other 90 or so tryosine kinases?  Could we cure that cancer?  That was the dream.

Kinases have inlets on their outer surfaces.  When these are filled by a small molecule that “fits,” the cell dies.  Locating the bad kinase and plugging it with the appropriate small molecule is a little like finding a needle in a haystack.  But that’s what the Swiss Geigy team lead by Alex Matter and Nick Lydon set out to do.  They started with a small molecule that they knew would selectively inactivate one and only one of the 90 or so “tyrosine kinases” found in each cell.  Making various small alterations to the protein, they created new molecules and tested them one by one.  A few seemed promising.  Gradually they made dozens of blockers, each of which inhibited the activity of one and only one kind of kinase.  The project took years and must have been quite costly. Geigy funded the studies “reluctantly.” At the time Matter’s was told to keep investigating other approaches to cancer.  The kinase program was supposed to be “very very small—hidden in plain sight. “

In the 1980s Lydon went to Boston in search of a cancer that might be susceptible to one of his kinase inhibitors.  He met Bryan Drucker, a lanky, soft-spoken physician from St. Paul Minnesota who had spent 9 years at the Dana Farber Institute.  He was studying chronic myelocytic leukemia and was interested in the drug.²⁸ For technical and legal reasons—lawyers for the Swiss company and the Dana Farber institute “could not find agreeable terms”–it took a few years before Drucker, then in Oregon, was able to obtain and test the kinase inhibitors.  When he did, he found a blocker that caused chronic myelocytic leukemia (CML) cells to die.

Most cases of Chronic Myelocytic Leukemia (CML) are caused by a genetic accident.  The tips of two chromosomes have “broken off”, switched location, and fused.  The resulting “hybrid” gene, called the Philadelphia chromosome, causes the abnormal cells to keep reproducing themselves. The defect had been elucidated and explained a decade earlier by a hematologist named Janet Rowley.

In the absence of a marrow transplant Chronic Myelocytic Leukemia (CML) was usually lethal.  If a person had an HLA identical sibling, and if they underwent a stem cell transplant, they subsequently had a 60-80% chance of surviving and being disease free five years out.  Without someone else’s’ bone marrow, half of the affected were dead in 3 years; less than one in 5 lasted 10.²

But now a dream was being realized.  A small molecule could selectively inhibit an enzyme and control or cure cancer.  Turning the protein into a drug a human could use required proving its safety in animals, then people.  Several hundred million dollars needed to be spent before the company could market the medication.  And it would only help a few thousand people.

Novartis (the company created by the Ciba-Geigy—Sandoz merger) decided to give the chemical a shot, to see what it did to the cancer in question.  It proved to be amazingly effective.  Chronic myelocytic Leukemia wasn’t cured but it became a chronic disease, and an entirely new era of research was launched.

The first clinical trial of Imatinib mesylate (Gleevec), took place in 1998.  In 2001 the FDA approved the new medication and granted Novartis a 5 year monopoly.

When it first came out the company knew that when patients had CML—chronic myelocytic leukemia, and they took a Gleevec pill each day, they were alive and well three years out.  But they worried because most cancers eventually become resistant to therapy.  They were pleasantly surprised.  Gleevec and a slightly altered later iteration “changed the natural course of the malignancy. 

Each year an additional group of people developed CML, and they started taking a pill a day for the rest of their lives.  A 2015 study of people who had taken the drug for 10 years, found that 82% of them were alive and progression-free³.”    By 2018 “an estimated 8,430 people in the United States” were living with the diagnosis.

And they were living with the price– which “passed $60,000 a year in 2010, and exceeded the $100,000 a year mark in 2013⁴.”  The increases “sparked a nationwide conversation on cancer drug prices and value.”

Then the first generic form of the drug entered the U.S. market and it wasn’t much cheaper⁵. (Though it was sold in Canada at a third the U.S. price.)    

 In 2015 Novartis sold $4.65 billion of the drug.  Between 2001 to 2011, sales of Gleevec world wide totaled $27.8 billion.  Its 2015 price in the U.K. was “$31,867, France paid $28,675 and Russia spent $8370⁶.” 

The company, no doubt, spent millions, maybe more than a billion dollars over the years bringing a great drug to market.  But even if the initial price reflected their research and development costs, it clearly had little bearing on the subsequent annual increase in the price point.²⁵  

In the U.S the consumer typically pays a percentage of the official list price for the very expensive medications.  By 2014 the drug’s list price was close to a $100,000.  Medicare is (by law) not allowed to negotiate.  Insurers and pharmacy benefit managers can bargain.  They sometimes obtain significant rebates and discounts, but they are usually not passed on to the consumer. Our current system creates a burden for many⁷.     

In 1970 India allowed drug makers to patent their manufacturing processes but not the active chemical or the drug.  As a result a number of cheap generic drugs were developed and marketed. In 1993 Novartis filed a patent application for Gleevec and in 1998 they filed a patent for a new form of the medication.  A few years later India joined the World Trade Organization, and started allowing companies to patent the drugs themselves.  That year Novartis filed a patent for the 1998 form of Gleevec, and their claim was challenged and rejected.  The court felt the company didn’t prove the new iteration worked better than the form that was being sold in India.  They accused the company of “evergreening”, extending the life of a medication by altering it just enough to warrant patent extensions without changing the underlying mechanism of the drug.”  Indian law seems to be more in tune with the needs of their nation’s people than they are with the tricks used by the powerful pharmaceutical industry to further enrich itself.⁸

Novartis researchers, looking for a molecule that was as effective as or better than Gleevec,” modified the protein and tested some of their creations.  One of the new molecules, Nilotinib (Tasigna), did a better job at targeting the kinase in question.  It rescued some people whose disease no longer responded to Gleevec.  In new patients it more rapidly and effectively reversed the biochemical markers of chronic myelocytic leukemia. But it was not better than Gleevec at halting disease progression–and it wasn’t worse.  In 2007 the FDA released Tasigna and Novartis started selling it.  A few years later a Canadian study showed that 5-6% of people treated with the new medication developed an arterial disease and had a heart attack, stroke, or some other “atherosclerosis-related ailment.”  The FDA allowed the company to keep marketing the medication, but Novartis had to put a black box warning on the drug insert⁹. 

The year Nilotinib was approved it was costing people $6900 a month. (Median monthly payment). 7 years later, a month of medicine was costing $8806.  According to the watchdog web site FiercePharma, generic Gleevec was selling for as little as $40 to $50 a month in 2018.  That year Nilotinib was expecting revenues in excess of $2.5 billion.  Some doctors and people seem to believe that newer is better. 

Researchers for Bristol Myers Squibb created another drug that successfully controlled CML: Sprycel (dasatinib).  Like Nilotinib it “produced a faster, deeper response,” but didn’t make people live any longer.  It also did not significantly price compete.  When approved by the FDA it sold for $5477 a month.  In 2014 its monthly list price was $9300.

On August 1, 2019 the New England Journal of Medicine published a study that showed that Ibrutinib, a small molecule– kinase inhibitor that interferes with signals within lymphocytes– improves the survival of people with Chronic Lymphocytic Leukemia.  Its side effects: hypertension and heart rhythm problems, were discussed in great detail, but its cost was treated as little more than an afterthought. “Indefinite use of Ibrutinib therapy has been associated with substantial expense.”  To the authors and editors of the journal, a price that made a medication unobtainable for some was not a significant side effect. “The typical cost of ibrutinib in the United States will be about $148,000 a year”.  People insured by Medicare D typically have co-pays that are 1/3 of the list price.

A second inhibitor of the tyrosine kinase that lymphocytes need to survive, Acalabrutinib, was approved for sale in the U.S. in 2017.  It was created by a Dutch-run startup and was developed in the biotech center of the world, California.

In 2018, the cost of 30 days’ treatment with the Dutch drug, Acalabrutinib was $14,064.  Thirty days of Ibrutinib was costing $12,180. Competition didn’t seem to significantly affect price.²⁷ 

Our “free enterprise capitalist economy” encourages innovation by protecting the price of a new medication with patents and a multiyear FDA granted exclusivity.  When their monopoly ends, theoretically at least, the amount manufacturers charge should be modified by competition. 

When Roy Vagelos was head of Merck, the company “vowed to only increase prices in line with the Consumer Price Index, plus or minus one percent.  About half the industry followed suit.”  When some companies used loopholes in the drug laws to extend the patents of their successful drugs, Vagelos refused to join in.

Vagelos, a physician and academic lipid researcher, became the company’s CEO in 1966. The son of immigrant Greeks, as a young man Roy worked after school in the family restaurant.  In his free time he played the violin.  His father’s father had been a physician in the old country and had died young, and Roy’s father felt that to succeed in life his son would need a good education.  Vagelos studied hard and went to college on a scholarship.  He always remembered the Johns Hopkins interview.  It was going well but ended abruptly when the man conducting the interrogation learned the young man’s parents had not gone to college.  As a university student Vagelos developed a love for chemistry.  During his first year in medical school he “had a very tough time because he had a terrible memory.  Anatomy almost wiped him out.”  Fortunately, there was also biochemistry and he “survived” and became a talented researcher.

Under Vagelos’ leadership Merck developed Lovastatin and Simvastatin, the first drugs that limited the body’s production of cholesterol.  The company then sponsored studies that proved that the drugs lowered the risk of heart attacks and death.

Merck started in Germany in the 1800s and opened its U.S. branch in 1891.  In its early days it made medicinal morphine and codeine, and it had been the birthplace of one of the first medical books for the masses, the Merck Manual.  While Vagelos was in charge, one of the company’s labs developed a drug that killed a number of the worms that attacked cattle, sheep and horses.  Called Ivermectin it was marketed as a means of preventing heartworm in dogs, but it didn’t do much for the hookworm like parasites that lived in the intestines of man.  Its commercial value seemed limited.  Further research on the chemical was suspended, and it was shelved until the day that Mohammed Aziz, a staff researcher, met with Vagelos and got permission to perform additional studies.  Aziz had been in Africa and had seen people infected with the filariae that caused river blindness.  100 million Africans were at risk for the condition and the parasite had blinded 18 million of them.  The invading worm existed in two forms: adults, which can be 6 to 15 inches long and exist as lumps under an infected person’s skin; and the filariae, a small organism that infiltrated the skin and caused intense itching.  The black fly that lived in the river spread the parasites from one person to the next.

People who had the problem were constantly scratching themselves.  When kids scraped their skin, then touched their lids, the microfilaria got into their eyes.  The subsequent eye inflammation, lead to scarring and blindness.  In some villages 25% of the inhabitants couldn’t see.  In an attempt to escape, many moved away from the river to less fertile ground and suffered from malnutrition.

Ivermectin, a Merck drug that had been one of the large pharmaceutical company’s financial failures, destroyed the filariae that attacked horses.  Aziz suggested it might have an effect on the creatures that blinded so many Africans.  Merck produced a quantity of pills, and Aziz went to Senegal to study their effect. Pinch biopsies of the skin of infected people showed huge numbers of the filariae.  Half of the people who were infected got a pill and the other half didn’t.  A month later a second biopsy showed the filariae had been eradicated from the people who had been treated.

Based on the positive results Merck spent years performing tests that proved Ivermectin was safe and effective.  Then they went to the African leaders and tried to sell it for a dollar a pill.  The government had no money. The discussion went something like: OK, 50 cents a pill, a dime.  The governments really didn’t have enough money.  The World Health Organization was spraying rivers with insecticides (though the black flies were already becoming resistant to the spray).  The WHO wasn’t interested. Officials in the U.S. State department and at the White House were excited but “the government was broke.”  (Ronald Reagan was president.)  The French were about to approve the drug. (There were cases in Paris that had originated in colonial Africa), but in the U.S. the FDA wasn’t interested.

Merck was in business to make money and to enrich its officers and stockholders.  But the drug was ready.  These were the 1980s, and Roy Vagelos was a doctor as well as a business man.  The leadership at Merck decided they would provide the medication free of cost to anyone who would use it.  They had spent millions to develop the medication.  Providing it gratis would cost the company (and its shareholders) tens of millions of dollars, but Vagelos made the announcement and waited to see how the stockholders would react.  He claims he received a lot of positive feedback but he didn’t get one negative letter.  For years, thereafter, the best of the best researchers in the country wanted to come to and work for Merck.  And Vagelos stayed on as head of Merck for an additional 6 years.

When he reached the mandatory retirement age in 1994, Merck “was number one in sales, size, and marketing force”.  As a successor Vagelos recommended a number of Pharma savvy colleagues, but the world was changing.  The board chose a real business man—a non-scientist, Harvard MBA, and former CEO of a medical device company named Ray Gilmartin.¹³

In 2017 Roy Vagelos, former CEO of Merck took part the great debate on the ethics of drug pricing.  He wasn’t pleased with the way Pharma had changed.  He maintained that “The industry has a lousy image and it should, until it reforms itself.”  “He attributed Pharma’s failings to “a lack of understanding of what people respect, and a lack of respect for human beings.¹¹”

Some think the astronomical increase in drug prices was the result of greed.  Others blame the trust that pharmaceutical companies built during the early post world war 2 decades.  The healthy didn’t seem to detect the dramatic rise in medication fees, and the ill were too demoralized to speak up.  Too few of the people in power seemed to be paying attention.  Unlike the frog that, if placed in boiling water would have jumped out, the populace of the U.S. was plunked into cold water and we didn’t realize the liquid was slowly being brought to a boil. 

I don’t believe the leaders of industry are to blame.  They just did what comes naturally.  Congress passed laws, and lobbyists for the industry fashioned loopholes that could be exploited. Companies became corporations with stockholders.  CEOs reported to boards of directors.  Pharmaceutical companies acted more and more like real businesses.  In house investigators with quirky innovate ideas and notions were reigned in.  Researchers were increasingly tasked to focus, to develop marketable products.

After a specified number of years best selling drugs would lose their exclusivity and generic competitive products would enter the market.  If the company didn’t have an emerging replacement, revenues and the price of the company’s stock would fall. To maintain the bottom line industry leaders started raising prices. 

The initial price increases must have pleased stockholders and boards of directors.  If industry leaders wanted to keep their jobs or get bonuses they had to raise prices the subsequent year, and the year after that.  If a CEO wasn’t willing to charge substantially more each year he or she could easily be replaced.

Companies also exploited loopholes in the laws, rules that gave them a few more years of exclusivity.  For a blockbuster drug that meant at least an additional billion dollars of revenue per year.   Legal teams that took advantage of the cracks in the system proved they were worth the big bucks. (If a football team is losing by a touchdown and its coach doesn’t try an onside kick or a Hail Mary pass during the last seconds of the game –he or she is not trying to win, and will be fired.)  Corporations were in the business of making money.  Failure of a corporate lawyer to exploit the available legal gimmicks was akin to misconduct.

The increases started at companies with targeted treatments for cancer.  They “set the bar” that led to prices that “were many times more than most people’s yearly salaries, prices that were not necessarily related to value.” 

The true costs of getting a drug to market are a black hole and are largely irrelevant.   

The success of Imatinib-Gleevec showed researchers that it’s possible to develop small molecules that are highly specific to one of the hundreds of tyrosine kinase inhibitors, medications that can inactivate a specific critical enzyme in chosen targeted cell.  There were a few known targets.¹⁷—so called low hanging fruit– and researchers in startups and in the labs of big Pharma started making thousands of molecules and testing them with their biologic assays.  Not that it was easy.  Developing a molecule that targeted a specific genetic alteration took time, luck, optimism, and money.¹⁷.

Most of the targeted cancer drugs are made in the labs of big companies and we don’t know much about the true cost of their research and development.¹⁷   The Tarceva story provides a window.  An EGFR (epidermal growth factor receptor) blocker, in a minority of cancers it blocks the activity of a kinase that causes malignant cells to grow and divide.  It was developed by OSI (originally named Oncogene Science) a small pharmaceutical company that was founded by Gary Takata, a “shaggy-haired, Manhattan-based venture capitalist.  In March 1983 he persuaded an entire laboratory of National Cancer Institute scientists to join his new company and start developing drugs.²⁹ Located in Long Island, New York, it had twenty employees when Colin Goddard became its CEO in 1989.  There was a biology group and a small molecule discovery group. A Brit, its leader Goddard had a biochemistry degree.  He had been a runner and soccer player at his university and had considered a career in sports.  Then a friend developed a brain tumor, a Glioma, and Goddard decided “maybe there are other things in life to do besides play sports.” The startup was looking for a chemical that would block the action of EGFR.  They had a relationship with researchers at a nearby mega company, Pfizer, and people at OSI persuaded investigators at the big company to screen a number of their small molecules.  At the time Pfizer was evaluating molecules for a different cancer target: Her-2 Neu, and they needed a “control,” a pill that was harmless and had no therapeutic effect.  When they checked the compounds for OSI, Pfizer scientists identified Tarceva. OSI subsequently kept the “lead rights” to the chemical and Pfizer had some ownership.

Pfizer agreed to give the drug to a few people with advanced cancer and see what happened.  They bailed when they learned the drug caused a rash.

About this time Pfizer was buying the company that owned Lipitor.  It was an expensive hostile takeover, and Pfizer gave their Tarceva ownership back to OSI—free.  (They later went on to acquire the company that owned Lipitor.)

OSI raised $440 million, ran clinical trials, and found out their drug, in fact, made some people with cancer live longer.

A few years back an athletic, non smoking friend had a nagging back ache that kept getting worse.  An MRI showed bony defects caused by metastatic lung cancer.  His brain was involved, and it was radiated.  The X-ray treatment caused terrible side effects–a month of no appetite or thirst.  When he recovered he knew he was not interested in conventional, toxic chemotherapy.  But he spoke of a dream– of sitting on a boat in the bay and fishing.  Would that be possible?  His tumor was positive for EGFR and he was given Tarceva.  His back pain improved, he got stronger, and he was able fish and enjoy life for about a year.  Then the tumors in his brain started growing. 

Genentech and Roche bought $35 million worth of OSI stock and commercialized Tarceva.   The internet says Tarceva costs Americans $2600 a month.  That’s more than the British National Health Service was willing to pay.  In 2007 the Swiss drug maker Roche negotiated and agreed to cut the U.K. price from $2766 a month to $2133 a month.  The online Canadian pharmacy, Northwest, claims they get drugs from reputable factories in many parts of the world, then ship it directly to patients who mailed valid prescriptions.  Their price for brand name Tarceva 150 mg per month is $3174.  Their generic version goes for $1384 a month.  Approved by the FDA in 2004, it became a $94,000-a-year medication.  Genentech sold $564.2 million of Tarceva in 2011 and over a million dollars worth in 2016.  (An article in the LA times questioned its effectiveness.¹⁴)

In India, in 2012, the Cipla pharmaceutical company produced a generic version of Tarceva, and lowered the price of the medicine from $459 dollars a month to $182 dollars a month.  The Delhi court ruled that the Swiss patent was valid, but that the generic product didn’t infringe.¹²

Some argue that pharmaceutical companies make the majority of their profit in the U.S.  Our high prices are subsidizing the rest of the world, and people in other countries aren’t paying enough.

Others contend that Pharma makes so much profit in America that they don’t have to bargain in good faith with other nations.  When a company has a new important drug and there’s no competition they can hang tough.  Negotiators can pay the asking price (with a small discount); or they can leave it.

• DONATED & TAX DOLLARS

Your tax and donated dollars at work

This chapter takes issue with the Pharmaceutical manufacturer’s claim that they charge astronomically high prices for new drugs because research is costly and they need high profits if they are going to continue to play an important role in the development of the medical miracles of the future.

It tells the story of two recently marketed medications that improve the lives of people with metastatic prostate cancer.  Each drug was created with dollars (and pounds) supplied by taxpayers and charitable institutions.

The research labs of big Pharma were not part of the process– though Pharma did pay for most of the studies run on humans, and they did manufacture, distribute, and promote the medications, both of which have huge price tags.

I got interested in one of the medications after I spoke with a young man while our launch was speeding through the dark waters of the Grand Canal of Venice.  He explained he finally had enough money to bring his wife and child to Europe, thanks to a bonus he received.  He had recently acquired the rights to a new drug for the pharmaceutical company he worked for.  Called Enzalutamide it was a treatment for prostate cancer and it was going to be big.

Prostate cancer, one of the western world’s common lethal malignancies, was found in almost a quarter of a million American prostates last year, and it killed 33,000.  When advanced and widespread the disease is incurable, and if it grows in bones it can be quite painful.

Located between the bladder and the penis, a young man’s prostate is the size of a walnut.  It grows as men age and eventually becomes large enough to slow or obstruct the flow of urine.  Now and then a mutated cell reproduces more rapidly, lives longer, and its offspring form a cluster.  Over time there are additional mutations.  One of the abnormal cells can become cancerous, clone itself, and spread to other parts of the body.  Its growth and spread can be slowed or halted for a period of time by interfering with the hormone that fans the fire, by eliminating testosterone.

We’ve long known that male hormones encourage prostate cancer cells to grow faster, and that surgical castration is therapeutic.  The role of male hormones was firmly established in the 1940’s when a Canadian born physician, Charles Huggins, showed that metastatic prostate cancer could be controlled for a few years with surgical castration or female hormones.  During the subsequent decades orchiectomy– removing the testicles—commonly kept the cancer from growing for a period of time–after which the malignancy typically started expanding.

In recent years physicians have fought the malignancy with drugs that antagonize testosterone.  When the medications stop working and the disease becomes aggressive, the growth is usually stimulated by a protein inside the cancer cells, a molecule called the androgen receptor (AR).

And that’s what researchers at UCLA and Sloan Kettering tried to neutralize.  Funded by the government and people who donate money to prostate cancer research, the medical teams spent years developing a drug that could block the cancer cell’s androgen receptor (AR).  Starting with a protein that was known to have “a high affinity for the receptor, they spent years chemically altering it.” (Like– take a dress pattern and add one pocket or two pockets; a zipper or buttons.)  They added carbons, hydrogens, etc, came up with 200 candidate molecules.  They tested them in the lab, using “human prostate cancer cells that had been engineered to express increased levels of the receptor.”

Two of the 200 potential drugs seemed promising.  Well absorbed and not toxic, they were effective blockers.  UCLA patented the chemicals in 2006 and tested them on mice.  They worked, –stopped mouse prostate cancer from growing and spreading.

In 2005 Medivation, a San Francisco based “Biopharmaceutical Company” somehow learned about the drug.  Signing a license with UCLA they walked away with a majority of the patent rights.  In return they agreed to fund all costs associated with the development and commercialization of MCV3100 (Enzalutamide).

The next big study was probably not funded by Medivation.  It was performed in 2009 by the U.S. department of defense, and it showed that MCV3100 had “significant antitumor activity.”

In October of 2009 Medivation got a partner.  They made a deal with Astellas, a large Japanese pharmaceutical company.  Medivation received $655 million and Astellas got global rights” to the drug.  The two companies then financed a huge international assessment:  1200 men with metastatic disease got either the drug or a placebo.  The men who took Enzalutamide on average lived 5 months longer than those receiving placebo.  During the study treated patients had “a 37% reduction in the risk of death.”

FDA approved the use of Enzalutamide in men who had failed standard chemotherapy.  The initial planned price of Enzalutamide was $7450 a month— $59,000 for 8 cycles — $89,000 a year.

In 2014, based on a new study, the FDA approved the use of Enzalutamide as the first drug given to people with metastatic disease.  Patients didn’t have to first fail treatment with something else.  The new indication meant patients would live longer after they started therapy.  They would now ingest more pills and buy more medicine.  A year of therapy in the U.S. would cost $129,000.

Astellas had international rights and sold the medicine for a lot less in other countries.  A 40 mg pill, for example, was sold in the U.S. for $88.  Medicare paid $69.  And the price for the same product in Canada, France, and the U.K, was $20, $27, and $36.  In the two years between 2012 an 2014, Medicare’s Enzalutamide cost went from $35 million to over $440 million annually. 

The price Americans paid troubled some.  UCLA owned over 40 percent of the drug’s patent, and in 2016 sold their residual rights to Royalty Pharma for $1.14 billion—paid over many years.  They then settled for an up-front cash payment of $520 million.

In 2015 Astellas sold $2.2 billion of the drug.  The following year Pfizer bought Medivation for $14 billion, and in the first quarter of 2017 sold $131 million worth of the medication.

In the West it seems you almost have to get industry involved if you want to get a drug tested, approved, produced, distributed, and used.  Not that UCLA and Sloan Kettering didn’t know how to run a controlled trial.  They did.  But pharmaceutical companies have big bucks and are better equipped to coordinate the testing of over a thousand people in 15 countries.  They are experienced at moving drugs through the FDA and getting them approved promptly and efficiently.  And, of course, they know how to market.

Once corporations are involved, the price being charged has little to do with the cost of creating a drug.  In the case of Enzalutamide, before they could make a profit Pfizer had to sell enough high priced medication to recover their $14 billion investment.

In the Enzalutamide case many were happy.  UCLA got an infusion of cash.  The poor guy with prostate cancer got an extra 5 months of life, and according to Astellas, he didn’t have to go into bankruptcy to be treated.    ”80% of patients with Medicare or private insurance have a monthly co-payment of $25 or less. 2,000 men with poor or no insurance and household incomes of $100,000 or less received Xtandi free.”

The system we’ve created is not really “capitalism” and it’s not fair to call it “corporate welfare”.  It allowed the lead researchers to claim a”37.5% stake in the drug’s royalty interest.”  Private industry, investors, the Howard Hughes Foundation, and Medivation made money. 

Few seemed  troubled by the fact that a drug developed with public and donated money ended up enriching a few and selling for a pretty penny—a price that was usually paid by a needy taxpayer’s private or public insurance.

Bernie Sanders claims that in 2014 nearly one in five Americans between the ages of 19 and 64–35 million people – decided to NOT fill their prescriptions.  They decided the drugs cost too much. 

At the same time spokesmen for the pharmaceutical industry were repeating their mantra:  the high costs are needed to support medical research.   If we want to cure Alzheimer’s and cancer we need Innovation.

Enzalutamide’s chief competitor, Abiraterone (Zytiga), was created at Cancer Research UK, a charitable fund with its own research institute.  In 2012 an anonymous donor gave the organization ten million pounds, (13 million dollars) and asserted that “if you do what you’ve always done, you’ll get what you’ve always got.” Promoting scientists who “think differently,” the huge concern finances “the work of more than 4,000 researchers, doctors and nurses throughout the UK, and it supports over 200 clinical trials and cancer related studies.”  The drug its scientists created, Abiraterone (Zytiga), is a bit cheaper than the U.S creation, but for years it was pricey and not really affordable to a guy without good insurance.

Here again Pharma wasn’t brought in until the medication was created and was ready to be tested on humans.  And once more the enemy was testosterone. Researchers wondered if the cells had lost their dependence on male hormones—or if they were responding to testosterone made somewhere in the body.   What would happen, they asked, if a drug totally impeded a person’s ability to make male hormones–androgens?

The body makes male hormones and cortisone from cholesterol.  (Raisins and wine are made from grapes.)  Both use an enzyme, CPY17, for the conversion, and the reaction can be blocked by the antifungal agent, Ketoconazole.  All this was known.

Ketoconazole is toxic and in patients with prostate cancer it’s not a useful drug, so investigators decided to modify it.   Using three dimensional models an Institute of Cancer Research (IRC) team (working in a unit of Cancer Research UK) studied a number of compounds, and they eventually found one that worked.  It didn’t seem to be toxic and it “specifically and irreversibly” blocked CYP17.

The “team” filed a patent and licensed the drug to a German Pharma company, Boehringer Ingleman.  Phase one studies showed the drug blocked androgen and cortisone production in people, but the pharmaceutical company’s scientists believed that late stage prostate cancer no longer needed male hormones to grow.  Feeling they didn’t want to spend money on a lost cause, Boehringer returned the drug’s license and IRC started over.¹

Arguing that they wanted to get the drug into needy people’s hands as soon as possible, the IRC next assigned the rights for commercialization to publically traded BTG, a UK-based healthcare company.  BTG, in turn, licensed the product to Cougar Biotechnology.  And Cougar “began to develop a commercial product”.  Studies proved the drug worked, helped cancer patients.  In May 2009 Cougar was acquired by Johnson and Johnson for about $1 billion.  Two years later the FDA approved abiraterone’s use in combination with prednisone—a form of cortisone. (In addition to blocking the body’s production of androgens, Abiraterone blocks the body’s ability to produce cortisone, a hormone the body needs.)  Abiraterone was approved for use as a treatment for late-stage prostate cancer in men who have already received standard chemotherapy.  Called Zytiga, it initially sold for $5000 a month in the U.S., and it’s not a cure.  After a mean of 8 months the drug stops working or the average patient has died.  Thus the cost of treating a person was averaging about $40,000.

In the UK where it was developed by a charitably funded organization, the drug is marketed by Janssen.  Its original cost was 2930 pounds –$3820 a month, a price that British regulators (NICE) decided was not cost effective.  The National Health Service wouldn’t pay.  The company then negotiated.  The government was willing to walk away so negotiations worked.  The U.K. got a “deal.”  The NHS subsequently paid 2300 pounds ($3000) a month “for the first 10 months of therapy.  For people who remain on treatment for more than 10 months, Janssen agreed to rebate the drug cost of abiraterone from the 11th month until the end of treatment.”

By 2019 two additional very expensive drugs for prostate cancer:  apalutamide and darolutamide—had joined the fray, and the U.S. price of “full-dose abiraterone” had risen to $10,000 per month.  But a $2800 monthly generic form of the medication was now available; and a quarter of the initial dose of abiraterone was showing “similar benefits and similar pharmacokinetic and pharmacodynamic effects.²”

 “A decade ago cancer drugs cost around $5000 per month; that has now doubled to more than $10,000 per month.  I think (companies) charge what they think they can get away with, which goes up every year,” Peter Bach, MD, Sloan Kettering, New York. 

—-Is a pharmaceutical company really needed when we want to effectively manufacture and distribute an important drug?  The answer seems to be yes.

• SWISS MOVE IN

The Swiss take control 

Thirty percent of the money spent on pharmaceuticals is used to purchase a relatively small number of very expensive “designer” drugs.  The medications are often extremely pricey (in large part–I believe) because the company that produces and markets them needs to recoup the billions they paid to acquire the drug and/or the company that created it.

Novartis and Roche, two of the top 4 Pharma companies, with gross incomes in 2018 of $35 and $46 billion–are headquartered in Switzerland. I have no doubt they are two of the many “Pharma companies that seem to believe acquisitions are the only way to keep their revenues growing as fast as investors expect.  With today’s complex breakthrough medicines, it’s often cheaper for a company to acquire the next blockbuster drug than to develop it in-house.¹”

In 2006 Novartis paid $5.4 billion, took over Chiron, and planted its feet solidly on American soil.   The company they bought was 25 years old and had been created by Bill Rutter, a visionary biochemistry professor. 

The son of a Mormon elder from Liverpool England, Rutter was born and educated in Malad a small town in southern Idaho.  His grandfather had been a British Army officer in India and had told William about the poverty and exotic parasitic diseases he had witnessed.  As a youth William wanted to go to the school of tropical medicine in Calcutta. At age 15 he spent a year at Brigham Young University then lied about his age and joined the navy.  World War Two was raging.  When the conflict ended Rutter went to Harvard and was drawn to science.  After he graduated he was accepted to Harvard medical school, attended a few medical school classes with a cousin, and realized he wanted to be a scientist, not a doctor.  He earned a Ph.D. at the University of Illinois and spent a decade as a researcher and professor at the University of Illinois, Stanford, and the University of Washington.

In 1968, after refusing the job offer three times, he agreed to become the chief of the biochemistry department at the University of California in San Francisco.  The unit had been leaderless for six years and (he once quipped) “every good scientist in the United States had probably been asked to take that job and turned it down.” He claimed he accepted the post because twenty faculty positions were open, and that was a “bonanza for recruiting^1” Rutter gathered top notch researchers and got them to work collaboratively.   In academia investigators don’t always cooperate and share.  He knew “science was competitive.  “Everyone is trying to beat you and will use every trick in the book.  You try to cover your bets in many different ways.⁸”His associates shared their knowledge.

In 1981, deciding NIH would not allow him to use genetic engineering to develop a hepatitis B vaccine, he acquired venture funding, hired great researchers, and formed Chiron. “It was not an issue of damn the torpedoes, full speed ahead. The business of the company initially was research, pure and simple–understanding the potential of a set of technologies.  The major pharmaceutical companies didn’t want to become polluted by something that was “controversial” like genetic engineering, and they stayed on the sidelines.  He had great confidence he’d be able to do things that helped human beings.”¹⁴ 

.           The disease he wanted to put a stop to, Hepatitis B was caused by a virus.  It was present, though usually inactive, in the livers of over 200 million people, 1.2 million of whom were Americans.⁸  

Maurice Hilleman at the pharmaceutical company Merck had developed a vaccine that prevented the disease, by inactivating live viruses.  His creation was safe and effective but people were afraid to use it.  They recalled how, in 1955, the Cutter lab was making the Salk vaccine and failed to adequately kill the polio virus.  Two hundred children were partially paralyzed and 10 died. I remember British Liver Professor Sheila Sherlock giving a lecture to a group of doctors back then and asking how many had taken the B vaccine.   When but two hands went up she said: “Shame on you.  Shame.”

Rutter had worked with Herbert Boyer and others at the University of California.  He knew how to genetically engineer yeast and make it grow the shell of the virus.  Researchers could then use the viral surface protein to create the vaccine.  The idea of using implanted genes frightened some politicians, and the NIH might not fund the research.  “Some portion of scientists was genuinely concerned. Others enjoyed the debate and the public controversy.” 

There was a Senate hearing on the topic of genetic engineering and Bill Rutter attended.  Margaret Mead arrived wearing a huge long robe and carrying a shepherd’s staff.  “Adlai Stevenson, a Senator and a lawyer who would later run for the presidency of the U.S., ran the proceeding and introduced Margaret Mead as a world-renowned scientist who could give guidance on these issues.”  Mead was an anthropologist who became famous after she spent 9 months in Samoa and learned that “adolescence on the island was not a stressful time for girls because their cultural patterns were different than those in the U.S.”¹⁸

At the hearing stood and repeatedly said something like, “You’re going to hear today from these scientists that this (genetic engineering) is not dangerous. I’m here to tell you it is dangerous.” After each repetition of her statement she pounded the floor with her staff for emphasis. “Boom! Boom!¹⁶” To Rutter “A social anthropologist with her shepherd’s staff giving advice on molecular, microbiological, and physiological science’” seemed incongruous.  Observing the theatrics and attitudes Rutter realized that if he wanted to make the hepatitis B vaccine his way he would have to give up his job as chief of biochemistry and go private.

Growing the hepatitis B surface antigen in yeast, Rutter’s team “demonstrated how to do it in the laboratory.” Working with Merck, Chiron marketed a successful “B” vaccine.  Then, since the company had money and talent, their researchers solved a whodunit that had eluded investigators for years.  They identified the virus responsible for Hepatitis C, and we learned 200 million people worldwide and more than 2 million Americans were carrying the intruder in their liver.  Some of them would develop cirrhosis and liver cancer. 

Located in the right upper abdomen just under and below the ribs the liver is the body’s largest organ.  Blood carrying nutrients from the intestine, filters through it before it enters the circulation.  The organ metabolizes, detoxifies and produces needed proteins. It dumps unwanted wastes into the yellow bile that it secretes.  It’s also commonly infected by several viruses, two of which, Hepatitis B and Hepatitis C often set up shop and become lifelong inhabitants.

Over the next few years Chiron acquired a number of European and U.S vaccine businesses and became one of the world’s largest vaccine makers.  With a second company Chiron commercialized DNA and RNA tests that allowed blood banks to make transfused blood safer.  The process they developed could detect minute amounts of live hepatitis and HIV viruses in donated blood.  Chiron had a biopharmaceutical division, and to the displeasure of their Swiss partner Novartis, often participated in joint ventures with other pharmaceutical companies.  In 1984 their scientists worked on the first sequencing of the HIV genome, and in 1987discovered, sequenced, and cloned the Hepatitis C virus.⁸

In 2006, already owning 49 percent of Chiron, Novartis bought the other 51%, started wearing the mantle of a U.S. corporation, and began to act more like a commercial business.  In 2015 the company marketed and charged a little less than a competitor for the first U.S. biosimilar, Zarxio.  It’s a medication that stimulates the bone marrow to produce more neutrophilic white cells.  In 2018 Novartis paid $8.7 billion for the therapeutic gene that treated and hopefully prevented the worsening of spinal muscular atrophy, a lethal genetic disease. (As mentioned earlier they plan to sell the treatment to Americans for $2.1 million for a course of therapy.)

---

By 2009 the other Swiss giant, Roche, had a 15 year history pharmaceutical company acquisitions–like Syntex in 1994 and Chugai Pharmaceuticals in 2002.  Their CEO was an Austrian born economist.  Married with three children he skied, hiked, and made movies in his spare time.  Initially thought of as shy he led the company when it plunked down billions and entered the cancer drug fray.   Buying California based Genentech for $46.8 billion, Roche acquired a lot of debt and three antibodies that were used to fight cancer:  bevacizumab, herceptin, and rituximab.   They also had to deal with a “clash of cultures between a freewheeling Californian biotech company and a buttoned-up Swiss multinational.”  There was plenty that could go wrong. The California innovator “was full of smart people who were very upset and worried about the idea of another company coming in and making the decisions.⁶”

The cost of their acquisition virtually cemented Roche’s need to charge high prices and to sell a lot of these drugs.  If, at the time, some companies were uncomfortable charging a lot for anti cancer drugs, seems to me that they now no longer had much of a choice.  Their shareholders would (no doubt) expect little less than a $100,000 a year price tag for significant products.

The entity Roche purchased, Genentech had started as a company that used genetic engineering to produce hormones.  Hormones are molecules that are made in glands.  They travel to, turn on and off, and adjust the activities of target organs in various parts of the body.  

The existence of these important proteins was unknown before the 20^th century.  Prior to the 1970s they had been extracted from the glands of dead animals and human cadavers.  They were then purified and manufactured.  Contaminants were always a concern.

The seed that grew into Genentech was planted during a meeting that took place in 1973.  A scientist from UCSF and one from Stanford discussed the small collections of DNA in the cell’s cytoplasm.  They met at a conference in Hawaii and at the end of a long day “took in the balmy evening air as they strolled and talked.”¹²

One of them, Herbert Boyer, “blue jean clad, with a cherubic face; outwardly relaxed and unassuming”, grew up in a small railroad town near Pittsburg.  As a college student he had at times hitchhiked to classes at a nearby college.  Majoring in biology and chemistry he was “really taken with the Watson-Crick structure of DNA”, and he earned his PhD in bacteriology.  At age 37 he was a researcher at the University of California in San Francisco when one of his graduate students isolated an important enzyme.  It sliced DNA at a specific position.  The raw exposed nucleotide ends were sticky.  Lengths of DNA could be attached.

The other man who walked leisurely in the warm air that evening was Stan Cohen, a 36 year old “trim, bald, bearded” Stanford hematologist.  When he was young he wrote a pop song that made the hit parade.  He was studying circles of DNA in the cytoplasm of bacteria that were spreading antibiotic resistance from one germ to another—plasmids.

The two investigators wondered if it was possible to use Boyer’s enzyme to hook a DNA fragment, a gene, onto the sticky ends of a plasmid’s DNA.  Would the gene then tell the bacteria what to do and make? Would the transformed plasmid survive and clone itself?

It took a few months to do the research, but the following March they tested their idea and it worked.  In November 1974 both medical schools filed a patent application, and the academic world debated the potential hazards of genetic engineering.

Over the next few years, surviving on money gathered by a venture capitalist named Bob Swanson,  Boyer formed a company and called it Genentech.  In its early years the company made somatostatin.  A peptide that reduces secretory diarrhea and that blocks the action of some hormones like insulin and growth hormone.  The product was not a big money maker.

Genentech then produced genetically engineered human insulin.  At the time people were using purified animal insulin.  It’s chemically a bit different from human insulin, but it works well.  Genentech also produced genetically engineered human growth hormone. It too was not a big money maker.

In 1978 the start-up leased a 10,000 square foot section of an airfreight warehouse near the San Francisco Airport.

In 1980 the company’s technology was up and running and Genentech had a public stock offering.  It was wildly successful and Swanson, one of the founders, called gene cloning “the cornerstone of a future billion dollar business.”

During the next decade Genentech developed TPA, Tissue Plasminogen Activator, protein that dissolves clots.  It was used to treat “massive pulmonary embolisms” –blood clots that traveled from a person’s legs to their lungs.”

They also developed several cancer fighting medications.  One of them, the antibody Avastin, inhibited the growth of the blood vessels that nourished tumors.  In 2010 it generated $7.4 billion in revenue for its new Swiss owner, Roche. 

The concept that tumors produce a gene that stimulates the growth of the blood vessels that nourish it–wasn’t originally Genentech’s.  It was conceived of by Judah Folkman, a surgeon who would later quip that science goes where you imagine it.  As a boy, Judah accompanied his rabbi father when he visited people in the hospital. “His father would pray through oxygen tents and Judah would sit in a chair and be very quiet.  About age seven to eight he noticed doctors could open the tents and do things, and he told his father he wanted to become a doctor not a rabbi.  He thought his father would be upset, but has dad wasn’t.  He said you can be a rabbi-like doctor, and Folkman knew he thought it was fine”.²¹

 He served in the navy for two years, went to med school, and became a surgeon.  In the 1950s “he developed the first implantable pacemaker that targeted the atrioventricular region of the heart, and he “pioneered the first implantable polymers that allowed drugs to be released slowly.  And at age 34 Folkman was “the youngest ever Harvard Professor of surgery.¹⁷” He had a research lab and studied the blood supply of tumors.  By 1971 he had learned about the way cancers develop their blood supply and he shared his findings in an article in the New England journal of Medicine.

“The growth of solid neoplasms is always accompanied by vigorous new capillaries that come from the host.”  Time-lapse movies of an animal experiment demonstrated vessels advancing towards and penetrating a tumor implant and establishing blood flow.  If new vessels don’t develop, most solid tumors stop growing when they are 2 to 3 mm in size.  They don’t die but the growths become inactive.  Folkman’s lab isolated a factor that stimulated rapid formation of new capillaries in animals, and his people tried to develop an antibody to the factor.  They were not successful.¹¹”

Folkman kept promoting the concept of cancer enlargement being slowed by blocking a factor that stimulated blood vessel growth.  In the years that followed Folkman’s paper he noticed that when he rose to speak at medical meetings a number of doctors in the audience filed out.  Some physicians thought his idea was farfetched and were apparently tired of hearing his pitch.  Believing there’s a fine line between persistence and obstinacy Folkman kept at it.⁹

In 1989, a Genentech investigator isolated and cloned 3 isoforms of“vascular endothelial growth factor” (VEGF), a gene that caused blood vessels to grow.  Then they developed an antibody to VEGF.   Subsequently a slew of additional vascular stimulating factors have been discovered.

The researcher in charge of developing the antibody, Napoleone Ferrara, was born in Catania, a Sicilian town near the Mediterranean Sea and not far from the highest volcano in Europe.  His interest in science was ignited by his grandfather, a high school science teacher who had a 5000 book library.  The Sicilian went to medical school.  Then he heard the fascinating lectures of a charismatic Professor of Pharmacology named Umberto Scapagnini, and he decided to become a researcher.   Joining Genentech in 1988, Ferrara and his group spent years characterizing the protein and developing the humanized antibody that became Avastin.   The years of research were costly.  They were funded by Genentech, and the company was ultimately richly rewarded.  Ferrara was lecturing in Sienna the day he learned that a pivotal study had shown that his antibody successfully helped treat colon cancer.  He recalled he celebrated by drinking a whole bottle of Chianti.

Avastin remains pricey and is not always covered by insurers.  Using it can create an additional burden for people who are living on a tight budget and have widespread disease.⁷

In 2008 Roy Vagelos, the chief executive of Merck commented on the price trend.  His remarks were reported in the New York Times.  He said he was troubled by an unnamed drug (thought to be Avastin) that “costs $50,000 a year and adds four months of life.  He called it a shocking disparity between value and price.²”

Vagelos was 79 at the time.  His attitude and remarks were influenced by what he did when he was the CEO of Merck in the 1960s.  In his New York Times quoted speech he said the high prices charged for Avastin were, “not sustainable.”  He was wrong.

Keeping the price of Avastin high has been a struggle.  That year (2015) the British National Health Service and some insurance companies were disturbed by the thought of spending tens of thousands of dollars for the extra months of life the drug could provide.  Headquartered in Switzerland, Hoffman La Roche–According to “The Street’—had to resist an effort by many European countries to lower the price of their expensive, cancer fighting drugs.  “A bid to push down drug prices by the Swiss health ministry “infuriated drugmakers”.. and the company warned that such a move would hurt employment and would have a “negative impact on their future contribution to the Swiss economy.”  In the years subsequent to its release Avastin’s annual revenue always topped $5 billion.³

The second drug Roche acquired, herceptin, was also an antibody.  Most cancer causing genes “are sequestered deep in the cell.”  By contrast, the gene in question, neu, is connected to the cell membrane and “a large fragment hangs outside.”

It was discovered in the 1970s after a researcher (working with Robert Weinberg at MIT) injected the “DNA from neurological tumors in rats, into normal mouse cells.  The injected cells turned cancerous.”  After the gene was discovered it was “more or less forgotten,⁴” and largely ignored before one Genentech’s scientists, Axel Ulrich made an antibody that targeted it.

After Ulrich’s antibody attached to neu it created an abnormal complex.  A macrophage, a white cell that “engulfs and rids the body of cellular debris” would float by.  It would sense the antigen-antibody combination, know it didn’t belong, and clean up the “mess,” obliterate the antibody and the cell that it’s attached to.

Once created, the antibody to neu might have intrigued some people but it was not really useful. Ulrich talked about it when he gave a seminar at UCLA in 1986.  One of the attendees, Dr. Dennis Salmon, was interested.

A university hematologist, Salmon grew up in a coal mining town and, as a boy, had been impressed by the doctors who came to the house to tend to his father.  His dad survived two mine cave-ins, then lost a leg in an auto accident.  The doctors making house calls “made people feel better.”  Salmon “saw the respect my parents gave them. So (he) always thought it would make a pretty cool profession.”  In high school he “developed a keen interest in biology.” and in college he spent summers working in a steel mill.  The job was tolerable for a few months, but the experience showed him what his life as a factory worker could be like and it “cemented his resolve. This wasn’t what I wanted to do with my life.” After med school Salmon had offers, but took a job at UCLA because “It wasn’t ossified, and if you had some resources and a good idea, you could pursue it.¹⁵”

According to Mukherjee, Salmon thought he and Ulrich should collaborate.  Ulrich gave UCLA a DNA probe that identified neu, and Salmon checked his array of cancer samples to see if any of them were, perhaps, driven by the gene.  Until that time it had only been found in mouse brain tumors.  There didn’t seem to be much chance that it would turn up in a human tumor.

But it did.  The oncogene, now called Her-2/neu, was found in some breast cancers, and it turned out to be an important reason for their rapid growth.  Some breast cancers made and used it in large quantities.  Scientists implanted Her-2 containing cancers in a mouse and watched them grow wildly.  Traztuzumab, the antibody that inactivated Her-2 caused the cancer cells to die.

The scientific findings were intriguing, but it took a while before Genentech was fully committed to the idea of making a cancer drug.  It would be a first for them.  A drug that interfered with cancer was still a reach.

Salmon kept working the project.  They couldn’t use the standard mouse monoclonal antibody.  It could trigger an immune response.  They found a Genentech scientist who knew how to create a mouse that produced monoclonal antibodies that a body would think came from a human.  In the summer of 1990 they successfully created Herceptin.  Women with breast cancer became experimental subjects.  15 were studied in 1992.  900 were given the drug in 1996.  It kept making a difference.  When, in 1998, the drug application was submitted to the FDA it was quickly approved.  Its initial monthly price was $3,208.  It rose to $4,573–$54,000 a year in 2013.

The research and development costs were part of the overall lab costs of Genentech, and before the company found a useful antibody their scientists probably produced a lot of duds.  The overall cost of creating a new drug was significant.  Testing, development, and getting FDA approval cost a lot.   I suspect hundreds of millions of dollars were spent in the process.

But the reward, $6 billion plus a year, dwarfs the expenses.  The high price tag has little to do with research and development and much more to do with the way the market works.  The pharmaceutical manufacturer has a five year monopoly.  During that time they have no competition and can charge whatever they think they can get away with.  People with insurance often have a co-pay, and it can be substantial.  But no company would price compete.  They wouldn’t want to charge less for a new cancer medication.  Others might follow suit, and that might upset the apple cart.  To enhance stockholder value prices need to stay high.  And of course once they owned the drug the Swiss company Roche “needed” to recoup the $46.8 billion they paid when they bought Genentech in 2009.

When Roche announced their revenues in 2016, the third antibody they had acquired from Genentech, Rituximab topped the list.  With $7.3 billion in annual sales worldwide and $3.9 billion in the U.S., the drug was on fire.

When pharmaceutical spokes people justify the high price of drugs they commonly invoke the cost of research, but are unable to supply details.   Rituximab provides a window into how much it really costs to create an innovative medication when researchers have a strong sense of where they are going and how they are planning to get there.

Approved by the FDA in 2012 the injectable antibody has revolutionized the treatment of some lymphomas.   It targets a unique protein called CD20 that is found on the surface of only one kind of human cell: the B cell.  Part mouse and part human (chimeric) in origin, the antibody was first tested for dose and toxicity in 1994.  After rituximab is infused it circulates and “tends to stick to the side of B cells that’s rich in CD20.  Natural killer cells then destroy up to 80%of a body’s B cells.”

The drug was developed by a San Diego start up called Idec.  Its founders included several Stanford university researchers and Ivor Royston, a San Diego immunologist. 

The son of a Polish sheet metal worker who entered Great Britain via the beaches of Dunkirk, Royston always remembered the summer when he and his mother lived in the castle his father was re-roofing that was once the home of Henry VIII and Anne Boleyn.  In 1954 the family moved to America.  In the U.S. Ivor, a good student, went to medical school, and married.  His first wife’s father was a successful business man who liked to “challenge the young man with business problems.” If the son-in-law couldn’t solve the problem, his father-in-law would tell Ivor how stupid he was.”  Years later when he was running Idec, Royston “wasn’t afraid to get involved with business people because “if I could deal with my father-in-law, I could deal with anybody.”  

After medical school Royston carried out research at the NIH, became board certified in oncology and tried “to understand how the body recognizes cancer cells, and how can we get the body to make an immune reaction to cancer cells.”  When he was a low level research doc at Stanford, Royston was stirred when he learned how to make monoclonal antibodies. “You could produce antibodies by fusing lymphocytes with myeloma cells and create a cell that don’t die and keeps making antibodies.”  A colleague went to England, contacted the physicians who made the discovery, brought back cells from the “the myeloma line, the immortalizing cell line” and gave a few of the precious “hybridomas” to Royston.  Ivor spent the next 22 years trying “to figure out how to make antibodies against cancer cells.¹³”

From the outset (1985) Idec researchers were looking for a monoclonal antibody that could be used to treat B-cell lymphomas.  There are about 240,000 cases of the disease in the U.S. each year.  The antibody they were trying to develop could also be used to improve some autoimmune and inflammatory diseases.  Their efforts consumed millions of dollars.

In 1991 they needed more money and had an initial public stock offering.  The proceeds netted enough money to get through FDA phase one testing–(toxicity and dose) and phase 2: treating patients without a control group to see if the drug seemed to work.  The company had allegedly spent $80 million to this point.  But they did not have the money necessary to perform the phase 3, the double blind, control versus treatment group, studies that the FDA requires before they approve a drug.  The startup couldn’t get the medication to market.

In 1995 their CEO, a former Genentech guy, signed a collaboration agreement with his former employer, Genentech.  The giant chipped in $60 million and acquired “a majority of the sales and profits that Rituxan would generate if it earned FDA approval.”

It was initially approved in 1997.  Out of the gate Genentech charged $3475 for a month’s worth of the infusion.  In 2002 $1.47 billion of the drug was sold.  Genentech got most of the money.  Idec got $370 million.  By 2013 the average 30 day cost of infusions had gone up to $5031.

Vis-a-vis the price having something to do with the cost of development, Idec spent $80 million and walked away with $370 million.  Genentech spent $60 million and hit the jackpot.  The cost of research, development and getting the drug to market was $140 million.  In 2017 it brought in over $7000 million—$7 billion.

In 2017 the antibodies Roche acquired with Genentech accounted for more than half of the company’s revenue.  That year they sold $7 billion worth of Avastin; $7.4 billion worth of Herceptin; and $9.2 billion worth of Rituxan.⁵

• DOMINATING THE MARKET

 There are many reasons to question the widely held notion that high drug prices and innovative research are inextricably linked.⁹ EZEKIEL J. EMANUEL

For decades companies have been buying one another, combining, and attempting to control segments of the market.  Large pharmaceutical companies purchase small startups or large competitors to gain control of a drug and/or the technology that led to its creation.  Many acquisitions cost billions.  To survive the purchasing company has to sell a lot of product, so they market aggressively and charge as much as they dare.  And we all pick up the bill.

In 2011 Gilead bought Pharmasset for $11 billion and gained control of the company’s potent Hepatitis C medication, sofosbuvir.  When combined with a second, though less potent anti – viral, Pharmasset’s medication cured most people quickly with minimal side effects. Gilead researchers had developed a drug ledipasvir.  It suppressed hepatitis C, but when used alone it wasn’t curative. 

The drug combination was great news for the 2.7 to 3.9 million Americans and the 71 million worldwide who carry the bug.  Some of the people who are chronically infected with Hepatitis C develop cirrhosis or liver cancer; the virus is responsible for the deaths of 400,000 people each year.

Hepatitis C was identified in the 70’s by researchers in at the Emeryville startup called Chiron.  It’s one of several viruses that inflames the liver, turns a person’s skin and eyeballs yellow, and drains their energy.  It becomes chronic in 70-85% of those who acquire the disease when they are adults.   A third of the infected people develop cirrhosis, and they die within 20 years.  A third never have significant problems. And in a third the virus isn’t harmful for many years, but at some point, for some reason, their liver slowly and progressively becomes inflamed.

By contrast, hepatitis A doesn’t become chronic.  Hepatitis E can become a persistent problem in people who are immune-suppressed.  Hepatitis B usually causes a self limited illness in newly affected adults, but becomes a lifelong problem for infants who acquire the disease from their infected mother.

For decades “C” was treated and often cured with interferon.  A year long ordeal, the treatment consisted of weekly injections that cause fever and exhaustion.  The bad effects usually lasted a few days and subsided before it was time to get the next shot.   As I once explained to a young man who developed a fever and had no energy for the first two days after he received interferon:  “If you get an injection on a Friday you will be sick on Saturday and Sunday, but will probably be well enough to go to work Monday.  Would you like to be treated that way?” 

 “And ruin my weekend?” he shook his head.  “I don’t think so.”   He requested and I wrote for him a year- long excuse from work.

My colleagues and I treated hundreds of people using this regimen.  The process was emotionally trying, but the people who desperately wanted to be cured, endured the weekly draining days.  In a significant minority the treatment didn’t eradicate their disease.  For many that was heartbreaking.  

The doctors who developed the curative drug were scientists at Emory University.   One of them, Raymond Schinazi, was a Jew who was born in Alexandria Egypt.  In 1956 Israel and Egypt fought a war and Egyptian Jews became personae non grata.  His family moved to Italy, and he later studied at Bath in the UK.  “As a student he lived on 100 English pounds a month, worked as a parking attendant to help pay his way, and didn’t have real money in his pocket until he won 3000 pounds in the Spanish lottery.”  After receiving his British degree he did his post doc work in Yale and spent three years making “chemicals similar to Nucleosides.” A bear-sized man who speaks bluntly, negotiates fiercely, and favors splashy, multicolored shirts, Dr Schinazi enjoyed the science but not the weather at Yale.”  “We had two really cold winters in a row in New Haven, with tons and tons of snow.⁵” So he moved south.

When the world learned HIV was caused by a virus, Schinazi was a professor of Pediatrics at the VA hospital in Atlanta.  As he explained (in interviews) he “couldn’t just sit around and do nothing.  We had the tools, the brains and the information” (He had done research on the Herpes Virus.)  He wanted to attack the virus with nucleoside analogues.  The VA resisted then assented, and Schinazi helped develop two of the more significant anti HIV drugs.  Profits from the sale of the medication went to his university.

Encouraged by his success Schinazi wanted to try to develop an anti Hepatitis C drug.  The NIH, allegedly, turned down his application for the project.  He and a partner got venture funding and founded Pharmasset.  One of their company chemists, Michael Sofia, developed Sofosbuvir, a drug that, with a little help, cured hepatitis C. “

“Pharmasset planned to sell the drug at a total cost for the treatment of around $30,000.⁴  

In 2011 Gilead bought Pharmasset for $11 bn.   Schinazi received $440 million and went on to do further research. Gilead now had to sell and charge a lot for the medication.  The original list U.S. price for the company’s two drug combination, Harvoni, was $94,000.

During an interview with journalist Jon Cohn, Schinazi was asked about “Sofosbuvir’s price tag of $1000 per pill.”Shinazi pointed out that Gilead decides how much they will charge and he called the price “obscene” but not unreasonable. “Is it fair to pay $3 for a bottle of water when you’re thirsty? This is something that cures you from a disease.”

For most of those infected treatment wasn’t urgent, but Gilead had to move a lot of their product before competitors developed a drug combination that worked as well as Solvadi.  The company spent $60 to $80 million on TV ads in which people said they were “ready” to be cured.

Approved late in 2013, Gilead’s drug combination, Harvoni (ledipasvir/sofosbuvir) created revenues of more than $10 billion in 2014.  Then Gilead marketed two additional anti viral combinations. Each was made up of sofosbuvir plus one or two other drugs that suppressed Hepatitis C.  Each cured most people who had the disease.  Gilead’s revenue from the sale of the anti-virals neared $20 billion in 2015.

In August of 2017 the FDA approved a second combination of anti Hepatitis C drugs.  Called Mavyret, “It was initially priced at $13,200 per month, or $26,400 per treatment course, before discounts.” At the time a curative course of Gilead’s three Sofosbuvir combinations:  Epclusa, Solvadi, and Harvoni were priced at $74,760, $84,000, and $94,500 respectively.  Gilead sold $13 billion worth of anti virals in 2015.  In 2018 the company projected “$3.5 billion to $4 billion in U.S. sales.”

When companies spend billions to control the sale of a drug, we all pick up the bill.¹

Gilead, the company that made the $11.9 billion gamble was founded in 1987 by Michel Riordan, a 29 year old M.D. and business major.  Enthusiastic and committed, Riordan convinced heavy hitters George Schultz and Donald Rumsfeld to join the company’s board of directors.  During its first 15 years the company created a few drugs, “took in 2 billion dollars from investors and lost ¾ billion dollars.” 

In 1990, the head of Gilead embarked on a new approach.  He convinced John Martin, the Bristol Myer Squibb head of antiviral chemistry, to jump ship and come to his failing company.  Then Squibb decided “they no longer wanted to develop” the promising antiviral that had been created in Prague by the intuitive Czech researcher, Antonin Holy.  Squibb’s rejection “hit like a ton of bricks”.  It came 2 years after Gorbachev allowed Czechoslovakia to free itself from Russia’s grip.  Years earlier as an employee of Bristol Myers, John Martin had flown to Prague and spent a day with Holy walking through the streets of the city on the Vltava River.  When he heard about Squibb’s decision, knowing the potential of Holy’s creation, Martin phoned his old acquaintance.  He convinced Holy to sign a licensing agreement with Gilead….which they did a few months later—on a napkin–in a restaurant near the Eiffel Tower.¹² (I tell this story in the chapter on HIV)  Gilead tweeked the nucleotide and it became the basis of several potent Gilead medications that are currently used to prevent and treat HIV and active hepatitis B.  They helped Gilead become solvent, and they, no doubt, added to the confidence and fire power it took for Gilead to purchase Pharmasset and later Kite, the company that is developing CAR-T therapy for lymphoma.⁸   In 1996 Martin became Gilead’s chief executive, replacing Riordan, who retired and went on to other ventures.¹⁰

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In 1999, as part of a hostile takeover Pfizer paid $90 billion and swallowed Warner Lambert, the corporation that owned/controlled Lipitor.  Pfizer went on to sell a lot of the medication. It became the world’s best selling drug.  In a 12 year span (1997-2009) Pfizer sold more than $80 billion of the pharmaceutical for $5-$6 per 20mg pill.

To understand the drug’s appeal we have to remember that 800,000 people a year–one in three deaths in this country are the result of a heart attack or stroke.  92 million adults are living with heart disease or the after effects of a stroke.  Vascular disease isn’t preventable, but it’s more likely to occur in people with a family history, high blood pressure, diabetes, or to those who smoke or have a high serum cholesterol.

Since the 1950s doctors have believed that if they could lower the level of cholesterol in the blood they could prevent some heart attacks.  A low fat diet helps, but major dietary restrictions sometimes fail.  Our bodies require cholesterol.  It’s a component of cell membranes, hormones and much more.  We mainly produce it in the liver.  When we make too much our blood levels rise and we are at risk for heart disease.  Over a few decades researchers have unsuccessfully sought a molecule that would block the synthesis of cholesterol.  The chemicals they came up with were toxic or not very effective.

In 1973 a researcher in Japan, Akira Endo, extracted a statin from a blue-green mold.  When taken by a human it caused the blood cholesterol level to drop.  Born in a rural northern Japan, Endo “grew fascinated with mushrooms and other molds when he was young.”  As a college student he read and was inspired by a biography of Alexander Fleming, the man who discovered penicillin, the protective juice that was produced by a blue-green mold.  What other amazing juices do these growths fabricate? After a few years as a researcher he spent 2 years in the U.S and “was surprised by the rather rich dietary habits of Americans compared to those of the Japanese.” While living in the Bronx he recalled seeing ambulances that took people who had suffered a heart attack to the hospital. When he returned to Japan he became an investigator for a Japanese pharmaceutical company.  At one point he wondered if “fungi like molds and mushrooms could produce antibiotics that affected the synthesis of cholesterol.”  His company allowed him to choose his field of research, and over a number of years he studied the “juice”–the metabolites and toxins produced by over 6,000 types of fungi.  In the early 1970s he cultured the fluid created by a blue green mold that was growing on a rice sample in a grain shop in Kyoto.¹³   It blocked the cholesterol synthesis pathway and became the first statin.  Endo’s discovery was huge.⁶The recipe it provided was, over time, modified and tweeked by researchers who developed increasingly better cholesterol lowering medications.  

After confirming Endo’s findings, Merck scientists, used an aspergillus (and Endos methods) to create the cholesterol lowering drug Lovastatin.¹¹   A 1994 Scandinavian study showed that statins “led to a sharp drop in fatal heart attacks for patients with heart disease.”  The following year Merck sold more than 4 billion dollars worth of Simvastatin and Lovasatin.

Many tried to make a superior statin.  Bruce Roth, a researcher at Warner Lambert in Ann Arbor synthesized Lipitor and showed it was very potent –the strongest available.  The drugs inventor had grown up outside Philadelphia, loved the night sky, and initially wanted to be an astronomer.  One day when he was in high school reality struck.  He “realized there were only like three jobs in the whole world for astronomers,” and he decided to become a chemist.  While learning the craft he came to believe that “there really are true artists in organic chemistry.” He got his Ph.D. and played intramural softball at Iowa State University.  At age 30 he moved to Ann Arbor, Michigan and “used his skills” to create the statin molecule called Atorvasttin.¹⁴

After it was tested and FDA approved, Warner Lambert joined forces with Pfizer, and the drug was “aggressively” priced and promoted.

Then (apparently) something went wrong and Warner sought to be acquired by someone other than Pfizer, and Pfizer wasn’t having it.  In 1999, as part of a hostile takeover, Pfizer paid $90 billion, swallowed Warner Lambert, and went on to sell lot of Lipitor.  When Pfizer’s monopoly ended their profits dropped and the company attempted to avoid U.S. taxes by moving their headquarters to Ireland.³

Staying alive

“To sustain a $20 billion-a-year business (a firm like Pfizer”) needs to add one new blockbuster medication to its portfolio each year.” Large companies in general need four “$1 billion-per-year drugs to maintain their revenue base.”  (That’s the conclusion of Bernard Munos, a leading thinker.)  He says the pharmaceutical industry of the 1980s was a “haven” for creative scientists whose work was based on “cutting edge discoveries coming mostly from academia.” Proceeding at their own pace and pursuing clues as they went, these researchers would steer their own course and pace.  Industry assumed some would eventually create a commercial product.  The approach was “risky”– but it led to a lot of innovative medications.⁷

In the 1990s business savvy CEOs became the leaders of most of the large corporations.  They tended to be scientifically untrained or illiterate, and they were troubled by the apparent disarray in their R and D divisions.  Scientists kept changing course.  There were no deliverables.   “To them (what they saw) epitomized mismanagement.”  So the CEOs changed the culture.  Researchers were now expected to be “responsive to the marketplace”.  A “process” driven–goal driven culture was created, and true innovation was largely “destroyed.”  

Munos believes leading edge innovators aren’t focused on the existing customers and markets.  They want to make something that “transforms—obliterates” the status quo.²

• 2019 SENATE HEARINGS

On Feb 26, 2019 the heads of 7 pharmaceutical manufacturers appeared before a congressional committee.  The CEO’s of Roche and Novartis—the Swiss—were notably absent.   Senators were trying to learn why the cost of medicine was much higher in America than it was in any other advanced country.   At the end of her 5 minute interrogation Debbie Stabenow of Michigan seemed frustrated by the evasive non-answers she was evoking, and she concluded that companies raise prices because they can. 

She was right and wrong.  I believe CEO’s believe they have no choice.  They are accountable to stock holders. If the company is not profitable their jobs are in jeopardy.  The marketplace they face is not one where their “competitors” are trying to grow market share by cutting their prices.  Quite the contrary.  Industry leaders are charging more each year.  As long as price increases stay below 10% and are some odd number, they don’t seem arbitrary.  Most importantly, when pharmaceutical prices rise no one who matters seems to care.

Not that the spokespeople that defend Pharma are wrong.  Some of the drugs that company researchers spend years developing fail.  When tested, they aren’t effective or are they are toxic, or they don’t have a market niche that makes them profitable. When company money makers lose their exclusivity, generics move in.   

Most advanced nations keep prices down by using a system called “reference pricing”.  They cluster medications that “have identical or similar therapeutic effects”.  Then some insuring nations (like Italy) pay the cost of the cheapest drug in each grouping, and in other countries (like Germany) shell out the price of the average medicine in the collection.  In America the government hasn’t instituted a pharmaceutical price control system. Insurers, phamaceutical benefit managers and the VA negotiate drug prices; Medicare, by law, can’t. ¹ 

 Many of the CEOs that were in Washington that day seemed less than proud of their contribution to the price problem.  Some seemed anxious to lower prices and/or tie increases to inflation.  In return they wanted to stop giving discounts and rebates to middle men and women–pharmaceutical managers– or give rebates directly to the person that needs them. And if they were going to lower prices they wanted the other companies to follow suit.

Kenneth Frazier, the son of a janitor, and grandson of a South Carolina share cropper was the CEO of Merck. A graduate of Harvard, he was the first black man to head a fortune 500 corporation.  Initially a member of the defense team when Merck was sued because its arthritis medication, Vioxx, increased the risk of heart attacks and strokes, he had also practiced criminal law. He was part of a legal team that won a new trial and eventual acquittal for an Alabama man who had been convicted of murder.⁵ 

He told the senators that he felt his company had a duty to be responsible in pricing practices and to contribute to solutions that address patient affordability.  He said that the previous year Merck had decided to not annually increase the net price of their portfolio by more than inflation.  And he pointed out that his company had deployed 70k doses of experimental Ebola vaccine in the Congo. 

The French company Sanofi’s head, Olivier Brandicourt, had, as young doctor “spent two years in the Republic of the Congo, and he had then studied malaria during his eight years at the institute of infectious and tropical diseases in Paris.”  He said that two years earlier his company had pledged to keep price increases at or below the U.S. national health expenditure projected growth rate.  He talked about the gap between net and list prices.  Lantus, the company’s long acting insulin had seen a 30% decrease in net at a time when U.S. patients out of pocket costs had increased 60%.  He felt dealing with list price alone would not solve the problem of patient out of pocket costs.⁶ 

Pascal Soriot head of Astra-Zeneca agreed:  “The government has to step up and change the rules.”  Born in France, Soriot currently calls Australia his home. An avid bicyclist he keeps a road bike in the Alps, another in the US, and a third one in Cambridge England.⁷ He grew up in the north of Paris and when young was a member of a “team”. His story suggests it might have been a bit like a gang. There were “many fist fights.” He was trained in veterinary medicine before he started working for Pharma.   

The new CEO of Pfizer apparently believed the group was not brought to Washington to provide certain senators with an opportunity to publically chastise big shots and show their voters they cared.  He thought the senators wanted suggestions.  Named Albert Bourla, he was a Greek veterinarian who was a former director of Pfizer’s animal health group.  When his turn came he stated he was “particularly humble to take part in such an important policy discussion within the U.S. Senate.  When he immigrated 18 years earlier he could never have imagined such an honor.”  And he told the senators–at the end of the session–that he had made it clear to investors: Pricing will not be a growth driver for the company now or in years to come.  (I wonder how long he will last.)

 Unlike the other CEOs he didn’t point out how many billions of dollars his company was spending on research, how they desperately wanted to discover and develop a new super drug for mankind—not for their bottom line.  And he didn’t talk about his company’s risks and failures.  The suggestions he made provided a decent summary of what everyone (aside from AbbVie) was saying.

Medical breakthroughs, he said, “won’t do anyone any good if patients can’t afford them, and unfortunately the horribly misaligned incentives within our health care system often makes medicines unaffordable for American patients.  We need to fix this.”  

In part restating the thoughts of the other CEOs, Bourla presented four ideas:

All rebates should go to patients. He believes too much money is being swallowed up in the supply chain. His company paid $12 billion this year in rebates.  He didn’t think any of the money found its way to patients.  If discounts were provided to the people who take medications, seniors could save hundreds of dollars a year.  

Bourla suggested capping the amount seniors pay out-of-pocket.  Americans are paying a greater percentage of the cost of their medicines (14%) than they do for their time in the hospital (3%).  If someone doesn’t take a needed medication and as a result lands in the hospital, it’s more costly to the health care system.  (Lids on drug costs will also get some of the noisy voters off the backs of the companies and the legislators).

Finally Bourla touched on the problem that congress created and that only congress could fix.  Our laws are keeping Biosimilars off the American market.

Biosimilars are generic monoclonal antibodies.  They bind to the same antigen as an approved monoclonal antibody and work as well, but they are not identical.  Humira is a monoclonal antibody and to date four pharmaceutical manufacturers have developed and tested effective Humira biosimilars.

The Biosimilars Act of March 23, 2010, gave biosimilars 12 years of marketplace exclusivity.  Standard medications were getting a 5 year monopoly.  At the end of those years (in the absence of legal gamesmanship) the first standard generic (biosimilar) would theoretically be allowed to compete —unless a valid patent stood in the way. And that’s the rub. All new pharmaceuticals are “protected” by significant and insignificant patents. Pharmaceutical companies have long used insignificant patents –that their lawyers could allege were important–to keep generics off the market for a few years. They have long used a provision in the 1984 Hatch-Waxman act to delay the entry of competitors. Then in 2010, in the guise of speeding biosimilars to the market, industry lobbyists did it again. They shaped a new rule as an amendment to the Public Health Service act.  They titled it an innovation, and they slipped it into the Affordable Care Act—Obama care.  And Ron Wyden, the senator who was most troubled when AbbVie used the loophole, voted for the bill.

AbbVie used loopholes in the law to keep four Humira biosimilars, off the American market for 5 years. Presumably they would have driven down the price of Humira. The company’s lawyers probably had one or several patents that were allegedly being infringed. Abbvie owns 126 Humira patents.  Most (I assume) have little nothing to do with the core drug. Under the new law when there was a patent dispute–in the place of litigation “negotiation was encouraged”.  The bargaining rules (called a dance) are complex, Byzantine.³

In Humira’s case the manufacturers reached an agreement. 4 companies were allowed to market their biosimilars in all countries of the world outside the U.S.  AbbVie kept exclusive control of the American market.  That’s over $9 billion a year for 5 years.  Thanks to our legislators, the U.S. will have to wait for biosimilars until September 2023.⁴ Bourla explained our law created “reverse incentives that favor higher cost biologics and are keeping biosimilars from reaching patients.  In many cases insurance companies decline to include lower price biosimilars in their formularies because they would risk losing rebates from higher cost medicines.”

Parenthetically Bourla suggested that the administration should obtain trade agreements that prevent foreigners from freely using American innovations.  He didn’t think Americans should pay less for drugs. He thought people in the other western countries should pay more.  “The price control mechanisms of many nations are giving others a free ride on American innovations.”

Richard Gonzalez, the CEO of AbbVie was the target of Senator Wyden’s wrath; One of Pharma’s few CEO’s without a college degree, Gonzalez worked for Abbott for 30 years and retired when he developed throat cancer.  Declared cured, he returned in 2009 as head of a spinoff called Abbvie.⁸ Gonzalez stated there’s no one solution; and he did his best to avoid discussing the biosimilar elephant in the room.  He pointed out that since its inception in 2013 his company had spent 50 billion dollars in research and had a hepatitis C drug that financially failed. He felt price was only a part of the problem.  Stating a willlingness to work with the committee, he pointed out that his company is charitable. 81,000 patients got free drugs (for an unspecified period of time.)

AbbVie, he explained, has 30,000 employees (and they need to eat). Senator Wyden, in turn, pointed out that Gonzalez’s salary was $22.6 million.  And he got a bonus of $4.3 million dollars.  Was, Wyden asked, the bonus tied to the financial performance of Humira.

In September 2018 congress passed John Sarbanes’ Biosimilars Competition Act.  It is supposed to “shine a light” on backroom, “so-called “pay-for-delay” deals – often made in secret.  They must now be reported to the federal trade commission who, with the justice department, will review agreements, look for anti- trust and anti-competitive behavior and “punish bad actors.”  In other words if a company has a drug with an annual revenue of $10 billion and they keep other drugs off the market for 5 more years (and make an additional $50 billion in U.S. sales) they may be sued, and their lawyers may be forced to settle with the government, admit no wrong, and pay a fine of a few million dollars.  Great law.   

“By 2014” (according to a Harvard Public Health school intellectual-property consultant) “biologics were expected to account for half of all pharmaceutical sales.”  Their prices are often quite high. If congress doesn’t modify the rules we can expect high priced biologics for a long time.

ARE GENERIC DRUGS SAFE AND EFFECTIVE?

Reality is a crutch for people who can’t cope with drugs.     Lily Tomlin

A New York Times article tells of employees at the large Wockhardt facility in India who were “knowingly throwing away vials of insulin that contained metal fragments” and were caught.  They were seen by Peter Baker, a man who spent six years inspecting generic factories in India.  He discovered some if the company’s employees were fabricating, backdating and falsifying.  Some of the data in 29 of the 38 plants he inspected was allegedly fraudulent or deceptive.² 

Wockhardt is India’s 5th largest pharmaceutical manufacture and has 8600 employees worldwide, and it’s not the only company where short cuts and violations were detected.  In 2014 the FDA sent cautionary letters … to companies operating plants in Australia, Austria, Canada, China, Germany, Japan, Ireland, and Spain.” They discussed manufacturing and packaging violations, testing, quality checks,..data collection, and contaminated products.^”

I’m not saying that brand name medications are safer than generics. According to Consumer reports “Many brand-name drugs are produced overseas, often in the same plants as the generic equivalents.”³

In her excellent book, Bottle of Lies, Katherine Eban tells the story of how one of the large producers of drugs in India entered the American market.  Then they cheated, deceived, and ultimately went under.⁴

The company in question, Ranbaxy, was incorporated in 1961 by Bhai Singh, a member of a wealthy Sikh family.  It initially distributed cheap Japanese pharmaceuticals and had one factory that “reformulated bulk drugs into tablets and capsules.”  In 1968 the company created and marketed a generic version of Valium.  The drug became a best seller and Ranbaxy had value.  The sons of the founder were studying in the U.S. and they came home.  Over the next twenty years they were welcomed into the family businesses, and they eventually started fighting over who was in charge.  In 1995 Ranbaxy entered the U.S. market and seemed to be playing by rules set down by the food and drug administration, the FDA. 

The U.S food and drug administration inspects and checks manufacturers, but they also expect companies to police themselves, keep records, and submit them to the FDA.  The rules for good manufacturing practices were created in the early 1960s.  Each critical step has to be performed and documented competently. Each batch of drugs needs a record.  The policy calls for “preventative and corrective action,” and Ranbaxy seemed to be compliant.  Not that the company had the same ethos as their competitor Cipla. A Gandhi inspired pharmaceutical company, Cipla was clean, well run, and was devoted to supplying medicines to the underserved.   Ranbaxy was in business to make a profit.  But they were competent and efficient; and the company grew in size and importance.  Then they hired an expert to computerize their data, he took his job seriously and the company started to unravel.

In November 1984 Congress unanimously passed the law that turned the drug market on its head.  It allowed generic drugs to enter the market without undergoing redundant testing. It had its flaws and created new dilemmas. (See Hatch Waxman in the FDA chapter.).  Some contend that the recent creation of a number of high priced medications is in part a reaction to the revenue big Pharma lost to generic competitors.¹³ 

Before the 1984 law most U.S. medications whose patents had expired—drugs that were in the public domain –were still made and sold by one and only one pharmaceutical company.  They distributed the medication and determined its price. Other companies could not market an exact replica of a drug U.S. unless or until their product survived a double blind control study. Half the subjects had to be given a real drug and half a placebo—a dud.   These kinds of investigations were expensive, time consuming, and, since half the people were being deprived of a known medication, the studies were potentially unethical.  Only 13 percent of U.S. prescriptions were written for generic medications. 

The new law changed everything, and by 1994 copy cats accounted for half the drugs that were prescribed.  During the early months and years that followed the changes, the FDA was flooded with fraudulent drug applications, and the agency got tough and created and enforced a number of new policies.

Each drug producing establishment was supposed to be checked every 2 years. That wasn’t possible, so the FDA employed a model that relied in part on the risk.  The company’s inspection history helped tell them which facilities to scrutinize. Foreign offices did some of the inspections.  Between the years 2000 and 2008 the FDA conducted over a 1000 domestic inspections a year and fewer than 400 check ups in foreign countries. ¹⁴    

By 2012, 84 percent of the pharmaceuticals used by Americans moved along the assembly lines of generic manufacturers. 

It’s not easy to create a drug that is truly generic.  Not because manufacturers have a problem acquiring the needed chemicals. They don’t.   A medication’s active ingredient, the substance that lowers a person’s blood pressure, slows clotting, or sinks the level of sugar in the blood can usually be purchased. It’s often produced in large quantities in factories (commonly in China.).  Once the patent for the original medication has expired sophisticated chemists seem to know what to do.

Most medications are part API’s—active pharmaceutical ingredients.  And part “excipients”–inactive substances. Drugs become truly generic when their active and inactive substances are absorbed like the brand named drug, when they circulate, reach the right blood level at the right time, and when they work as long as the original drug.  Nowadays the original fabricator usually patents the various manufacturing steps, so generic manufacturers have to use a different path to produce the product.    

 “The U.S.’s top 5 sources of pharmaceutical imports by “value”–not quantity– (in 2015) were Ireland, Germany, the U.K., Switzerland and India.” Indian companies produce large volumes of cheap generics that are no longer patent protected. The medications “account for 22 percent of U.S. spending,” China doesn’t sell many “finished drugs” but they produce 40% of the global chemical components used for our medications.¹ 

Companies that produce a drug and sell a medication in the U.S. need to tell the FDA the name and business address of the manufacturer. In 2009 over a thousand generic plants applied to the FDA for permission to sell their drugs here.  43% of the plants were in China; 39% in India.

One of the problems that doomed Ranbaxy, the company that motivated Eban to question generic drugs, was the way the company handled their version of the acne medicine Accutane.  Their product was called Storet.  Ranbaxy was ready to market their drug when further testing showed the generic formulation wasn’t absorbed appropriately.  Small quantities of the drug had worked in the lab, but when the company started producing it in quantity it “was failing”.  Ranbaxy should have delayed its launch, kept it off the market until they figured out how to correct the problem.  But they decided to sell the defective medication to the public while the company’s scientists tried to figure out what they were doing wrong.  They “concealed the problem from regulators”, and they memorialized their findings and decisions in a dossier that was labeled “DON’T SHOW TO THE FDA.”  That decision would come back to haunt them.     

As Eban explained in her book, drug companies were expected to emphasize quality over cost.  “Manufacturing processes had to be transparent, repeatable, and investigate-able.” There’s, apparently, always some variation between batches of medicine, so companies are expected to test each group and keep real time records of each drug making step.

At one point Ranbaxy was getting big, and it was hard to keep track of what was happening in their factories.  So they hired a data expert who was born in India and learned his trade while working for the American drug manufacturer Bristol Myers Squibb.  His name was Dinesh Thakur and he took his job seriously.  Before he could computerize figures from the company’s many factories he had to collect the information. He sent his assistants to the facilities, and one by one they came back empty handed. Ranbaxy, it turned out, had been faking the data that “showed” each batch was tested.  They were telling the FDA they were regularly checking the drugs that came off their assembly lines, and they were claiming they had proved that each batch was “properly formulated, stable, and effective.”  But half the information submitted to American and European regulators was bogus.  Drugs sold to people in India were not tested for stability and bioequivalence.  Adverse events were not reported to the FDA.   The drugs may or may not have performed appropriately.  The data that said they were up to snuff looked impressive, but it was phony.  Drugs made for third world countries were formulated using relatively impure, cheaper ingredients.  Sometimes, instead of testing products they made, people at their factories would crush and test brand named drugs.  Documents were back dated. 

In 2004 after his team gathered proof, Thakur reported to his boss, Raj Kumar.  It took a little convincing but eventually Raj was persuaded.  The company was systematically faking data.  The board of directors had to be notified.  Raj created a power point explanation of what was happening.  He believed the drugs that had been misrepresented had to be pulled from the market and the company had to reapply to the FDA. 

He made his presentation to the people in charge.  It was called a self assessment report (SAR). When Raj finished, his statement to the board was met with silence.  The company leaders didn’t seem surprised, and they weren’t willing to admit they were wrong. They would not reapply to the FDA.  Kumar was told to destroy his slides and presentation—the SAR.  As a result of the leadership’s refusal Kumar resigned.  That was in October 2004. 

Thakur stayed but was troubled by many of the company’s products.  He worried about the HIV fighting drugs that were being shipped to Africa.  “He knew they were bad, degraded easily, and would be useless in the heat of Sub Saharan Africa.”  Two years after he joined the company Thakur resigned.  But he remained troubled.  Four months later Thakur assumed a pseudonym and started writing, initially to the World Health Organization, then to several FDA officials, and ultimately an FDA commissioner. He told them Ranbaxy was faking data.  –that they were fabricating information to support stability.”  At the time whistle blowers in India had sometimes been killed, and Thakur felt he had to hide his identity.  But he also felt compelled to act because he believed “executives at India’s biggest pharmaceutical company had committed intentional global fraud.”       The people at the FDA who received the emails Thakur sent didn’t know what to do.  Ranbaxy was a huge company with multiple factories and paper work that seemed impeccable. 

In India companies were always notified when the FDA was sending an inspector.  Visits were scheduled and manufacturers had days to make their facility spotless.  And that was a potential problem.  Sometime during the subsequent year the company was checked out by an FDA examiner who, apparently, didn’t know about the allegations.  He believed the company was honest and honorable.  He spent his days identifying and pointing out deficiencies, and he gave the factory a passing grade.  The people at Ranbaxy thanked him and promised to fix the problems.  By February 2006, having received multiple surreptitious emails from Thakur, a few people in the FDA had grown suspicious.  The Ranbaxy factory was re-inspected.  This time two hardnosed investigators surveyed the plant.  They found deficiencies, and the FDA stalled one of the company’s new drug applications. 

Eventually, on Feb 14, 2007 officers carrying guns and wearing bullet proof vests raided Ranbaxy’s New Jersey facility.  They carried away hard drives and a copy of the company’s internal report on their Accutane drug.  It was labeled DO NOT GIVE TO FDA, and it proved someone in the company had lied.  But it didn’t provide evidence of systemic fraud.  FDA investigators tried to contact Raj Kumar, the man who gave the power point presentation, and he evaded them. A company lawyer warned Raj to “be careful about what he tells the FDA because he had exposure.”  Some leaders at the FDA found it hard to believe that a company with manufacturing plants in eleven countries and sales in 125 nations was systematically providing fraudulent data. 

About that time Tsutomo Une, a leader of a Japanese pharmaceutical house Daiichi Sankyo, contacted the head of Ranbaxy and spoke of a joint venture.  His company wanted to grow.  Japanese drug manufactures were at the time (and still are) known to be leaders in the field of quality control.  The leaders of the two firms met a number of times. Within 4 months a merger of sorts seemed likely, but Une was hesitant.  It was public knowledge that the Indian company had been raided and had received warning letters from the FDA.  Malvinder, head of Ranbaxy told Une that the raid was really incited by Pfizer.  They were trying to get back at Ranbaxy because the Indian company had “prevailed in the Lipitor patent litigation.”  And Une believed him. 

But Malvinder was worried.  His lawyers learned that when the FDA raided the New Jersey Ranbaxy headquarters, among the data they had hauled away was the 2004 SAR.  It was a smoking gun and showed that Ranbaxy had been faking the data they presented to the FDA.   Malvinder fretted but didn’t tell his Japanese counterpart.

In 2008 Daiichi Sankyo became Ranbaxy’s principle share holder.  In September 2008 the FDA barred the import of 30 drugs from two Ranbaxy plants, and in early 2009 the FDA formally issued an “AIP.” The letter notified the company that the agency believed it had evidence that the company’s applications had been “fraudulent or unreliable.”  Malvinder was forced to resign as head of Ranbaxy. He paid a large fine to the FDA but avoided criminal prosecution.  At a later time he was sued by the Japanese and was forced to pay them $550 million for overstating the value of his company.  Ranbaxy agreed to plead guilty to three felony counts of violating the federal drug safety law and four counts of making false statements to the F.D.A. The company also admitted that they failed to complete the proper safety and quality control tests on several of the drugs that were manufactured in the Indian factories.  We probably would not have learned that Ranbaxy was faking their data had it not been for a troubled whistle blower.

In subsequent years the FDA’s presence in India has gradually expanded.  They claim to have more than a dozen full-time staff.  Inspections are (officially) frequent and increasingly unannounced. If the agency finds problems, it issues a Form 483, a notice outlining the violations, which if not resolved can lead to a warning letter and in worst case, a ban. Violations range from hygiene, such as rat traps and dirty laboratories, to inadequate controls on systems that store data, leaving it open to tampering.⁵.

Eban’s book goes on to tell of a few other companies that cheated.   . 

In the early 1990s an FDA inspector observed Sherman Pharmaceuticals of Louisiana burning medication that was returned due to contamination.  Penalized in 1995, the company went out of business. 

In 2007, the anticoagulant heparin was manufactured by the American company, Baxter, and it made kids who were receiving kidney dialysis sick.  The substance that caused the harm turned out to be a contaminant in the Chinese chemicals that were used to make the heparin. And there were others.

In 2012, Congress passed the FDA Safety and Innovation Act.  It directed the FDA to inspect foreign facilities as frequently as domestic plants.

In 2013 “the Indian government approved the addition of seven new FDA drug investigators, and brought the total number of Americans checking their facilities to 19. 

That year the number of inspectors in China went from 8 to 27.”

By 2014 the FDA was complying with the law. They conducted over 800 inspections in the U.S. that year and they checked an equal number of facilities abroad.

By July 2016, 965 foreign production facilities had never been inspected.  And before 2020 the agency had, at least once, assessed 495 or 51% of them.¹⁴

Based on the Ranbaxy story and numerous interviews Eban asks a very important question:  Should brand name and/or generic pharmaceuticals be trusted?  It’s an especially important question because more than 40 percent of finished drugs used in the U.S., and 80 percent of active pharmaceutical ingredients are produced overseas.  Pharmaceutical factories are scattered around the globe. There’s a lot of money involved, and people sometimes cheat. 

• Deception by major players, sadly, is not confined to the generic pharmaceutical industry. 
• In 2015 the environmental protection agency discovered that 11 million diesel autos made by Volkswagen contained a special device that allowed the company to intentionally lie about their emissions.  The company admitted guilt and paid a $25 billion fine. 
• In 2008 the former head of Nasdaq, Bernie Madoff, admitted he had, over many decades, “conned his investors out of $65 billion.”  He went to jail. 
• More recently airplane manufacturer Boeing, fitted some of its newer planes with large engines and special software but failed to train some of the pilots.  Their actions led to the crash of two air craft and the loss of hundreds of lives. 
• Early in this century huge trusted banks sold collections of mortgages whose quality was falsely inflated.  When housing prices started dropping in 2007, the values of these mortgages plummeted and the banks didn’t have enough cash to avoid a run.  The economy was saved by a $16.8 trillion dollar government bailout. . 

In the EU, national competent authorities are responsible for inspecting manufacturing sites located within their own territories. Sites outside the EU are inspected by the State where the EU importer is located or by the manufacturing country’s examiners.

If products are imported directly into more than one member state from a manufacturing site outside the EU, there may be more than one responsible authority. Routine inspections are performed using a risk-based approach and when there is suspicion of non-compliance.⁷

Facilities in Europe apparently are rarely inspected by our FDA.  Thanks to the 2012 Food and Drug Administration Safety and Innovation Act, the FDA turned over the inspection of meds made in Europe to the inspectors of each country.⁸  

• Pharmaceutical manufacturing is a large global industry.
• In 2003, worldwide pharmaceutical industry sales totaled $491.8 billion. 
• The U.S. accounted for 44 percent of global industry sales for a total of $216.4 billion. 
• The ten largest pharmaceutical corporations made almost 60 percent of total U.S. sales in 2004. 
• There are a few pharmaceutical companies that participate in both the branded and generic parts of the industry. 

All manufacturers use electronic bar-coding technology on drug packaging. Hospitals claim bar coding each pill makes it less likely a sick in-patient will be given the wrong medication. In Europe (starting in 2019), all marketed medicines need a 2D Barcode.  Central verification systems are supposed to be able to trace each and every medication.

Hospitals in Holland have shown that when all Single Unit of Use Packages contain the correct barcode – record, doctors and nurses make fewer mistakes.¹⁰ . 

The side of the refill bottle of a prescription medicine I take has a bar code.  It is 8 numbers long and I don’t know how to access the information it encodes.  If the pill doesn’t work or causes a reaction I currently am unable type the numbers into a web site and get that information. What if everyone could post medication problems with details about where the drug was manufactured on a web site that others or the FDA could check? 

Pharmacy benefit managers choose which drugs we take on the basis of price, kickbacks, quality, and reliability.  How do financial incentives affect quality of our drugs?

ARE GENERIC DRUGS SAFE AND EFFECIVE? The world has bad actors and cheaters, but most companies and inspectors take pride in their work.  They don’t want to let their friends and neighbors down, and they strive to avoid creating or choosing an inferior, worthless or harmful product.

Chapter 14-NEGOTIATING

 

When we talk about the cost of a unique new life saving medication (see gene therapy) the process is a little like hostage negotiation.  The government gives the pharmaceutical manufacturer a 5 year monopoly and allows the company to set the price.  The insurer has meetings with itself and decides how it’s going to deal with the situation, and to the patient and family it becomes a “your money or your life” situation. 

When legislators decry Medicare’s inability to negotiate with a pharmaceutical company they are revisiting a politically influenced law that Congress passed in the wee hours of the morning December 8, 2003.  (see FDA chapter)  Some believe Medicare D could save a lot of money if they were allowed to negotiate with the companies that sell costly medications.  Currently by law they can’t. 

The law didn’t become a big political issue because of a later law that protects most of the people on Medicare.  If the yearly outlay for a drug exceeds $6350, the situation is officially a “catastrophe,” and the Medicare recipient is only responsible for a small copayment.

The legislation that authorizes the government to pay the other 80 percent of the annual cost of the expensive drugs started as a bill that limited “total out-of-pocket charges for people on Medicare.” It was championed by Otis Bowen.  A country doctor from a town of 5000 in northern Indiana, Otis was his state’s governor before he was appointed secretary of Health and Human Services by Ronald Reagan.  Known as “Doc” Bowen, he “kept a prescription pad handy, and recommended remedies to cure the common cold and sore throat for both colleagues and members of the press.”   When his bill to help people on Medicare was introduced Reagan wasn’t keen on the idea.  But his administration was caught red handed giving weapons to Iran and money to the Central American counter revolutionary fighters known as “contras.”  His party was in the midst of a huge scandal and the Republicans lost control of Congress. 

In 1988 a few liberal senators promoted the Medicare Catastrophic Coverage Act.  It included a tax that was controversial, and it had a drug benefit that, at the time, didn’t amount to much. 

Senator Lloyd Bentsen made sure the legislation didn’t cover most medicines.  It was just for catastrophes and at the time, there weren’t many.  Bentsen, the senator who brokered the compromise, was a fearsome poker player.  You never knew what cards he held.  He was a B-24 bomber pilot during the Second World War and was shot down on twice.  Looking and dressing like Hollywood’s version of a successful politician, the senator was tall and thin, had a deep, voice, and wore elegant clothes.  When he went to a party and his wife wouldn’t leave he, famously, would playfully toss her over his shoulder like a sack of potatoes and carry her out.¹⁹” In 1988 when Michael Dukakis was the Democratic presidential candidate, Bentsen was his running mate and they lost.  

In most of Europe, when a new drug becomes available countries go through a process. Germany makes sure the medication is safe and effective.  Then the country allows the manufacturer to set a price and sell it. During its first year the new drug is compared to existing therapies and its relative “value” is determined. Then the company and government authorities bargain and usually arrive at an acceptable price.  If they disagree they arbitrate.  The panel of five that hears both sides includes a representative of the government and a person who speaks for the insurer, and their decision is binding—if the manufacturer doesn’t strongly disagree and doesn’t choose to stop selling the drug in the country. In seven years Germany has assessed “More than 300 drugs and fewer than 30 were withdrawn.¹⁸”

In the U.S. doctors often don’t know (and many don’t want to know) how much people pay for their medications. Health insurance policies often have formularies that cover part of the cost, so some people pay more out-of-pocket than others for the same drug.  

Most of the medications people take are generics.  When there are more than two manufacturers price competition can be intense.

Pharmaceutical Manufacturers handle the negotiations for unions, hospitals, benefit managers, the military, and the Veterans Administration. Formulary management works for the Veterans Administration.  They, for example, only carry one or two beta blockers.  Companies bid for the contract.  All the VA business goes to the brand that provides the best price.

Medicaid doesn’t have to parley.  The law says the program automatically gets the best price available.

In the world where everyone negotiates, health insurance plans include a prescription drug benefit.  Their programs are managed by PBM’s, prescription drug management companies.  Some of them are owned by a large health insurance company.  Three independent management corporations control 75% of the market.  They bargain, receive a service fee from their clients, share their financial gains with health plans,” and commonly determine the drugs that insurers cover, and their “tier” position.³

Cheap generics have low co-pays.  Preferred brand name drugs are up a step.  The newer, very expensive medications are typically in the top row.  The person who takes the pricy drug and is not on Medicare commonly has to pay a percent of the list price.

For illustration, the formulary of the University of Maryland Health Advantage has 5 drug levels, and five escalating sums of money.  The following is taken from their web site.  It is the 30 day co-pay for each filled subscription.¹³

• Tier one: $4 co-pay for preferred generic drugs.
• Tier two: $15 co-pay for generic drugs that didn’t make the preferred list.
• Tier three: $47 co-pay for preferred brand name medications.
• Tier 4:  $100 co-pay for brand named products that didn’t make the preferred list.
• Tier 5:  33% of the manufacturer’s list price.

The medications on the top row are “specialty drugs” and typically cost $50,000 to $100,000 a year.  The amount Medicare Part D spent on specialty drugs nearly quadrupled in the five years between 2010 and 2015.  Their cost rose from $8.7 billion to $32.8 billion a year.  By 2015 they accounted for 31 percent of the programs net spending.⁴   Drugs in the most expensive group usually include:

• combinations of anti retroviral (HIV) drugs,
• multiple sclerosis modifying agents,
• Orphan drugs—medications that are not in high demand for people over 65.
• A number of the very expensive, cancer fighting medications.

Thirty three percent of a costly drug’s list price is a lot of money for most Americans who are not on Medicare.  Pharmacy committees that place the drugs in tiers meet regularly.  When the drug insurer also covers a person’s general medical care, committees realize some expensive prescriptions are not being filled.  If a person can’t afford a needed medicine, the drug’s absence may allow their condition to become so bad that they need to be hospitalized.  If that happens, the insurer will be on the hook for the cost of at least part of the resulting medical care.  Thus these committees need to walk the tight rope between keeping their plan solvent and avoiding prices that make people choose between their money and their health.⁵

One variety of $60,000 to $100,000 per year drugs that are on the top tier are medications used to help prevent flares of multiple sclerosis.  These are among the medications whose prices matter the most to manufacturers because they account for a major part of the profits.  An estimated million Americans are living with the chronic neurologic condition.  The cause is unknown but the immune system of people with the problem, attacks and destroys the myelin, the insulation that surrounds nerve fibers.  Over time the axons, the part of the nerve cell that conducts electrical impulses, can be destroyed. “The disease has a highly variable pace and many atypical forms.¹⁶.”   In 85% of the people neurologic deficits (which come in many forms and can be quite significant) come, stay for a while, and then disappear.  Symptomatic remissions can then improve or disappear over a period of time.

A number of drugs that block parts of the immune system seem to minimize the flares.  They are different in many ways, but each requires years of follow up on or off therapy to see if they prevent symptomatic flares or MRI changes.  And each of them, for unclear reasons, costs about $62,000 a year⁶

CURRENT CASH PRICES FOR A ONE MONTH SUPPLY OF Multiple Sclerosis MEDICATION

DRUG NAME——-DOSE————-WALMART–WALGREEN

Aubagio (Genzyme)	14MG (30)	(Pharmacist could not locate in database)	$4,757.19
Avonex (Biogen Idec)	Prefill 30MCG/0.5ML Kit	$4,877.08	$5,058.19
Betaseron (Bayer)	0.3MG INJ (14)	$5,154.54	$5,809.69
Copaxone (Teva)	20MG 1PK=30 INJ	$5,507.32	$6,000.09
Extavia (Bayer)	0.3MG INJ (15)	$4,430.46	$5,589.99
Gilenya (Novartis)	0.5MG CAP (28)	$5,372.18 FINGOLIMOD	$4,790.19
*	…	…	…
Rebif (Merck KGaA/Pfizer)	44MCG/0.5SYG INJ (12)	$5,150.54	$5,304.49
TysabriBiogen idec			$$5629.49

The man responsible for the 1990 law that ties the costs of drugs provided by Medicaid to the bargains obtained by insurance companies was Senator David Pryor.  The son and grandson of sheriff’s, he was “arguably the most popular Arkansas politician of the modern era.”  In 1975, when he was the state’s governor his “frazzled wife ran away from the state’s mansion and left her  three sons in the care of her husband, setting Little Rock on its thoroughly Southern ear.”   She went to school for two years, and produced a feature length film, a “kind of a witchcraft western”.  Then she returned to her family “as a complete person.”¹⁴

As the Chairman of the Senate Special Committee on Aging, Pryor believed “the high cost of prescription drugs was one of the biggest problems burdening seniors.” He held hearings and “attacked drug Industry leaders.”  Then he decided to help Medicaid—the government program for the poor and disabled.  It covers the cost of nursing homes for many and is funded by the state and federal government.  The feds on average, pay 57%, of the costs: 50% in wealthier states: up to 75% in states with lower per capita incomes. The program provides health coverage to about 64 million Americans.

In the late 1980s many states were in financial trouble.  They tried to limit the use of prescribed drugs by people on Medicaid by creating “restrictive formularies, co-pays, and monthly maximums.”  It didn’t work and their costs remained high.  At the time states were paying full sticker price for prescribed medicine while insurance companies and the VA were often given discounts of 30% to 40%.

Two states tried to bargain with Pharma and were attacked by industry.   Pharma argued that if states withheld “brand-name drugs without generic equivalents from a Medicaid enrollee (they would be) endorsing “second-class medical treatment for the poor.”

In the late 1980s President George H.W. Bush and his White House staff decided to “shrink the budget deficit by about $50.5 billion.  The legislation they produced was “massive”– 533-pages long—“the 5-year Omnibus Budget Reconciliation Act (OBRA 1990)”.  Its size and scope allowed Pryor and colleagues to add their “Medicaid Prescription Drug Rebate Program” to the bill.  It granted Medicaid “most-favored customer” status, and required drug manufacturers to sell their meds to Medicaid at the “best price” available to any other purchaser.  If a company wanted their products to be covered by each state’s Medicaid prescription program they had to accept the federal pricing provisions.

In 1992 Congress created the 340B program.  It protected hospitals and some clinics from drug price increases.⁸

Countries around the world negotiate, but each nation does it a little differently:

• In most countries governments create formularies–lists of medicines they will, at least partially pay for.
• When a new drug is introduced in France the drug makers sign a series of five year price contracts.
• The Brits won’t pay for a cancer medication if an extra month of life costs too much.  The country’s “excellence institute,” NICE, usually only approves drugs that cost less than 30,000 pounds ($39,000) per quality adjusted life-year, which is equal to a year of life in perfect health.”

The Brits with prostate cancer recently bumped up against the institute and refused to keep a stiff upper lip.  Enzalutamide and abiraterone are expensive drugs.  Each of them can stop the growth of castration resistant prostate cancer for months.  They work in different ways and it’s possible that when one fails the other might still be effective.

Enzalutamide was approved by the British National Health Service in October 2013.  The following January NICE tried to prevent the government from paying for Enzalutamide if a man in England or Wales had already been treated with another expensive drug for prostate cancer, abiraterone.  Men in Scotland weren’t affected and they could still receive Enzalutamide.  There was an outcry and a petition.  Political leaders and “Tackle Prostate Cancer”, (an organization) protested.  And NICE changed its guidance saying:  “there is not enough evidence to make a recommendation about how the two drugs should be used.”

Chapter 15 CANDADIAN PHARMACIES

I used a Canadian Pharmacy to buy the eye drops I needed for my glaucoma.  The medicine would have cost $90 a month in the U.S.  Ordered through a Canadian pharmacy the thirty day price was $30.  I chose an online pharmacy that, best I could tell, was legit.  After speaking to a representative by phone, I placed my order, supplied proof that I was a licensed physician, and e-mailed a hand written prescription.  At the time I was able to pay with a credit card.  (That was three years ago and cards are no longer accepted.  I wonder why?)

Under the Prescription Drug Marketing Act of 1987, it is illegal for foreign “e-pharmacies” or anyone other than the original manufacturer to bring prescription drugs into the country.  My medication never touched ground in Canada.  It was processed by a Canadian pharmacy, but was mailed directly to my home from a factory in Germany (once) and Turkey (once.) The drops were brought into the country legally.

I’m a doctor and Bernie Sanders thinks everyone should be able to do what I did.  In 2017 the senator from Vermont introduced a bill that would allow the importation of prescription drugs from Canadian pharmacies, as long as they meet certain safety standards.”  Bernie’s bill, of course, went nowhere.

For Americans who live near one of the nation’s boundaries, it’s possible to buy cheaper drugs by walking or driving over the border.  There are special lanes in Tijuana for U.S. citizens to cross to Mexico and buy medications.  A million Americans use them each year.  The FDA told Vice News: it is “illegal” for individuals to import drugs into the U.S. for personal use.  As a practical matter, customs allows Americans to bring in 90 days worth of medications for personal use.

Vice news used the price of insulin to show why so many people turn to medical tourism.   The list price for a 5 pack of a brand of insulin made by Eli Lilly, (according to Vice) was $147 in 2007, $295 6 years later, and $530 by 2017.  Insulin was first isolated and purified in the 1920s. People injected various forms of animal insulin for over 70 years and the medicine was safe and effective.  In the late 1970s scientists at Genentech using microbes and recombinant technology learned how to make human insulin and since the 1980s most American diabetics have been injecting the human hormone. 

90 percent of the global supply of insulin is made by Eli Lilly, Novo Nordics, and Sanofi.  Eli Lilly told Vice News that their net cost to make a box of insulin pens is $122.   That includes “manufacturing, labor, research and development, regulatory fees, promotional expenses, insulin donations and profits.”  The list price is $530.  In May 2019 Lilly introduced the generic version of its insulin (same drug, same packaging, and the same manufacturer). The price was cut in half.   The head of the diabetic association, like the manufacturers who appeared before Congress, argued that the discounts that currently go to pharmacy benefit managers should go to the patient.³

In most states drugs ordered through legit Canadian pharmacies are not paid for by insurance or Medicaid or Medical.  They require a lot effort by doctors and patients and take two weeks to get processed.  If they are newly released they often aren’t cheap.  Half of the businesses that sell pharmaceuticals on the web are located in the U.S. Some call themselves prescription referral services.

The National Association of Boards of Pharmacy claims “Rogue websites may be selling drugs that are counterfeit, contaminated, or otherwise unsafe.”  I’m sure they are right.  People have always been tricked by charlatans promoting cure-alls.  It’s hard to know how often we or our friends have been fooled by internet fraudsters.  People who use Canadian Pharmacies need to be attentive and cautious.

A number of international internet pharmacies import, process, and directly dispense medications.  A private company earns its keep by certifying their legitimacy.  Called PharmacyChecker.com, the “verifying” company charges an annual fee and insists that a licensed pharmacist makes sure the “medication is selected and labeled correctly.”

To be an “approved” marketer a pharmacy needs a license.  US pharmacies also need a DEA (drug enforcement authority) license.  International pharmacies are not allowed to send controlled substances to U.S. buyers.  Each medication filled must have a valid prescription.

 “In countries with the strongest regulations, Pharmacy Checker inspectors don’t visit pharmacies.  They verify their licenses with the relevant governing body like the College of Pharmacists of Manitoba, and the Singapore Ministry of Health.

In Mauritius, Turkey and Singapore, company representatives conduct onsite inspections during the application process and every 1-2 years thereafter.  In India they only certify pharmacies that dispense drugs that are made by manufacturers that have a global presence.

With regard to the drugs these pharmacies dispense:  More than half the medications Americans take are made in other countries.  The Swiss company Novartis produces pills in factories located in Spain, Germany, Switzerland, the U.S., the UK, Slovenia, Belgium, and Poland. Most of the North American supply of aspirin comes from China.  Over the counter Prilosec and the cholesterol lowering drug Simvastatin often come from Puerto Rico and India.

FDA inspectors are supposed visit the plants that supply our drugs and make sure they “are clean, follow proper manufacturing techniques and contain what is on the label (and nothing else)” To date agency inspectors have visited a little over half of the factories they have approved.  One day the FDA will have the money and manpower to comply with the law Congress passed but didn’t fund.

An agency of the Canadian government that regulates “foreign-sourced drug products… “conducted 35 inspections at foreign sites in the last five years”   76% of drug products imported into Canada come from countries whose plants Canadians (apparently) don’t inspect.

The companies that run American pharmacies are large and presumably politically influential.  The two largest by revenue in 2014 were CVS and Walgreen.   CVS Health took in $48 billion that year.  One billion seven hundred thousand prescriptions accounted for over 70% of the company’s revenue.  Mail-order service added an additional $88.4 billion.  Walgreen’s gross income was over $76.billion and prescription drugs accounted for nearly 2/3 of sales.⁵

MALPRACTICE

“Never go to a doctor whose office plants have died.” —Erma Bombeck

At 80 he was grey, trim, and smiled a lot. His heart had been damaged by a prior heart attack, but it still pumped well enough to get him through his daily 9 holes of golf. 

His abdominal aorta, the main blood conduit in his abdomen, was bulging,

had an aneurysm that was visible on X ray because a rim of calcium had formed on the inner wall of the large artery.  When it reached a size where the risk of rupture and sudden death outweighed the hazard of an operation I sent him to a surgeon. 

The operation went well and 6 weeks post op he was again golfing His only complaint was abdominal pain that was tolerable but strange.  I ordered an x ray.  Later that day the radiologist called.  The surgeon had left a sponge in the abdomen.  Surgical sponges are marked with radio opaque threads and are easy to spot on x-ray. 

Replacing an aorta is bloody business.  A portion of the large vessel has to be closed off at both ends before the replacement graft is sewn or stapled in.  When the bulge is cut out blood leaks into the abdomen and the surgical team suctions some from the cavity and blots the rest with cotton diaper like “sponges”.  The outside of the intestines and organs are covered with a red film and it gets hard to tell a rag from normal tissue.  When the sponges are thoroughly soaked, they are removed and stacked in a corner of the room.  Before the operation starts the sponges are counted and before the abdomen is sewn shut they are counted again.  If a sponge is missing the abdomen is scoured until the fabric is found.  In this man’s case someone obviously counted wrong. 

Large foreign materials left in the abdomen don’t always cause problems, but they can get infected and their presence is a clear sign that a mistake was made and another operation is indicated.  The Latin term res ipsa loquitur, the thing speaks for itself, indicates a situation where lawyers don’t need a witness to prove malpractice.  The evidence of “wrong doing” is obvious and irrefutable. 

I called the patient and told him about the x ray findings.  When he met with the surgeon my colleague was contrite and offered to perform another operation.

First thing doctors are taught in malpractice lectures.  If there’s a mistake admit it as soon as you know something went wrong.  Accept the blame.  Treat the injured party as you would like to be treated.  Most mistakes don’t lead to a law suit.  Legal action becomes more likely when the harm is great and prolonged or when the patient or family is upset with the care they received and/or the attitude of the medical staff.

My patient wasn’t angry or vengeful, and he didn’t want to risk a second operation.  He filed a law suit and asked for $50,000.  Our insurance people reviewed the file, admitted guilt, and offered $10,000.  They may have been low balling him, but it didn’t work.   

Months passed, neither side was giving in, and an expensive trial seemed imminent.  Then one day my patient had a heart attack on the golf course and died.  His family was not compensated.

During the last 50 years medical providers have grown in their ability to improve the quantity and quality of the average person’s life, and physicians and patients are taking more risks.  At the same time the price of medical care has grown and “medical liability costs (as well as malpractice insurance premiums) are thought to be the source of 2.4 percent of the money we spend.¹¹   

Unfortunately at times doctors and nurses seem to have poor people skills.  We doctors may be good students, technically proficient, and methodical.  But too often we are running late.  Our schedules are too tight.  We seem to be impatient, and –in the age of computerization– we spend too much of the visit looking at a screen. .    

Errors happen.  The wrong medicine. The wrong dose.  Bed sores.  A preventable fall that leads to an injury.  A sponge left in an abdomen.  A cancer that should have been discovered early. Harm at the time of birth that has lifelong consequences. 

The majority of physicians in a quoted survey said that when something goes wrong they provide “only a limited or no apology; limited or no explanation; and limited or no information about the cause.”   The article’s author, a physician who specializes in malpractice, thinks that too often the problem is caused by a physician’s  need to protect his or her ego and a system that allows doctors to blame shift.¹

Prior to 1970 medical malpractice suits were rare.   That year an estimated 12,000 claims were filed but a third were quickly dropped.  Many who had a legitimate case did not sue.  Of those who did, four of five cases ended in favor of defendant.  Many of the awards didn’t cover the victim’s litigation cost.¹³

As the 20^th century wore on the legal rules of the road changed in one state after another.  Lawyers were increasingly allowed to file claims based on errors that were so obvious that –res ipsa loquitur – the blunder “spoke for itself.”  Claims could be based on the absence of adequate informed consent.  Charitable and nonprofit hospitals had for decades had been shielded from litigation—in the belief that “paying money to the victims could damage the facility’s ability to treat patients.”  In one state after another, hospitals now became responsible for errors that were their fault. (Massachusetts limited their financial vulnerability to $20,000.⁷)  Jury awards started fluctuating wildly.  At one point injured parties in “California and Nebraska” on average received awards that were 20 times higher than they were in “low-activity states, such as Maine.⁸

The majority of the injured don’t sue.  In one analysis “Approximately 70 percent of claims were closed with no payment.  Defendants won the majority of cases that went to trial.”  People who litigate tend to have more severe injuries and there has been an increase in the number of million dollar plus awards.  (In New York in 1984 one percent (20,000) of the people who had been hospitalized suffered an in- hospital “negligent adverse event” and 7000 died, but only 3500 of the injured filed a law suit.¹¹)

During the last half century there were three periods of time when malpractice insurance premiums rose dramatically and insurers left some states.  When the lack of “coverage” for medical care was deemed “critical” some legislatures established patient-compensation funds and joint underwriting associations.”   In 1975 California lawmakers limited medical malpractice non-economic damages—compensation for “pain and suffering to $250,000.  No limit was place on the amount of money that could be awarded for costly medical care, lost income, or inability to earn a living because of the malpractice.^10.’

Insurance policies have gotten pricey, and they contribute to the cost of medical care.  Between 2008 and 2017 for example, the annual cost of insurance for obstetricians and gynecologists in Connecticut, Illinois, and Pennsylvania was in the $170,000 to $200,000 range.  In California similar premiums had price tags of $50,000 to $60,000 a year.¹² 

I was a salaried doctor in a large physician owned group (Kaiser). During my 40 years I was sued a few times, and it was emotionally painful.  I’d prefer to not judge myself.

I don’t really know what happens to physicians who practice fee for service medicine.  Some share small offices with one or several colleagues.  When sued I assume they are forced to deal directly with representatives of an insurance company. 

I never had to pay a malpractice premium.  Kaiser, my employer, was big enough to be self insured.  In the event of a multi-million dollar settlement—a severe injury that led to expensive lifelong care—an umbrella insurance policy kicked in.

I wasn’t forced to deal with a representative of an insurance business or company lawyers whose chief tactic was delay and endless expensive depositions. 

Suits that alleged malpractice initially went to a fellow physician who was not always that sympathetic, but who usually was one of the groups brightest and best.  Our malpractice doctor typically spent half of his or her time deal with legal allegations and the other half dealing with patients.  After a lawsuit arrived on his or her desk, our colleague read the chart, evaluated the case, and reached a preliminary conclusion. 

All doctors who participated in the care of the injured person were always named, and everyone who was being sued was informed. In serious cases the group hired one or several outside experts and asked them to assess the case.  When necessary they got opinions from additional experts. Physicians who were paid for advising us could not become a witness or consultant for the plaintiff.  If the outside experts thought we were negligent, our people tried to settle.

A large medical-legal department handled the paper work, the release of information and the technical matters associated with lawsuits.  Skilled, knowledgeable company lawyers gave advice and guided physicians through depositions.  When indicated, outside lawyers were hired to handle individual cases.        .

In my later years working for Kaiser everyone insured by the plan signed an arbitration contract. Cases could not go to a jury.  The Judges chosen were acceptable to the lawyers from each side.  I’m told the approach does not affect overall malpractice costs, but it was easier on the psyche.

          When a plaintiff is awarded compensation in excess of $30,000 the state of California gets involved.  If the case was settled our group has to name the physician most responsible, and that name is posted on a state web site.   If there was a trial and the money was awarded by a judge, the board of medical examiners gets to decide who to blame.    

Doctors responsible for larger settlements often have to appear before a really tough California medical board.  Most walk away with a reprimand, but about one in 10 medical licenses are revoked or suspended.  .

Our tort system is based on blame and fault.   To prevail—to win– a plaintiff has to prove that the defendant owed a duty of care, that the defendant breached the duty, and that the breach caused an injury.”

In California people must file suit within a year after they learn they were negligently harmed. (As mentioned previously) the state capped the amount that’s paid for pain and suffering at $250,000 per person.  There is no dollar limit on actual injuries. 

Plaintiffs’ attorneys usually work on a contingency-fee basis, and take a percentage of the award when they win and nothing when they lose. 

Numerous surveys have concluded that in most cases of negligence the doctor was not sued, and when doctors are sued the harm was usually NOT the result of negligence.

In one recent study (12,000 to 17,000 insurance policies a year), 7.4% of the doctors were sued at least once annually.  Most of the allegations were dropped or dismissed, but 1.6% of those suing were paid some money.  The most targeted subspecialties were neurosurgeons, chest surgeons, and general surgeons.  On average 15 to 19 percent of them were sued each year.  That turns out to be an average of a suit every 5 to 6.5 years. The least targeted physicians were generalists, pediatricians and psychiatrists.  Physicians in these specialties generally got legal notice every 20 to 40 years, or one to two times during their medical careers.²

The number of “paid medical malpractice claims” decreased significantly between 2001 and 2016.  They went from 16,000 to 8500 a year, and the average payout “dropped about 23%”.  During that 15 year period the number of suits where people are paid more than half a million dollars didn’t change much.  They led to annual payouts of about $2.5 billion.  Between 2012 and 2016 as many as 60 in a million people filed malpractice claims in our two most litigious states New York and New Jersey.³

Some doctors claim that the fear of malpractice leads to unnecessary testing and plays a major role in health care costs.

“Many countries- like Sweden, Finland, New Zealand, Quebec Canada, and Australia, have a no-fault system”.  Compensation is based on proof of “causal” connection between treatment and injury. Their structure awards damages to patients without proof of provider’s fault or negligence, and it encourages physicians to collaborate in their search for the cause of the injuries.  Although the application of no-fault system differs slightly in each country, the basic idea is to eliminate fault or blame and make the claim process simple so patients with meritorious cases can access the system easily.” It also makes it easier to identify and fix problems.⁴

It’s possible to get some sense of what would happen if American physicians could no longer be sued for medical malpractice.  Doctors in the military aren’t immune from patient complaints or administrative action, but the government can’t be sued.

In the 1940s a serviceman died after a surgeon “left a towel in his abdomen”.  The family sued. In 1950 the U.S. Supreme court, by creating a “doctrine” called the Feres rule, decided the government was not liable.  The decision was later extended to include anyone receiving medical care from “the government.”  The court rationalized the approach by discussing the special relationship that exists between service members and the U.S. and they pointed out that the laws of malpractice vary from state to state.  That makes litigation complex.  They noted that injured service members who were disabled were paid accordingly.  Some judges apparently feared law suits might affect military discipline.  The decision of the court has been challenged.  Additional suits have been filed, but the court did not choose to re-hear the matter. 

In a recent article a few lawyers felt “repeal (of Feres) may not serve the best interests of service members.”  Most people who are harmed, they pointed out, don’t sue.  Without the threat of legal action, mistakes could be openly discussed, problems could be identified and the system could be improved.   We don’t know, they argued, that giving lawyers standing would make the care people received any better or safer.  “There is little empirical evidence,” they wrote that civilian malpractice litigation provides incentives to improve the safety of care.⁵”

Sometimes doctors can’t fix or help some sick people because we don’t know how.  Metastatic cancer and dementia top the lack of knowledge list.  But too often the knowledge exists but we don’t deliver.  Gawande.¹⁵ (paraphrase)

Delays in retrieving a person’s records, time pressures, and illegible physician notes are common impediments.  Robert Pearl, the former head of Kaiser thinks a computerized health record that pops up every time a physician is visited, one where a person’s medical information is presented to each treating doctor, should make a big difference.¹⁶

Chapter 14-GOUGING

To be audacious with tact you must know when you’ve gone too far.  Jean Cocteau

When I started learning about Martin Shkreli I expected to find a canary in a coal mine– the Edward Snowden of drug prices– an in your face rebel trying to force the country to stare hard at its absurd drug pricing system.  But that wasn’t who he was.  Shkreli, the son of immigrants, went to business school and worked on Wall Street.  He allegedly (when young and new) exaggerated or lied to some of his hedge fund clients.  He insists the people who stuck with him all made a profit, so no harm done.  He later became the head of a pharmaceutical company and overpaid for a drug called Daraprim.

The medication was developed 75 years ago and was originally used to fight Malaria.  It was one of many drugs developed by Nobel Prize winner Gertrude B. Elion, a woman who rose to the top in a discipline dominated by men.  The daughter of a Lithuanian dentist who was bankrupted by the 1929 stock market crash, she graduated from tuition free Hunter College, and worked as a lab assistant to earn the money needed for her graduate studies.  When she was finally able to study advanced chemistry she noticed she was the only female in the class. 

The medication she created, Daraprim was owned by Glaxo Smith Kline.  It had been around for decades and couldn’t have been very profitable. In 2010 the drug was sometimes used to treat Toxoplasmosis, a parasite transmitted by cats that can damage the eyes and brains of newborns.

In people with advanced AIDS, people whose immune system has lost its ability to protect them from the microscopic organisms that live harmlessly and unobtrusively in our bodies, the parasite can invade the central nervous system.  After it gets a foothold it can cause focal cranial lesions and encephalitis, a potentially lethal inflammation of the brain.  Daraprim, also known as pyrimethamine, plus sulfadiazine and anti viral therapy is the treatment of choice for the infection.    

HIV destroys T cells, immune cells that protect us from invaders. Over years untreated people with HIV have fewer and fewer of these defenders.  When their CD4 count, the number of circulating T cells, drops below 200, the person affected has the full blown disease– “AIDS”.  Creatures that were barely surviving start to wreak havoc.  When the  CD4 count goes below 100, the parasite that causes Toxoplasmosis can become a problem.

A little over a million Americans are living with HIV.  The majority are taking drugs every day.  The virus is suppressed and is not destructive. 15% of those infected are unaware.  A little over 6000 U.S. deaths annually are attributed to HIV.  I don’t know how often Toxoplasmosis contributes to their demise.

Made in a few places in the world, Daraprim had long been available and cheap.  Glaxo Smith Kline couldn’t or wouldn’t raise the drug’s price for practical, philosophic, and public perception reasons.  So it was kind of a financial loser.  One of several drugs that was sold or dumped by GSK, Daraprim was briefly owned by a drug company called Tower holdings.  After a series of drug company acquisitions and mergers the drug became the property of Impax of Hayward California.

The company (allegedly) claimed they sold $9 million dollars worth each year and made little or no profit.  In August 2015 they got rid of the product.  They convinced Turing Pharmaceutical to buy it for $55 million.  At the time Turing was a privately held start up with offices in Switzerland and New York.  According to its LinkedIn page, the company once had 50 to 200 employees.

After the drug was acquired, Turing tried to start campaign to make mothers aware of the possibility of transmitting Toxoplasmosis to their fetus.  I’m not sure why.  Toxoplasmosis in newborns is uncommon.  Of the 4 million children born in the U.S. each year, an estimated 400 have Toxoplasmosis.  That’s .01 percent.  When Daraprim (pyrimethamine) is fed to pregnant animals many of their offspring are born with abnormalities.  So we avoid giving the medication to pregnant women.

Once Daraprim was part of Turing’s arsenal, the company’s CEO, Shkreli, raised its price from $13.50 to $750 per pill.  A self professed Republican he chose to not explain the price hike.  It was legal.  Drug companies raise their prices all the time.

“You can get away with high drug prices if you do it right,” Barrie Werth once said.  “If he had raised the price 30 times instead of 5,000 times, he could have gotten away with it.¹“

Because of its high cost, pharmacies and hospitals were reluctant to stock the medication, and it was hard to obtain on short notice.  Then a person with AIDS was hospitalized with a Toxoplasmosis brain infection.  His doctor found it difficult to get the drug and Dr. Judith Aberg, the head of infectious disease at a New York medical center got involved.  Outraged by the price she told the person’s story to the New York Times and Shkreli was vilified.¹² 

And he wasn’t contrite.  When he later appeared before a congressional committee he refused to answer questions.  He took the fifth.  The amount charged for the drug was legal, and Shkreli was not apologetic.  He was interviewed repeatedly by Journalists and became infamous. 

His company, Turing was sued by Impax.  They no longer owned the drug but, reportedly, still owed the government $30 million for Daraprim related Medicaid requirements.  Impax wanted Turing to pay, but a judge found it wasn’t part of the contract.   Then the department of justice indicted Shkreli for alleged misconduct as a hedge fund manager.  He was found guilty on 5 of 8 charges, he lost his job, and the company laid-off a lot of people.

As Shkreli said on an internet talk show (edited) “in life you can play the game or you can give up the fakeness and be yourself.  It has drawbacks.  We saw a major insider trading case that was settled by the SEC.  Big banks take millions in fines.  No one gets arrested.  There was a security charge that I manipulated stock price and another that I defrauded investors.  They all made money.”

“People with insurance or under Medicaid don’t pay for their drugs.  They pay co-payments”…. (which can be quite significant.)  Much of the cost of Daraprim, like most expensive drugs, is borne by the tax payer or it becomes part of the rising cost of health insurance.  And that wasn’t Shkreli’s problem.  He wasn’t a rebel.  He had no cause.

I don’t know what Daraprim costs today.  Shkreli, who was out on bail was rearrested for a stupid internet prank, and the judge had him imprisoned.  I have no idea what makes him tick, but I know his antics have little to do with the high cost of many drugs in this country.

Numerous Americans are bothered by the cost of the medications they take, but they don’t usually focus their ire on the big pharmaceutical companies.  Instead they talk about “the gougers”—the notorious few who dramatically jacked up the price of the drug that helped a few people who were dying of AIDS or Epipen.  Their antics grabbed the headlines. Congress held publically televised hearings, and in the eyes of many Martin Shkreli, and Heather Bresch, became public enemy number one and two.

When Heather Bresch appeared before Jason Chaffetz’s congressional committee in September 2016, the congressmen and women probably assumed she would quietly accept their outrage and verbal reprimand then continue “getting filthy rich at the expense of their constituents…and have no remorse.” As a leader at Mylan Pharmaceuticals she was in charge of a product, EpiPen.  Her company had purchased the contrivance from Merck in 2007. There was a marketing campaign.  The awareness of the device’s importance as an emergency treatment for severe allergic reactions had grown.  The company “had pushed through legislation that made EpiPen a main stay in schools.”   And the sale and price of EpiPen grew dramatically.

After her congressional appearance, in at least one subsequent TV interview Bresch, a mother of 4, and the daughter of West Virginia Senator Joe Manchin, appeared thoughtful and concerned.  She answered questions like a well schooled politician–with her talking points:  The system incentivizes higher prices for brand named products.  Too many schools did not stock Epipens. They were underserved.  The company spent a billion dollars improving access and awareness about severe allergic reactions and how to treat them.

The Autoinjector, the device that automatically squeezes the drug into a person’s body, was invented in the mid 1970’s   The FDA approved its use in 1987.  It is presumably no longer patented.

The drug, epinephrine, was one of the world’s first hormones.  Isolated from the adrenal glands of animals in the late 1800s, it was purified and patented in 1902 by Jokichi Takamine a Japanese chemist living in the U.S., and has long been the antidote for a severe allergic reaction.¹³  When a susceptible individual senses his or her body reacting to an allergen, when they develop hives, wheezing, or become faint because their blood pressure is dropping– if they are severely allergic to bees, have just been stung, and are starting to react, they take out their device, remove the top, put the needle end against their thigh, and press a button.  A sharp painless needle bursts out of the syringe, pops through their clothes and skin, and enters their thigh muscle. Then the “plunger” automatically pushes the drug into the person’s body. 

          Between 2007 and 2016 the list price of a two-pack went from $94 to $609, an increase of 500%.²  EpiPen generated $184 million in net sales revenue in 2008, and Mylan thought they would take in $1.1 billion in 2016.  That was a fivefold increase in gross income. At the time of the Congressional hearings two prefilled syringes were selling for over $600.  A Congress person derided company’s “simple corrupt business model.”  Find an older cheap drug that has virtually no competition and raise the price over and over, taking advantage of the monopoly.  

Bresch was repeatedly asked how much of the money was profit, and she kept changing the subject.  The FDA representative sitting next to Bresch said the agency would review new applications for epinephrine injectors within 10 months.

The rapid rise in price had created a stir.  Representatives and reporters needed to express their indignation.  And they did.  The publicized outrage also alerted a few entrepreneurs who were watching or reading about the hearing.  Some saw a way to earn a quick buck.  If EpiPen could bring Mylan hundreds of millions in profits each year, and if there was nothing keeping other companies from making and selling an identical product, why not get a piece of the action.

A few companies joined the fray and by the summer of 2017 EpiPen must have been feeling the heat.  In Canada and the U.S. the price of EpiPen and a recently approved self injecting epinephrine Allerject sold for $130 a syringe.

CVS Health had a deal with epinephrine syringe provider Impax Labs, and was selling their authorized generic product, Adrenaclick, for $109.99 for a 2-pack.

And by 2011 a fourth epinephrine auto injector Symjepi, produced by San Diego’s Adamis company had been approved but had not yet been priced.

Bresch may have been unashamed, but the massive price hike opened a few eyes; and they saw gold in them there syringes.

A few years back a Philadelphia drug manufacturer got exclusive FDA rights (a many year U.S. monopoly) to a drug I had been using for 40 years.  The medication, Colchicine, is a plant extract that was used to treat gout before Jesus was born.  It is one of a handful of ancient cures that withstood the test of time.  The flower that produces the alkaloid was introduced to the new world by none other than Ben Franklin, an innovative guy who used the ancient remedy to treat his painful joints.  I learned about the medication in medical school, and have advised many to take it.  It has its share of side effects, and over the years has helped many of my patients, while making a few sick.  The books back then told doctors to give repeated doses to people with acute painful joints.  We didn’t stop till the pain subsided or the patient became nauseated or developed loose bowels.  That turned out to be too aggressive for a few of my patients, and I quickly adjusted my approach.

For centuries physicians have successfully used it, but no one did a double blind controlled study. Most docs would have thought withholding the drug from the control group would neither be necessary nor ethical.  Then, 23 years ago, doctors in New Zealand did the study.  Their 1987 paper was titled: Does colchicine work? The results of the first controlled study in acute gout.⁹   Half the people with an acutely inflamed joint took the real drug; the other half a placebo (an inert look alike pill.)  People taking colchicine improved more rapidly and more completely.

In the company’s defense, clinical experience is sometimes misleading.  On occasion useful drugs fail or people get well in spite of us.  But colchicine has been used a lot over the centuries, and if the test of time means anything, the medication has always passed with flying colors.

The drug was available, cheap, on the pharmacy shelf.  No one had to go to the FDA to bring it to market.  Then some whiz kid figured out how his company could get exclusive rights to the old herbal remedy.  They ran a trial where neither the investigator nor the patient knew what substance was being used.  (Though, frankly, it’s hard to not know when the pill you are testing causes nausea and diarrhea at high doses.)  Colchicine, of course, worked.  The results were presented to the FDA and the whiz kid’s company got exclusive rights to sell the herb extract in this country.  “After the FDA approved Colcrys, the manufacturer brought a lawsuit seeking to remove any other versions of colchicine from the market; and it raised the price by a factor of more than 50, from $0.09 per pill to $4.85 per pill.”  Since this is a widely used medication they apparently stand to take in an additional 50 million dollars a year during the next 7 years.   (The manufacturer received 3 years of exclusivity for gout and 7 years for Familial Mediterranean Fever, although no new FMF studies were conducted).  (Outside the U.S. colchicine still costs 9 cents a pill.) 

On May 6^th 2018 the TV show 60 minutes explored Mallinckrodt Pharmaceutical’s decision to sell Acthar Gel for $40,000 a vial. (7 years earlier the same vial was priced at $40.) 

The product is one of many hormones made in the pituitary, a small gland located at the bottom of the brain.  Acthar, the brand name for a hormone called ACTH, is extracted from slaughtered pigs, and it tells the adrenal gland to make cortisol.   In the early 1950s it was a means of giving some patients cortisone. In 1955 prednisone became available and doctors largely stopped using Acthar.  The product was left with but two “accepted” indications:  It uniquely helped a rare seizure disorder– infantile spasm; and it was used to help diagnose the cause of adrenal insufficiency.  By 2001 doctors were only prescribing Acthar now and then, and it was a money loser.  But some kids needed it, and its manufacturer, Aventis, apparently felt someone should keep producing it.  That year the French pharmaceutical company managed to sell the drug to Questcor, a California “pharmaceutical company” that was losing money.  Questcor paid $100,000 for the medication, raised the price, promoted the hormone for a few additional “indications”, and turned a profit.  In 2013 Forbes named Questcor the best small company of 2013, and in 2014 Mallinckrodt paid 5.6 billion for Questcor and its money maker, Acthar.

In 2018 the FDC charged Mallinckrodt with price fixing.  To keep the price high the company paid Novartis $135 million dollars and acquired the rights to Synacthen, a drug that is biologically similar to Acthar and was Acthar’s only competition.  Once they owned the competition Mallinckrodt “put the drug on the shelf.”  At the time Synacthen was selling for 33 dollars in Canada.¹¹  Mallinckrodt was charged with antitrust and, admitting no wrong, settled the case for a hundred million dollars. The company makes more than a billion dollars a year on Acthar alone. With only 2000 cases a year of infantile spasm, the company started marketing their hormone stimulator for a few additional diseases, like rheumatoid arthritis, and they were successful.  According to 60 minutes, in 2015 “Medicare was spending half a billion a year on Acthar⁶.”

In April 2017 Maryland passed a price gouging law.  It empowered the attorney general to indict companies if they “shocked the conscience” by dramatically raising the price of an off patent drug.  The following year the Court of Appeals ruled the law was unconstitutional, and the Supreme Court did not weigh in.  Absent a new amendment to the Constitution, Americans who “shock the conscience” have the inalienable right to gouge.⁷

Journey

the history of medicine and of the delivery of health care.

by Steve Fredman m.d.

A montage of people, insights, drugs, devices, money and the struggle to deliver care.

Montage:  the process of selecting, editing, and piecing together events and people and forming a continuous whole.

Our ancestors would have called it Magical realism

 Like Aladdin being able to fly to the far corners of the earth

Like a mystic being able to gaze and talk to people thousands of miles away or hear symphonies or amazing melodic voice while strolling in the park

And, of course healing

A new heart –a new liver—knee—hip

Going poof and witnessing the death of bugs that once caused a lethal strep throat or pneumonia

Observing the inner workings of a body

Allowing a person who was bitten by a rabid dog to be avoid a slow painful death

Turning a deadly heart attack into day at the hospital.

This is the story of the how we created a magical world. 

it’s also the story of how we are delivering and distributing –or failing to deliver and distribute–the wonders, marvels, and miracles—and about looming problems.

Books that I referred to, learned from, and quoted from:

A Crack in Creation, Jennifer A. Doudna and Samuel H. Sternberg, Mariner Books, 2017

An American Sickness, Elizabeth Rosenthal, Penguin Press, 2017

Angiogenesis, Napoleone Ferrara, Taylor and Francis Group LLC. 2007

Better, Atul Gawande, Metropolitan Books, 2007

Bottle of Lies, Katherine Eban, HarperCollins, 2019

Cold War Triangle, Renilde Loeckx, Leuven University Press, 2017

Complictions, Atul Gawande, A Metropolitan Book, 2002

Cutting Edge, Norman M. Covert, Public Affairs Office U.S. Army, 1997

Deadly Spin, Wendell Potter, Bloomsbury Press, 2010

Eminent Victorians, Lynn Strachey

Evarts A. Graham, C. Barbara Mueller, BC Decker Inc., 2002

Genentech, Sally Smith Hughes, University of Chicago Press, 2013

King of Hearts, G Wayne Miller, Crown Publishers, 2000

Love and Science, Jan Vilcek, Seven Stories Press, 2016

Mistreated, Robert Pearl, Public Affairs, 2017

The Antidote, Barry Werth, Simon and Shuster, 2014

The Emperor of all Maladies, Siddhartha, Mukherjee

The Merck Druggernaut, Fran Hawthorne,John Wiley and Sons, 2003

Privatization of Public Hospitals, Charles Brecher, Sheila Spiezio

The Puzzle People, Thomas E. Starzl, University of Pittsburg Press, 1992

The Rise of the For-Profit Hospital Chains, Dave Lindorff

The Scalpel and the Silver Bear, Lori Arviso Alvord and Elizabeth Cohen, Van Pelt, Bantam, 1999

The Troubled Health Dollar, Steve Fredman, Virtualbookworm, 2012

The Truth About the Drug Companies, Marcia Angell, Random House Trade Paperbacks, 2004

Vaccinated, Paul A. Offit, Harper Perennial, 2007

Websites that are available by subscription

New England Journal of Medicine, UpToDate

Each chapter has a bibliography.  Some are extensive. 

I decided to both identify my sources and make them easily accessible. 

My approach is twenty first century and uses every day technology

In the past, to write a history authors would spend hours in libraries. 

The quoted sources would be listed but they would be hard or impossible to access. 

In 2020 many old original sources are available on the web.  They are available and accessible.

For the convenience of the reader I have listed most sources by their URL.  Instead of putting them in the back of the book I put them on a website.

A reader who wishes to check out and learn from a source can copy its URL and paste it into a browser.

They website that contains the bibliography is  www.savingobamacare.com    

CHAPTER 13  BLACKS ARE ALLOWED TO PARTICIPATE

During the last century and a half the right to receive state-of-the-art care was periodically granted to one group, then another. 

Black men and women were gradually and reluctantly allowed to fully participate. 

After the American Civil War ended the government faced a humanitarian crisis.  Four million former slaves were abruptly told you’re free to leave, but they had no resources and nowhere to go to-– no basic shelter.  Often cramped together in abandoned buildings, they couldn’t maintain basic hygiene, and many got sick.  Privately run institutions for the very poor existed, but there were no hospitals, and the private shelters wouldn’t accept the newly emancipated.  Former slaves died in large numbers.  In some places “their bodies were littering the streets.”  About that time there were 54,000 male and 300 female medical doctors in the U.S. and only a few were people of color.^41,42

Congress established the Freedman’s Bureau in the South.”  It “fed millions of former slaves and poor whites, built hospitals, and provided medical aid.  But its hospitals didn’t have enough beds, linens, quarantine facilities.  There were merely 120 doctors for the entire population.  And there was a smallpox outbreak.  In July of 1872, “responding to the continued hostility of white Southerners, Congress terminated the Freedman’s bureau.”

In the early post Civil war years the government founded a number of black schools and colleges.  In 1868, one of them, Howard University in Washington D.C., “became the first school to have a medical program for blacks.”².

The country’s first black surgeon, James McCune Smith, had to go abroad to get his medical degree.  He grew up in New York and had a white father and a black mother who had once been a slave. Educated in the city’s African Free School, he was denied entrance to an American University and went to college in Glasgow. In 1937 he graduated from a London medical school, returned to the U.S. and became a vocal abolitionist.  He wrote the introduction to the Frederick Douglass book “My bondage and my freedom,” and was practicing medicine in Brooklyn when the Civil War ended.⁴⁰ 

In 1864 Rebecca Lee Crumpler became the country’s first black “doctress” of medicine.  Born a “free” black in Delaware in 1831, she later wrote about her journey in the Book of Medical Discourses.  “Having been reared by a kind aunt in Pennsylvania, whose usefulness with the sick was continually sought, I early conceived a liking for, and sought every opportunity to relieve the sufferings of others.” The book was published in 1883. 

Between 1852 and 1860 Crumpler “served as a nurse under several doctors.  In 1860 she “was admitted to the New England Female Medical College, the first institution in the U.S. to train women in medicine.”  It merged with Boston University in 1873.⁴⁰ Students were “taught by rote–four lectures each day, often clocking in at eight hours total. A systematic course of study with nominal variation from college to college didn’t exist, and there were no “medical licenses” or exiting exams.” ⁴¹

Educated in the days before Pasteur and Koch discovered that bacteria—germs– cause infections, Crumpler explained that infectious diarrhea—she called it cholera infantum– was caused by “poor milk, bad air arising from old water-soaked cellars, or some atmospheric phenomena.”

I grew up in a suburb of St. Louis in a white man’s world and for much of my life had limited exposure to world and the struggles of the black men and women who lived so near yet so far.  My awareness went up a few notches after I entered Washington U medical school.  My 1958 freshman class contained 75 white men, 8 women and the school’s first black student.  His name was James Sweatt and for decades he “had the impression that it was routine for all the professors of the departments in the ­medical school to sit around and quiz applicants for ­admission.  At the 25th class reunion he found out that everyone else who was interviewed for medical school had been seen by one person and that was that.”

Dr. Sweatt grew up in Dallas, a town where, in the 1950s,”Whites Only” signs peppered the landscape.  Blacks were allowed to buy clothes in the town’s department stores, but they weren’t allowed to try them on.”  His mother was an 8^th grade teacher, his father a high school principle and he was educated in white schools and at a university where he was one of each institution’s 2- 3 black students. 

Officially desegregated in 1947, Washington U had only 2 black medical students during the subsequent decade. ³⁹

After Jim graduated from Medical School in 1962 he became a thoracic surgeon and practiced in Dallas. In 1995, he became the first African-American president of the Dallas County Medical Society.  

During the years when I was a student, St. Louis had an all black hospital.  Founded in 1937 after a political struggle, Homer G Phillips had 600 patient beds and was the primary source of health care for the area’s indigent blacks, and a major training center for young black doctors. It was also affiliated with the medical school.  White guys like me spent three of our med school weeks at the facility learning how to deliver babies.  During my time there the color of my skin was obvious but insignificant.  I was treated as just another no-nothing med student.

At the time black physicians, by and large, couldn’t get privileges to practice at hospitals dominated by whites.  Ninety six percent of the patient’s in New York’s for-profit hospitals were white and 97% of the people in the city’s private and semi-private not-for-profit hospitals were caucasian.²⁶” Throughout the American South and in many of the border states black physicians were denied membership in the local medical association, and non members could not get hospital admitting privileges.³⁷

As late as 1968, the AMA (American Medical Association) condemned racial discrimination, but allowed its member medical societies to refuse admission to black doctors.  Physicians who were not members of the AMA could not get admitting privileges to most U.S. hospitals.

Seemingly politically influential, the AMA is a national conglomeration of physician groups, and it has often been on the wrong side of history.  It opposed national health insurance and currently disapproves of the single payer option.  For years their journal, the JAMA ran cigarette advertisements that touted the health benefits of filtered cigarettes.  They didn’t consider smoking a health risk until 1963, the year before the U.S. surgeon general– on the basis of more than 7,000 medical articles that were available and that doctors should have read–“ concluded”:  Cigarettes cause lung cancer, laryngeal cancer, and chronic bronchitis³⁰. . 

Many primary care doctors had separate waiting rooms.  Black patients were seen after the white patients were seen. Some of the ill went to county hospitals—where they often sat for hours on wooden benches waiting to be called.  In white hospitals they were often bedded in the basement wards. 

Chapter 13  Medicare and Medicaid

It’s difficult to get a man to understand something when his salary depends on his not understanding it.  –Upton Sinclair. 

In 1940, after conquering most of Western Europe, Hitler mercilessly bombed British cities and tried to bring England to its knees.  18,000 tons of explosives over 8 months killed close to 40,000 people.¹⁶ 3 ½ million people were moved to the countryside and the Ministry of Health “built or expanded hundreds of hospitals”, updated laboratories, X-ray facilities.  The country began paying for ambulances and the care of civilians and combatants who suffered fractures, burns, and head injuries. The ill and injured were transferred to private suburban hospitals and “doctors received government salaries.” Unexpectedly amidst the death and destruction most Brits got healthier, and when the war ended the people didn’t want government care to end.  In 1948 parliament formally passed the National Health Service act and health care became a taxpayer funded right. ⁴

Postwar France was devastated.  “Seventy-five per cent of the population paid cash for private medical care.  Many people had become too destitute to afford heat, let alone medications or hospital visits.”  However, pre war, some manufacturers and unions had instituted a self imposed payroll tax. They now used the money for medical care.  As an outgrowth, the French government currently oversees an integrated network of hospitals and service providers that deliver health care with a small co-pay to all citizens.

In the U.S. president Franklin Roosevelt didn’t mention health care or use the word “rights” in his famous 1941 speech to congress.  The four freedoms he championed were speech and expression, “the freedom to worship God in a person’s own way, freedom from want and freedom from fear.” He had wanted federally sponsored health insurance to be part of the 1935 Social Security act, but “he allowed it to be thrown out in order to hurry the bill through Congress.²” 

Before health insurance was more than a concept, the military and VA were caring for the wounded. During the Second World War employers attracted workers by offering health insurance.  At the time the wages industry could offer were restricted as part of the 1942 Emergency Stabilization Act.  Our nation’s work related system created inequities and it helped foster the rugged individualistic belief that people don’t deserve health care.  They have to earn it.   

In 1947 health care costs were rising and it was too expensive for many. That January in his State of the Union address, President Truman said: “Of all our basic resources none is more valuable than the health of our people.” He proposed a plan that provided medical care to all who need it.  “A government funded health care program that everyone pays into and from which they can withdraw when they need it.  Not a charity, but (care) on the basis of payments made by the beneficiaries of the program.” 

Truman’s idea initially had widespread support. Then the powerful white male American Medical Association (AMA) launched a massive campaign:  Radio and newspaper ads. Pamphlets and mailers.  “Keep politics out of medicine.”  Truman was a Communist. (At the time Communism was a real scare.)  “His plan was socialized medicine.  Government officials will intervene in medical decisions and destroy the “sacred doctor patient relationship.”

Popular support plummeted and the bill failed to get through congress.⁶” Efforts by subsequent politicians to provide government sponsored health insurance was repeatedly opposed by the “influential” American Medical Association.

In the post war years Blue Cross and Blue Shield were started in one state, then another as public, tax-exempt corporations. By 1945 the “blues” were responsible for 2/3 of the nations’ hospital insurance, and by 1955, 60 percent of Americans had an insurance policy.¹

Aetna and Cigna began marketing medical policies in 1951.  They tended to target people who were healthy and unlikely to need expensive care. The IRS did not treat employer provided health care as part of a person’s taxable income and the Revenue Act of 1954 made it official.⁶

In 1960 John Kennedy, the son of a wealthy Irish immigrant became the nation’s youngest ever president. In 1959, the year before Kennedy was elected, Cuban revolutionaries ousted their ruler, a dictator named Batista, and Fidel Castro became the country’s leader. He was a communist and “Under communism, virtually everything belongs to the state.”  Large single owner farms were taken over by the government and “either redistributed to peasants or run as communes.” The U.S. and Russia were in the midst of a “cold war”, and the thought of a Soviet ally a mere 110 miles south of Florida troubled some of the nation’s leaders. In 1961 a group of Cubans, sponsored by the CIA invaded the island.  The U.S military didn’t get involved and the intruders were quickly defeated and captured.  After that the popularity of the U.S. president waned.⁹

At the time Kennedy was trying to change the system that prevented blacks in the South from voting.  His efforts went nowhere.  Nor was he able to convince Congress to pass legislation that provided medical care to our older citizens.

Then in the fall of 1963 Kennedy was assassinated.  The nation mourned, and Lyndon Johnson, former leader of the senate, became the nation’s president.  Under his direction Congress paid tribute to their slain leader. 

Congress passed and President Johnson signed a law that established a new “right” –and created two new programs:  Medicare and Medicaid.  The entities were funded by a payroll tax; an additional 2.9% of a person’s earnings were taken from each paycheck. 

• Medicare– paid for the hospital care and some home services for citizens over 65. 
• Medicaid covered the care of citizens who were “poor enough”–whose “resources were insufficient to pay for health care.²⁹”
• Medicaid also covers nursing home costs for people who meet the eligibility requirements.
• 50 to 75% of Medicaid’s costs were paid by the feds and each state paid the rest.   States with higher per capita income paid more.
• Every state got to limit the amount a family could earn before they no longer qualified.  Criteria for inclusion in the “program” have changed over time, so there are variations in Medicaid coverage across the country.¹
• Additionally—Medicare later established a hospice benefit.  Dying people now had help and many could and preferred to manage their pain and problems in their own homes. 
• As part of The Emergency Medical Treatment and Labor law, hospitals had to provide pregnant women “appropriate medical screenings and stabilizing treatments.
• Medicaid coverage for pregnant women and infants (up to 1 year of age) was established as a state option for people who earned up to 100% of the Federal Poverty Level (FPL).
• “In 1964, a year before it enacted Medicare, Congress passed the Civil Rights Act.  One of its provisions, Title VI, prohibited discrimination on the bases of race, color, or national origin in programs that received federal funding. 

The following year when Medicare was being debated there was no mention of Title VI.  It didn’t come up and nobody wanted to raise it. “The assumption was that some accommodation would be made that would allow segregation to continue on a separate but equal basis.” The nation’s response to the 1954 Brown v. Board of Education Supreme Court decision had shown that when it comes to race, changes don’t  happen very much or very fast.   The ruling ordered states to put a stop to segregation in schools with “all deliberate speed.”  But “The vagueness about how to enforce the ruling gave segregationists an opportunity to organize resistance.”

In 1956, two years after the Supreme Court decision, the University of Alabama enrolled the first black student, Autherine Lucy. Then “riots engulfed the campus and she was expelled for “her own safety”.  In 1962 demonstrations greeted James Meredith, the first black student to attend the University of Mississippi. (A veteran of 9 years in the U.S. Air Force and a man who felt it was important to make a statement, he was ready.)  My medical school, Washington U. in St. Louis, didn’t graduate its first black physician until 1962.  Berkeley California became the first sizable city that had a “substantial portion of black students” to voluntarily begin two way bussing.   Some white children were transported to schools in black neighborhoods and some black students were bused to schools that were largely white. Their program didn’t start until 12 years after the Supreme Court ruling. 

          “The Medicare law might carry the threat that federal funding could be withheld from any hospital that practiced racial discrimination.  That’s what Title VI of the Civil Rights Act “required.”   But the Office of Equal Health Opportunity was in charge of federal funding based on the presence or absence of discrimination, and it only had five employees. Swift action seemed unlikely.  “Hospitals might have to come up with a plan, but they could presumably proceed gradually and cautiously.  Ultimately racial changes wouldn’t get done; hospitals would operate on a business as usual basis.”

Then HEW (Health Education and Welfare) Secretary John Gardner, put out a quiet call for volunteers. More than 1,000 people from federal agencies offered to help, along with tens of thousands of Civil Rights organizers. Field inspectors fanned out to hospitals to make sure they were in compliance with the law and eligible for federal funds. As David Barton Smith explained in his book, “They wouldn’t let anybody off the hook,” “The reason they were so successful is that they had this secret army of local civil rights workers and local health workers making sure [the hospitals] complied. Hospitals quickly figured out that they couldn’t fake it.”²

CHAPTER 15—government grants right to renal failure

On Oct 30, 1972 The U.S. government chose a very expensive pre-existing condition (advanced renal –kidney failure) and made its care a “right.”  

Kidney failure wasn’t part of the bill the Senate debated during a rare Saturday morning session on September 30, 1972.  Nor was it part of the legislation passed earlier by the House of Representatives.  The amendment that added dialysis to the Medicare bill was introduced late that Saturday morning.  There was 30 minutes of debate before it was accepted by a 52 to 3 vote.  Weeks later a House, Senate Committee discussed the kidney amendment for 10 minutes, and left it in the bill.  Nixon, who was a pro health care president, signed the legislation with a flourish a week before he was re elected. 

Bodies have two kidneys.  They are located near the back of the upper abdomen on both sides of the spine.  They strain the blood and produce urine, fluid that is unneeded and unwanted.  The urine, in turn, is “flavored” by a number of soluble additives: debris, break down wastes, and proteins that in high concentrations are toxic.  After the blood is filtered the processed liquid is returned to the body.  A number of conditions and diseases can cause the kidneys to malfunction or fail.  

When I started medical school people with chronic renal failure died.  “In 1960, a group led by Dr. Belding Scribner, a man who called himself Scrib, used a Teflon catheter to connect the artery and vein on the under-surface of a person’s forearm.  The shunt allowed doctors to repeatedly draw blood from a body, cleanse it, and return it.  Located on the skin surface, and subject to infection, and displacement, the device needed a lot of care.  But it allowed physicians to start and keep people on intermittent hemodialysis.” The vision of the man who created the pivotal gadget had been threatened then preserved as a result of transplants of his cornea, the outer lens of his eye. Over time the transplants “became very scarred,” but he didn’t need to drive to work. He lived on a houseboat on a lake near the Seattle hospital where he practiced, and he rowed a canoe to work each day.³⁸

In 1963 “the Veterans Administration (VA) decided to “establish approximately 30 dialysis treatment units in VA hospitals across the country.”  In 1964 learning that “immunosuppressive drugs prevented the rejection of transplanted kidneys, the NIH established a program in transplant immunology.”

Over the subsequent 8 years “Programs sprang up across the country,” By 1972 10,000 Americans with renal failure were being dialyzed.  Funding was a problem and some people were left out.³

Once Medicare was paying the bill dialysis became a big business and a significant part of the program’s budget.  4000+ free-standing centers were established in hundreds of cities by corporations, not hospitals. Their number in the U.S. has increased 4% a year.  More than half are owned by Denver-based DaVita, a Fortune 500 company.  The other big player, Fresenius is a subsidiary of a German company that operates centers in 28 countries and also sells the machines and other supplies.    

Dialysis accounts for 6% of Medicare money.  In the first quarter of 2008 DaVita’s revenues were $1.45 billion, up more than 8% from the first quarter of 2008. Fresenius’ revenues from dialysis in North America were $1.57 billion.

The external shunt is no longer used.  Before hemodialysis is initiated an artery and a vein are sewed together to create a large blood vessel under the skin.  Then three times a week patients with end stage renal disease come to a center and sit in a lounge chair for a few hours.  A needle is inserted into the artery-vein, and blood is drawn into a machine.  It flows past the “cleansing” membrane.  The toxin level in the blood is lowered, the excess fluid is removed, and the blood is returned to the body via the same shunt.     

Some people opt for peritoneal dialysis, using the lining wall of the abdomen, the peritoneum, as the filter.  Initially a physician places a permanent catheter deep in the cavity.  Then, usually nightly in the person’s home, a patient pours a sterile solution (dialysate) into the peritoneal cavity. The membrane’s pores allow waste products like urea and creatinine to seep into the fluid. The liquid is left alone for a few hours, then it is drained.  Some studies suggest that people who use this approach do better the first year, and they are more independent. A year of hemodialysis can cost up to $88,000, while a year of peritoneal dialysis costs about $53,000, according to information from the U.S. Renal Data System.

People with very diseased kidneys are usually anemic. To stimulate the production of red cells people on dialysis are also commonly given injections of erythropoietin, a costly hormone, normally produced by healthy kidneys.

A fourth of the people who were being dialyzed died annually, and 80% who started live for less than 5 years.  That’s largely because more people starting dialysis were over 50.  The mortality rate in the older and sicker people was higher than it was in younger patients or individuals who had hereditary polycystic kidneys.  In 1972 high blood pressure was the leading cause of end stage renal disease. Today obesity and diabetes are keeping the dialysis machines whirring.  The annual death rate of Americans on dialysis (20.1 % in the U.S. in 2006) is higher than it is in France, 8%, or Japan, 7%.  Americans who started dialysis after they were confined to a nursing home did poorly. The first year 58% died and 29% were less functional.⁶   Nearly 20 percent of dialysis patients stop dialysis prior to death.⁹

That’s what happened to the famous humorist Art Buchwald.  In his later years he had diabetes and high blood pressure; when he was 74 he had a significant stroke.  6 years later a leg was amputated.  I don’t know when or if he started dialyzing his blood, but in 2006, when he was 80 he decided to stop and apparently described his decision as his last hurrah.  Contemplating death he wrote “the question isn’t where you are going, it’s what you are doing here in the first place.” Known in the hospice as the man who wouldn’t die, he once quipped:  “to land a big obituary in the New York Times you have to “make sure no head of state or Nobel Prize winner dies on the same day” and “Whether it’s the best of times or the worst of time it’s the only time we’ve got.  The best things in life aren’t things.” A year after he stopped dialysis his heart stopped beating. The cause of death was kidney failure.

Medicare also pays for kidney transplantation.  The procedure wasn’t very good until we had adequate immunosuppressive drugs, but by 1974 over 3000 kidneys were being transplanted annually in the U.S. The number tripled by 1986 and in 2016 reached 13,431.  5600 of the kidneys came from live donors. 

We were visiting an acquaintance who was in the hospital recovering from a transplant.  “So” she said, “things kept going wrong with my shunt and my dialysis and it seemed like I was always in the hospital on the phone complaining.  One day I was in the midst of a tirade and the friend I was talking to stopped me cold.  “Ok, ok” she said.  I’ll give you a kidney, and here I am.

Nine of ten transplanted kidneys were alive and working a year after they were implanted, and half lasted at least 10 years.   93,000 people in our country are currently on waiting lists.  The wait is longer, and the people are sicker in New York and California than they are in many other parts of the country. For transplant reasons, the nation was divided into 11 geographic regions; some cover large areas.  Committees establish recipient transplant criteria—how sick, how old, body mass index, drug addiction, alcoholism, HIV.  And “federal mandate prohibits the allocation of solid organs for transplantation based on “accidents of geography.”

The feds pay for most of the charges associated with a kidney transplantation and pay for the drugs that prevent the body from rejecting a kidney for the first three years post transplant.  After 36 months patients are expected to pay for their own medications. 

Liver, lung, and heart transplantation is also a “right” for those who “already have Medicare due to age or disability.”²⁸

41 years after the Medicare dialysis benefit was initiated the NIH reported that 63.7 percent of people with advanced renal disease were receiving hemodialysis, 6.8 percent were being treated with peritoneal dialysis, and 29.2 percent had a functioning kidney transplant.⁷

6000 undocumented Americans have end stage renal disease.  A few came to this country when they were young and never lived anywhere else.  They went to school, paid taxes, and worked until they got sick.  Unfortunately decades back, sometimes when they were children, they crossed the border illegally.

For context there are 11 million undocumented people in this country of which one in 1833 needs dialysis.  More than 400,000 documented Americans are dialyzed on a regular basis.

Federal funds can’t be used to dialyze undocumented individuals.  California and Massachusetts pay for the procedure with county taxes or state-allocated Medicaid funds.  Texas and most other states only detoxify the blood of people whose serum potassium is so high or whose build up of toxins is so extreme that death is imminent.  People have to wait until dialysis has literally become a matter of life and death. 

180 of the 6000 undocumented people with end stage kidney disease live semi-near the Texas Baylor Emergency room.  Each day many come to the E.R. and wait.  Their blood is drawn; EKG’s are obtained, and they are assessed.  The hospital has 12 dialysis chairs, and the people who occupy hospital beds are dialyzed first.  Then the sickest of the undocumented are served.⁸

In 1997 congress granted the “right” to health and preventative care to kids from very poor families who didn’t qualify for Medicaid. The program goes by the initials CHIP, is individually run by each state, and is funded by the Medicaid – state/federal formula.   It took years before most of the kids who are eligible signed up.  But the program was popular, and granted coverage in 2009. 

The program was partially paid for by raising the federal cigarette tax from 24-cents-a-pack to 67 cents.  That rangled some Republicans whose election campaigns were aided by the cigarette industry.  Their policy committee argued “the lost cigarette revenue would cost too much.  States and localities would lose $6.5 billion over five years.”  Orin Hatch, a Republican who supported the program found their argument “absolutely preposterous.  Does that mean that 419,000 Americans must die every year in order to preserve the state tobacco revenues? That’s like saying we should withhold life-saving treatment from senior citizens in order to save Medicare money.”³⁶

In 1976 the U.S. Supreme Court created a right for medical care to people who are incarcerated.  Eight of nine justices “acknowledged that the eight and fourteenth amendments required the Texas government to provide medical care for prisoners.¹⁰” The eighth amendment of the U.S. Constitution prohibits governments from imposing cruel and unusual punishments. When the Supreme Court rules that a practice is unconstitutional in one state it’s automatically unconstitutional in all states.

          To be meaningful, of course, rights need to lead to action. Each state deals with its inmates a little differently.  California, for example, has more than 150,000 prisoners.  In 2006, in response to a law suit, a federal judge learned that prison conditions were “disgraceful”, declared the health care the institutions provided was unconstitutional,”  and put the California State facilities into receivership.¹¹ 

San Quentin Prison sits on San Francisco Bay and houses over 5000 inmates.  Many have mental health problems. In 2009, as a result of a judge’s order, the facility opened a $136 million, 5 story hospital, and it was employing 10 full time psychiatrists.  Pay, according to one internet ad, started at $19,000 a month plus benefits.  According to Eric Monthei the chief psychologist, clinicians try to give care similar to that of their colleagues in the community. But they must deal with the prison environment, something we can’t begin to understand on a gut level.  The population contains a disproportionate number of people with personality disorders, depression, and substance abuse issues.  Psychiatrists see people for medication management if they have serious symptoms or if they wish to be seen.   If there is a psychiatric emergency, if someone who is incarcerated becomes suicidal or homicidal, there is a 7 bed psychiatric ward.  In the private world psychiatrists are responsible for hospitalized people and drugs.  In prison a psychologist works in the hospital. Some of the prisoners are “Axis one”.  They have major mental health disorders like Schizophrenia, bipolar or schizo- affective disease.  Some committed crimes under the influence of methamphetamine, alcohol or other drugs.  There are non violent offenders who have committed their third felony and are thus in prison for life because of the California three strike law.¹²

According to the psychiatrist I interviewed, when prisoners arrive they are screened by a psychologist and interviewed by a social worker.  They are assigned a case worker who is responsible for their medical care (with the exception of medication.)   Some people are already on drugs, so called “bus meds”, pharmaceuticals like the anti depressant Prozac.  They need to see a Psychiatrist for refills.  Prisoners who are “triple CMS”, those taking psychiatric drugs who have medical problems, are placed in single cells.            

When the MD psychiatrist arrived in the morning he or she was given a “docket”, a list of people he/she had to see that day.  There could be as few as 4 to 5 and as many as 14; visits commonly ran 30 to 45 minutes.  Inmates who were not administratively segregated or in protective custody came as a group and waited in a holding area. Others arrived one by one heavily guarded and shackled.  The “non dangerous” people were seen in an office.  The “dangerous” prisoners were seen while they sit in corrugated metal “cages.”  The interface between physician and inmate was like a heavy metal chain link fence.  There was a spit mask and the prisoners were tied.  The psychiatrist carried a fire arm and a whistle.  When the doctor spoke to the patient, the guard was usually outside the door, just out of ear shot.

The psychiatrist I interviewed worked at San Quentin, California’s oldest.  Located on 400 acres of prime real estate, it borders San Francisco Bay, and is largely sheltered from the fog and ocean breezes that batter some of the areas multimillion dollar houses. The home of some of the nation’s more significant criminals, it has a death row that houses 737 individuals. In the U.S., a nation of 76 million people, 2.3 million people were confined in March 2020; 450,000 people were locked  up for a non violent drug offense each day. Most of the crimes that lead to jail or prison time are non violent.   Many who are jailed will soon make bail or can’t afford it and plan to stand trial.

The nation has 1,833 state prisons, 110 federal prisons, 1,772 juvenile correctional facilities, 3,134 local jails, 218 immigration detention facilities, 80 Indian Country jails, and many more.  9% of the prisons are run by private for profit organizations.³⁴

In the spring of 2020, there was an outbreak of coronavirus at the state prison in Chino California and 121 untested inmates were transferred to San Quentin.  Within a month San Quentin was dealing with a major coronavirus outbreak.

“Incarcerated persons have high rates of communicable and chronic diseases, and though health care is a “right”, “the type and quality of the care depends to some extent on variations in policies, budgets, and staffing across federal, state, and local jurisdictions.”³²

Chapter 17 FEDERAL EMPLOYES ; NATIVE AMERICANS

Affordable quality health care became a “right” for federal employees in 1960 when “The government began to contribute 72% to 75% of the cost of the health care insurance premiums.” That brought the price of the policies way down. “At least 10 fee-for-service plans” compete in a special marketplace congress created.  Applicants don’t have to worry about their age or any pre existing conditions. More than 8 million people who work or have worked for the federal government—and their spouses, dependents, and retirees—and legislators and their families– were allowed to buy the insurance. About 90 percent of the employees of the federal government participate.  The FEHB, federal employees’ health benefit program, is administered by an agency of the government whose director is appointed by the president. The privilege/right is technically called a managed care scheme.   (when a righ is granted and funded by the government it exists.¹⁷) 

As part of the Affordable Care Act, members of congress and their staff members lost the ability to purchase insurance through the FEHB. To maintain their “right” to affordable, quality medical care they established a new way to buy highly subsidized care.  They are using the DC health care exchange, and the government still kicks in 72% of the cost of the premium—for those who chose a gold plan.  When and if one of them retires with five years of government service under their belt they can again be insured through the FEHB.¹⁹

          In 1993 children whose insurance didn’t cover the cost of 16 important vaccines were given the right to receive them free.  Congress created the Vaccines for Children Program, the CDC (center for disease control) managed it, and 40,000 doctors throughout the country administer the vaccines.

In 1811 federal legislators established and funded a home and medical clinic for military veterans. Fifty years later, after half a million fighting men died of wounds and illness in our destructive civil war (1860-64),the government created a number of veterans homes – that “incidentally” provided medical and hospital treatment.

50 years thereafter our nation entered the First World War (1917-18).  116,000 men lost their lives.  Many more were wounded and disabled–and a number of facilities were built.  After they were officially launched in 1921, the Veterans Administration started building hospitals. By 1948 there were 125, and the VA currently says they operate 1600 health care facilities.⁵ They once cared for all service men and women who had been on active duty, even briefly. 

After September 1980 the government began limiting the pool by requiring a “minimum length of service.”

Indian Health, while being a right, is also a small underfunded and significant part of the care supplied by the federal government.  In the centuries that followed Columbus first voyage, 95% of the continent’s indigenous people died.  The Europeans brought infectious illnesses with them that were unknown and had never been confronted by the immune systems of the people of the continent.³³ “Smallpox undoubtedly played a huge part in the fall of the Aztec Empire.” Early settlers alternatively courted and hunted the people of the land.  Some of our elders tried to integrate natives into our society.  Others gave them terrain which was “eternally theirs”, and still others reneged on one promise or another.   In 1830 President Andrew Jackson signed the law that officially required tribes living east of the Mississippi River to relocate on lands west of the waterway.  They moved only to later discover that many Americans believed the United States was “destined to expand across the North American continent, from the Atlantic seaboard to the Pacific Ocean.”   Over the centuries some natives came to our cities and many blended in.  (There are clinics for Native Americans in Oakland California and many other large towns.)  For others there were reservations, (areas of self government that are “managed” by the U.S. Bureau of Indian Affairs). 

The war department got involved in the health of the Native populations in the 1800s after they decided to vaccinate the indigenous people against Small pox to protect soldiers in remote forts.   In the 1880s the Department of the Interior constructed infirmaries and hospitals.   

The government’s involvement in any kind of health care was pretty limited until Congress passed the massive Public Health Service Act of 1944 and established the NIH (National Institute of Health) the CDC (Center for Disease Control), and the now defunct Public Health Service hospitals.  The Indian Health Service was created and added to the mix in 1955.  Serving half of the known Native Americans of the day, the VA like system covers the people who lived on the remote rural reservations, and they run urban clinics that do what they can for the indigent Native Americans in our cities.  Half the identified Indians try to maintain their distinctiveness.  The service is “culturally sensitive.”  Local beliefs and traditional practices are blended with the modern medical model.  The emphasis is on public health and community outreach activities.  In her book The Scalpel and the Silver Bear, Lori Alvord M.D. a Stanford educated, half Navajo, physician who practiced medicine at an Indian Hospital recalled how the chant of a medicine man gave emotional strength to a male with advanced cancer.  She had removed his tumor and he was receiving chemotherapy, but he was despondent and had lost hope before the “singer” arrived and performed a ceremony known as a Chantaway.  As she explained, different songs and ceremonies help different illnesses:  If an accident caused the disability, the Lifeaway ceremony was performed.  The Shooting way was chanted if an arrow or lightning was the source of the problem.²⁰  

The federal government spends $3.5 billion a year for a service that delivers health care to 1.9 million of the nation’s 3.3 million American and Alaska Natives.  The “system” is large and spread out.  By their count there are 31 hospitals, 63 health centers, and 30 health stations plus 34 urban Indian health projects.  They are staffed by 2,400 nurses, 800 physicians, 400 engineers, 500 pharmacists, 300 dentists, and 300 sanitarians. The patient pays nothing, not even a co pay, for testing, drugs, or hospitalization. Part of the funding for the Indian health service comes from other government programs.  If a patient was covered by Medicare, Medicaid, or had insurance through their work, the insurer could be billed, and the money could be used to help cover the costs of care. 

The facilities are up to snuff.   All 31 IHS-operated and all 14 of the tribally operated hospitals have been inspected and accredited.  

Despite this the Indian life expectancy (72.3 years) is still about 4.6 years less than that for the U.S. general population (76.9 years). Death rates for some conditions are significantly higher.  Tuberculosis is 750% more common, and there are elevated rates of alcoholism (550% higher), diabetes (190% higher), unintentional injuries (150% higher), homicide (100% higher), and suicide (70% higher).

Juliet told Romeo that a rose by any other name would smell as sweet.  In this country most have the right to affordable health care.  Many are left out.  We don’t call a spade a spade.  And many have lost their ability to smell.

Over the last 80 years one group of Americans then another has acquired the right or expectation that they will receive the health care they want or need.  At times their access is funded by the government through taxes.  On other occasions employees receive benefits in place of a good wage or the care is provided by employers who get tax breaks.  At the same time many people living in our country are excluded.

When asked if they thought health care was a right, people interviewed in Athens Ohio pointed to neighbors who were unwilling to work yet qualified for “Medicaid”, the taxpayer funded program for the very poor.  One of the people interviewed thought “People should contribute to the cost”.  Health care shouldn’t be free unless you’re really hard up.  At the same time, as one citizen explained, “You shouldn’t have to worry about medical care anymore than you worry about “the fire department, or the police…or the roads we travel on.”⁴³

CHAPTER 18  EMERGENCY CARE

In 1986 by passing the Emergency Medical treatment and Active Labor Act, (EMTALA) congress created an important right for everyone. 

• That includes –the insured and uninsured.
• Citizens, foreigners, and “illegals”. 
• Anyone who suffers an acute illness or injury;
• people who show up in the emergency room and
• those who call an ambulance.

They all have to be treated. Hospitals that take Medicare funds, in other word almost every hospital in the country, is required to provide emergency and necessary hospital care for: serious illnesses, injuries-for women in labor—the ill and injured.  The care must continue until they are “stable.¹³”   

Before the law was passed some hospitals wouldn’t care for you if you couldn’t pay.  Sick unstable uninsured people were “dumped”.  People were “transferred for financial reasons, from private to public hospitals without consideration of their medical condition or stability.” Some of them died.

After Congress passed the law one of the government agencies, the HCFA, (Health Care Finance Administration) held hearings and created a number of rules and regulations.  Their guidelines “have the force of law” and they apply to all of the 98% of U.S hospitals who participate in Medicare.  Hospitals are required to medically screen any person who comes to the hospital emergency room and asks to be checked out.  If the person has an “emergency” problem the hospital must stabilize the situation if they can. For example:  a person with a ruptured appendix must be treated medically and/or surgically before he or she is discharged. 

• A person with an acute myocardial infarction (if medically appropriate) must be catheterized, stented, and observed before he or she is released. 
• If the hospital doesn’t have the expertise or equipment to care for a person, they must transfer the patient to an appropriate hospital. 
• They are in violation of the law if they delay services “in order to inquire about the individual’s method of payment or insurance status”  
• The sick person doesn’t have to be in the emergency room.  They can be in almost “any area of the hospital “campus” including structures and all areas that are not strictly contiguous with the main building but are located within 250 yards of it –or of hospital owned and operated ambulances.

Doctors who are on call are also, often, on the hook.  In some states they must show up within 30 minutes of being notified.  There are rules, and physicians face fines if they violate them.  We’re talking up to $50,000, money that is not covered by malpractice insurance.  Transfers are possible with a patient’s consent, if they are “stable.¹⁴ “

          A friend awoke one night with chest pain.  He was sweating and dizzy, and his daughter called 911.  The ambulance arrived quickly.  The paramedic determined he was having an acute myocardial infarction.  He was rushed to the county hospital where a skilled cardiologist was ready to act.  Within minutes a tube was inserted into an artery in his leg and threaded up the aorta.  When it reached the heart it entered a coronary artery.  Injected dye revealed an important artery was obstructed.  The tube was removed and was replaced by a catheter and stent.  A balloon on the catheter opened the artery and the stent kept it open.  Blood flowed to the oxygen starved portion of the heart muscle, and it looked like the heart had escaped serious injury.  My friend lived from paycheck to paycheck, didn’t own a home, and had allowed his insurance to lapse.  He was observed for a day, went home, and was sent a bill. .

The Emergency Care Law (EMTALA) gave people having an acute medical problem the right to receive one of the benefits of modern life— but it was not funded.  The care is not free.

U.S. hospitals and doctors accept the amount paid by Medicare and Medicaid as payment in full. (That’s the law.) There’s a website that tells how much insurance companies really pay.  Called Healthcare Bluebook, it allows people to punch in their disease and zip code.  The program provides a dollar amount.  If the website is correct the bill my friend with a heart attack received was outrageous.

The “fair price” for a coronary angioplasty and three days in a hospital in his zip code (per the Bluebook) was $24, 853.  (That covers the cost of the catheterization room, the equipment, and the hospital bed.)

The “fair” physician remuneration for stenting a single vessel was $1105.   (Add 25% for additional arteries.) The “fair” anesthesiologist fee for close to three hours of work was $1325.¹⁸ 

My friend’s bill for his heart stent and two days in the hospital was in excess of $100,000. 

What will it cost if you’re appendix bursts or you have a severe asthma attack when you’re in Paris?  Not much.  Health Care is good in France; an emergency room visit costs about $120, and a doctor’s visit goes for less than $30. 

When someone is in the U.S. doesn’t have insurance and has an emergency, they get a bill.  When the hospital or physician that provided the care didn’t have a contract with the person’s insurance company, and the policy only covers in-network emergencies the bills for the service can be enormous. 

In San Francisco, as the local newspaper, the Chronicle put it, injured parties “can (now) rest easy,’ “If you’re hit by a car, shot, fall off a roof or suffer any other major injury, you can now receive top-notch medical care at the city’s only trauma center without risking bankruptcy.”³⁵

In early 2019, San Francisco General Hospital, the city’s trauma center, was under pressure for its unfair billing system.  The hospital had no contracts with insurance companies.  All the care it provided was out-of-network.  As a result the city could bill as much as their self-determined rates allowed.  Health Insurance companies would then kick in as little as their self-determined policies permit.  The difference, thousands of charged and unpaid dollars, became the burden of the ill and injured people who showed up in the facility’s emergency room. 

“Three simple appendectomies left stunned patients on the hook for bills ranging from “$54,000 to $92,000”.  Well meaning doctors, nurses, clerks, and ambulance drivers were treating people’s physical maladies and destroying their economic well being.  The city owned the hospital, and taxes paid for some of the care.  Then, in place of being fiscally “prudent”, the hospital did something that, best I can tell, was unprecedented.  They adopted a humane approach.  They stopped billing poor people.  And they charged a maximum of $4800 to people who earned $121,000 (single person) or $250,000 (family). The affect on the hospital’s income was a fifth of a percent. 

Insurance companies have long argued that “networks” allow them to control the cost of care. They meet with hospitals, agree on fees, and sign in-network agreements. New York and a number of other states have laws “that cap or limit charges for services that are delivered out-of-network, especially for emergency care.”²³  

“Between 2010 and 2016 the number of and price tag of the charges went up pretty dramatically.

(For readers who are into numbers:  Out of network bills rose from 32.3% to 42.8%; the number of inpatients who got an out of network bill for some of their care rose from 26.3% to 42%.  The cost of an ER visit, in that six year period increased, on average from $220 to $628 and hospitalization charges rose from $804 to $2,040.”  Fifteen percent of hospitals have out-of-network billing rates that are 80 percent above the standard rate.  Some of the physicians in one study charged over 600% of the Medicare rate.²³)

California AB 1611 would have limited the fees charged for people who have insurance, but have a medical emergency and are seen at a hospital that’s “out of network.”  As it was about to be presented to the state Senate health committee when the sponsoring legislator “pulled” it as a result of “insurmountable” opposition from lobbyists and CEOS for California hospitals”¹⁵  

10 percent of anesthesiologists, pathologists, and surgical assistants sent patients who have insurance a bill because their insurer refuses to pay or only pays a portion of the bill.

They call the process “balanced billing” and it’s no longer legal in California.  (In 2009 the California Supreme court ruled that the 1975 Knox-Keene act implicitly forbids “balanced billing” for certain but not all types of insurance.)   

It’s a big glitch in the system.  (At present, there are more than 4,500 emergency departments in the country, and they are staffed by about 40,000 physicians.  One investigator found that “65 percent of hospitals contract out their emergency providers.²⁴” Another that two large companies EmCare and TeamHealth control 30 percent of the physician market, establish fees, and send bills.  In Texas the three largest insurance companies “had no in-network emergency room doctors²⁴.”)

California bill AB72 limited the amount people pay when they get elective care at an “in network” facility but part of the care is provided by a physician who is “not in network.” Physicians can’t charge “more than the in-network cost-sharing amount.”

I’m a physician. 2 decades back an out-of-network physician operated on a disc in my neck. I asked him how much he would charge and he said he didn’t know.  Someone would send me a bill.  Our visit lasted half an hour in the office and Surgery may have taken two hours. He was great and the operation went well.  I spent the night in the hospital and didn’t need any post op pain medicine.  Just coffee. My bill for “his role” arrived in the mail.  $8000.    I saw him a few weeks later for my only post op visit and I handed him a check for $4000.  Is that O.K.?  He looked stunned.  I have no idea what he was thinking, but he took the money and when I left he shook my hand.   

Chapter 19 INSURERS MOVE IN

It’s difficult to get a man to understand something when his salary depends on his not understanding it.  –Upton Sinclair. 

In the post World War Two years Blue Cross and Blue Shield were started in one state, then another.  They were public, tax-exempt corporations. By 1945 the “blues” were responsible for 2/3 of the nations’ hospital insurance, and by 1955, 60 percent of Americans had an insurance policy.¹

Aetna and Cigna began marketing medical policies in 1951.  They tended to target people who were healthy and unlikely to need expensive care. The IRS did not treat employer provided health care as part of a person’s taxable income and the Revenue Act of 1954 made it official.⁶

During the subsequent decade medical care became more effective, technical, and hospital based.  Costs escalated.  In the early 1970s the political elite felt there was a “crisis”.  In 1973, during the Nixon presidency, the HMO: health maintenance organization–act was passed.  The idea was to get groups of doctors working together.  In addition to treating illnesses physicians were now being asked to keep people healthy.  Companies with more than 25 employees were required to offer this new entity as an option. 

Groups popped up all over the country, and they took customers away from the ‘indemnity” insurance companies.  In response traditional insurers started buying HMO’s and the new bosses put pressure doctors and hospitals.  They tried to modify the way medicine was practiced by enforcing “guidelines”, recommendations by authoritative medical committees that told doctors what tests to perform in certain situations.  Physicians were paid less.  Knowing they would only be compensated for a portion of their charges, doctors and hospitals raised the “list price” of their surgeries, visits, and procedures. 

At one time HMOs tried to kick women out of the hospital the day after they delivered a child or had a breast surgically removed.  Some of the patients were ready to go home, but others had medical or physical problems that created risks.  An outcry led to publicity and lobbying.  Laws were passed, and the practice ended. 

The law restricted the amount a sick person in an HMO had to pay in the form of co-pays and deductibles.  And it required HMOs to hold an annual open enrollment period.  During that time people with pre-existing conditions could become members.   HMOs were required to provide insurance “without regard to health status.”

For-profit companies could exclude high risk individuals.  A law passed in 1945, the McCarran-Ferguson Act, had “exempted the business of insurance from most federal regulation.”  For profit companies were able to cherry pick—to offer the young, healthy, and employed, low cost policies, and they were able to reject individuals with medical problems, people who needed health care.   An expectation—a de-facto right—was created for young, healthy, and employed and it was taken away from others.  HMO’s could not offer companies high deductible or low benefit policies, but for-profit insurers could and did. Employers and healthy individuals increasingly bought policies from for profit companies.

Over the years the high risk populations of HMOs like Kaiser of Northern California and the Blues grew. For the young and healthy the plans they offered were costlier than those offered by for- profit companies, and the young and healthy increasingly chose private insurers.  In time “the Blues were hemorrhaging money”. The HMO I worked for was in grave risk of failing.

          In 1993 Bill Clinton became president and he asked his wife, Hillary, to form a committee and come up with a bill that would do something about the rising cost of health insurance.  The premiums people paid were going up 8.5% a year; many Americans were dropping their coverage, and polls indicated the public would welcome controls.

At the time the government, under Medicare and Medicaid (and to a lesser extent the Public Health Service, the National Institutes of Health (NIH), Indian Health etc.) was on the hook for more than half of the nation’s health care costs. 

Blue Cross controlled a large part of the private insurance market.  The Blues weren’t a single large company.  They were a conglomeration of state by state plans that were non-profit and tax exempt.  Their boards and CEOs were very well (and sometimes quite richly) compensated, but they had no shareholders.  They didn’t need to earn money or pay dividends. 

When Bill Clinton entered the White House he decided to tackle the “health care crisis.”  He asked his wife Hillary to create and lead a task force and to take some of the heat.  And she accepted. 

As Hillary later put it “I wanted to try to make a difference in people’s lives.  What could be more important than solving our nation’s health care crisis?  She spoke to people who had been denied coverage and she publically unloaded on the industry:  “It’s almost like they decided we should just drop dead without ever going into the hospital.”

Her goal, she told Congress, was “guaranteed universal health coverage at an affordable cost for every American.  A comprehensive package of benefits.  Health care that can never be taken away.”

In 1990, while Hillary Clinton’s group was working on their bill, the CEOs of insurance companies pow-wowed with the people in charge of hospitals, and with drug and medical device manufacturers.  They formed a group called the HLC., the Health Care Leadership Council.

I suspect the Clintons thought their proposals would be popular. They were obviously not prepared for the HLC attack and spin that followed. 

The plan Hillary and her medical advisors (Atul Gawande was one of them) came up with sounds a lot like Bernie’s Medicare for all. It didn’t pass so it’s not really part of the “real history of medicine.” Many of the details are in the foot notes.¹¹

The proposed legislation would have required health plans to provide an all inclusive benefit package. It would have been regulated by a regional non-profit organization or an agency of the state. When people got their insurance from their jobs the employer had to pay 80 percent of the cost of the premiums.

AND, it WAS comprehensive.  Hospital, outpatient, drug, and dental care were part of the scheme.

To keep costs from going through the roof there was a regional money target.  If it was exceeded the payments to hospitals and doctors would drop. Out of network emergency charges couldn’t be inflated. Balanced billing–making the patient kick in when the insurance company refused, was prohibited. There were caps on premiums and drug prices would have been “reviewed.” A tax increase was not recommended.

Bill Frist, physician, senator, republican, and founder of a huge for-profit hospital chain said “Hillary Clinton was seen as more rigid, probably more principled.  She was out front on the issues that “maybe half the country didn’t think should go that far” so she was easy to demonize.  One of their ads talked about a whole bunch of guys who were in Hillary’s testicle lock box.  Bill was portrayed as Hillary’s poodle.  Rush Limbaugh pulled out a picture of her as an evil witch and showed photos of her daughter.

  The HLC claimed that if the proposals became law: Health care would be rationed. Patient’s rights would be compromised.  The Clinton plan “was formed by academic elites behind closed doors.”   

T.V. ads featured Harry and Louise, two fictional Americans who thought the suggestions would let “Washington bureaucrats decide how much care you and your family receive.”

Congressmen and women were lobbied.  There were letter writing campaigns.  The Medicare program was pronounced “dysfunctional”.

The effort to prevent health care reform cost $300 million.  Insurance companies argued that the “free market could work if government got out of the way. “

In the end the Clinton proposals were not accepted by Congress, and Clinton went on to fight other battles.

As I read about the political clout of the AMA, American Medical Association, I began wondering how doctors decades later allowed the for profit insurance companies to totally take over the entirety of health insurance.  Where were we?  Why didn’t we do or say something?

My answer:  Doctors in the 50s and 60s had feared and fought government involvement, but they found Medicare led to better care and higher salaries.  I think the experience lulled the profession and made us more trusting and complacent.  Big organizations, it turned out, weren’t bad after all. 

Insurance company representatives were smooth and seemed to be good guys.  A prominent Georgia doctor named Leaderman was convinced the companies would “respect physicians” and allow them to provide high quality, cost effective care.”

At the time that Clintons released their plan, Blue Cross and Blue Shield created obstacles to the for-profit companies.  They controlled a large part of the health care market.  The money they took in was actually used to pay for medical care.  Driven by “need” not “greed”, these companies only charged what they needed to cover their costs.  By so doing they established a de-facto price boundary, and it limited the amount the for-profits could charge for policies. 

But over many decades the Blues had gradually lost market share, and they were about to crack³.

Then, one day in 1994 I heard a group at the nurses’ station discussing an article in the local paper.  The board of directors of Blue Cross had resigned.  They formed a for-profit health care organization and took all the low risk policies with them. 

We now know⁷ that in 1994 the national Blue Cross and Blue Shields board of directors met in Washington D.C. and voted to allow its members to “operate as for profit companies.”  Blue Cross of California changed its name to WellPoint, took a bulk of the policies that insured low risk individuals, and they became a new, for-profit company.  They then bought the non- profit Blues plans in Missouri and Wisconsin.  Blue Cross of Indiana became Anthem, and merged with WellPoint.  By 1996 California, Colorado, Ohio, Virginia, Kansas, Maine, Missouri and Georgia had changed over.  There were few remaining not-for-profit insurance plans.  But the private companies were in charge and could now call the shots. 

The for-profits were not required to “provide affordable, accessible health care” to all the people of their state.  They could, instead, provide and/or charge for health care according to risk, and they could concentrate on making money for their stockholders. Kaiser, the group I worked for, modified its business model.

In 1987, the for-profit companies contended they were providing a service to the community and convinced the IRS to give them “special tax benefits.”

In 2008 a former insurance executive named Wendell Potter had enough, quit, and wrote an “expose”, a book titled Deadly Spin.  His revelations didn’t make headlines or shake events much.  But his story is similar in some ways to that of the man who exposed big tobacco.  Formerly one of the nation’s better PR people, he was a “spin” expert.  When the press came after his company for misdeeds, questions were not answered.  He taught his people to respond with talking points.  CEOs were trained. Potter attended interviews, and he limited the scope and duration of the sessions.

In his book he explained the “right way” to reply to questions about the 45 million Americans who didn’t have health insurance.  Spokesmen and women were taught to blame the victim:  40% of the uninsured were young adults, and company representatives explained that many of the uninsured believed the risk of injury or illness was too low to justify the cost of the premium.  35% earned $50,000 a year and should be able to afford insurance, so it was a question of choice.  20% were not citizens. 

Potter, a poor boy from the back country of Tennessee, was the first in his family to go to college.  His father served in Europe and North Africa during the Second World War, then came home, married, and opened a grocery store.  When the business lost money his dad got a job in a “brutally hot factory”, and toiled there until he retired. 

In and after college Potter was briefly a journalist.  Later he became a press secretary for a man who ran for governor and lost, and he next became a “spokesman for a failing banking empire.”  In time the health insurer Cigna hired him “to help boost awareness” of the company’s health care business.  He became a PR man extraordinaire and helped devise the messages of some of the nation’s leading insurance companies.  He participated in the demolition of Bill Clinton’s health bill.   Well paid, important, and at the top of his game, he paid a visit to his parents in July 2007.  While there he learned that John Edwards, the presidential candidate, was scheduled to talk about health care reform at a fair in nearby Wise County Virginia.  Wendell decided to attend and listen.  He was devising talking points for his company and was looking for inspiration.

The health fair was produced by an adventurer and T.V. personality named Stan Brock.  In 1985 Brock had founded a nonprofit organization called Remote Area Medical.  “Volunteer doctors, nurses, technicians, and veterinarians, at their own expense, were taken on expeditions where they treated hundreds of patients a day under some of the worst conditions.”  Crews worked in Katrina after the hurricane, Haiti after the earthquake, and held day long clinics in underserved areas in the U.S.  Wise County Virginia was one of those locations. 

Potter arrived early and parked in a jammed lot.  Some of the people who formed long lines had slept in their vehicles.  It had rained the night before and it was damp.   Inside the treatment area large numbers of people waited in lines that led to clinics.  Some people got their care in tents or animal stalls.  Dentists pulled teeth.  Nurses performed pap smears.  Potter recalled mammograms, sigmoidoscopies, and doctors cutting out skin tumors. 

He was troubled by what he saw.  This wasn’t happening in a third world country.  This was America, the land with the best health care in the world.  Two thirds of the people at the health fair had no insurance, but a third did.  Problem was many of their policies didn’t kick in until thousands of medical dollars were paid by the policy holder.  In some cases we’re talking about $15,000 each year.  In other cases the amount was $30,000.  The average income in the nearby counties was $23,000 to $26,000.  A “family health insurance” policy went for $13,375. 

62% of bankruptcy filings in 2007 were the result of healthcare costs.⁵

What Potter witnessed could have been spun. The young uninsured were risk takers.  People who earned $50,000 a year were shirking their responsibilities.  Non citizens would be lumped and denounced as illegal aliens, though many were students.  Other non citizens were in the country legally, and were performing jobs Americans couldn’t or wouldn’t do.  They didn’t have health care because they couldn’t afford it. 

Potter knew how to tell the story, but when he looked into the faces of the people standing in the line in the rain for hours to get care in animal stalls, Wendell saw folks who could have been his relatives or neighbors.  He didn’t know them, but they seemed so familiar.  They were like his dad and mother.  The army had sent Potter’s father to Europe and North Africa during World War Two.  When his dad returned, both parents dropped out of high school and worked.  “They sacrificed years to send Wendell to college.” The people Potter was being paid to vilify were no longer anonymous or faceless. 

A few days later Wendell was aboard a company jet.  When his food arrived on a gold trimmed plate, he thought about the people who days earlier were receiving medical care in animal stalls.  That’s when he decided to quit the spin game.  The contrast between the compensation executives exacted and the care they denied was something that Potter pointed out in his book.

When Edward Hanaway left Cigna in 2009 he wrote a book blaming the health care consumer for the rising cost of health care.  His retirement package was valued at $111 million.  In 2007 a top average Health Insurance CEO had a salary of over $11 million.  William McGuire of UnitedHealth backdated his stock options, was caught, and paid back $620 million dollars.  He then managed to survive on $530 million in non stock compensation plus an additional $800 million in stock options. 

In his book Potter documented, but avoided direct comments about the pay executives received, dollars that could have gone into providing better or more care (or even used as dividends for investors).⁴

Corporations in this country are strange inventions.  They are endowed with the same freedoms of speech the constitution gives to humans.  Some tend to only have the conscience and ethics needed to mollify the public and the government.  They make no bones about their purpose for being.  Their job is to make money, nothing more. 

Chapter 7 FDA AND THE RULES

The protection of a man’s person is more sacred than the protection of his property.  Thomas Paine.

If some critics were correct, if it once took too long for new drugs to be evaluated and approved, that’s no longer the case.  If anything, the FDA is tilted in the other direction: 

Drugs are often approved when their long term effect won’t be known for years. 

Cancer drugs that may or may not make people live longer are marketed. 

And physicians don’t have to wait for FDA approval before they prescribe an experimental medication.  There’s a mechanism that allows physicians to legally use a drug that is still being tested.  Called the IND, (Investigational New Drug) permit, the process has been around since 1987.  If a therapy is needed urgently and a manufacturer has an experimental product that might help, a doctor can apply.  The FDA received over 500 commercial, research, and emergency IND requests in 2018 and in 2019.¹

Using a different tool, 5 months into the coronavirus epidemic the Food and Drug Administration made the anti-viral drug remdesivir available under an “emergency-use authorization.”  A month long study of over 600 hospitalized patients with severe disease had shown that the median time for recovery in people NOT given the medication was 15 days.  For those who received Remdesivir intravenously daily for 10 days it was 11 days.²²

The TV is full of ads for diabetic drugs that lower the A1C.  That’s a marker of a diabetic’s average blood sugar.  Tight control may or may not lead to a better outcome.  When the average blood sugar is close to normal there’s less damage to the small blood vessels of the eyes and kidney.  But in a study of the frail elderly, an emphasis on keeping the average blood sugar low led to “increased mortality and did not significantly reduce major cardiovascular events.”  Hypoglycemia, a blood sugar that’s very low, can cause irrational behavior, falls, and even death.²

The FDA protects us from harm and misrepresentation.  That’s what it is there for.  And it likes to illustrate how important this can be by retelling the story of Thalidomide.

When it was introduced in 1958, the medication was hailed as the tranquilizer of the future.  It put you to sleep without the expectation of a hangover, could be used for “over tired” children, and wasn’t fatal, even in a massive overdose.  Chemie-Gruenthal, the manufacturer quickly found acceptance for its product thorough out the world.  Three countries held out against approval:  France cited “technical reasons”; Israel kept delaying without giving a reason.  And in the United States there was Frances Kelsey. 

Competent and a bit over educated for her FDA position, Frances had, as she put it, “entered college in the depth of the depression and graduated when there were absolutely no jobs.”  Deducing she could choose “either to do graduate studies or join the breadline,” she studied and acquired a Masters degree.  There still were no jobs so she earned a PhD.  In 1943 she was a biochemist at the University of Chicago and she met and married a fellow biochemist.  At the time “two members of the same family could not be employed in the same department”, so (she wrote) “needing all the help I could get to obtain a job I entered medical school.¹⁶”

She was hired to be a medical reviewer for the FDA at a time when the agency was required to pass on a drug within 60 days or it would automatically be approved.  By chance, Kelsey was assigned to the thalidomide case.  It would be marketed by Merrell under the name Kevadon.  As the sixty-day period came up Dr. Kelsey routinely rejected Merrell’s application as “incomplete.” 

She was dissatisfied with the quality of thalidomide application.  The submitted clinical reports were testimonials, not well-executed studies.  She learned that when the sedative was taken for a period of time it sometimes caused peripheral neuritis, a very painful tingling of the arms and feet. The effect had been recognized in Europe, and was the main reason the medication had lost its over-the-counter status in Germany.  About that time, the FDA was also an interested in the effects of drugs on the fetus. Embryos and newborns are unable to handle drugs in the same way that an adult can.  If a person taking the medication for three or four months could develop a severe neuropathy, how would it affect an infant that might be exposed to it for months?  “We were NOT thinking in terms of absent arms or legs, but just– if it did something to the adult over time, it might just as well have an adverse effect on the child.¹⁶“

Within a year of the introduction of Thalidomide a very rare deformity in newborn babies began to appear in Germany.  It was called phycomelia.  In the place of arms and legs babies were born with something like fins.  From 12 cases in 1959 the number grew to 83 in 1960 and 302 in 1961.  Near the end of 1961 a Hamburg pediatrician made a statistical connection between this ominous health problem and mothers who had taken Thalidomide while pregnant.  The manufacturer was sufficiently concerned, and withdrew the drug from the market just as Israel was about to approve it.  According to the FDA 10,000 people in 20 countries were victims of the simple sedative.³    

At the time Senator Estes Kefauver was investigating “the escalating expense of lifesaving prescription drugs.”  He openly berated pharmaceutical executives for profiteering.  Doctors were portrayed as dupes of the companies that produced our medications.¹⁹ A household name in the 1950s, the Tennessee Senator campaigned for office wearing the kind of coonskin cap David Crockett wore when, in 1836, he died defending the Alamo.  Kefauver’s committee had questioned mob leaders on live TV, and in 1956 he ran for Vice President of the U.S. and lost. 

The “endlessly polite Southern senator in horn-rimmed glasses” unsuccessfully attempted to require newly approved drugs to “generate competitive markets after 3 years” and he failed to eliminate the promotion of “me-too drugs” and “molecular modifications.^5,22”   

But, thanks to thalidomide, the Kefauver-Harris amendments to the Food, Drug, and Cosmetic act of 1938 became law in 1962.  Proving a drug was safe in mice and a rat was no longer enough.  A drug now had to be shown effective as well as relatively safe.

The drug companies fought back in the courts.  In 1974 the Supreme Court allowed the FDA to rule that drugs in use before 1962 were no longer protected by a “grandfather clause.” It gave the FDA full authority to demand double-blind studies.”

A federal agency with more than 22,000 employees, the modern FDA does much more than give marketing approval to drugs and monitors their side effects in humans.  Among other tasks, it ensures “the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices.” And, of course, it’s responsible for the safety of our food supply.

Its precursor was created in 1906 when Congress passed the original Pure Food and Drugs Act.   The law “prohibited misbranded and adulterated foods, drinks and drugs in interstate commerce.” After spending time as a subdivision of the department of agriculture, the FDA became an independent agency in 1930.

The FDA’s next boost in responsibility came after Bayer developed, but was unable to patent mankind’s first antibiotic, Sulfanilamide.  It was made and sold in pill form by manufacturers throughout the world, and it was widely used.  Then a company in Tennessee created an elixir.  Their chemist dissolved the medication in diethylene glycol, a compound normally used as antifreeze.  Flavored with raspberry extract, saccharin, and caramel it was a commercial success.²⁰ But it was also toxic and caused kidney failure and the death of over 107 men, women and children.  As a PhD student, Frances Kelsey had been part of the team that, after Sulfanilamide had been recalled, tried to understand what went wrong.  She gave the solvent to rats, and watched as their urine turned red and they died.  In its liquid form the antibiotic had never been tested in animals.  “It was just put right on the market and sold like wildfire.”

Following a public outcry about the “wonder drug”, Congress passed, and President Franklin Roosevelt signed the Federal Food, Drug, and Cosmetic (FD&C) Act of 1938.  “For the first time, manufacturers were required to show a drug was safe before it could be marketed³

In 1980 congress passed the Bayh-Dole act.  At the time research and discoveries that were paid for with government (tax payer) moneys were available to all comers.  They were in the “public domain.”  The legislation changed the rules.  After 1980 universities and the NIH were allowed to patent their discoveries, and they could sell licenses to drug companies.  With the license in hand the drug companies could use the “taxpayer funded research” as a basis for pharmaceuticals.

In India, the patent law of 1970 took a different approach.  New medications –the drugs themselves–could not be patented, but the process, the way it they were produced, could.  In 2005, as part of the international agreement–TRIPS (Trade-Related Aspects of Intellectual Property Rights)–product patents became available.¹⁴

In 1984 the Hatch-Waxman Act “created a period of exclusivity, an amount of time when a drug that was newly approved by the FDA was protected from competition.¹⁸ The law also made it easier for generic drugs to come to market.  Companies making these medications had been forced to repeat clinical controlled trials, to start from scratch even though the drugs had been used for years and were relatively safe.  The law ended that requirement and the market for copy cat drugs went wild. (See chapter on generic drugs.)  

After 1984, when a drug’s FDA granted monopoly ended, a generic company could ask for permission to produce the medicine.  The law gave the first appropriate applicant a 180 day restricted head start on the competition…unless the product was covered by a “valid patent”.  If the drug was “protected,” the original manufacturer could file suit and allege violations.  That was the loophole that lobbyists presumably inserted. 

Most drugs were initially covered by a patent whose 20 year life-span starts early in the research process.  Additional patents are typically filed at various stages of the medication’s development.  Many deal with non essential ingredients, like the color of a pill or the starches used as filler. When a drug’s years of private ownership ended, the additional patents were sometimes used by a company to sue alleging its product was “patent protected”.

When a very profitable drug’s “privilege” expired, they filed.  The legal allegations were often capricious.  But that didn’t matter.  The law said that once the suit was filed, the FDA had to automatically delay the approval of the generic drug for 30 months “to permit litigation.”

At this point both manufacturers knew the generic drug maker would probably win, but lawyers know how to drag things out.  Court battles are lengthy and expensive.  So lawyers got together.  The company that owned the revenue generating medicine typically paid millions of dollars a month, and the generic drug maker waited a bit before it produced and marketed their version.   There were 33 pay-for-delay settlements in 2010.  In 2013 the Supreme Court ruled the practice was subject to antitrust laws and in 2015 the generic drug company, Teva, settled a pay for delay lawsuit for $1.2 billion.  In 2012, 40 pay-for-delay law suits were filed.  The number dropped to 29 in 2013 and 21 in 2012.

In 1992, after Congress passed the Prescription Drug User Fee Act (PDUFA), Two thirds of drug approval expenses were paid by big Pharma.  The fox was paying the regulators who were guarding the hen house.

In 1997 drugs that had only been tested on adults were sometimes given to children and Congress passed a law.  It required medications that were prescribed for kids to be proven safe and effective IN KIDS, and it gave the manufacturers who got approval an additional 6 months of exclusivity.   

That, of course meant that when a drug that brought in more than a billion dollars a year was about to lose its monopoly, a company could give the medication to a few kids, write up a study, and shut generic drug makers out of the market for an additional 6 months.

The FDA uses a number of advisory boards, groups of physicians who are experts in the field.  The FDA officer makes the final decision, but, in tough situations, it must be nice and at the same time awful to have a group of M.D.’s who serve as a sounding board and buffer.

The 2007 their approach to Avandia (rosiglitazone)—a “glitazone” that is used to lower the blood sugar level in diabetes– is an example of how wrong these boards can be.  Made by SmithKline Beecham, Avandia had a side effect.  It raised the level of cholesterol in the blood.  You don’t have to be a doctor to know that a high serum cholesterol creates an additional risk for people with diabetes.  The condition increases the likelihood that they will have a heart attack or stroke. 

The other glitazone, (Actos),Pioglitazone didn’t worsen blood lipids.   

In 1999 the agency approved both rosiglitazone (Avandia) and pioglitazone (Actos)for use in people with diabetes.  Doctors could prescribe either, but the FDA wanted companies to monitor the drugs for problems.

By 2006 both drugs were grossing more than 1.5 billion dollars a year.

Actos did not increase the risk of coronary disease, but Avandia did.  It also, sometimes caused heart failure, fluid in the lungs and legs. FDA panels were convened.  The experts voted to keep Avandia on the market, but black box warnings were added to the packaging.  Physicians on the panels hoped doctors would read them and use the drug sparingly.

They didn’t, and a 2007 medical study convincingly showed that Avandia caused heart disease.  The drug’s sales dropped, but a million prescriptions a year were still being written.

The panels of experts convened by the FDA agreed that Avandia “posed significant cardiovascular risk”.  Then they voted.  Twelve of the 33 doctors thought the drug should be removed from the market.

The chairman and 9 others voted for much stricter controls.  The doctor in charge wrote that “several meta-analyses revealed a significant increase in the risk of myocardial ischemic events among patients taking rosiglitazone…  But a second analysis, failed to demonstrate a similar risk.”  Then he added a little gibberish:  “the results regarding the safety of rosiglitazone raised new questions about relative and absolute risks.^4”

In July 2010 the manufacturer of Avandia settled a lawsuit for the harm the medication did for $460 million.  Compared to revenue of $1.1 billion dollars the prior year and much more in the years before the 2007 hearings, the monies paid did relatively little harm to the company’s bottom line.  Pioglitazone– Actos, is still being widely used.

Then in the early morning hours of June 27, 2003 a controversial law was enacted.  A mere thirteen years had passed since Congress granted Medicaid “most-favored customer” status, and required drug manufacturers to sell their meds to Medicaid at the “best price” available to any other purchaser.  This time, however, congress passed a law that said pharmaceutical manufacturers can charge what they want to charge and the government can’t price negotiate.  The Secretary of HHS was prohibited from negotiating lower drug prices on behalf of Medicare Part D beneficiaries. When asked why he thought House leaders had scheduled the vote long after most Americans had gone to bed, Representative Dan Burton (R-IN) said “a lot of shenanigans were going on that night (that) they didn’t want on national television.”  According to Walter Jones, a disgusted North Carolina Republican who voted “no”, it was the “ugliest night” he had witnessed in more than two decades as a member of Congress.  “Pharmaceutical lobbyists wrote the bill;” ¹⁷ 

Touted as a means of providing cheap or free drugs for people on Medicare, the bill did not include any new taxes.  The entitlement was not funded, though part of the cost was paid by enrollees.  Seniors paid $265 to receive the benefit, and then kicked in $25 + a month.  When a person took and expensive drugs and the annual cost exceeded $2400 a year the government stopped paying for a while.  Enrollees had to shell out for the next $4000 worth.  If the annual drug cost exceeded $6400 a year, the government started paying again.  The $4000 was called the donut hole, and it was eliminated by Obamacare.

After the bill was passed the government accounting office claimed that American prescription drug prices rose 6.6% a year between 2006 and 2010.  By contrast the price of generic pharmaceuticals increased by 2.6 percent annually and overall medical costs rose 3.8% a year.

“Representative Billy Tauzin (R-La.),the “Cagey Cajun”–he came from a French Speaking Louisiana family–  coauthored the bill, then negotiated a $2-million-per-year job as a lobbyist for the drug industry’s trade organization.”  Thomas Scully, a Bush Medicare official who misstated the program’s cost, became a health industry lobbyist.”

During the following decades the FDA used a number of techniques to drugs that seemed promising to people who were willing guinea pigs.

(FOR THOSE INTERESTED IN THE DETAILS: At the height of the AIDs epidemic, activists protested the delay between a new drug’s submission and approval.   In response the agency created fast-track rules that sped up the development, assessment, and sales of new treatments– for life threatening conditions.  The FDA also made unapproved drugs available to people who had AIDS (and other serious conditions) who were unable to enroll in clinical trials.²³ 

In the 1980s it created “treatment INDs.”  To obtain a medication a provider has to submit a form that can usually be filled out in 45 minutes.  The agency then takes up to 4 days to process a non-emergency application; emergency requests are approved in less a day.  Between 2005 and 2014, 1200 forms were submitted each year; over 99% were approved.  Most were for a single patient and half were for an emergency.¹³ 

          In 1970 a strong demand for experimental cancer drugs led the FDA to adapt an early-access policy.   In 1992, the agency started allowing speedy approval on the basis of end points that were seen as “reasonably likely to predict patient benefit.”

During the 2014 African Ebola outbreak, acting on preliminary data, the FDA authorized the use of six tests that rapidly identified infected patients, and they reviewed IND applications for 2 investigational vaccines in less than a week.  Then they allowed developers to proceed with phase 1 clinical trials.⁷)

In 1992 Congress passed the prescription drug user act.  It authorized the FDA to collect money from pharmaceutical manufacturers, and told the FDA to review special drug applications within 6 months.  Ordinary applications had to be assessed within a year.

As therapies were developed and authorized more quickly, the FDA started “requesting” post approval studies. Under the 2007 FDA amendments act, congress allowed the FDA to “require” studies after a drug was approved. 

In spite of the law only half of the post approval studies were completed within 5 years.  “20% had not been started; and 25% were delayed or ongoing.”¹⁵ 

In 2012 the FDA didn’t approve Solanezumab. “The drug binds the amyloid-B peptides that form plaques in the brain”, that many believe are the cause of Alzheimer’s dementia.  They hoped the Solanezumab monoclonal antibody would help clear amyloid from the brain.  The company’s original placebo study, performed 4 years earlier, had shown Solanezumab didn’t work—“didn’t improve cognitive function in people with mild to moderate Alzheimer’s.”

At the same time “there appeared to be a statistically significant benefit for the subgroup of patients with mild dementia–a 34% reduction in cognitive deterioration” Maybe Lilly had something.  The company went to the FDA and sought tentative approval, and the FDA turned them down.  They demanded further testing.

In recent years, the FDA’s testing requirements have been under attack.  One section of a new law “allows the secretary of health and human services to rely more heavily on surrogate measures, or “drug development tools,”  Using these softer criteria, FDA leaders could theoretically have approved the drug.  It seemed safe enough.  The agency could have then required post marketing testing–studies that take years to perform.  But why would anyone with mild dementia risk getting a placebo rather than the real thing?

Lilly enrolled 2100 people with mild dementia and followed them for 18 months.  They learned their drug didn’t slow the disease. The money saved by waiting was substantial.  People are desperate for something that can stop, prevent, or reverse Alzheimer’s.  2.5 million Americans would have been able to access the medication.  Drugs like this almost always cost more than $10,000 per patient per year.  So, using surrogate criteria, we would have paid billions for a useless drug.⁸

Legislators probably thought they were making one-small-step towards lower drug prices when they passed the Biologics Price Competition and Innovation Act (BPCI Act) of 2009. (The Europeans took similar action in 2006).   Our country now allows companies to market “interchangeables”– medications that are “different chemically” but work as well and are just as safe as a currently marketed drug.

In fact, industry had been marketing biosimilars for years.  But– in the past they didn’t “price compete.”  Companies marketed biosimilars so they could charge higher prices.  Prilosec, a drug that stops the stomach from making acid, is chemically the mirror image of Nexium.  Their actions are the same and they are similarly safe and effective.  The milligram dose is a little different.  40 mg of Nexium has the same acid lowering effect as 20 mg of Prilosec.   The new drug was introduced at a time that Prilosec was losing its hold on the market.  The owner, AstraZeneca, funded a study that showed that in people with severe erosive esophagitis, 80 mg of Nexium was more effective than 20 mg of Prilosec.  In other words doubling the dose of the drug decreased the amount of acid a stomach makes a bit more.  The idea wasn’t new.  We doctors had long been using double doses of Prilosec for severe esophagitis.  The company marketed Nexium as a new drug, and they used clever marketing to gross over $5 billion a year for a few years.  For starters they sold their old drug, Prilosec over the counter for 75 cents to a dollar a pill.  That can be $30 a month.  Nexium was a prescription and was covered by most drug plans.  So for people with good drug insurance Nexium could be purchased with a low co-pay.  That made it cheaper than Prilosec.

People who take the Prilosec or Nexium for a period of time can’t stop easily.  The medications keep the stomach parietal cells from making acid.  That’s what some gastric cells do—they make hydrochloric acid.  Over time stomachs respond to the absence of acid by growing more and bigger parietal cells.  These cells are inactive as long as a person keeps ingesting a pill a day.  When or if a chronic user stops the drug for a day or two, the parietal cells wake up and go to work.  The stomach starts producing huge quantities of acid, and many people develop chest pain or severe heartburn.⁹

Despite the cleverly crafted loopholes in the law and pressure from industry, amid a culture where there’s a tendency to mainly recognize government employees when they screw up, the FDA is doing what it’s supposed to do. It was created to keep us safe and it’s doing its job.  And that’s good.

 

HOSPITALS

In the summer of 2005, Charity Hospital, the country’s second largest, provided medical care to the poor and uninsured of New Orleans and had one of the nation’s busiest emergency rooms. Rebuilt for the sixth time in 1939, it had 2680 beds, and was a major teaching hospital for Louisiana State University. That August Hurricane Katrina struck the city and flooded the first floor of the structure. Aside for a few generators for breathing machines there was no power, no lights, and food was scarce.   On more than one occasion the thermometer topped 100 degrees.  Toilets didn’t flush. There was no water for hand washing and the port-a- potty at the end of the hall smelled.  Observing from the forsaken building, a physician painfully watched each day as helicopters evacuated patients from the roof of the nearby Tulane Hospital, a facility that was 80% owned by the for-profit Hospital Corporation of America, “while our 250 patients were evacuated by twos or threes in boats”.  It took nearly a week before the final 200 were rescued.¹⁹ 

Of the for-profit institutions, HCA, Hospital Corporation of America is the largest.  The chain was started in Nashville in 1968 by a cardiologist named Thomas Frist.  “The hospital he worked in was poorly run and equipped,” and he and a few colleagues decided to build another one.  He met and partnered with Jack Massey, the man who developed the Kentucky Fried Chicken chain.  They built Parkview hospital in Nashville and bought a second one.  When Thomas junior talked to investors he encountered skepticism.  They didn’t believe a doctor could be a good business man.  The secret of his success, he once said, was the idea of bigness itself. 

The company he founded has become quite large and has “164 hospitals and 106 freestanding surgery centers in 20 states and Great Britain”–and a “market cap” of over 9 billion dollars.

Another of the big four, Humana was established after a few Louisville realtors figured they could make money operating nursing homes. They chose the company name from a list of 500 submitted by a corporate identity consultant. After buying one, then a few hospitals they went public in 1968.  By 1972 they were running 45 hospitals.   In 1978 they took over a second hospital chain and more than doubled in size.  Then in 2018 the company paid $4.1 billion for a 40 percent stake in 76 long-term acute care and rehabilitation hospitals operated by Kindred Healthcare.    

Bob Appel founder of American Medical International worked for a medical diagnostics lab that served hospitals.  When his employer had financial problems Appel purchased the lab and later started acquiring hospitals. 

National Medical Enterprises, now Tenet was formed by three lawyers in 1967.  One was quoted as saying “doctors don’t generally know how to run a business.  A hospital is really just like a hotel.  You just have to know the medical side.¹⁵”

Community health systems of Franklin Tennessee once owned 25 of the 50 hospitals that were the nation’s most expensive.  In 2014 they controlled 200 hospitals and earned $18 billion in profits.  Then they paid $7.5 billion for a for-profit chain “that had a slew of financial and legal problems”, and they started losing money.  When their debt was close to $15 billion they sold 30 hospitals cheap and they are teetering.³

Currently about 1034 of the nation’s hospitals belong to one of several for-profit corporations.  They have stockholders, earn money, and pay taxes.  Their bottom line was boosted (and government revenues fell) in 2018 when the corporate tax rate dropped from 35% to 21%. 

Our nation’s first, Philadelphia’s “Pennsylvania Hospital’, was founded in 1751 “to care for the sick-poor and insane who were wandering the streets.” The facility was the idea of a Quaker who was medically educated in Paris a century before physicians believed bacteria and viruses cause infectious diseases.  He wanted to emulate Paris’ Hotel-Dieu, the continent’s second oldest. The Parisian facility was established by Saint Landry in 651 AD “to treat pilgrims and the poor.” By the early 21st century the facility had become central Paris’ “top casualty and emergency hospital.”  It closed in 2013.¹²

In 1811 federal legislators established and funded a home and medical clinic for military veterans. Fifty years later, after half a million fighting men died of wounds and illness in our destructive civil war (1860-64),the government created a number of veterans homes.  They “incidentally” also provided medical and hospital treatment.  50 years thereafter our nation entered the First World War (1917-18).  116,000 men lost their lives.  Many more were wounded and disabled–and a number of facilities were built. 

After they were officially launched in 1921, the Veterans Administration started building hospitals.  By 1948 there were 125, and the VA currently says they operate1600 health care facilities.⁵ They once cared for all service men and women who had been on active duty, even briefly.  After September 1980 the government began limiting the pool by requiring a “minimum length of service.” The VA and Indian health hospitals are directly and indirectly (through Medicare and Medicaid) federally funded.  

Before Medicare was passed in 1965 U.S. hospitals were largely segregated. Black physicians often couldn’t get privileges to practice at hospitals dominated by whites, and in some of our leading hospitals people of color were cared for in the basement wards of white hospitals.

After the American Civil War ended four million former slaves had abruptly been told you’re free to leave, but they had no resources and nowhere to go to-– no basic shelter.  Often cramped together in abandoned buildings, they couldn’t maintain basic hygiene, and many got sick.  Privately run institutions for the very poor existed, but there were no hospitals, and the private shelters wouldn’t accept the newly emancipated.  Former slaves died in large numbers.  In some places “their bodies were littering the streets.”  About that time there were 54,000 male and 300 female medical doctors in the U.S. and only a few were people of color.^41,42

Congress established the Freedman’s Bureau in the South.”  It “fed millions of former slaves and poor whites, built hospitals, and provided medical aid.  But its hospitals didn’t have enough beds, linens, quarantine facilities.  There were merely 120 doctors for the entire population.  And there was a smallpox outbreak.  In July of 1872, “responding to the continued hostility of white Southerners, Congress terminated the Freedman’s bureau.”

In the early post Civil war years the government founded a number of black schools and colleges.  In 1868, one of them, Howard University in Washington D.C., “became the first school to have a medical program for blacks.”².

The country’s first black surgeon, James McCune Smith, had to go abroad to get his medical degree.  He grew up in New York and had a white father and a black mother who had once been a slave. Educated in the city’s African Free School, he was denied entrance to an American University and went to college in Glasgow. In 1937 he graduated from a London medical school, returned to the U.S. and became a vocal abolitionist.  He wrote the introduction to the Frederick Douglass book “My bondage and my freedom,” and was practicing medicine in Brooklyn when the Civil War ended.⁴⁰ 

In 1864 Rebecca Lee Crumpler became the country’s first black “doctress” of medicine.  Born a “free” black in Delaware in 1831, she later wrote about her journey in the Book of Medical Discourses.  “Having been reared by a kind aunt in Pennsylvania, whose usefulness with the sick was continually sought, I early conceived a liking for, and sought every opportunity to relieve the sufferings of others.” The book was published in 1883. 

Between 1852 and 1860 Crumpler “served as a nurse under several doctors.  In 1860 she “was admitted to the New England Female Medical College, the first institution in the U.S. to train women in medicine.”  It merged with Boston University in 1873.⁴⁰ Students were “taught by rote–four lectures each day, often clocking in at eight hours total. A systematic course of study with nominal variation from college to college didn’t exist, and there were no “medical licenses” or exiting exams.” ⁴¹

Educated in the days before Pasteur and Koch discovered that bacteria—germs– cause infections, Crumpler explained that infectious diarrhea—she called it cholera infantum– was caused by “poor milk, bad air arising from old water-soaked cellars, or some atmospheric phenomena.”

Established In 1927 in the segregated south, the non-profit Houston Negro Hospital provided work for black physicians, and care for African Americans. 

In St. Louis a hospital for the cities black indigents opened its doors in 1937.  It was named for the Homer Phillips, a black lawyer from Sedalia, a small town in the middle of Missouri that was built on the main east west railroad line.  Raised in an orphanage, then by an aunt, Phillips became a lawyer at Howard University, and moved to St. Louis.  “Intensely interested in the Negro doctor”, he felt “more opportunities would be available for these men of medicine if there were a separate hospital.”  In 1922 St. Louis passed an $87 million bond issue and Phillips made sure the legislation designated one million of the dollars as funds for building a black run hospital.  Once the city had the money, it wasn’t easy to get them to turn it over.  For more than a decade Phillips fought “interests that sought to prevent the hospital’s construction.³⁹ It’s doors opened in 1937, and 2 years later Phillips needed to get additional funding.  The facility was inadequate. “Patients were crowded into dark corridors and their lives were often in jeopardy because of fire hazards.”  By 1961 the institution had trained the “largest number of black doctors and nurses in the world, and it was a leader in developing the practice of intravenous feeding and treatments for gunshot wounds, ulcers, and burns. It closed in 1979.¹

The hospital that provided a significant part of my medical training, St Louis City Hospital, was integrated and lost much of its clientele to more upscale facilities when Medicare and Medicaid became the law of the land.  The facility existed until 1985; then it closed.  City and county hospitals elsewhere (Cook County in Chicago, Bellevue in New York, San Francisco City Hospital, and Charity in New Orleans (to  name a few) remain very much alive and well.   

Cook County hospital in Chicago, the caregiver for the poor in our second largest city (committed to providing “quality care with respect and dignity regardless of their ability to pay”) gets close to 40 percent of its operating revenue from state and city taxes.  Of the remaining 60 percent, a third of the money comes from Medicaid, and 9 percent from Medicare.  I don’t know how much the institution gets from private insurance companies.  

New York City has 11 publically funded hospitals plus clinics and nursing homes.  With an annual budget exceeding $5 billion they provide emergency services and hospitalize close to a quarter of a million people a year.⁶

University hospitals, which are presumed to be “the best” by many, are staffed by esteemed professors who are often astute physicians and who write papers and books. These educational institutions provide complex services that require a team approach and interventions like liver, heart, and kidney transplants.  Many of the researchers who teach future physicians survive on research money supplied by the NIH or pharmaceutical companies.

By the 1950s all of our large cities and many small towns had a modern day facility. The government had constructed and ran military, Veterans administration, and public health service institutions.  Multiple hospitals were operated by religious groups or by university medical schools. 

According to one analysis, U.S. hospitals have been merging at a rapid pace for a decade, forming powerful organizations that influence nearly every health care decision consumers make.  The mergers have essentially banished price competition and raised prices for hospital admissions.  In one analysis of 25 metropolitan areas, between 2010 and 2013, prices rose 11 percent and 54 percent.¹⁷ 

Public and university hospitals derive their funds from private and governmental insurance, from taxpayers, and from donors. The law says that if charitable organizations want to avoid taxes they must be operated exclusively for “exempt purposes”.  None of the earnings can go to shareholders or individuals.  They can’t try to influence legislation as a “substantial part of their activities.” 

(The list of organizations that could potentially acquire tax exempt status is quite long.  It includes groups that are: “charitable, religious, educational, scientific, literary, testing for public safety, fostering national or international amateur sports competition, and preventing cruelty to children or animals.” Etc…) ⁴

Some universities and charitable hospitals make a lot of money, and their profits are not taxed.  The Affordable Care Act did not challenge their IRS exempt status.  It did, however, add a few hoops. 

The institutions are now required to have a financial assistance policy that’s written in “plain language” on their web site.  The “audience should be able to understand it the first time they read or hear it.”

They (theoretically, at least) can no longer generate inflated bills, claim they spent an unrealistic amount of money caring for a sick person.  Hospitals typically send out exaggerated bills knowing full well that Medicare or insurance companies will only pay a portion of them. They use the amplified numbers as a starting point for negotiations with insurers, and as a means of demonstrating how charitable they are.  As part of the ACA non-profit hospitals should no longer be able to generate inflated tabs—charges that are higher than the amount insurance companies and Medicare really pay for the services.  Additional charges–the portion of a hospital bill that Medicare and insurance companies don’t usually pay—can’t be pumped up. 

Finally, when a recently treated person doesn’t pay their share of the costs, these institutions are supposed to “make reasonable efforts to determine whether the individual is eligible for financial assistance” before they sick their dogs on them– before they take legal action, sell a person’s debt or notify a credit agency.

In 2013, of the ten most profitable U.S. hospitals, seven were non-profit.  They earned over $1.5 billion, and, of course, didn’t pay any taxes.  They included a few big name institutions:  Gundersen of La Crosse Wisconsin earned $300 million.   Stanford’s teaching hospital had a profit of $225 million”, and the University of Pennsylvania’s hospital in Philadelphia made 184.5 million.”  “The hospitals with the highest price markups earned the largest profits.”  These institutions could have returned some of the tax derived revenues to the government.  (Fat chance.)  They could have increased the number of non-paying patients they cared for.  Since the affordable care act went into effect, they’re often caring for fewer people who can’t pay. If we’re going to make health care affordable we should probably revisit the tax exempt status of some of these institutions.⁵

A few years back Senator Grassley considered “removing tax-exempt status from teaching hospitals and forcing them to do more for local low-income, urban communities.”   The hospitals fought him and won. 

Much of the care our hospitals provide takes place in one of the country’s 983 state and local government hospitals or in one of the 2845 community sponsored nonprofit institutions.

The people who live far from the cities are served by many smaller institutions that are the product of a community or creations of health care workers who had a dream. Some are financially struggling to exist. ⁷

In May 2020 the New York Times told how, as a result of the Coronavirus bailout, the non-profit Providence Health System received over $500 million in government funds.  The company was sitting on nearly $12 billion in cash and was earning, in a good year, over $1 billion tax free from its investments in venture capital funds. Two other for-profit hospital groups, HCA and Tenet Healthcare, had billions of dollars in reserves and received $1.5 billion from the government. Ascension Health in St. Louis, a chain that had $15.5 billion in cash, was given $211 million.  And the largest rural hospital system in eastern Kentucky got $3 million, enough for 2 weeks of payroll. 

“Even before the coronoavirus, roughly 400 hospitals in rural America were at risk of closing,” and the 2000 rural hospitals that are in the black, on average, only have enough cash to keep their doors open for 30 days.” ³⁶

In the last decade 113, mostly rural, facilities went out of business.  20 were in Texas, 12 in Tennessee and 7 each in Georgia and Oklahoma. Of the 283 rural hospitals that in 2015 were “vulnerable to closure”, those located in states that did NOT opt for Obamacare Medicaid expansion were especially hard hit.  16.5 percent of the hospitals in states that opted OUT were on the brink versus 8.5% in Medicaid and indigent patients than suburban hospitals.” 

Providing quality health care to our urban population is much more than a hospital issue.  60 million Americans—13 million of which are children lived in rural areas.  5.3 million resided in completely rural counties, 24.6 million in the mostly rural counties and 30.1 million in mostly urban counties. Their numbers have been dropping.  A non-profit: A Healthy Rural America is struggling with the problem.²³

A third of the Health Care dollar, $1.1 trillion (2017) is spent on hospital care. The Affordable Care Act led to increased hospital revenues and kept a number of smaller hospitals alive.  States that “expanded Medicaid” saw 7.4 percent more Medicaid discharges in 2014 versus 1.4 percent in non-expansion states.

Total Number of All U.S. Hospitals.18	6,210
Number of U.S. Community Hospitals	5,262
Number of Nongovernment Not-for-Profit Community Hospitals	2,968
Number of Investor-Owned (For-Profit) Community Hospitals	1,322
Number of State and Local Government Community Hospitals	972
Number of Federal Government Hospitals	208
Number of Nonfederal Psychiatric Hospitals	620
Other Hospitals	120

In 1981, a deranged 26-year-old man shot the president of the United States. A bullet hit a rib, and Ronald Reagan was in pain. At the time, neither he nor his aides sensed how close he was to death. As the presidential limousine sped to George Washington University Hospital, Reagan coughed up blood. When he tried to walk from the car to the emergency room, his legs collapsed, but his aides kept him from falling and dragged him to a gurney.  A senior surgeon arrived on the scene and realized the man had lost a lot of blood, and was still hemorrhaging. An operating room was empty and, as a gurney occupied by Reagan was wheeled in, O-negative blood was pumped into his veins. The urgent surgery and transfusions were so successful that few realized Reagan had used up one of his nine lives. 

The first U.S. level one trauma center was established in Chicago in 1970. By 2003 most states had at least one facility where surgeons, neurosurgeons, orthopedists, appropriate anesthetists and operating rooms are available 24 hours a day.  Some facilities have helicopter landing pads.³⁴ Others use nearby airports and bring the severely injured to a hospital by ambulance.  50 million Americans are unable reach one of these centers in less than an hour. 

E.R.s in the U.S. hospital clock 136 million visits a year.  Forty million of them are for minor injuries, auto accidents, and gunshot wounds.³⁵ Sixteen million of the people who are seen are admitted to the hospital.  People with myocardial infarctions who arrive by ambulance are sent to the catheterization/stent department.  Women in labor are wheel chaired to the hospital delivery areas.  The people with a new neurologic problem: a leg or arm that won’t move, inability to speak, loss of vision– are briefly assessed and routed to the CAT scan room.  An X-Ray without contrast only takes a few minutes, and doctors need to be sure the acute brain damage was not caused by a cerebral hemorrhage before can attempt to dissolve a clotted blood vessel.

A few years back (according to a colleague) the physician-in-chief of Northern California Kaiser was visiting one of our ERs and was disturbed by waiting rooms full of people. Some had minor injuries that needed a quick fix; others who were quite ill, had to wait a long time before they were triaged. He decided something needed to be done and he had clout. 

He met with the chiefs of our hospitals and an agreement was struck.  After a person entered the waiting room and registered, he or she would be taken to an exam room and evaluated by a doctor, nurse and tech within 15 minutes.  Lacerations had to be sewn shut, minor fractures casted, and a person sent home within an hour.  Sepsis, strokes, and bleeding were treated promptly.  Tests and consultations were ordered for problems of unclear significance and severity.  Efficient competent evaluation might not always be possible but that was the goal.

Then Dr Pearl retired and waiting room wait time worsened.

San Francisco General Hospital is a hybrid. It’s a trauma center and a teaching hospital. The doctors who care for patients come from the University of California Medical center. The facility also operates the city’s “Community Health Network.” 80% of its $600+ million operating budget is paid for by Medicaid, Medicare, and private insurance, and it gets the other 20% from the city’s general fund. As detailed in an earlier chapter, in response to criticism for their crazy high fees they recently lowered and capped the amount people pay when they are ill and injured and need care.  It’s too soon to tell if their billing approach will be viewed as a beacon for the rest of the country or as a hippy, odd ball gesture.    

A few decades back “the general” developed a unique approach to its visitors who slept outside in unsheltered locations. Many suffered and died prematurely from diseases caused by alcohol, smoking, exposure, and poor sanitation. Violence, mental disorders and suicides were common. San Francisco General “identified individuals who had visited their emergency room five times in 12 months. With the help of attorneys and with a staff of case managers, a primary care physician, nurse practitioner(s), and a psychiatrist, they got many of the people permanent shelter, a primary care doctor, and “benefits.” It was quite a legal feat in people who are disabled by mental illness. In time, 70-75% of the homeless were housed, and emergency department use decreased 50-75%.  That was a few years back, the homeless problem in Northern California has gotten worse and the funding has changed.¹¹

In the 1960s intensive care units were created.  By the end of the 70s each nurse in one of the units cares for one or at most two patients.  Machines monitor blood pressure, pulse, and blood oxygen levels.  Respirators filled lungs. When appropriate food is dripped into stomachs through naso-gastric conduits.  Multiple IV tubes infuse bodies with nutrients and a variety of chemicals and blood products. 

Nurses have always been “the glue that held hospitals²⁷ together.  Their numbers increased during the Second World War II.”  At the end of the conflict RNs earned an average of $2,100 a year, somewhat less than most male workers.  Their wages didn’t rise and their numbers started going down.  There increasingly weren’t enough RN’s to do the job right and those who remained had to work longer and harder.  To keep costs down hospitals froze their wages. These women were dedicated, right?  They wouldn’t quit.  By 1966 the average RN earned $5,200 a year.  At the city hospital where I was a resident one nurse passed medications and tried to handle the needs of the ill on an entire ward.  The women (and at the time they were all women) were energetic, amazing, and often exhausted.  Their wages were so low that none of their nursing school graduates wanted to work at our hospital.  When our few nurses went on strike in 1965 the papers thought their action was outrageous.

The idea that in America workers could strike if they were underpaid, was challenged when the nation’s Air Traffic Controllers struck in 1981.  President Reagan said they were federal employees and were breaking the law. He gave them 48 hours to return to work or be fired.   His anti union stance changed attitudes.  In a decade, major strikes plummeted from an average of 300 each year to fewer than 30.   Despite an average annual inflation rate of 2.9% and a huge surge in productivity, the federal minimal wage, which was $3.35 in 1981, barely doubled in the 3 post-Reagan decades.   

In the San Francisco Bay Area 2 types of union actions have continued to be effective.  The interruption of BART commuter trains by striking workers always leads to jammed freeways and lengthy commutes.  When the police struck a few decades back the chief went on T.V. and warned that criminals, murderers, and rapists would have a field day.

At Kaiser where I worked, nurses felt they were underpaid.  They knew how to take care of sick or needy patients, but they soon learned that dealing with management was something else.  Every 5 to 10 years or so their contract came up for renewal, they asked for a raise, management hung tough and the nurses decided they needed to strike. 

That was fine with Kaiser.  The insurance money kept coming in.  People didn’t like to cross picket lines unless they were quite ill.  

Before the strike started traveling nurses were hired, elective surgery was canceled, and the very ill were sent to other hospitals. I remember driving to work and seeing throngs of young and middle aged nurses carrying picket signs, and standing by the entrance of the parking structure. They were friends, colleagues.  Many hated the thought of abandoning their patients and some believed strikes were unethical. 

After three weeks of pacing in the heat of the day or under an umbrella nurses started coming back to work.  Most had loans, rent, bills, and lived from one pay check to the next.  When a majority of worses had returned to the job management offered a small raise and signed a long term contract. 

Eventually the nurses hired a labor organizer named Rose Ann DeMoro and everything changed.  In 1968 she declared a 2 day strike, and the hospital prepared.  Critical patients were moved out, elective surgery was cancelled, and traveling nurses were hired.  A few days prior to the date, the strike was cancelled, but it was rescheduled for a date 60 days hence. 

Two months passed.  As before, very ill patients were moved out, nurses brought in, and elective surgeries cancelled.  This time the nurses struck for two days and no one lost much money.  As the strike was ending the union announced it would soon strike again. Management understood what was going on and cried “uncle.” The nurses pay rose substantially and they later fought for and won the right to make improvements to the quality of care they provided.   

Nationwide, one in five nurses belong to a collective bargaining unit. On average their wages are 20% higher than the pay of the nurses who are not in unions. In 2020 the average hourly wage of a registered nurse in half the states in our country was $28 to $34.  The other half earned $35 to $48 an hour. In Hawaii and California the average hourly wage was $50 to $54. 

Inside the large multispecialty hospital where I worked there is a large birthing wing. Large rooms accommodated doulas and invited family.  Nurse midwives handled the uncomplicated vaginal deliveries.  An anesthesiologist or nurse anesthetist was always on duty and performed epidurals.  Needles are inserted into the lower back, into the space between the vertebrae and the membrane that surrounds the spinal canal and lidocaine, a numbing agent was infused. The drug blunted much of the pelvic pain of childbirth.  An obstetrician was hanging around and was available for consultation and urgent C sections. 

In the hospital’s basement 2 CAT scanners and 2 MRI machines created detailed body images far into the night.  The pictures of the sliced body sections were immediately visible on every computer screen in the facility. A radiologist sat in a dark room, carefully checked the images, and looked for anything that didn’t belong.  He or she dictated a report that was transcribed by trained worker in the facility, or increasingly by people in the Philippines, India, or some other country.

A multi bed outpatient recovery area was staffed by nurses.  They prepared and observed patients before and after interventional radiologists performed biopsies or invasive procedures.  The unit also served as the pre and post procedure area for people having an emergency heart catheterization.  A cardiologist was always on call, no more than 15 minutes from the hospital, and available 24 hours a day, to catheterize and stent the coronary arteries of people who are probably having an acute myocardial infarction.

Gastroenterologists, who sometimes worked at bedside in the intensive care unit, had a dedicated in-patient procedure room, with equipment. If needed we would insert a scope and treat people whose upper GI bleeding was ongoing or those who had a bolus of food lodged in their esophagus.

There were medical, surgical, and pediatric intensive care units and a coronary care unit.

Hospital rooms had piped in oxygen and suction, a place where a partner or parent could spend the night and an annoying T.V. on the wall. 

A special inpatient pharmacy provided a large range of medications, including specialized drugs and infusions, 24 hours a day.

Pathologists processed, stained, examined, and interpreted the significance of tissue that was removed from bodies.  Samples were often sent “out” for molecular diagnostics (DNA/RNA analysis).

Phlebotomists drew blood and brought it to the lab where it was extensively tested.  The labs also cultured and assessed stool, urine, blood, spinal fluid, sputum etc.

And there were clerks, social workers, discharge planners, janitors, patient transporters, painters, security people, guards, physical, occupational, and speech therapists, dieticians, telephone operators, IT personnel, people who provide food for the patient and staff, and engineers who regulate and repair the electrical, cooling-heating and other building systems.

In 2017 American hospitals were responsible for $1.1 trillion of the nation’s $3.5 trillion in health care expenditures, and an average day in the hospital was costing nearly $4 thousand.²⁸

I was employed by a pre-paid group, and all the physicians and surgeons were salaried.  The hospital had ten large operating spaces and the OR had a calendar that was controlled by a scheduler.  Each area was manned between 8 AM and 3 PM by a hundred or so nurses, technicians, and others.  In the late afternoon most of the rooms closed.  The few that remained open handled the overflow. One was available around the clock for urgent cases.  During the work day each of the designated areas was managed by a different surgical subspecialty, and had some unique equipment,

Gawande explained the importance of introducing the patient who will undergo surgery to everyone in the O.R., including the person who cleans the floor and the medical student.  He thinks the presentation gives everyone permission to sound an alarm if they notice a problem. Before a case starts, all the people who might play a role gather around the patient and are introduced. Then a “time out” is called.  The nurse or physician in charge would ask the patient their name and what they thought was about to happen, When indicated the involved breast or extremity was inked. (“In 1995 when a nurse told Florida Surgeon Rolando Sanchez he was cutting off the wrong leg, he kept going and she started to shake and cry. He felt he had gone too far.  The leg he had started to remove couldn’t be repaired and there was no turning back.”) ²⁹

A surgeon or team of surgeons usually performed all the cases in a morning or an afternoon block.  If three hips were replaced that half-day, one surgical team usually did them all.  After each operation, the room had to be cleaned and efficiently turned around.  In bloody cases, like a hip replacement, soaked pads were not thrown on the floor.  They were instead bagged, and the containers were tied and slipped into the hall outside the room.  Following invasive surgery, when blood in the abdomen made it hard to be sure no foreign objects remained in the area, the sponges were counted before and after the operation.  Post-operatively, people went to a recovery area where 20 to 30 nurses cared for them for variable periods of time.  If a spinal anesthetic was used, the patient remained in the observational area until the numbness had worn off.  

In fee-for-service facilities surgery accounts for a substantial part of hospital revenue.  Akron General Hospital published what it charges on its website. The bill for using the operating room at their facility, which is part of the Cleveland Clinic, depends on “the complexity” of the procedure.  Their billers created five intervention levels: For those on the lowest rungs the first hour costs $2718.  Each additional half hour adds $1100 to the bill.  For level 5 procedures—the most complex– the room cost is $4935 for the first hour and $2200 for each additional half hour.²⁰  

Free-standing facilities currently perform many of the “interventions” that were once done in hospitals: cataract surgery, colonoscopies, knee arthroscopies, cosmetic surgery, pain management, dental and ENT procedures. In 2019 there were 6100 ambulatory surgical centers in the U.S., and they performed more than half of that year’s 35 million operations and procedures.²¹

A 6 year old seemed cross eyed and saw an optometrist who realized the child had a 6th nerve palsy. The nerve that controls the lateral movement of his eye wasn’t working and that set off all kinds of alarms.  He was immediately sent to an ophthalmologist. The physician detected evidence of brain swelling and ordered an emergency MRI. That night one of the two hospital pediatric neurosurgeons told the parents their son had a brainstem tumor. The child was admitted and started on high dose steroids to decrease the pressure inside the skull. A few days later two pediatric neurosurgeons at Oakland Kaiser Hospital made a small opening in the rear of the child’s neck and removed the back of a vertebra.  They then sucked out the medulloblastoma cells (it is a friable malignant tumor) and rolled an MRI machine into the OR.  It revealed a tiny trace of tumor had invaded his spinal canal.  The vertebrae was replaced and fastened, and the wound was sewn shut.

Post operatively the child had obstructive hydrocephalus—fluid was not flowing from one chamber of the brain to the next one. It was possible he would need a shunt that transferred fluid from his brain to the space in the abdomen called the peritoneum. As a first step, under anesthesia a small hole was drilled in his skull and a thin sterile videoscope was passed through the brain into the fluid filled chamber in its middle.  The scope was maneuvered through the narrow passages that connected the ventricles, the fluid filled brain chambers. Cobweb like tissue was blocking the flow of fluids and it was pushed aside. Fluid started circulating normally and a shunt wasn’t needed.

After the child recovered from the surgery his insurer paid ¼ to ½ million dollars for proton beam radiation to destroy the small segment of tumor that remained.  It couldn’t be surgically removed without causing major neurologic damage.  Protons give off most of their energy (in a quick burst) to a precisely focused part of the body. This type of therapy decreases the amount of radiation to healthy tissues around the treated area.

The child was sent to the “Seattle Proton Therapy Center a facility where 10-foot-thick, lead-lined concrete walls isolate a particle accelerator that harnesses and fires protons generated from hydrogen gas. It was one in a national wave of costly facilities funded a decade or so back by private investors and lenders. The Seattle facility treats 500 people a year. “In 2018, after a net loss of $81 million over the prior two years, its original backers were handed a $135 million loss as part of a negotiated Chapter 11 bankruptcy.¹⁴” But they were still in business. At one time there were 27 proton centers in the U.S. They were expensive to build and maintain and their services are not covered by all insurance providers, so those that are still working are struggling financially.

Elsewhere on the planet, there are remote government funded community hospitals, in low and very low income countries—like Malawi and Bangladesh.  As described by the Harvard M.D. who spent time in Nepal, they are commonly located in far off corners of their nation and are the only options available to the poorest of the poor.  With 50 to 100 beds they serve 100,000 to a million people, and their doctors can usually perform a few orthopedic and general surgical procedures and C sections.  They have some X- ray capability, but commonly lack certain basics:  In Nepal 15% didn’t have piped in water; 20% lacked electricity; 55% didn’t have gloves, and 30% were unable to provide oxygen to those who need it²².

CHAPTER 8– OBAMACARE—THE AFFORDABLE CARE ACT

 “The people who are crazy enough to think they can change the world are the ones who do.” – Steve Jobs

 “Our healthcare insurance system is a mess.  We all know it, those who support Obamacare and those who oppose it. Something has to be done.” Senator John McCain—floor of Senate—July 25, 2017.⁹

By 2008 a number of insurance companies had instituted policies that, when investigated, troubled Congress and became the topic of exposés and newspaper articles.

People with serious pre existing medical conditions could not buy health insurance.  That now seemed to matter. 

When insurance companies couldn’t raise premiums they enhanced their profitability by creating large co-pays.  It diminished the value of health insurance and was troubling.

When someone in a small business developed an expensive problem, the cost of providing coverage to the company could exceed the value of the premiums of all the workers. In situations like this, for-profit insurance companies began substantially raising their rates.  Insurers knew that if the cost of care was high enough the companies would not renew their policies.  Aetna spent millions for technology that identified businesses that cost insurers more than the companies took in.  Health Net gave bonuses to employees who discovered them.  In the process “Aetna shed 8 million enrollees” in the early 1990s.”  

Most disturbingly there was a policy the companies called “recission”. When someone got sick their original questionnaire was scanned for minor, mostly irrelevant misstatements.  Wendell Potter tells of a man who had an angioplasty for coronary disease.  The insurer refused to pay because “he failed to disclose” a history of heartburn.  I guess it could have been angina.  It probably wasn’t, but it gave the company the foothold they then used to avoid paying $130,000 in medical costs.  The case was not unique.  When it was detailed in a Los Angeles newspaper letters poured in.

WellPoint, according to Reuters “singled out women with breast cancer for aggressive investigation.”  The company (presumably by finding insignificant misstatements in entry questionnaires) earned over a hundred million dollars by cancelling policies for females who had developed breast cancer. 

When questioned by a congressional committee, insurance companies CEOs were asked if they would end the policy of recission; and they said “no” they wouldn’t.²

In 2006 Massachusetts passed a health care law that in part became a blueprint for Obamacare.  At a time when a Republican, Mitt Romney was governor, Massachusetts extended “affordable”, compulsory, state subsidized health insurance to all its citizens, and it seemed to be working.  Vermont followed suit.  Some (perhaps Obama) wondered if this could be a model for other states.  Problem was, the Massachusetts situation was unique for a number of reasons.  When Dukakis was governor (in 1984) the legislature passed a law that helped protect the finances of people who were recovering from a catastrophic event, and that helped make sure hospitals got paid.  They established the “Uncompensated Care Pool.” It was funded by hospitals and insurance companies according to a formula, and it had accumulated a pile of usable money.  By 2003, the year Mitt Romney became governor, the (now called) Health Safety Net was bringing in $157 million a year. The state had funds they could work with. Mitt also got help from Ted Kennedy.  Through some legislative maneuver the state “secured three years of additional Medicaid funding, $1.05 billion.”

Massachusetts happened to be one of 11 states that still had a functioning 2.8 million members strong non-profit Blue Cross and Blue Shield.  The company used 90 percent of the money taken in to care for people. There were no shareholders to satisfy. For-profit companies had to compete with the premiums the Blues charged.

Medicare had been in existence since 1965.  The bureau that ran the program, the CMS, had 6000 employees and had established payment schedules for “more than 10,000 physician services”.  Prices were adjusted … “to reflect the variation in practice costs from area to area.”   The presence of an independent agency that was trying to assess the “worth” of a visit or intervention helped keep a cap on costs.³

The Massachusetts program was less comprehensive than Obama care would be.  The Affordable Care Act would pay a large part of the insurance premium for people who earned less than 400% of the federal poverty level. Massachusetts made the cut at 300%. 

By the time Obama became president in 2009, the ability of medicine to enhance the quality and quantity of most lives had grown and costs had risen dramatically.  Over 17% of the national GDP was spent on “health”.  A majority of Americans had government or business sponsored quality affordable health care, but many citizens were excluded, and the unregulated private insurance companies had grown powerful and arrogant. I voted for Barak Obama and assumed he would fix health care.  It was part of his platform; he favored the “public option”…like Medicare or Medicaid for those who want it. 

The 2008 election gave Democrats a majority in the House and Senate, but Obama believed in inclusion—working across the aisle—compromise.  And the Republicans weren’t having it.  For some it was because the nation rejected John McCain, a popular white candidate, or because of a perceived loss of status. Others were probably just sore losers. Many assumed Obama viewed the world through the eyes of a black man struggling for a better life for “his people.”  And he did.  His wife, Michelle grew up in a black, working class household in Chicago.  Barak Obama was also the son of a white mother.  When she died young Barak was raised by white grandparents.  His grandfather fought in the Second World War.  Obama had no ancestors who were former slaves, and his father was from British occupied Kenya.

The 2008 presidential election was the most racially and ethnically diverse in U.S. history and that troubled Beltway Republican politicians.⁶ On the evening of Obama’s inauguration, opposition leaders met and decided they would be against everything that he proposed.  The economy was on the edge of another great depression and Barak favored a Wall Street bail out.  Democrats voted with him and Republicans didn’t.   

He used the money to prop up the big banks, and decided to NOT punish their leaders.  The heads of the banks then gave themselves millions in bonuses.  At the same time they took homes away from people with mortgages who, as a result of the recession, had lost their jobs and couldn’t make the payments. To many it seemed like welfare for the privileged and bleak Capitalism for the common man.

Obama’s popularity declined.  It was still his first year in office and he decided to pass a health care bill based on his campaign promises and sought bipartisan support.  Republican Senators decided to oppose him, and they forced their fellow legislators to just say NO to any legislation Obama proposed.   According to Frontline, some thought the bill would be the president’s Waterloo, and that it would allow them to recapture the Senate. 

The legislative process took more than a year. The Senate would not pass a law unless 60 of the 100 senators voted for it, and there were exactly 60 Democratic senators. Obama needed every vote if he wanted to pass the bill. The insurance companies didn’t want a public option.  They wanted to require everyone to buy insurance.  The drug industry didn’t want Medicare to be able to negotiate drug prices. There were ups and downs, protests and an expensive insurance company advertising campaign.  Ultimately, to get the needed votes Obama had to “kill” the public option and water down a new, special tax on medical devices and equipment.  To obtain the vote of Nebraska’s democratic Senator, Ben Nelson, the federal government had to agree to pay the full price of his state’s Medicaid insurance. 

Then Democratic Senator Ted Kennedy died, and he was replaced by a Republican.  The Democrats no longer had a 60 vote “super majority.” 

In the end Obama campaigned hard, “expended a lot of political capital,” and Congress passed the current Affordable Care Act. In March 2010 Obamacare became law.¹ The Affordable Care Act got rid of recission.  The law prevents insurance companies from denying coverage or charging a higher price to someone with a pre-existing health problem.  Health plans can no longer set a lifetime limit on how much an insurer had to pay to cover someone.  Insurers are required to offer a minimum package of benefits.  Preventative health services must be provided without a co-payment.  Children are allowed to stay on their parents’ policies until age 26. In an effort to get enough money into the system, to make it workable, at the insistence of the insurance companies the law required people to buy a policy.  It enacted a tax penalty for large employers that failed to offer affordable coverage, or individuals who failed to obtain insurance.

If a state agreed, people whose incomes were a little above the poverty line were now eligible for Medicaid.  36 states signed up.  As of January 2020, fourteen states were still declining the freebie.  Without the extra patients some rural hospitals failed and people went without care.  Grace Marie Turner of the Galen institute, one of the loudest anti-expansion voices, thinks putting more people on Medicaid worsens the cycle of dependence and harms the economy.  Extra people mean more competition for the available physicians, and she worries about fraud and waste. ¹⁰

The ACA, Affordable Care Act, supplemented insurance premiums for people whose earnings were quite low but who didn’t qualify for Medicaid.

 It allowed premiums to be sensitive to the marketplace. 

The only insurer in a state can charge more. 

In the face of stiff competition companies can offer cheaper rates. 

Group policy rates are the result of bargaining.  The size and average age of the people to be insured matters. 

High deductibles are permitted. 

An older person can be charged up to three times as much as a 26 year old.  Tobacco users may be forced to pay twice as much as non users. 

Prices can’t be higher for a new enrollee who has metastatic cancer and is receiving expensive chemotherapy.  Nor can more be charged to the person who has hemophilia (and bleeds easily) or someone who just had a heart attack or a stroke.  A person’s “current health or medical history”—their pre-existing condition, can’t affect the premium’s price.  

The law’s approach runs contrary to the basic premise of insurance.  Companies evaluate risk. They charge more for flood insurance in a zone that is periodically inundated, more for fire insurance for homes in a highly wooded area, and more for earthquake insurance in California. On a societal level it’s not wrong to discourage people whose homes were washed out a few times to stop rebuilding in low lying areas that flood every few years. 

But most developed countries don’t risk assess before they decide if they will provide health care. And they don’t invoke an illness penalty. As Atul Gawande put it: A century ago the average American didn’t grow old.  When someone suffered a catastrophic event: pneumonia, a heart attack, a bad accident–- many died or were disabled but some walked away unharmed.  Modern medicine often rescues people who would have died.  We cure pneumonia, pin broken hips, and stent narrowed coronary arteries. Subsequently people may or may not be as healthy as they were, but they now have a “pre-existing condition.  Before the Affordable Care Act was enacted they found it difficult or impossible to acquire insurance⁵  

The funds insurers spend for medical care is called a loss.  If the company uses 20 percent of the money they take in for executives, payroll, and stockholders, their medical loss ratio is 80 percent.

The ACA, Affordable Care Act, capped the amount companies could keep at 20 percent for individuals and 15% for groups.  If a company spent less than 80 to 85 percent of their premiums on patient care they had to pay a fine.  (Medicare has an overhead of 3 to 5.2 percent.)⁴ 

As Elizabeth Rosenthal, author and editor of Kaiser Health News learned, a higher medical loss ratio didn’t dampen the amount the insurance company paid for patient services.  Her book tells the story of a person whose infusions at an influential hospital (NYU) cost the insurance company five times as much as they would have, had the patient received the same treatment at a nearby, presumably equally capable, facility.  Rosenthal asked herself why the insurance company was willing to pay so much. 

One possible explanation: Hospitals and physicians routinely over charge, and insurance companies pay a negotiated portion of the bill.  Then insurers show sick people the official bill and brag about the amount of money the person saved. 

 When insurers pay a higher portion of the bill and their profits fall below 15 to 20 percent they are allowed to hike the price of their premiums.  

When people pay more for insurance the company takes in more money and gets to keep 15 to 20 percent of the increased revenue. 

The establishment of an “acceptable” medical loss ratio perversely rewarded insurers who drive up the cost of medical care and insurance.  Health care premiums have risen 25% since Obamacare was enacted.   

The law was loved and decried by many.  The young and healthy had to purchase insurance and were grouped with people who had pre existing conditions.  Their premiums rose and the price increase didn’t seem fair.  Over time they had come to believe that cheap insurance was one of their unstated rights. 

Two new taxes were enacted: A medical devise tax and a “Cadillac” tax on high priced policies.

The Trump administration is establishing “association health plans.”  They still cover pre-existing illnesses but they “allow small businesses, including self-employed workers, (presumably groups that don’t have many people with serious pre-existing problems), to band together by geography or industry and obtain coverage as if they were a single large employer.”  The plans “don’t need the minimum benefits required by the ACA and they can drop maternity or mental health coverage.”  As the healthy are drawn away from the ACA, the exchange costs go up and the illness penalty returns.⁷

At 1:30 A.M on the morning on July 28, 2017, a bill that would have repealed Obamacare needed one final vote to pass. The person who cast it was Republican Senator John McCain, a man who had recently learned he had a lethal brain tumor.

He came to the Senate chamber, stood before his fellow legislators and voted thumbs down. No!   The repeal of the law failed. 

McCain was unhappy with the way Democrats had, years earlier, forced a “social and economic change as massive as Obamacare” through Congress.”  “Our healthcare insurance system is a mess. We all know it, those who support Obamacare and those who oppose it. Something has to be done.”  He didn’t suggest repairing and saving the Affordable Care Act.  But he spoke of “incremental progress, compromise, and chipping away at problems.⁹ ”

In 2018 congress repealed the law’s requirement that everyone “must “ buy insurance.  A federal judge in Texas decided that made the Affordable Care Act unconstitutional.  He argued the ACA obliges people to either buy insurance or pay a fine.  The requirement was a tax.  When Congress repealed the individual mandate the law stopped looking like a tax. 

August of 2018 the government started allowing states to take Medicaid coverage away from “people not engaging in work or work-related activities for a specified number of hours each month.”

 In Dec 2019 Congress passed a $1.4 trillion spending bill.

It repealed the medical device tax ($20 billion less for health care in a decade) The Cadillac tax ($193 billion saved by the wealthiest citizens in a decade.)  The Health insurance tax that was used to pay for the federal and state marketplace exchanges. ($164 billion over a decade.)  

The spending bill provided two years of Medicaid funding for Puerto Rico and other U.S. territories, and it barred HHS, the federal health and human services department, from ending auto-reenrollment.  They are not allowed to create a coverage gap for people who forget to enroll at the end of each year.

Atul Gawande once concluded that the United States may be the only developed country in the world where people are “unable to come to agreement” on the concept of health care as a right…….on the idea that all should be able to benefit from the medical advances of the last hundred years. Our nation’s health care road remains quite bumpy.

In 1914, when the First World War started, physicians had a better understanding of illnesses and their cause, but they still were unable to do much to prevent or treat them.  My dad was six when the family moved into a small, wooden, dirt floor, cottage in a Shtetl that straddled one of the main Ukrainian east- west highways.  That year acting on orders from the Czar, the Russian army attacked Germany, entered their enemy’s territory, and fell into a trap.  The second army was virtually` destroyed at the Battle off Tannenberg.  Thousands of the surviving soldiers retreated.  When they came through my father’s town the fleeing Cossacks burned the family home to the ground.  During the subsequent years the family crowded into one of the remaining cabins on the edge of the village.  It was owned by an elderly Ukrainian who hadn’t left for mother Russia with his family.

During the war years no one bathed or boiled their clothes.  Everyone’s garments and bedding contained body lice.  One winter there was a typhus outbreak.  The infectious disease is caused by a tiny bacterium (ricketsia) that lives in the lice.  When the creatures defecate their droppings itch, people scratch and tear their skin,   and bacteria enter their bodies.  One to two weeks later the aching starts. Many develop a severe illness: chills, high fevers, an unremitting headache, exhaustion.  My grandmother became confused and disoriented.  When the nurse from the Russian army came to inspect the house the family was unable hide her and the nurse summoned the wagon that took her to the school house, the large hall full of beds where most died.  My grandfather watched and cried as they carted her away. 

          “During the eight-year period from 1917 to 1925, over 25 million people living in Russia developed epidemic typhus; three million died.  Some claim epidemic typhus has caused more deaths than all the wars in history.³”

Antibiotics had not yet been discovered, so doctors could diagnose the disease but they had no treatment.  (In the 21^st century Typhus is easily cured and prevented with the antibiotic Doxycycline.)

My father always remembered his boyhood, and when I chose to go to medical school he shrugged.  Based on what he witnessed, he had concluded that doctors knew how to recognize and diagnose illness, but that’s all they could do.

Chapter 9. MEDICAL DEVICES

A friend awoke with chest pain and a cold sweat, and his daughter called 911.  The EKG in the ambulance showed evidence of an acute myocardial infarction.  Part of the heart muscle was dying. 

Developed in the early part of the 20^th century, the device the paramedics attached,the EKG, detects and records the flow of current as it travels along the heart’s “electrical” conduction fibers.  The up and down squiggles, the “wave”, has a distinctive pattern when a person is having a heart attack.  Like hieroglyphics on an ancient tomb, their meaning was baffling before Willem Einthoven learned how to interpret them.  A descendant of Spanish Jews who fled to Holland at the time of Spanish Inquisition, Willem was born in Java.  His father, a physician, died when Willem was 6 and a few years later his mother returned to the Netherlands. After college Willem went to medical school and he later became a professor of physiology at the University of Leiden, Holland’s oldest, a center of learning that was (according to local lore) created in 1575 by William of Orange for the town’s inhabitants after they were besieged by invading Spaniards and refused to surrender.  Married to a cousin and the father of 4 Willem was a gymnast and fencer.  He rode his bike to and from the university and often worked “until he was reminded to go home by his assistants upon request from his wife.”

After the computer in the ambulance interpreted the EKG, the paramedic radioed ahead, and the vehicle sped to a nearby hospital where a catheterization team was available 24 hours a day.  When they arrived the doctor and squad were ready to go. Within half an hour a mild sedative calmed the man’s brain and a cardiologist was advancing device one, a narrow rigid yet flexible tube he had been inserted through a groin artery. Under fluoroscopy the physician pushed and maneuvered the tip through the aorta– the body’s central blood vessel.  It quickly reached the coronary arteries– the vessels that drape over the surface of the heart and deliver oxygen to its muscles. The entrance to the coronary arteries is located in the aorta just beyond the point where it attaches to the heart.   

As we age, smoke and eat rich food, plaques develop on the inner wall of many of the arteries that supply oxygen and nutrition to our bodies.  These “barnacles” are full of inflammatory cells and fat.  When their fibrous cap ruptures the body tries keep the contents from escaping.  Platelets and clotting proteins pile onto the exposed gap.  If the reaction is large enough, like a jack knifed 18 wheeler, it can close down the highway– in this case obstruct the flow of blood.

Dye was injected into the coronary arteries and the occluded vessel was identified. Device one was removed and a second catheter, device two, was inserted and passed to and through the coronary artery occlusion.   This catheter had a strong balloon near its tip.  It was inflated, the narrowed area was forced open, and blood flowed and oxygenated the heart. A third device, a “stent”, a thin mesh hollow tube made of stainless steel and cobalt-chrome, was advanced to and through the vessel. Its outer surface was coated with a polymer that “carried” a drug that was slowly released.  The chemical helps preserve the stent’s patency. Blood now flowed through the tubing and the heart muscle was able to breathe again. 

A cousin dodged death.  Her surgeon had successfully clipped the bleeding brain aneurysm, the thin walled balloon like bulge in the wall of one of her arteries, but a few days later the cerebral spinal fluid that normally coats the outside of the brain wasn’t flowing.  Pressure was building in her head.  Her physician drilled a hole in her skull and inserted a thin tube into a liquid filled chamber in the center of the brain, the ventricle. He tunneled the other end of the tube under her skin and inserted it into her abdomen.  Spinal fluid poured out of the brain, and the force that was squeezing the brain decreased. 

The shunt, the small hose that relieved the pressure was created by an engineer in 1955.  He was the father of Casey, an infant who had hydrocephalus, too much fluid and pressure on the brain.  His doctors initially avoided the kid’s dad.  They didn’t want to deal with his reaction when they told him that his son was going to die.  John, the father, was 35, had been in Europe during the Second World War and was working in a hydraulics research laboratory.  When his only child was born with multiple congenital defects he watched as the infant underwent a number of operations.  Then his head started enlarging.  Liquid accumulated in the brain chamber, the pressure in the skull increased, and the doctors didn’t have a good way to treat it.  To decompress the situation, according to his troubled father, Casey was taken to “the torture chamber.”  A doctor would insert a needle through his fontanel, the area on the top of his head where the skull bones had not yet fused.  Using a syringe the M.D. withdrew fluid.  Doctors eventually talked to dad and explained that if they tried to fix the problem by inserting one end of a tube into the cerebral cavity, they would need to attach the other end to a vein.  Every time the child coughed or sneezed blood would flow up the tube, its hollow inside would fill with blood, and a clot would form. 

Holter pondered the problem.  He knew autos had pressure release valves. They used a ball that was displaced when the tension was high.  In people a similar approach would fail when the head was in certain positions.

Then Holter thought about the nipple on a baby bottle.  It only opened when the tension was high.  Then it closed.  Using it as a model he designed a pressure sensitive valve.  In place of a tip it had a “slit similar to the one on the nipple.  He hooked the valve to a rubber, later a plastic tube, and his device worked.  Unfortunately it lost its shape when the tubing was heat sterilized.  Then he learned that Dow made temperature resistant silicone tubing.  It didn’t take him long to sort out the details, and he created a pressure sensitive tube. 

In three weeks Holter solved a dilemma that had plagued doctors for more than a century and his invention “is still widely used.¹⁸” Before the doctors were able to put a device in Casey’s head the infant had a cardiac arrest that lasted 30 minutes and his brain was damaged.  With the shunt in place his very limited body survived five years.

At 96 a friend’s mother was clear minded and living alone when she fell and couldn’t get up.  Four hours later help arrived.  In the hospital physicians diagnosed and successfully treated sepsis caused by a urinary tract infection.  But when they examined her heart they heard a loud woosh of blood, a heart murmur.  A heart ultrasound revealed severe aortic stenosis.  The valve that swings open and closed when the heart contracts, the gate that allows blood to flow out of the heart and into the vessels of the body, had grown quite stiff.  Her days were numbered.  The valve could be surgically replaced, but she was old and frail.  Open heart surgery would be quite risky, but there now was another option.  A recently approved device, a replacement aortic valve could be inserted into a groin artery, slid up the aorta and through the old stiffened valve. Once in place it would, umbrella like, open and close each time the heart contracted. People in Europe had been using the device for 5 years.  At the end of that period of time the new valves were as successful as the surgically planted valves.  She opted for the new gadget and did well.

My wife’s cousin was in her 80s and lived on the second floor.  Her knees were arthritic and the pain of going up and down the stairs had become so intense that she seldom left home.  She had heard “horror stories” about knee joint replacement but dreading the thought of a nursing home, she bit the bullet.  Over the next year and a half each of her knee joints was replaced. The arthritic surface, the eroded area on the end of the bone, was sliced off and the raw area was “re-soled”.  The day after each operation she was able to walk.   Within months of the second procedure she felt normal, mobile, like she was ten years younger. 

The first really successful joint replacements were performed by a talented surgeon named Charnley.  A Brit with “febrile inventiveness and a powerful command of the English language” he helped care for the soldiers who were evacuated from Dunkirk, and spent most of the Second World War as a medical officer in Egypt.  When he was 46 and skiing in Austria, he met and married Jill the woman who became Lady Jill after Charnley was knighted.²⁰

In 1960, having established himself as an orthopedic innovator he turned an old T.B. hospital into a hip center.  A local medical equipment manufacturer, Thackeray’s, fashioned the “metal femoral stem and polyethylene cup (acetabular) component.” Charnley used acrylic bone cement as grout, not glue, and successfully produced a low friction prosthesis that when implanted allowed people with bad arthritis to walk without pain.  His achievement inspired a new approach to worn out joints.  According to Arthritis UK we’ve now gotten to a point where 80% of “cemented hips should last for 20 years” When or if they fail and a person is healthy enough to undergo repeat surgery, it’s usually successful. “The results are less good after each revision,but 80% of re-dos are good for 10 years.” 

While Charnley was developing his low friction hip, surgeons in various parts of the world tried to design workable knee replacements, and people with disabling pain were willing guinea pigs.  In 1969, feeling that he didn’t have a “reliable knee implant” New York orthopedist John Insall, “designed and developed 4 of the devices that are currently used.  A Brit, Insall was born in Bornemouth, a town on the U.K.’s south coast that boasts “seven miles of sandy beach and an exceptionally warm microclimate.”  He decided to go to medical school because too many members of his family were already in the military and police.  Turned down the first three times he applied, he graduated at the top of his medical school class, and worked for 2 years as a casualty medical officer.  Then he traveled to India to learn and work.  While there he wrote the hip transplant pioneer Charnley and asked for “an appointment as a House officer.”  ”Charnley wrote back “India needs doctors to treat fractures and tumors, not hip replacements.”  In 1963 war broke out between India and China and Insall left the country with eight dollars in his pocket.  He eventually became a hand surgeon at New York’s Hospital for Special Surgery (HSS).  Years later he met and played tennis with the engineer who helped him design the early knee prostheses.¹⁷ 

Currently over 700,000 American knees are restored annually.  Some think that by 2030, over three million Americans per year will get a new knee.  Four manufacturers make a majority of the implants.  Many of us have been saved from death, poor mobility, or disability at least once in our lives as a result of an amazing array of “devices”.²⁴

In 1895 a German researcher named Wilhelm Röntgen “noticed that when electric current was flowing through his Crook’s tube, a board on the wall that was covered with Phosphorus started to glow.”  He asked his wife, Anna Bertha, to place her hand in front of a photographic plate, activated the tube and visualized bones and a wedding ring.”²¹   An invisible wave had somehow passed through the walls of the sealed tube and through a human body.  He rechecked his findings a few times.  When he was convinced what he witnessed was real he announced his discovery to colleagues and the newspapers and it became a phenomenon.²⁶

He didn’t invent the sealed tube with the air sucked out of it.  Named for its creator it had been around for a few decades and was called the Crookes tube.  The wealthy British researcher who developed the device also happened to believe in the paranormal.  In his later life William Crookes tried to communicate with his dead wife through a medium and, along with Charles Dickens and Arthur Conan Doyle, Crookes was a member of the Ghost club.²⁷

In the years following the tube’s creation a few researchers had allegedly passed electricity through the airless device and had seen a weird glow, but they hadn’t discovered its significance.  Rontgen did and he became famous.  Not one of the creative geniuses of his day, Rontgen came from money so when he was expelled from a school in Holland for a boyhood prank he was able to go to get an education in Switzerland.  His wife was a waitress three years his senior who he met and fell for.  He was a good but not an amazing German researcher.  But he was the person who saw what other had seen, and wondered what was going on; and he made an important discovery.^1,25

Thanks to his invisible wave interventional radiologists are able to use a fluoroscope as a guide.  Slipping a needle through the outer wall of the abdomen or chest, they can jab it into the deep worrisome shadow that’s being biopsied. The beam, as we’ve learned has to be used sparingly.  Pulsing the x-ray lowers the radiation dose, and people who are exposed to the rays wear heavy lead aprons to protect themselves.  There is no absolutely safe dose of radiation.  When I was a medical student the head of radiology at Washington U was missing a few fingers.  They were damaged when he held people erect while taking x-ray pictures.

By the time I finished medical school x-ray films were taken from many angles.  Air (lung) was black.  Bone was white and tissue grey.  By altering the focus of our tube we could get a sharp view of various depths of a body.  As computing became faster and programs became increasingly sophisticated, algorithms were added.  Now, using advanced devices physicians can get deep detailed views of sections of the body, head and limbs. We can use x-ray beams (CAT scans) or strong magnets (MRI).  And we can visualize much with medical Radar, ultrasound machines.

In the last 70 or so years devices that allow interventional physicians to thread a catheter into a leg artery and advance its tip to the vessels of the brain, heart and abdomen have been created and modified. If the main abdominal artery, the aorta, is significantly bulging or enlarging, it can be replaced surgically, or it can be splinted by a device, a synthetic expandable stent graft that is inserted through a leg artery and becomes the aorta’s inner wall.“In 2003, the interventional approach passed open aortic surgery as the most common technique for repair of abdominal aortic aneurysm, and in 2010, the procedure accounted for 78% of the repairs of all U.S. aneurysms that had not already ruptured.¹³

The arteries of the brain are currently accessible.  Experts have learned how to thread hollow catheters through one of the four large arteries that supply blood to the region.  Two carotid arteries run on each side of the front of the neck.  Two “vertebral” arteries course through openings in the vertebrae of the spine. The vessels communicate and deliver blood to a ring of arteries on the underside of the brain.  An aneurysm, a weakness in the wall of an artery that becomes a bulge, isn’t that uncommon.  One in 50 of us will develop one.  Some say 1% others up to 3% will eventually rupture.  Half of the people whose aneurysms start bleeding die before they get to a hospital.  The other half stop leaking blood but the flow of can start again within a few days.  Surgically clipping a “ruptured” aneurysm is risky but it’s often necessary.  And a rupture can be prevented by filling the ballooned area with clotted blood.  Interventional radiologists have become proficient at inserting devices–small platinum coils, into aneurysmal defects. They detach, remain in the ballooned area, and a thrombus forms and fills the bulge.  The device that made it possible to disengage the wire was developed by an Italian neurosurgeon named Guido Gugliemi. Born and trained in Rome, Guido was the son of a physician and originally planned to be an electronic engineer.  In medical school he was drawn to the brain’s wiring.  He saw an area that “constituted of millions of relays and millions of wires that transmit electricity and are connected to one another.” As a neurosurgeon he witnessed and treated ruptured aneurysms.  Brain surgery was difficult and bloody. The engineer in him thought there must a way to use the interventional approach and induce a clot to form.  He wanted to insert magnets and use electricity, and a friend thought his idea might work. Guido got financing and moved to Los Angeles with his wife and children.  He checked out his approach and it didn’t pan out.  Deciding to stay in L.A., he used his knowledge of soldering and electricity to develop a detachable wire.  Turning the concept into a useable product required countless nights in the lab tweeking and testing his gadget.  He eventually was able to predictably insert and detach the coil.  His invention is currently used in 90 percent of the brain aneurysms that doctors treat.  Most of the aneurysms wouldn’t have ruptured and in some hospitals the device is probably over used.  After ten years in southern California Guido and family moved back to Rome.

In 1958 Earl Bakken Bakken created the first wearable battery-powered cardiac pacemaker.  He did it by modifying a circuit for a transistorized metronome, a gadget used by musicians to keep the beat.  He got the plans from a magazine called Popular Electronics.  The device was developed after a local heart surgeon named C. Walton Lillehei spoke with Bakken and asked him if it was possible.

The heart is a muscular cavity whose contraction is controlled by the special cells in the sino-atrial node.  One or more times a second they emit a quantum of energy.  The current flows down the main conduction fibers of the heart, reaches all the muscular filaments, and they shorten in unison.  After the cells have released their energy, sodium, potassium and calcium seep in and out and recharge the node. The power can’t be stored, so when the heart’s pacemaker is fully energized it discharges.  When our hearts don’t beat like they are supposed to, there are currently wide arrays of battery powered devices that take over and emit periodic mini jolts.  They are implanted on the heart’s outer surface or slipped into one of the upper heart chambers then attached onto the inner lining.  

 As a teenager Bakken was the “nerd who took care of the high school public address system, the movie projector, and other electrical equipment.”  After serving in the army signal corps during the Second World War, he married a medical technologist.  While courting her he hung out at the hospital and met doctors and others.  He repaired their broken devices and realized that hospitals need people to keep their medical equipment working.  He set up a shop in his garage and that’s where he made a wearable pacemaker that was the size of a few decks of cards.

          When he turned the first pacemaker over to the doctors they inserted it into the heart of an animal with heart block.   Dr Lillihei saw the gadget was working, removed it from the animal and planted it in a child whose ventricular septal defect  had just been sewn shut. 

The congenital opening between the two largest chambers of the heart, the ventriculo septal defect, is the heart’s most common congenital abnormality.  Doctor Lillihei, working at the Mayo Clinic started learning how to patch the gap in 1954 and by 1958 he had performed the operation a number of times.  While sewing in a patch, a suture can easily capture the electrical fiber that runs along the border of the heart defect.  When a surgeon ties the knot, the main fiber is constricted and the electrical energy can’t flow. Hearts stop beating or contract very slowly and children die.   .

It would be an understatement to say pacemakers have, over the last 60 years, become a big business.  There are multiple manufacturers in the U.S. Europe and Asia.  Over 200,000 devices are planted annually.  In the U.S. Cardiologists spend a lot of time, inserting them, checking battery life, replacing batteries if indicated, and remotely “interrogating” the devices and seeing how often and how well they worked. 

There’s also a pacemaker that’s inserted into the body of the occasional person who has recurrent ventricular fibrillation and survives.  The rhythmic catastrophe is usually seen when someone has an acute myocardial infarction or has a disease of the heart muscle, a cardiomyopathy.  Fibrils of the heart quiver and fail to beat in unison, the heart muscle doesn’t contract, blood stops flowing and a person drops dead.  .  

The arrhythmia can be treated with a sudden jolt of electricity.  The current brings all muscular activity to a screeching halt.  Fibrils of muscle rest for a second or two.  When they next shorten they tend to do so in unison and the heart starts pumping blood.  If a heart is shocked within the four minutes after it started fibrillating the brain isn’t usually damaged, and people have an excellent chance of surviving and continuing to be fully functioning individuals.

There are defibrillators in airports and many shopping centers.  They’re not pricey, and they are easy to operate.  But many are afraid to use them.  U.C. Berkeley put one near a volley ball court.  It’s in a locked case where no one can get to it if someone drops.  Hard to figure what they were thinking.

In the absence of a defibrillator we commonly resort to plan B and give CPR.  Our efforts push some blood through the system, but not nearly enough. 

My hospital required I retake a class in CPR every 2 years.  The last time I took the course the teacher said people who develop a lethal rhythm need to be shocked early.  If the jolt is delivered within a minute, 90% of people survive (presumably without noticeable brain damage).  After 2 minutes 75% survive and at 4 minutes only 55%.  

There are defibrillators up and down the halls of Chicago’s O’Hare Airport.  A survey performed shortly after they were installed found the gadgets had already been used 14 times, and 9 of those shocked came back to life. 

When someone witnesses a sudden death, confirms the heart isn’t beating, and has access to an AED –automated external defibrillator, they merely need to open the case and listen.

An automated recorded voice tells them what to do next: 

“Attach the electrode pads. 

Don’t touch the patient. 

Analyzing.  Shock advised. 

Charging.  Stand clear. 

Push the flashing button to deliver shock.  Stand clear.”

Most people who check out one of the brief You Tube videos on AED’s, automated external defibrillators, realize how simple their operation has become.  If they’ve seen episodes of the T.V shows like “ER” they’ve witnessed the drill a few times.  Which doesn’t mean it’s not frightening to perform the task on a live person. 

The devices that shock hearts have become more common but they aren’t ubiquitous and are only noticed by people who are tuned in.  A survey in a Netherlands train station (per a project manager from Kings County Washington) found that half the people questioned “couldn’t identify an AED”, and less than half of them wouldn’t consider using one of the devices. 

After 40 years 300,000 people are still dropping and dying each year and the survival rate to hospital discharge is 8.4%. 

Some people with damaged hearts have repeated episodes of Ventricular fibrillation.  Muscle cells periodically stop working as a group and their heart stops beating. A few wear pacemakers that shock the heart when it starts fibrillating.  Richard Cheney the former Vice President of the U.S. was one of those people.  He had the first of his five myocardial infarctions when he was 37 years old.  Unpopular in many circles, Cheney feared terrorists might try to assassinate him by remotely instructing his defibrillator to shock him, so he asked his doctor to replace his defibrillator with one that wasn’t remotely accessible.²²   When he was in his 60s his heart started failing, it didn’t propel enough blood with each contraction.  Doctors inserted one end of a tube into his left ventricle and the other end of the aorta.  Blood was pumped through it by a small electrical motor.  It helped for a while.  At age 71 Cheney received a heart transplant and did well.

When I was in medical school we were taught that most colon cancers originated near the lower end of the bowel and could be detected by a probing finger or by passing a well lit, metal, foot long, hollow sigmoidoscope through the anus.  Decades later doctors used snake like scopes with lenses connected to fiber optic bundles.  (The eyes of a fly are made up of thousands of individual visual receptors. They work together to create an image.)  Doctors learned how to guide the instruments around corners, view the entire large intestine, and biopsy or remove growths or tissue as needed. By the year 2000 our endoscopes had an optic chip near the tip and doctors monitored their progress on a T.V. screen.  The devices could be totally immersed in chemicals that killed any virus or bacteria that hadn’t been removed with vigorous washing.  Sedating drugs controlled the discomfort of the exam. 

In 1998 the 42 year old husband of a famous T.V. personality Katy Couric died of colon cancer.  She became a spokesperson for early detection of cancer by periodically screening the colons of people without symptoms, and colonoscopy became big business.  Gastroenterologists became skilled, could usually pass the scope to the far end of a colon in 5 to 10 minutes.  I typically performed  five or more procedures in a half day. A similar chip based scope allowed us to see the stomach and duodenum, treat bleeding vessels, and biopsy worrisome abnormalities.

The small intestine, the 9 to 30 foot long stretch of bowel between the stomach and the colon absorbs food and fluids and is essential to life.  It can be partially visualized with a scope, but passing the instrument is difficult and tedious. There’s a “capsule” that allows us to view the bowel another way.  It’s produced by a high tech company headquartered in a once sleepy Israeli town in the Jezreel valley, a village where, in the 1970s, immigrants from Yemen sold pita filled with falafel in the sun filled town square.  The small bowel device and its function are best understood by comparing it to an I-phone.  The phone can snap a picture and send it by text or Email to another I-phone half way around the world.  The Israeli company uses a camera and similar technology, packaged in a capsule.  The “pill” also contains a flash so it can take photos in the dark.  There’s a “transmitter and batteries that last 8 hours. “ 

A person with a potential small bowel problem swallows the gadget. As it passes through the stomach and lengthy small intestine it snaps two photos a second.  It can’t store the images, so it instantly transmits them wirelessly –like a text photo—to a receiver, worn on a belt by the patient who swallowed the pill. At the end of the exam the capsule is passed in the stool.  The storage disc is then plugged into a computer and a program turns the thousands of snapshots into a video that can be viewed and interpreted by a knowledgeable physician or technician.¹⁴

A medical “device”, according to the FDA, is something used to help “diagnose, treat, mitigate, or cure a human or animal disease or condition.  The category includes everything from instruments and apparatuses– to machines or implants.  Chemicals that don’t have to be metabolized to work are devices. Before they are sold in the U.S. “devices” must be registered, listed, and correctly labeled.   Production has to be performed “in accordance with good manufacturing practices.” If something goes wrong, if there is an adverse event, the FDA must be notified.³

Each year “over 4000 new, low-risk (class I) devices are marketed”.  They don’t need to be approved, but recalls and problems need to be reported to the agency. 

At the same time High riskdevices go through an extensive authorization process.  Annually 50 to 80 of them are approved by the FDA.

Most of the other 3500 devices that are “permitted” each year are minor modifications of an existing product. In terms of safety and effectiveness they are “substantially equivalent” to the currently used item.  The verification process they go through, called 501k, is not particularly stringent. Only 8 percent need “special controls and clinical data.”  “Bench testing “is sometimes adequate, and some gadget-tool-appliances have to be checked out “under conditions of clinical usage. “ When lasers for “cutting or ablation” of tissue replaced heated wire cautery, they were approved by the 501k process.

The substantially equivalent requirement has periodically been misapplied. On occasion a manufacturer obtained FDA clearance without revealing the actual use of the device.  At other times the FDA and manufacturer misjudged. The new product didn’t seem that different–but it was, and it should have been extensively tested before it was widely used.  In hindsight that probably was the scenario when the metal on metal hip prosthesis was approved.

For years surgeons had replaced painful arthritic hips by inserting a metal stem into the femur.  The socket in the pelvis was covered by a “plastic (polyethylene.)” insert.  It made sense to many that if both articulating surfaces were metal the joint would last longer and work better.  The manufacturer and FDA apparently decided that making the socket metal, not polyethylene, was a minor change—that the modified prosthesis was actually “substantially equivalent.¹⁶” It was not necessary to test people. Cobalt and chromium alloy prostheses received FDA clearance in July 2008 without a clinical study.  They were then implanted in 100,000 patients. Over time the metal on the articular connecting surface of the bone tended to erode.  Sometimes particles “migrated into the surrounding tissues and the bloodstream.   21% of the alloy prostheses had to be replaced or revised within 4 years and 49% within 6 years.”⁴ 

Also approved by the 501k process, transvaginal mesh was used when surgeons operated on pelvic organs that prolapsed, slipped down and were protruding into the vagina.    No clinical trials were conducted at the time, and sixty-one products were marketed between 1985 and 1996. Made of a type of plastic called polypropylene, their lattice corralled parts of the intestine or a bladder.   Over the years the mesh caused a number of complications “including pain, adhesions, bowel obstructions, and infections.” In January of 2016 the FDA issued a high risk warning, and in April 2019 the agency told manufacturers to stop selling the material.⁵

Manufacturers and clinical facilities have to report device-related deaths and serious injuries to the FDA.  In 2002 the agency received 2500 reports from clinical facilities and 3500 from consumers.

“Over 1000 devices are recalled each year.”  Half have low risk drawbacks.  Most of the rest are intermediate risk.  And 10 to 20 of the problems are serious.  Recalls require manufacturers halt production and dissemination of the devices, and they must alert clinicians.  Post recall doctors and nurses are supposed to keep an eye and ear out for difficulties with “Heart valves, joint prostheses, implants, cardioverters, defibrillators, respirators, infusion pumps, hemodialysis equipment, cutting and coagulation equipment, endoscopes, etc.”⁶

The FDA, via a new precertification program is working with industry to try to find a way to evaluate the effectiveness and safety of software as a device.”⁹ “81% of North American adults own a smart phone, and many companies are trying to use technology to monitor health and help manage certain chronic diseases.” Some devices can detect the heart rate; others the number of steps a person takes during a day. 

In 2020 a corona virus that modern man’s immune system had never previously encountered jumped from a bat to a man.  It often made people very ill and was extremely contagious.  At times it caused an infectious process that filled the lungs with fluid and made oxygenation impossible.  Many were saved by respirators that mechanically ventilated lungs for days to weeks.  But in hard hit areas like Italy and New York there weren’t enough ventilators for everyone who needed them.  The president, the press, and politicians of the time regularly attacked and blamed one another every time there was a mishap or an unheeded warning. 

The nation was caught shorthanded even though government officials had anticipated a potential need for the devices and had ordered many a few years earlier.  By April 20^th few had arrived.  The dearth of respirators was big news and people wanted to know who screwed up.

The blood that flows into the heart from the body enters through the right upper chamber, the atrium and progresses to the pumping chamber, the right ventricle. The ventricle pumps the blood into the lung.  The human lung is a collection of about 500 million tiny air chambers called alveoli.  A cubic millimeter of lung tissue contains about 170 of them. They are surrounded by thread like vessels, capillaries.  Erythrocytes, red blood cells stream through them. The cells deliver their carbon dioxide to the alveoli and collect oxygen. 

Air is sucked into the lungs when a vacuum is created by breathing– expanding our chest and lowering our diaphragms.  Earlier in the 20^th century when the muscles of a child with polio were so weak that the person couldn’t inhale, he or she was placed in a long sealed tube.  Their head hung out of the top. Multiple times a minute the machine created a vacuum and air was sucked into a person’s lungs. 

During the Second World War the military needed a device that forced air into the lungs.  Driving oxygen into the circulation allowed pilots to fly at high altitudes.  The devices were developed by Dr. V. Ray Bennett and Dr. Forrest Bird.  After the war each went on to develop forced air ventilators. One of the inventors, Forrest Bird, had a father who flew combat planes during the First World War and had taught his young son how to fly a plane. 

Positive pressure ventilators were commonly used in the 1950s for people with severe pneumonia who couldn’t move air into their lungs.  Over the subsequent 60 plus years Bird, Bennet, and others modified and improved the devices.  

Shortly after the 2003 SARS respiratory epidemic the department of Homeland Security decided to stockpile an additional 70,000 respirators.  They might be required in a moderate influenza pandemic. Before the government ordered the machines a panel of experts decided which bells, whistles and capabilities the respirators would need.  The machines on the market were costing $10,000 a unit and the group, presumably, thought they were overpriced.  They decided new respirators should not cost more than $3,000 each.  In 2008, the government asked companies to bid on the project.  As developer and supplier they chose Newport Medical Instruments, a small outfit in Costa Mesa, California, a company that was “small and nimble.” After the deal was inked the government gave Newport $6 million to develop the machines and said they would pay the rest when the devices were delivered.  Reading between the lines it sounds like the people at Newport knew they would lose money on the deal. “but would be able to make up for any losses by selling the ventilators around the world.”  

Research started and every three months, government officials visited Newport’s headquarters.  “There were monthly scheduled requirements and deliverables.”

In 2011, 3 prototypes were sent to Washington and the company planned to “file for market approval and start producing the machines in the fall of 2013.  Then the company was sold.  Established 45 years earlier by physicians, Newport Medical was Japanese owned.  Covidien, a company that was formed when Tyco “spun off” its health care division, purchased Newport for a little over $100 million.  Then Covidien wanted the government to provide additional funding and a higher sales price. The government said OK.  The U.S. gave Covidien an additional $1.4 million. The next year Covidien decided they wanted out the contract.  The deal “was not sufficiently profitable”   The government agreed and awarded a new contract for $13.8 million to the giant Dutch company Phillips.   In July 2019 the F.D.A. signed off on the new Philips ventilator, the Trilogy Evo. The government ordered 10,000 units in December, setting a delivery date in mid-2020.  In January 2020 a major coronavirus epidemic started spreading out of China.

On March 31, 2020 a Pennsylvania subsidiary of Phillips was producing the cheap portable ventilators but they didn’t deliver them to the U.S.  They sold them to other countries.  Called Trilogy Evo the ventilators were priced at $3,280 each. the company is currently negotiating with a White House team for43,000 additional ventilators.  In March 2020, invoking the defense production act, President Trump told General Motors to make the ventilators.

In 2017 the top 10 device makers had over $170 billion dollars in revenue and the top 30 took in more than $270 billion. Devices are responsible for roughly 6% of U.S. health care spending or about $200 million a year.¹⁰ 

Like pharmaceuticals –MRI machines, vascular catheters, endoscopes etc. are very expensive.  Little is known about how companies and hospitals negotiate.  A friend who purchased equipment for a chain talked about the days after the hospitals he worked for merged with another hospital group. He visited one newly acquired facility at a time and met with the local doctors.  They had attitudes and beliefs about which scopes, artificial joints, heart valves, etc. were easier to use, more effective, and more durable.  Some cared about the brand of material used to sew wounds shut. Since many surgeons could choose where they admitted their patients, where they performed their procedures, the hospitals needed their business.  At times my friend had to buy a brand of equipment that wasn’t perceivably better and was more expensive. 

Given our current system I think an attempt to regulate the cost of medical devices doesn’t make sense.  In Europe, on the other hand, medicine is commonly state run.  Administrators have a greater say and can more effectively use price as a bargaining factor.  Not surprisingly European nations pay less for medical devices than we do in the U.S.

To even out the costs and to help make health care affordable to all, Congress, as part of the Affordable Care Act (Obamacare), enacted a 2.3 percent medical devise tax.  It was briefly collected then put on hold, and recently was repealed. .   

The world’s largest device maker, Medtronic, the Minnesota Company with revenues of about $30 billion a year, spent a decade acquiring and integrating 20 smaller companies.  Then, in 2015, the American corporation purchased a company headquartered in Ireland called Covidien. As discussed earlier it was a 2007 spin off of Tyco.

After the merger was consummated Medtronic moved its official headquarters to Ireland.  According to The Street: Medtronic’s 49.9 billion acquisition of Dublin-based Covidien, the largest tax inversion deal ever — was going to leave shareholders with a big tax bill, while allowing the Minnesota-based company to pay little or no U.S. corporate taxes.

“It is not inconceivable that [Medtronic] may not be taxed at all.” on its U.S. operations, said Robert Willens, tax consultant and professor at Columbia University.¹¹

In 2018 Medtronic, now an Irish company, had net earnings of 3.104 billion,  Half the money came from sales to physicians and hospitals in the U.S. “Medtronic’s total revenues grew from $28.8 billion in fiscal 2016 to $30.6 billion in fiscal 2019.¹⁵ “

Chapter 10 SURGERY

55 Years ago, as an intern, I slept in a hospital provided room and worked most days.  Meals were free and I was paid $55 every 2 weeks.  When rotating through surgery I rolled out of bed between 5 and 6 A.M. and accompanied the cowboys of the hospital, the general surgeons, as they made in-patient rounds.  We ate breakfast and washed hands for 10 minutes by the clock.  Mornings were spent tugging on a retractor, stretching open the edges of the wound while a gall bladder was being removed.

Long skin incisions were usually needed when the surgeon was operating on someone who presented to the emergency room with severe pain and rigid abdominal muscles, or when merely touching the belly made the patient withdraw.  Sometimes we wondered if the appendix had ruptured?  Was blood pouring into the abdomen of a person who had been shot or stabbed?  Why did the X-Ray show air filling the abdomen?  Did an ulcer perforate?

The lengthy slash through the skin and the fat layer was followed by a pause to buzz (electrically cauterize) or tie off the severed ends of bleeding arterioles.  A series of additional gashes cut a path through layers of fat and muscle.  A scissors sliced open the peritoneum, the membrane that surrounds the organs.  The opening had to be large enough for the surgeons to see what they were doing and to get their tools and hands inside.  Sliding a large light over the opening, an assistant would aim the beam down the long, dark tunnel.  The smaller the gap, the more precise the ray had to be.  Deep inside tissue was cut, clamped, and sewn by skilled people using long handled tools.  Adhesions, fibrous tissue caused by prior operations, created matted intestines and made it hard to identify various organs, blood vessels, or nerves.  By slipping a hand into the cavity and palpating the edges of the liver, pancreas and other organs— by feeling for masses or abnormalities, the surgeon “explored the abdomen”.  Aware of “the possibility and consequences of failure,” the surgeons needed to be able to improvise when they had a complication or encountered something out of the ordinary.  The people doing the cutting had spent many of their waking hours practicing basic techniques like sewing and tying knots, and they were adept.  When I was a junior medical student one of my buddies bragged that the resident let him remove the patient’s appendix.  It made no sense at the time, and it still doesn’t.¹⁷

Man has long known how to “suture lacerations, amputate limbs, and drain pus.”   Prior to 1858 the people who cut and sawed learned their craft as apprentices.  When gangrenous or damaged limbs had to be amputated, resections were quick, bloody, and accompanied by loud shrieks. The fastest knife in England was wielded by Scottish surgeon Robert Liston. “Operating with a knife gripped between his teeth,” he could amputate a leg in two minutes. On one occasion he inadvertently cut off the fingers of someone holding a person down.  The stump end of the man’s fingers and the raw end of the hip got infected and both men died.

Elective surgery was uncommon.  Perforations or obstructions of the intestine were not approached.  In the U.S. and Europe, medical school learning was “wholly didactic: seven or eight hours of lectures a day, supplemented by textbook reading. Laboratory work was sparse, and there was no opportunity to work with patients.²⁸”

In the 1800s some surgical procedures were carried out in homes.  Doctors at a few prestigious hospitals performed operations on a stage that was surrounded by a semicircle of tiered seats. Observers apparently came to watch and perhaps be “thrilled by spectacular public performances.²⁴”

In the mid 19^th century we learned about and started using anesthesia to prevent pain.  Surgeons could now enter the abdomen or thorax, but they didn’t know what to do when they got there.  Operating rooms became “quiet and to the observer seemed tedious.” A number of new operations were developed and there were risks, failures, and deaths. Apprentices learned the techniques of one practicing surgeon, then struck out on their own. There were no blood banks or antibiotics.  It’s not clear how often the adage see one, do one, teach one was more than a tall story.^{25, 26}

In 1890, William Halsted, the son of a wealthy “tight-fisted, hard- nosed Presbyterian” started the nation’s first surgical residency program at Johns Hopkins University in Baltimore Maryland.  “Self trained, as were all U.S. surgeons of the day, he spent 1 year as an intern at Bellevue, 1 year as a house physician at New York Hospital, and then 2 years abroad as an observer.” While in Germany, Austria, and Switzerland, he saw how other countries trained young surgeons, and he realized the U.S. system was ineffective.  There was no mechanism for developing and passing knowledge on to other doctors.  Halsted developed the nation’s first residency program at Johns Hopkins Medical School. ³⁰

For many years Halsted trained many of the nation’s future teachers and professors.  The doctors on his service created and modified operations, and they taught one another. 11 of his 17 chief residents started training programs in hospitals in other parts of the country. 

A “bold aggressive surgeon” when young, Halsted was addicted to morphine and heroin when he came to Hopkins.  His operations were performed “almost excruciatingly slowly and meticulously.”  On one occasion he must have been under the influence because he stopped operating and asked an assistant to scoot over.  The man had been standing on his foot for the pervious half hour.”  Outwardly shy, Halsted was adamant about cleanliness, bleeding control and carefully reconstructing tissue.  He had quirks like shipping “dozens of his dress shirts to Paris or London every year for laundering.  His wife was only allowed to burn white oak and hickory in his fireplace.” In his operating room surgeons and nurses wore rubber gloves not to prevent infections but because one of the scrub nurses developed a rash when she immersed her hands in mercuric chloride.          

Dubbed the nation’s father of neurosurgery, Harvey Cushing, was born into status and privilege.  His father, grandfather, and great grandfather were all prominent Cleveland surgeons.  He was a descendent of the Puritans who landed in Boston 18 years after the Mayflower, and he was a descendent of the nation’s 4^th ever Supreme Court justice.  At Yale he was a gymnast and would somersault backwards with a lighted cigarette in his mouth.”   After medical school his money and influence allowed him tour Europe and meet and observe the world’s most prominent surgeons.  In 1913, after spending 4 years as one of Halsted’s surgical residents he moved to Boston.  When Harvard’s Peter Brent Brigham opened its doors in 1914 he was the hospital’s first chief of surgery and the founder of the country’s second surgical training program.

During the First World War Cushing performed surgery on soldiers with severe head wounds.  Up to 8 times a day he removed a part of the bone from the skull and exposed the brain.  Later at Harvard he learned and taught many others how to operate on brain tumors.  A talented surgeon, Cushing had removed 2000 brain tumors by the time he retired. His mortality rate was half that of his colleagues.

Described as “a man of ambition, boundless, driving energy, and a fanatical work ethic,” he also had “a penchant for self-promotion and ruthlessness.”  He insulted his residents and operating-room nurses for their errors and tended to blame others for his mistakes. Outside the hospital he paid little attention to his family and had no patience for women.  When “his oldest son, 22 year old William was killed in a traffic accident Cushing received the news in a telephone call in the morning, informed his wife, and continued to the hospital to perform his scheduled surgery.¹⁸ 

Two decades later in St Louis Missouri, Evarts Graham removed a lung that contained cancer and his patient survived.  Graham went on to become one of the giants of his era. 

Deciding at a young age that he would follow his father’s path and become a doctor, Graham went to Princeton, then Chicago’s Rush Medical school.  His father David, a professor of surgery at a women’s college and a hospital chief of staff, was well connected.  David presumably learned how to operate as an apprentice and he was not (according to his son) “by any means a polished or trained surgeon.”  I suspect he didn’t wear a mask when he operated because his son tells of how, prior to performing surgery, David Graham washed his hands then “washed his beard in antiseptic solution.” 

Evarts, ever ambitious, became the president of his class, performed 50 autopsies while in school, and wrote a number of journal articles.  In 1907 when most graduates “left school and became general practitioners,” he spent five months as a surgical intern.  He assisted his father, “occasionally performed operations under his dad’s supervision,” and at the end of his internship believed he was qualified. 

Joining a group of physicians in Mason City Iowa a town of 22,000, he was appalled when he learned that surgeons paid colleagues a portion of their fee for referring the patient.  Surgeons, he believed, should not be chosen on the basis of how much they pay the referring doctor.  Becoming embroiled in a campaign to end “fee splitting,” he was considered an upstart by some colleagues, and was the brunt of “personal attacks.” When the U.S. entered the First World War in 1917 he volunteered for the army and left town. 

Unable to become a battlefront surgeon because his vision was “defective”, he became an assistant Surgeon General.  Young and inexperienced, he was sent to Alabama and given orders to take charge of the local military hospital.  When he presented his papers to the facility’s medical commander, the doctor refused to step down.  He “didn’t give a damn about Graham’s orders” and called Graham a fly-by night major.  Evarts fought back, tried to label the Colonel a German sympathizer, and got the Surgeon General involved.  The hospital eventually became Graham’s, but the facility wasn’t sent to Europe until November 1918, the month the war ended.  Graham was in charge during the 1917 and 1918 influenza pandemic.  It devastated the world and killed more soldiers than the enemy fire had. 

While in the military, Graham studied empyema, pus that developed in the space just outside the lungs but inside the thorax, in some people who had pneumonia.  The smelly material had to be removed but “open drainage resulted in a high immediate mortality rate.”³² Graham was part of a group that figured out the safest time to draw off the fluid.  In civilian life the infected liquid was usually a result of pneumococcal pneumonia.  It typically appeared after the infection was improving, at a time when the lung was partially attached to the chest wall by scar tissue. Drainage was safe. 

In people with battlefield wounds the pneumonia was often caused by streptococcus.  The fluid appeared early, was massive and thin “like pea soup.”  Adhesions would not form for a few weeks   When a large amount of fluid was drained too early the mediastinum, the structure that encased the heart, often shifted dramatically and the good lung collapsed.  Many died.³⁵

After the war ended, based on recommendations from doctors in Chicago, Graham was chosen to be the professor of surgery at Washington University in St. Louis, a school that was growing and reorganizing.  In the early 1900s the university had been rated as “a little better than the worst”.  After the world war it received funding from Rockefeller and Robert Brookings, a St Louis millionaire who grew rich selling wooden spoons and bowls.  The school was hiring and paying full time professors.  No longer needing a private practice on the side, doctors were salaried and could devote all their time to teaching and research.  The concept was new, but Graham embraced it, his department developed surgical subspecialties, and the school flourished. After he successfully removed a cancerous lung Graham operated on two more cancer patients.  Both died.  Then 5 in a row survived.

An avid smoker Graham “openly scolded colleagues for suggesting that cigarettes caused lung cancer. “Yes, there is a parallel between the sale of cigarettes and the incidence of cancer of the lung, but there is also a parallel between the sale of nylon stockings and the incidence of lung cancer.” Shortly before he died of lung cancer in 1957 Graham publically conceded cigarettes were responsible for his malignancy.  In 1965 his successor Thomas Burford, a heavy smoker who operated on countless smokers with lung cancer told a Senate committee that he did not believe cancer was caused by cigarettes.  His death was in part due to emphysema caused by his heavy smoking²² 

In the early 20^th century surgeons increasingly learned how to remove tonsils, appendices, gallbladders, and cancers.  Other skills and techniques were acquired while caring for the wounded in First World War.  As the century wore on operating rooms became cash cows for many hospitals. 

In 1961, during my third year in medical school I spent a week with a physician in a small town an hour drive from St. Louis.   The doctor was a friend of the family and had removed my tonsils when I was 6.  Like most general practitioners of the day he cared for common injuries, delivered babies, and performed a few operations.  People who needed complex interventions were sent to an experienced surgeon in St. Louis.  For standard operations like hernias and diseased gall bladders a surgeon came from the big city once a week and operated in the local hospital.  The visiting surgeon earned a bit of money and taught the local docs who assisted him.  They scrubbed in and learned how and when to cut into an abdomen.  They needed to know because some problems couldn’t wait.  On occasion a patient’s condition was such that he or she might not survive if their operation was delayed for the few hours it took to travel to St. Louis and find an available surgical crew and operating room suite.   

Prior to the 1950s, with a few documented exceptions, the inside of the heart and major blood vessels were off limits. 

One of the “exceptions” occurred when bullets and shrapnel entered a soldier’s heart during battle.  During the Second World War, Dwight Harken, a battlefield surgeon wrote his wife about a time he used a clamp to grasp a piece of metal deep in a heart’s ventricle.  He felt the pressure force the fragment to jump out.  It was sudden and like uncorking a bottle of champagne.  “Blood poured out in a torrent.”  Harken sewed the opening in the muscle closed and the patient survived.  He later removed bullets and shrapnel from 56 wounds “in or in relation to the heart.” 

Son of a physician who made house calls on horseback and a former prize fighter, Harken was harsh, energetic, and aggressive.  He became a Harvard professor and at one point decided to fix “rusty” mitral valves.  That’s the gate that opens and closes when blood flows from the atrium (the collecting chamber) to the ventricle (the muscular compartment that forces blood out.) The valve can become calcified and stiff.  Harken thought he could pry the area open with a finger or cut it open with a blade that he inserted through an incision in the atrium.  In 1948 he operated on 10 patients.  In the process he sometimes loosened a blood clot, it traveled to the person’s brain, and they had a massive stroke.  Six of his first ten patients died.  Harken kept at it and 14 of the next 15 patients survived¹⁹.   

The other notable “heart exception” took place in the major vessels just beyond the heart.   The fetus receives oxygen rich blood from the placenta and shunts most of it around the lung.  .  A surgical resident named Richard Gross learned how to seal a detour between the upper aorta and the pulmonary artery that generally closes by the time a newborn is 6 weeks old.  When the ductus (we still call it by its Latin name) remains “patent” it puts pressure on the right side of the heart and the baby has problems. 

In 1938 Gross was a chief resident at Boston Children’s Hospital and he learned how to close the defect in dogs.  He wanted to try his technique on a child, but his chief of service “forbade” human surgery.  Gross waited till the chief was on vacation.  Then he operated on a 7 year old girl.  The anesthesia nurse who helped him “was scared to death.” The operation had been tried at another hospital and the child had died.  Gross’ patient did well, but the chief of service was “furious.” “Some accounts say Gross was fired.”  Years later when the chief retired Gross succeeded him. 

The son of a German immigrant, Gross was blind in one eye.  He had a congenital cataract.  To compensate for his lack of depth perception his father encouraged him to take clocks apart and put them back together.  The exercise helped him develop depth perception and motor skills and it “instilled a love for tinkering.”  A cardiac innovator he once said “an academic surgeon has to pull a new rabbit out of a hat every few years.²⁰”

In 1950 president Harry Truman called heart disease “our most challenging medical problem” and federal funding started flowing.   In 1947 the NIH was spending $4 million a year and by 1950 $46 million.  A number of medical schools wanted some of that money and recruited and hired talented physicians who were ambitious and wanted to make a difference. Two of the major programs were located 90 miles apart in Minnesota.

The major defects that were tackled early were openings between the heart’s receiving chambers, the right and left atria or between the heart’s pumping chambers, the right and left ventricles.  They couldn’t be sewn or patched shut because a surgeon couldn’t see what he or she was doing when the heart was beating and full of blood.  When the “defects” stayed open blood was pushed from the left to right side with each heart beat.  The left heart muscle is more powerful than the right.  Over time the atria or ventricle on right side gets would get full, then stuffed and stretched. 

By the time cardiac surgeons started tackling the problem started John Gibbon had spent 15 years trying to build a machine that could keep the body alive when the heart chambers were empty.  To work, his pump had to be filled with a lot of blood.  It was hard to sterilize and would periodically break down.  In 1935 using his machine Gibbon kept a cat whose heart wasn’t beating alive for 20 minutes.  That made the papers.  In the 1950s he was introduced to Tom Watson, head of IBM, and Watson asked one of his engineers to help Gibbon.  Three years later the Gibbon machine kept a young woman alive long enough for Gibbon, a surgeon, to sew shut a hole between the upper chambers of her heart.  His efforts and limited success showed that much could be done if surgeons had a good heart lung machine. 

The descendent of a long line of doctors Gibbon was the 6^th physician in the chain.  As a sophomore he wanted to quit medicine and become a writer, but his father talked him out of it and convinced him to use his writing urge to promote medical research. Graduating from medical school in 1927, he was an intern when a young woman who broke her leg developed a blood clot that traveled to her lungs and killed her. He thought he could have saved her life if he had a machine that bypassed the lungs, a “heart lung machine.”  In the 1930s as a Harvard research fellow, he tried to construct such an apparatus.  Harvard gave him a small grant.  The chief of surgery, who thought the project was nonsense, gave Gibbon lab space. 

A surgeon by day, Gibbon spent his evenings “in the little room in the cellar of the Massachusetts General Hospital.”  A nurse helped him.  They were together every night, and they eventually married⁹” and moved to Philadelphia.  The machine Gibbon developed was a conglomeration of a filter from here and a pump from Michael DeBakey, a future vascular surgeon.  DeBakey’s device, designed when he was a medical student, was based on the irrigation pump developed by the Sicilian Archimedes in the 2^nd century B.C. 

When the Second World War ended Gibbon became a medical school professor in Philadelphia.  After he successfully sewed an interatrial septal defect closed in 1953, Gibbon operated on 5 kids with holes in their hearts.   They all did and Gibbon “led a movement to have Congress ban or have a moratorium on heart lung surgery for an indefinite time.  It didn’t succeed.

By the early 1950s surgeons at the Mayo Clinic and 90 miles away at the University of

Minnesota started operating on kids with congenital heart defects.  Each group used a different heart lung machine and each center suffered through the tragic deaths of a number of children. 

 The University of Minnesota group was led by Walt Lillehei, a bright talented suburban kid whose father was a doctor.  During the Second World War Lillehei accompanied the troops that landed on the Italian coast, 35 miles south west of Rome.  The Germans allowed them to come ashore then mercilessly bombarded them for four months.  Seven thousand Americans and Brits were killed and 80,000 were wounded, missing, or hospitalized.  Lillehei “saw the horrors of modern warfare” and it may have had an effect on the way he emotionally dealt with death.

In 1945 he became one of the young surgeons at the University of Minnesota.   Wangensteen, the chief of surgery at the time, was the son of an immigrant farmer.  He had a photographic memory and was the best student in each class, but he didn’t want to be a doctor.  Then his father exposed him to the harsh reality of farming.  The summer before he was scheduled to enter medical school Wangensteen spent his days hauling manure.  At the end of the summer he decided “anything would be better than this.” When fall rolled around and classes began Owen was a medical student and excelled.  

The Mayo Clinic attempt to fix heart defects was led by a young surgeon named John Kirklin.  He graduated from Harvard Medical School In 1942 and was stationed in Missouri during the Second World War.  Before returning to Minnesota Kirklin visited Gibbon, and he brought a Gibbon heart lung machine and/or its specs with him to Minnesota.  He then convinced a few engineers to help him improve it. In 1955, after 9 of 10 dogs survived the machine, Kirklin used the heart lung bypass and operated on 8 kids with congenital heart problems. 4 died and Kirklin learned what he was doing wrong. By the end of the year Kirklin had sewn closed holes between the upper chambers of the heart in 29 additional kids without another death.

            Fixing the gap between the two ventricles proved to be risky. The wiring that stimulates the pumping chambers sits on the edge of the opening between the right and left pumping chambers. When the wiring is inadvertently tied off, the heart slows and sometimes stops beating. 

The Lillehei heart lung machine didn’t always supply enough oxygen and early on  surgeons got extra oxygen rich blood by connecting the arteries and veins of the patient with those of a parent.  That put two individuals in harm’s way.  Thomas Starzl was present during one of those operations and “witnessed a tragedy.”  A parent veins were pumped full of air when a pressurized bottle ran out of fluid and no one noticed.  Her heart stopped, she was resuscitated, and she had permanent brain injury.  Ultimately she died.”  After a few cases Lillehei stopped using cross circulation.  16 of the kids he operated on had ventricular septal defects and over half survived²³. 

In the early 1950s the heart-lung pump wasn’t very good and Bill Bigelow, a Canadian Surgeon told the world about hypothermia.  Bigelow began pondering the effect of cold on a body after he cut the fingers off a man who developed frost bite, then gangrene.  He, of course, knew that some animals hibernate and survive “cold dark winters by turning down their metabolism.” One day he awoke with the thought that maybe hypothermia could be used to “decrease the body’s need for oxygen and thus allow surgeons to operate on a heart.”  Working in a basement room in Toronto he learned how to control a dog’s shivering and lowered the animal’s body temperature to 68 degrees Fahrenheit. After waiting 15 minutes he warmed the animal.  It was unharmed.  He presented his findings at a medical meeting and John Lewis, a Minnesota cardiac surgeon was inspired.^33,34.

Working with dogs Lewis learned how to safely cool the animal and clamp the vessels that supplied blood to the heart.  In 1952 he slowly lowered the temperature of a 5 year old girl who had a hole between the atria of her heart.  When it fell below 86 degrees Fahrenheit Lewis blocked blood flow to and from the organ, opened the atria, and sewed the defect shut within 5 minutes.  During the next 3 years he repeated the operation in 60 more people²¹. 

In the spring of 1958 Dr. Albert Starr was running the only heart surgery team in Oregon, and was mainly performing surgery on kids with congenital defects.  He was “up to his eyeballs” in clinical work when a 60 year old engineer with a “background in hydraulics” Miles Edwards, arranged a meeting.  They talked about an artificial heart and decided to “start” improving the heart one valve at a time.  It took two years before they were able to implant an artificial gate that opens to let blood through, then closes to prevent it from pouring back in the chamber that ejected it.  The valve was handmade and acrylic.  Later valves were made of stainless steel, and still later a non corrosive material¹⁰.    By 2018, 182,000 metal and tissue heart valves were being replaced each year in the U.S.¹¹

Periodically a technique or technology shook things up and made surgery easier or better.  Doctors slowly adjusted, and the new gradually became the norm.

In 1984 Eddie Joe Reddick, the doctor who made surgeons alter their approach, moved to Nashville.  He came “in part because he loved the music.” The grandson of an Arkansas soy bean farmer, Reddick went to medical school, was drafted, and while in the army became a trained surgeon.  As a military doc, he used a long hollow tube with a light on its end, a laparoscope, to help a colleague locate and biopsy a liver.  He learned how to manipulate the instrument.  After he was discharged, he moved to Music City and wrote country music.  (His song, “I’m Listening to Hank” made it to number 70 on the country music billboard.)

As the new guy in Nashville he struggled financially for a while, and made a little money assisting gynecologists perform laparoscopic procedures.  Early scopes that allowed us to see areas deep in the abdomen were rigid metal tubes with tiny bulbs on the end.  Gynecologists could introduce a laparoscope, and insert grasping or sewing instruments through the scope or through adjacent tiny incisions.  They would watch through a magnifying lens as they tied fallopian tubes shut, biopsied suspicious growths, checked out ovarian cysts, or tore through adhesions. In the early 1960s, older models were gradually replaced by instruments that used quartz light rods.  A few decades later, video chips on their tips allowed surgeons and their assistants to see what was happening by studying TV monitors.  

In 1988 Reddick met a Georgia surgeon named McKernan at a medical meeting, and he was intrigued by his fellow doctor’s plan to remove a gall bladder using the laparoscope.  A few months later, McKernan found a willing patient and would have become the first American to remove a gall bladder through a tiny hole, but the stone in the “bile bag” was big, and McKernan had to make an incision to get it out.  Two days later, this time in Nashville, Reddick used a laparoscope. Assisted by a scrub nurse he excised a diseased gall bladder and pulled it out through the tiny hole.  He cut through tissue with a laser, and didn’t use a needle and thread to tie off the cystic duct and artery.  He clamped them shut with a homemade clip.  The patient recovered and went home in short order. 

People obsessed with detail are quick to point out that the two southern doctors were not the first to remove a gall bladder laparoscopically.  A surgeon in Germany named Muhe removed one in 1985.  His patient died post–operatively and there was a subsequent legal hassle.  Two Frenchmen removed gall bladders by this technique in 1988, but their colleagues apparently didn’t think it was a big deal, and they temporarily ended their venture. 

Reddick’s patients by and large got well quickly, and his complication rate was low.  He had the touch, the knack, the hidden quality that makes some surgeons really good.  But he didn’t come from a big medical school, wasn’t a professor, and I suspect he was looked down on by the men who gave lectures and wrote books.  Reddick published his results and wrote about the successes of McKernan and a doctor named Saye.  At a medical meeting the following September, he gave a talk and played a three-minute video of a gall bladder being removed laparoscopically.  In subsequent months, surgeons were invited to his O.R. to watch and assist.  A few came.  Some of the surgeons at his hospital were nervous and “urged that he not be allowed to perform the procedure,” but the hospital review board gave him the green light. 

Someone alerted the media.  The Wall Street Journal wrote an article about the medical maverick, and ABC World News ran a story that was seen by millions.  At a subsequent surgical meeting, a few instrument companies ran tapes of his surgeries in their booths, and crowds of doctors gathered around.  Then Reddick and Saye opened a training center in Nashville for doctors who had long since completed their formal training.¹

As skills grew and people recovered from their operations relatively quickly, surgeons increasingly removed stone–filled gall bladders that may or may not have been causing problems.  Within a few years, twice, then four times as many of the muscular sacs were excised annually.  Over the subsequent 20 years, surgeons learned to perform a slew of additional operations laparoscopically.  Inflamed appendices were removed, hernias were plugged from the inside, and cancer containing portions of colon were resected.  Renamed minimally invasive surgery, the approach was used to treat heartburn that was caused by the reflux of stomach juices and hadn’t responded to pills.  It was long known that the problem could be controlled by wrapping the upper stomach around the esophagus, but a surgeon had to get his or her hand into the narrow space under the rib cage.  Access was difficult, and the spleen (which was often in the way) was sometimes damaged.  The laparoscope made the procedure safer.  The minimally invasive approach was also used to turn many a large stomach into a receptacle the size of a shot glass, and to thus help obese people lose weight. 

Chest surgeons increasingly used scopes inside the thoracic cavity to identify and biopsy abnormalities, to remove parts of a lung or pleura, and to perform a number of procedures on the esophagus, the swallowing tube that runs through the back of the chest.  Problems that used to require a long incision and spreading of ribs could often be solved with VATS, –video–assisted thoracic surgery. 

Using a similar rigid scope and a camera, orthopedists entered knee joints without damaging the surrounding muscles and ligaments.  They repaired torn internal ligaments and injured cushions (menisci).  Some used the approach to mend torn shoulder rotator cuffs and to patch tears in the cartilage that lines the rim of the shoulder joint—the labrum.

Back surgeons call surgery performed through a small incision using a scope with a camera on it–minimally invasive surgery.  They are sometimes able to employ the technique to remove herniated discs and fuse vertebrae.  A few years back I had sciatica.  The pain was in the left leg and was caused by pressure on the nerve that traversed the space between my 4^th and fifth lumbar vertebrae.  The MRI showed a cyst was causing the problem.  A back surgeon inserted a scope, removed the cyst, the pain disappeared, and I went home. 

Ear, nose, and throat surgeons who wanted to visualize and remove head and neck tumors had approached growths with incisions made in the chin or neck.  Over time, they learned to put a thin video endoscope through the mouth and advance it until they saw the enemy.  Jaws were only “cracked” when a tumor had invaded.  Called “small field” surgery, the approach allowed experts to destroy tissue and control bleeding with cautery or the beam of a laser.  After a growth was removed, the remaining tissue was biopsied and pathologists could tell if cancer cells were left behind.  Less blood was lost, and vocal cord function was preserved.

Fiber optic and later video endoscopes and colonoscopies were used by gastroenterologists.  They allowed ENT doctors to better evaluate vocal cord paralysis and other benign laryngeal problems.  Plugged sinuses could be opened and debris sucked out.

Neurosurgeons used scopes to remove pituitary tumors.  The gland they tackled is normally the size of a grape; it hangs below the brain in a “bony hollow in the base of the skull.” Some of the organ’s small tumors produce hormones that cause harm in dramatic and weird ways.  Before a local neurosurgeon entered a patient’s skull, my ENT colleague would “shove” his scope through the nose and breech the wall between the adjacent sinus cavity and the brain.  The abnormal pituitary growth usually looked like the top of an ice cream cone.  A neurosurgeon would take over and remove all or part of the gland piecemeal.   

A company called Di Vinci developed flexible small internal robotic hands whose actions could be monitored through a three–dimensional viewer.  Surgeons maneuvered the appendages remotely, using external, space age, knob-dial–fingers.  Those who mastered the approach claimed their resections were more precise.  The technique required a person to visualize tissue a little differently, and there was a learning curve. 

Medicine, like industry, has innovators who can mentally visualize the “possible” and find a way to make it happen.  In 1964 Michael DeBakey a Houston doctor used a vein from a person’s leg to create a tube that bypassed a narrowing in one of the coronary arteries.  The vein allowed blood from the aorta to circumvent the diseased vessel.  He didn’t report it to the medical community until 1973, when he could prove the graft had remained patent.⁹“

“You learn on animals.  We did hundreds of bypasses on dogs and were 50% successful.  The first coronary bypass was an accident.  The patient was scheduled for an endarterectomy, separating the plaque (the deposit of cholesterol and fiber) from the inner lining of a diseased vessel.  We’d been doing the operation since 1964.  The nature of the first patient’s coronary artery blockage was such that we couldn’t separate the plaque.  His coronary arteries were so bad that we couldn’t get him off the table (and expect him to survive.)  So we did what we had been doing in dogs.  It was the first heart bypass. Fortunately it worked.  You have to take risks.  The first carotid endarterectomy was done on a man with recurrent episodes of temporary paralysis —TIA’s.  The carotid artery supplies blood to the brain and his artery had plaques.  He was a bus driver.  Surgery stopped his TIA’S. He lived for 19 years and died of a heart attack.  The first aneurysm of the aorta in the chest was causing pain.  We knew how to fix aneurysms in the abdomen and the man was hurting so he took the risk and agreed to surgery.¹³”

DeBakey virtually created vascular surgery.  The son of Lebanese immigrants and a combat surgeon during the Second World War, he “convinced the surgeon general to form what would become the mobile army surgical hospital MASH unit.”  Later, as a Baylor University surgeon, he revolutionized our approach to narrowed blood vessels.  “In 1953, he performed the first successful carotid endarterectomy;” (he cleaned out one of the arteries that supplied blood to the brain.) 

As a youth he liked working with his hands. He and his brother took apart car engines and reassembled them. His mother taught him to knit and sew and “By the age of ten he could cut his own shirts from patterns and assemble them.¹⁴”

He later used his boyhood skills to create a vascular graft from Dacron.   As he said in an interview: “When I went down to the department store … she said, ‘we are fresh out of nylon, but we do have a new material called Dacron.’ I felt it, and it looked good to me. So I bought a yard of it. … I took this yard of Dacron cloth, I cut two sheets the width I wanted, sewed the edges on each side, and made a tube out of it. .. . We put the graft on a stent, wrapped nylon thread around it, pushed it together, and baked it. … After about two or three years of laboratory work (and performing experiments in dogs), I decided that it was time to put the graft in a human being. I did not have a committee to approve it. … In 1954, I put the first one in during an abdominal aortic aneurysm. That first patient lived, I think, for 13 years and never had any trouble.²”  

Years later as a medical student at Baylor, TV doc Gabe Mirkin recalled that Debakey liked to visit the patients he had recently operated on at 5 AM.^{16  “}He often was accompanied by an entourage of more than 50 people composed of medical students, surgeons-in-training and some of the most famous surgeons from all over the world. Mirkin “saw first-hand his incredible drive for perfection. As medical students, we would often study at the medical school through much of the night, and I saw the light at his office stay on as he wrote papers often beyond 3:00 in the morning.”²⁷ 

Three years after his first wife died, the 67 year old surgeon met and married an attractive 33 year old German woman “who dabbled in acting and painting.”  When the pastor performing the ceremony asked if Debakey preferred to sit during the ceremony his bride said “he stands for hours for his operations.  He’ll stand for this.”  Debakey performed over 60,000 operations in his lifetime and became a surgeon to the stars.  His patients included the Duke of Windsor and the Shah of Iran. 

The transplantion of one person’s organs into the bodies of another is a story of surgery, immunosuppression, and delivery of care.  It’s in the game changer chapter.

Many of the tasks of general surgeons are now performed by interventional radiologists.  Over the last half–century our ability to see structures within the body increased dramatically.  X-ray doctors who call themselves “Interventionalists” use the fluoroscope and drain pockets of fluid, biopsy shadows that look like tumors, pass catheters through blood vessels, and perform complicated procedures that halt or prevent blood loss. 

Some interventionists perform TIPPS in people with cirrhosis and stretched out esophageal veins that bleed.  The livers of these individuals are scarred; blood from the intestines can’t flow into or through them, and the vessels that carry blood around the organ enlarge and can leak or rupture.  To decompress the situation, trained radiologists create a tunnel through the liver. 

Cataracts, cloudy eye lenses, are now removed and replaced with artificial implants in 6 to 14 minutes—then people go home.

Knees are resurfaced; hips are replaced- and people with the new joints walk out of the hospital the same day.

Video scopes allow gastroenterologists to screen colons and stomachs, to biopsy or remove abnormalities, control gi bleeding, remove bile duct stones, remove foreign bodies—and much more.

Our approach to combat injuries has changed.  In a recent war, surgical teams—surgeons, nurses, and medics, traveled in Humvees directly behind the troops.  When a soldier was wounded they would “focus on damage control, stop bleeding from the liver with sterile packs, staple perforated bowels, and wash out dirty wounds.”  Since blast injuries can cause bleeding from multiple locations, they would cut the abdomen open, pack areas at risk, and cover the area with saran wrap. When the surgeons had done their best–and always within two hours–the injured were flown by helicopter to a hospital less than an hour from the zone of combat.⁴

Worldwide “about 234 million operations performed annually.⁵

 ”44,000 and 98,000 patients die each year in the United States as a result of preventable medical errors. “Adverse events in surgery account for between one-half and two-thirds of all such events in hospitals and half are potentially preventable.”⁸

In 2007 Atul Gawande, a Harvard surgeon, wrote an article that promoted the use of checklists before during and after surgery.  He pointed out that even surgeons who are super-specialists sometimes neglect small details.   The idea of a directory of procedural steps had previously been developed by the aircraft industry, as a result of crashes that were caused by a minor oversight. ⁶ 

In 2008, the World Health Organization (WHO) published a 19-item checklist intended to be globally applicable, and hospital operating rooms became even more compulsive.  Are antibiotics or blood available?  Did we mark the breast or limb that we’re going to operate on? 

Between 2007 and 2008 the WHO checklist was used in 3733 surgeries in 8 hospitals in Canada, New Zealand, the U.S., England, India, Jordan and the Phillipines. The death rate fell from 1.5% to 0.8%, and inpatient complications decreased from 11 to 7 percent.⁷ The checklists, however, did not make a detectable difference in hospitals in Ontario Canada. They are increasingly being required by governments in certain U.S. states and in various countries, and they were mandated by the U.K. National Patient Safety Agency in 2009.⁸

A medical educator interviewed by Atul Gawande asserted the innately exceptional surgeon, the doctor who, as a trainee, can figuratively “see one, do one, and teach one” is pretty rare. For the vast majority competence is not the result of a God given skill.  It’s the result of diligence and by young doctors who keep practicing difficult tasks.    

And (Gawande again) “while the best possible care is more important than teaching novices, everyone is harmed if no one is trained.”  Not surprisingly in “teaching” hospitals, the poorest, the uninsured, and the demented” are disproportionally the responsibility of surgical trainees. That’s how it always was and still is.

CHAPTER 11  CHILDBIRTH

I was in the delivery room for his final performance–the last time an obstetrician named Bill Masters, a doctor who would go on to become a world famous sex specialist, helped a child slide through a woman’s birth canal.  I don’t remember the baby’s sex or weight or its mother’s glee.  But I remember Masters presenting the newborn to its mom with the flourish of a circus maestro, and I recall my fellow med student fainting. His wife was pregnant.

As a junior in medical school I spent three weeks catching babies at Homer G. Phillips, the black public hospital in North St. Louis.  I and my fellow student were the only white guys in the facility.  Napping in a sleeping room on the second floor we were periodically awakened by a nurse yelling “don’t push—don’t push” as the creaky elevator carrying the almost-mother slowly whirred upwards.

Shortly after my grandmother was born her mother died.  In her day death was common when childbirth was complicated by “post partum bleeding, or infections” or when the baby was unable to get through the pelvis.

The U.S. has the unenviable honor of having the “highest rate of maternal mortality in the industrialized world.” —17.8 per 100,000 in 2009.  It’s especially high for African American women.⁶

The global maternal death rate has decreased by 44% in the last 25 years, but each year in the world’s 24 poorest countries, 400 women die for every 100,000 live births.  In recent decades most western countries have cut their death rates in half; in the U.S. the number of women dying almost doubled.  In California focused healthcare significantly helped reduce the mortality rate. ⁵

Throughout recorded history women “midwives” have assisted other members of their sex give birth.  In the late 1800s and 1900s physicians, virtually all of whom were men, moved in and took over.  In 1915 40% of all births were attended by midwives and by 1935, 20 years later, close to 90% of births were performed by male physicians.

In the U.S. Thirty three percent of children are delivered by C-section. (9% of the women who give birth this way had prior C-sections.)  The nurse midwife who brought me up to date explained that in her practice about seven percent of women are delivered by C-sections and only one in 400 women require an episiotomy, and incision to widen the birth canal.

Giving birth vaginally is usually painful and half of the deliveries performed by the midwife I consulted had epidurals.  A derivative of Novocaine is infused into the space outside the lower end of the spinal canal.  The drug usually controls the pain of child birth. When a physician delivers the frequency of an epidural nears 95%.

C-sections carry the risk of bleeding, infection, and of nicking the bowel and bladder. ⁷ When the mother has active vaginal herpes or the infant would have to come out feet or bottom first, vaginal delivery brings with it an extra possibility of harm that usually more than justifies the approach.  But that’s not the reason for the “worldwide explosion.” In Mexico City C -sections are performed for 45% of births.⁷   In China the C-section rate was 35% in 2014.

At $10-15,000 a try, in vitro fertilization (and other forms of assisted reproductive technology) led to the birth of a million babies between 1987 and 2015.  The Center for Disease Control keeps track of successful births after 37 weeks of single, live, normal weight children.  The number depends on factors such as: was the embryo fresh or frozen?  Did it come from donor or non donor eggs?  How many attempts were made? and how old was the woman?¹³  Under ideal conditions the process is successful, per attempt, 21% of the time.⁴

Before Obamacare became law, pregnancy was commonly classified as a pre existing condition.  Medicaid picked up the bill if the woman was sufficiently “low income”.  But some of the uninsured earned a bit too much.   After 2010 expectant women could purchase insurance and they couldn’t be charged more because they were pregnant.  If they wanted marketplace coverage they had to “enroll in a health plan during the open enrollment period, set by either the employer or the feds.”

During the first seven years after the ACA (Affordable Care Act) became law 13 million pregnant women “gained access to maternity services.”  Medicaid expansion played a role. (Medicaid also covered “contraceptive supplies, sexually transmitted infections, and “screening” for sexual violence and breast and cervical cancer.”) ^1,2

In 2006 the 4.3 million births in this country rang up a bill of $14.8 billion.  A vaginal birth in 2010 was costing between $5000 and $7000; C sections went for about $10, 000. 

The care of low and very low birth weight infants contributed another $18.1 billion to the birthing price tag.  Modern doctors have the incredible ability to keep not-quite-ripe small infants alive, and premature newborns account for half a million of the live births in this country.  Some of these kids spend weeks in neonatal intensive care units at a cost, nationwide, of $26 billion.  That turns out to be “about half of all the money hospitals spend on newborns.” 1.7 percent of newborns weighed less than a thousand grams when born and one half of one percent were under 500 grams.  Eighty five percent of the infants “survived to be discharged from the hospital.”^3.

Prenatally doctors and nurse midwives check pregnant women for diseases that can be transmitted to their new born–infections like HIV and hepatitis B.   Obstetricians checking for fetal abnormalities usually perform the first fetal ultrasound when a woman is 18 to 20 weeks pregnant. Screening tests are also performed for genetic and developmental problems.  The second decade of the 21^st century saw the emergence of blood tests that analyze fragments of placental DNA floating in the mother’s blood.  Fetal DNA and placental DNA are identical.  By pregnancy week 10 the level of fetal DNA in the blood of the pregnant woman is usually high enough to perform an accurate test. The studies look for chromosomal abnormalities and they aren’t perfect. The alternative, amniocentesis, is “invasive” and can induce a miscarriage one half to one percent of the time.  Near birth ultrasound exams are performed to check the baby’s position and detect problems like placenta previa, a situation where the placenta covers the opening of the cervix and prevents a normal birth.

The fear of malpractice haunts the birthing profession.   Childbirth mishaps, mistakes, and bad outcomes still account for close to 10% of all malpractice suits, and the amount awarded to injured children can easily be a million dollars or more.  It takes an immense amount of money to care for a damaged child for 80 years.  Not surprisingly the malpractice insurance rates for gynecologists are among the highest.  (see malpractice.⁹)

For a period of time health insurers were overly aggressive in their attempt to get women out of the hospital shortly after they gave birth.  Congress reacted.  The Newborns’ Act was signed into law on September 26, 1996.  It includes important protections for mothers and their newborn children with regard to the length of the hospital stay following childbirth.  (HMOs) that are subject to the Newborns’ Act “may not restrict benefits for a hospital stay in connection with childbirth to less than 48 hours following a vaginal delivery or 96 hours following a delivery by cesarean section.”

There are about 40,000 Ob/Gyn physicians in the U.S. When I graduated medical school (1962) most were men.  In their early years in practice they delivered babies.  As they and their cliental aged the doctors spent an increasing portion of their time tending to the organs of conception.  That’s changed.  By 2001 seventy two percent of the residents in the subspecialty were women.  During the last 35 years our local medical school, the University of California in San Francisco, trained and deployed hundreds of nurse midwives some of whom practice at local hospitals.  The safety of home deliveries on low risk women by nurse midwives has been documented time after time, but this approach still accounts for less than 30,000 of the babies born in the U.S. each year.

In addition to caring for women during the birthing years, gynecologists have traditionally been the primary care physicians of many otherwise healthy women as they age.  Among other things these physicians pay a lot of attention to the organs of conception.

Cancer of the cervix is “worldwide the third most common malignancy in women.”  It’s much less common in this country (11,000 cases a year) because many women have regular “Pap smears.”  It’s a test that was developed by a New York cytologist named Georgios Papanikolaou.  A Greek who finished medical school in Athens in 1904 then served in the army, Papanikolaou decided early that he wanted to be a researcher.  He was 30 when he and his wife Andromache came to the U.S.  They didn’t speak English and “had little money.”  She got a job as a button sewer for a department store and he tried to sell rugs.  His job only “lasted a day.”  He ended up earning money during his first year in the country playing a violin in restaurants.  Then he got a job in the anatomy department of Cornell Medical College.  His wife was hired as his assistant.¹² Using Andromache as a subject he studied the appearance of cells from the lower part of the uterus, the cervix, and he noticed cancer cells looked different.  When he brushed, stained, and evaluated tissue that the end of the uterus was about to shed, he sometimes found “bizarre” changes that indicated a cancer was present.  It took years till his findings were accepted, but he eventually was able to teach doctors to recognize changes that indicated part of the cervix was almost, but not quite malignant.¹⁰ 

Responsible for over 33,000 cervical and vaginal cancers annually in the U.S., human papilloma virus is sexually transmitted and usually causes no symptoms.  Most infections clear within two years, but 14 million Americans are infected annually and 80 million are, at least temporarily, sexually “contagious.”  In 2014 the FDA approved two shot vaccine that effectively prevents the disease.  It works best when it’s given to young women before they are likely to be sexually active, and it covers genotypes 16 and 18 (responsible worldwide for 70% of cervical cancers) and 4 additional genotypes that account for 20%.¹¹

Some parents feel that by immunizing their daughters they are saying we assume you will become sexually active, and that’s a message they’d rather not send

Early on the tools of the GYN trade relied on feel and a speculum.  The uterus and ovaries were felt by trained fingers in the vaginal canal pushing up towards and equally aware fingers on the abdomen pushing down.  When the exam was painful or the woman was large or tense the exam had limited value.

Shadows of the uterus and ovaries are now sometimes visualized using an abdominal ultrasound, a CAT scan, or by placing an ultrasound probe into the vagina and watching a T.V. screen.  The probe charge, in one location (chosen randomly on the Internet), is $200 per exam. I don’t know if insurance companies will pay for the test in the absence of a clear indication. It has not, best I can tell, become “routine”, though actress Fran Dresher and others thinks it should be.  The $6.5 million dollar bill President Bush signed in 2007 “authorized the development of a national gynecologic cancer awareness campaign” but did not mandate screening vaginal ultrasounds.

Gynecologists have long evaluated the inside walls of the uterus with an operation known as a D and C.  They dilate or stretch the cervical area. Then a sharp instrument is placed inside the uterus and the lining cells are scraped off, collected, and examined under a microscope.  The main indication for the operation is unexplained uterine bleeding which could be caused by cancer of the inner lining wall of the uterus. Nowadays there’s a thin narrow scope that can slip into the uterine cavity and allow doctors to look for abnormalities.  In this country hysteroscopy is usually performed in anesthetized patients.  In Australia and elsewhere it’s sometimes performed with light sedation and numbing agents.

Finally the gynecologists were pioneers in the use of a tiny incision and a laparoscope (see surgery) to evaluate ovaries, treat cysts, or tie fallopian tubes so a woman could avoid pregnancy.

Gynecologic surgery is a relatively large ticket item.  In this country 600,000 women have hysterectomies annually.  180,000 (30%) of the operations are done for “fibroids” benign growths that can cause symptoms.⁸Some hysterectomies are performed in an attempt to reduce or eliminate lower abdominal pain.  The discomfort is sometimes caused by endometriosis, a condition where the kind of tissue that normally lines the inner wall of the uterus is growing elsewhere in the pelvis. Abnormal cells are sensitive to female hormones and can bleed when women are having a menstrual period.  The condition is the alleged cause of the discomfort suffered by millions.

Close to ten million women “have trouble controlling their bladders.” Surgery in addition to medication and pessary (a flexible device that’s placed into the vaginal canal) sometimes helps.  Operations also treat prolapse, a condition where a uterus, stretched by prior child birth, drops into the vagina or bulges into the bladder or rectum.

Finally the fear of ovarian cancer leads to a lot of testing.  This is a real and worrisome condition, but it’s not on the rise.  By age 30 it strikes one in 15,000 and by age 60 afflicts no more than one woman in 1500.   It’s hard to detect at an early stage and benign ovarian cysts found on an ultrasound commonly lead to a number of additional exams and a modicum of anxiety.  Given our current system and abilities, experts tend to discourage routine screening.

Chapter 12—sight

 

Blind as a bat– -Better than a poke in the eye—–

During the last one and one half centuries we’ve learned how to treat or correct most of the conditions that inhibit our ability to see.

One of them, Trachoma, has been a problem for mankind for thousands of years.  Hippocrates thought it made eyelids, look like cut ripe figs.  During the Napoleonic wars, it “raged” through the armies of Europe; and over the centuries it often occurred in clusters within villages or families.¹¹ Caused by a Chlamydia, a type of bacteria that lives and reproduces inside the cell of the host, it leads to scarring of eyelids, and causes eyelashes to damage the cornea.  Antibiotics kill the bug, but it tends to recur.⁹    The number of people who currently have “the late blinding stage of the disease dropped to 2.5 million in 2019.” 

The prevention of river blindness remains another work in progress. Found chiefly in parts of Africa, the condition is caused by a tiny parasite and is spread by black flies that “breed in fast flowing streams.” In the 1990s The African Programme for Onchocerciasis Control (APOC) successfully treated more than a million at risk people with the anti parasitic drug Ivermectin, and it made a significant difference. Globally, it is estimated that 18 million people are infected and 270,000 have been blinded by the condition.  It’s called onchocerciasis.⁶”

There’s little available data on infants who survive wars, droughts, suffer from malnutrition and develop a vitamin A deficiency.  The resulting dryness and scarring of the conjunctiva, the mucous membrane that coats the inside of the eyelids, can cause them to lose their ability to see.¹

The leading causes of blindness in this country are cataracts, glaucoma, macular degeneration, and diabetes.⁵

Cataracts:  To create a sharp image the eye like the microscope and the telescope needs two lenses. Cataracts occur when the eye’s inner lens becomes cloudy and opaque.  Most develop slowly as we age, though they are sometimes seen in children for a variety of reasons.  Worldwide they diminished vision in many and are the leading cause of blindness.   

A century ago when a person’s lens got so dense that they couldn’t see, the structure was surgically removed.  Afterwards a person could see light and little more unless they wore thick glasses.  No on liked wearing Mr. Magoo glasses, and everyone hated feeling helpless when they woke and couldn’t locate their spectacles.  I remember the days when people didn’t have cataract surgery until they were literally no longer able to see.  The lens removal operation is, apparently, still done in some countries.

Harold Ridley of England is the father of the implantable lens.  The son of a physician he spent his early doctoring days working on cruise ships.  During the Second World War he spent 18 months in Ghana.  Later in Burma, he provided care for former British prisoners of war who had nutritional amblyopia, lazy eye. At some point he treated members of the RAF whose airplanes were damaged by enemy fire and whose cornea’s, the front lens of the eye, had been penetrated by pieces of the plane’s windshield.  The acrylic plastic did not cause an inflammatory reaction. Years later, he was removing a cataract and he recalls that one of his students remarked: “It’s a pity you can’t replace the cataract with a clear lens.” That got Ridley thinking.  He started crafting implants from the material that was used to make airplane cockpits and he implanted them into eyes after he removed an opaque lens.” “Sterilization of the lenses was a major problem and he was afraid to tell anyone.  Powerful colleagues had shown hostility to the idea of putting a foreign body in the eye.¹⁰

There was a learning curve but Ridley and a pupil perfected the surgical technique and a company in East Sussex (Rayner) manufactured the implant.  In 1981 the FDA approved the use of implantable lenses in the U.S. and American eye surgeons adopted the approach.  It’s now part of the bread and butter of ophthalmology. 

The last 50 plus years have witnessed the development and modification of many replacement lenses.  By 2015, 9000 American ophthalmologists were replacing 3.6 million lenses a year.  Worldwide 20 million cataract surgeries are performed annually.²            

In the U.S. most surgeons numb the eye, insert a small ultrasound probe, and phacoemulsify (liquify) the dense lens.  Then they suck out the debris, insert a small plastic or silicone lens, and if necessary, sew the incision shut.  My ophthalmologist at Kaiser Oakland told me she doesn’t specialize in cataract surgery.  The eyes she deals with often have additional problems.  So on her surgical half days she only performs 9 operations.  Each takes 6 to 14 minutes.  The complication rate for Canadian surgeons who performed 50 to 250 operations a year was 8 in a thousand.  It was one in a thousand for surgeons who replace a thousand cataracts a year.  In poorer countries phacoemulsification is less common.  Most Americans who need cataract surgery are of Medicare age and the government pays $2500 per eye.  Special lenses can cost an extra $1500 to $2500.  

In India, a land with over a billion inhabitants, cataract surgery took a giant step forward in 1983 when an American Doctor named David Green met a 58 year old eye surgeon named Govindappa Venkataswamy.  When they reconnected 5 years later the Indian physician had mortgaged his home, built an 11 bed hospital and was performing 5000 eye operations a year, 70 percent of them at no charge.  Given the need he was barely scratching the surface.  In the late 1990s it was estimated that 9.5 million people in India were blind as a result of cataracts and 3.8 million were losing their vision annually. The cost of implantable lenses, $100 to $150 per eye was too high for the average Indian. Green and the doctor established a nonprofit manufacturing plant in India and were able to produce an inexpensive quality lenses.  In 2016 the company they founded, Aurolab, manufactured 2.6 million intra ocular lenses, 10% of all produced in the world.  The majority of the lenses are “distributed to NGOs in India and in developing countries.” The company is profitable.
          In 1999 doctors in India performed 1.6 to 1.9 million surgeries in a single year and plans were made to increase the numbers of operations that would be carried out. By 2006 cataract surgery in India, Nepal, and Bangladesh was costing $20 and the lens sold for less than $5.³

Glaucoma:  Often caused by elevated pressures in the eye, Glaucoma is a number of conditions that damage the nerve that transmits images from the eye to the brain. The dramatic, painful eye of angle closure glaucoma is a medical emergency and can lead to visual loss. It occurs relatively infrequently. Open angle glaucoma, on the other hand is relatively common. Experts have learned a lot about the more usual condition, but we don’t know what causes it, and it’s no longer defined merely as a condition where the pressures inside the eye are too high–though they commonly are.  The middle of the eye produces a watery aqueous fluid.  It flows through the pupil, enters the space in the front of the eye, and exits through the spongy tissue that surrounds the edge of the cornea.  In people with the condition fluid is over produced or doesn’t drain normally. The retinal nerve layer thins. People lose peripheral vision and eventually can substantially lose much of their ability to see.

In the western world some ophthalmologists spend a year or more becoming glaucoma specialists.  They learn how to carry out and interpret tests, and when and how to perform one of many operations.  Sophisticated machines allow experts to photograph and follow the appearance of the layers of the retina, the nerve rich stratum that collects the focused light that our brain turns into images.  Gadgets that detect early loss of peripheral vision and that measure the pressure in the eye have entered the digital era. 

The drugs that control the pressure in the eye include beta blockers and prostaglandin inhibitors. Beta blockers cause the eye to produce less fluid and Prostaglandin inhibitors promote drainage. In 2004 when the FDA gave Pfizer the exclusive right to the prostaglandin inhibitor Xalatan, they sold $1.23 million worth of the drug.  Before a generic competitor entered the U.S. market, a month’s worth was costing $80 a month.  Pfizer manufactures and sells its products worldwide and has 43 manufacturing plants in: Ireland, Puerto Rico, the U.S., UK, Germany, Amboise, France; Ascoli, Italy; Belgium and Perth, Australia. 

According to the World Bank, “almost half the world’s population — 3.4 billion people — live on less than $5.50 a day.  For them eye drops aren’t an option. Laser surgery can increase the outflow of fluid.  If that doesn’t work an older operation called a “trabeculectomy”, removing a bit of the mesh network the fluid pours through, can create “a new drainage path.”  In 20 percent of the people who undergo surgery the openings stop working during the first year and two percent fail each year thereafter.¹⁵

Researchers checked the records of 113 Brits with open angle glaucoma who failed their last glaucoma appointment due to death.  They had been followed for 7 to 25 years.  During those years about half had undergone surgery for cataracts and 45% for glaucoma. “At final visit, vision was inadequate for driving in the UK in close to half. In 18%, this was due to glaucoma alone, while in 28.9%, other ocular pathologies contributed to poor vision.¹³”  

AMD, age related macular degeneration, is a major cause of vision loss as we get older.  Something goes wrong in the layer under the retina, and the macula, the part of the eye that provides sharp, central vision, is damaged or destroyed.  The so called “dry” form of the disease mainly affects white people who are 80 or older and we have no effective treatment.                

The less common “wet” form of the disease is sometimes helped by laser coagulation or photodynamic therapy and is commonly treated with Avastin, an antibody that “blocks” the growth of the new blood vessels.  When an ophthalmologist injects the medication into the eye of someone with wet macular degeneration, the disease process slows or turns off.  “Blindness is prevented in most patients, and the majority of treated patients go on to have some improvement in vision.”

Before using it the doctor evaluates the patient.  He or she discusses the risks of injecting the drug, and explains downsides like bleeding and retinal detachment.  On the appointed day the patient is brought to the procedure room and checked.  The edge of the eye is injected with a numbing agent.  A second needle is then passed into the inner cavity of the eye, a chamber full of a gelatinous material known as the vitreous.  The medication is injected and the pressure in the eye is raised for a brief period of time.  Vision is temporarily blurry.  After a period of observation the patient can go home. 

A law caps the amount a U.S. doctor can charge for an Avastin injection.  It can’t be more than 6% of the drug’s price.  The small amount needed to treat an eye had a cost of $50, so the fee Medicare paid for the injection and observation was capped at $3.

Avastin was FDA approved as a drug that slows the growth of cancer.  When the FDA approves a medication for one indication (cancer), the company that produces and markets it is not allowed to talk about other possible ways the drug can make a difference.  Doctors who read the medical literature and learn a drug helps an additional–different condition, do have the legal right to use it for that condition. The doctor does not have to wait for the drug company or the FDA to act.  In spite of the economics eye doctors were injecting Avastin into the eyes of people with wet macular degeneration.  In 2006 the FDA approved a biosimilar, Lucentis.¹⁷ It was an almost identical antibody.  It blocked the growth of blood vessels, was made by the same company as Avastin, and it worked as well.  In 2014 the company was selling it for over $2000 a month, and doctors who used it in their office were able to charge $180 for the visit and the injection.¹⁶

Refractory problem:  At some point in most of our lives we can’t see well because our eyes are unable to focus light on the layer of cells at the back of our eyeballs, the retina.  Some people are born with refractory errors.  Others find it increasingly difficult to read small print after they turn 40.  Wearable eye glasses have been used for many centuries. 

In the 1950s people started correcting their vision by placing a thin lens on the surface of their eye.  Contact lenses were initially small and had to be removed at night.

In 1965 Bausch and Lomb, bought the rights to contact lenses that were soft and were created in the kitchen of a Czech chemist.  Once they owned the product’s license the once American, currently Canadian company started a billion dollar industry.¹⁴

The man who developed the lens, Otto Wichterle, was a Czech dissident who was jailed by the Nazis in 1942.  In 1958 he lost his University job because he criticized the country’s Communist government. 

Once he was fired he continued his work on the kitchen table of his Prague apartment.  He used an instrument made from a child’s building kit (similar to an erector set) and a phonograph motor, and he produced four hydrogel contact lenses.¹⁷  When he put them in his own eyes they were comfortable.                  Ever a protester, Otto was expelled from the nation’s chemistry institute in 1970 because he supported Czechoslovakia’s attempt to become independent of Russia—the Prague Spring of 1968.  When the cold war ended Otto resumed his scientific activities.  In 1962 he patented his invention and produced an additional 5500 lenses.  At one point he met and learned to trust an American optometrist named Robert Morrison.  When he was harassed by patent attorneys Otto asked Morrison to come to Prague.  “Wichterle said, “Robert, I have decided that I must give patent rights to the gel to someone who can use them in the Western Hemisphere and, perhaps, in some other areas as well.¹⁸”   Ulitmately the US National Patent Development Corporation (NPDC) bought the American rights to the lenses from the Czechoslovak government for $330,000.  Then they sublicensed the patent to the Bausch and Lomb Corporation.  Wichterle was paid less than 1/10 of 1 % of the money, but he was now free to speak and travel and he had no regrets. 

In 1989 Gholam A. Peyman, an ophthalmologist and inventor patented Lasik, a laser and computer assisted device that allowed doctors to peel back a flap of the outer skin of the cornea, the front lens of the eye.  The inner corneal layer could then be altered with the beam of a laser, and eyes could focus better.  At the end of the procedure the flap was replaced.  The inventor, Dr. Peyman, was born in Shiraz Iran and went to medical school in Germany.  He’s a constant innovator and has held more than 100 patents.  In 2010 it was estimated that 8 million Americans have undergone the Lasik procedure at a cost of about $2000 per year.

Finally, no sooner is one problem solved than a new one develops.  In a country where the incidence of obesity is increasing as a result of our high caloric diets and diminished activity, more and more individuals become diabetic.  People with longstanding diabetes develop a number of eye problems and can go blind. 

By 2010 close to 7 billion people lived on earth and about 32 million, one in 200 were blind.  An additional 191 million, one in 40, were visually impaired. 

Blood sugars usually have to be elevated for ten to 15 years before blood vessels on the surface of the retina become permeable and weepy and the amount of oxygen that reaches the cells of the eye decreases.  New vessels, signaled by VEGF, grow and impair eyesight.  “Left untreated, nearly half of eyes that develop proliferative diabetic retinopathy will have profound vision loss.”

Lasers are used to destroy the blood vessels that are overgrowing.  Sometimes the antibodies that block VEGF, the hormone that encourages new blood vessel growth, are injected into eyes.  In 2020, the Medicare paid $1000 to $1800 a session for the VEGF inhibitors that were FDA approved for use in the eye. 

Chapter 7.  THE IMMUNE SYSTEM

• Tutorial: Our skin and intestinal track create barriers that protect our bodies from a world full of bacteria viruses, and the other microscopic creatures. 
• Immune cells float through our blood and lymph and identify, imprison, and destroy invaders. 
• In the process of protecting a body they can unleash an inflammatory attack that is painful and debilitating. 
• At times defenders mistake good guys for bad guys and attack joints (rheumatoid arthritis), the intestine (Crohn’s), the kidney (lupus) or the nervous system (multiple sclerosis.). 

There are over ten billion B lymphocytes in the blood and lymphatic systems of each human body.  Like a hive of bees, they are an ecosystem.³ Each can identify one and only one unique sequence of alien DNA or RNA.  When a B cell encounters its fated invader it rapidly clones itself, makes a huge number of carbon copies.  Some of the offspring become memory cells.   Most, now called “plasma cells”, fabricate free floating antibodies that attach themselves to the foreign protein, and mark it for destruction. 

Some immune cells are sentinelsthat recognize and ingest foreign protein and “process” it.   Called dendritic or antigen presenting cells they don’t destroy, they display the distilled protein on their outer membrane in an area called the “MHC complex.” 

The T lymphocyte has receptors that recognize the offering and grab it.  Some T-lymphocytes exterminate viruses; others destroy malignant cells. 

Macrophages “surround and kill microorganisms and remove dead cells.”  Much as a caterpillar turns into a butterfly, macrophages begin life as monocytes.²⁸

Immune cells communicate and influence one another by secreting small molecules called cytokines.² Some of these play a role in the inflammation that protects us from invaders.  Others are a major contributor to the pain and damage caused by one of several autoimmune diseases.

We can usually temporarily control immunologic assaults with cortisone derivatives.  To block the inflammatory cytokines physicians are increasingly using monoclonal antibodies. 

TNF—tumor necrosis factor—is a misleading, inappropriate name—for a family of cytokines that is the major cause of the pain, swelling and inflammation suffered by people who have any of a number of auto-immune diseases. The name was chosen by researchers who were trying to understand how some malignancies were cured when they were intentionally infected with virulent bacteria.³¹

Intentionally infect a cancer?   Some doctors had tried it here and there for a few centuries, but it wasn’t studied and promoted before William Coley, a physician at a major New York hospital became a believer. 

An upper “crusty,” Coley could trace his American lineage to the Mayflower era.  He graduated from Harvard Medical School in 1988 and during his apprentice years learned that half the surgical repairs of abdominal hernias in kids didn’t work very long. (Hernias are weak areas the belly wall that intestines can protrude through.). He introduced the European approach, using sutures and sewing and resewing.  He was successful and “admired.”³²

He started suspecting that infections can lead to a cure for cancer when he saw a malignancy disappear after a man with cancer developed erysipelas, a streptococcal infection of the face.  The cancer was infected and it faded away. Years later Coley located the man and the cancer was still gone.  An influential surgeon Coley decided to infect the throat tumor of an Italian immigrant who couldn’t speak or eat.  Making small incisions in the growth, Coley rubbed streptococcus into the wound.  At one point “the patient became extremely ill and looked like he might die.”  But he survived and the tumor “liquefied.”      Coley published a case report and promoted the approach. As head of the bone tumor service at New York hospital he injected streptococcus into 1000 malignant sarcomas. After they were infected  about 10 percent of them regressed and disappeared.²⁹  In subsequent years the drug company Parke-Davis marketed a mixture of two virulent bacteria that could be used to treat cancers.  In 1962 the government clamped down on medications that weren’t proven safe and effective. Coley couldn’t prove his approach worked and Parke-Davis stopped marketing the bacteria.

Decades later a team of researchers in Belgium led by Walter Fiers discovered a cytokine that eradicated human tumors that were planted into laboratory mice.  They named the cytokine family TNF—tumor necrosis factor. 

Researchers have developed antibodies that block TNF cytokines.  The medications they developed are among the most costly and profitable pharmaceuticals of the day.  Humira generated $19.9 billion in 2018.  Enbrel/etanercept had $7.1 billion in revenue.  Remicaid/infliximab-$5.9 billion.

The story of the cytokine TNF and the creation of antibodies that block their action starts in 1980.  A researcher named Hilary Koprowski, “a colorful, prominent Polish-born virologist” patented a process he had used in his research—a method for making monoclonal antibodies.⁴

The technique was developed 6 years earlier in Cambridge England by George Kohler and Cesar Milstein.  They won a Nobel Prize for the process, but they didn’t bother to file a patent. 

Their project started when they injected purified protein into a mouse.  One of the lymphocytes floating in the creature’s blood realized the injected amino acid was foreign and it had to be destroyed.  The lymphocyte started cloning, making huge numbers of copies of itself.  The numerous identical lymphocytes all made the same antibody to the foreign protein.  Days went by.  Then one of the researchers drew blood from the animal’s spleen, a large blood filled organ..  As expected, a sizeable proportion of the mouse’s lymphocytes were now clones of the original cell, and each of the lymphocytes made the same antibody. So far nothing that happened was exceptional.  

At this point they fused some of the lymphocytes to mouse myeloma cells, malignant plasma cells that keep reproducing and don’t die.  The hybrid they created made and kept making large quantities of one and only one antibody.  .  

As Kohler, a shy, gentle Swiss German immunologist later explained, the fusion approach was new and unique.  “If by blind chance the right lymphocyte, the one producing the antibody against the injected antigen had fused with the myeloma cell and was forming daughter cells that were locked into producing the same pure antibody. …it was a long shot.”  Around Christmas 1974 Kohler added the antigen to the fused cells and went home.  If the experiment worked the antibodies produced by the fused cells would combine with the antigens and they would precipitate.  Halos would form around the cells.  He returned hours later and fearing failure brought his wife along to console him.  They looked in the window, saw the halos and were elated.  “I kissed my wife.  I was all happy.²⁶”

Kohler’s partner, Milstein was a Jewish researcher from Argentina.  His 14 year old father had exited Russia the year before the country became embroiled in the First World War.  His Argentina born mother was the head mistress of a school and encouraged her son to study hard and to go to the University of Buenos Aires.  At one point she helped type his PhD thesis.  Married and a post doc researcher, Milstein spent three years in the 50s working at a lab in Cambridge England. He returned to Argentina in 1961 as head of a university department, but a military coup had taken control of the country.  It conducted a campaign against political dissenters, and Millstein had been a prominent anti – Peron student when he was an undergraduate.  It was also targeting Jews.  Milstein felt unsafe and returned to the lab at Cambridge.

In the 1960s and 70s a number of scientists developed mouse myeloma cells (malignant plasma cells) that could be grown in tissue culture and were “immortal”..They or their progeny survived indefinitely.  Milstein learned how to turn two small myeloma cells into one larger cell.  In 1974 he was joined by Georges Kohler, a Swiss postgraduate researcher who was also interested in fusing myeloma cells.  Together they developed the first “hybridoma”—part lymphocyte—part myeloma cell—the first “factory” that produced monoclonal antibodies.  

With a patent in hand, Koprowski owned the process for making monoclonal antibodies.  Along with an entrepreneur named Michael Wall, he formed a company named Centacor, and they tried to figure out how turn mouse monoclonal antibodies into gold. 

In the summer of 1982 Michael re-met Jan Vilcek, a man who studied cytokines and who worked at a New York hospital.  A Czech researcher, Jan was a 6 year old Jewish kid in 1939 when his country was occupied by Nazi Germany.  During the next few years the Nazis rounded up and killed Jews.  Vilcek wrote that he and his parents survived in a hostile environment because they had “a complicated attitude toward their Jewishness.”  At some point they converted to Catholicism.  Later they moved. Jan’s father joined the underground.  One way or another they managed to avoid the death camps.  After the Second World War Russia took control of Czechoslovakia, and the country became part of the Eastern Bloc.  The Soviet Union and the U.S. feared one another, built nuclear missiles, and created armies that could defend their nation.  Travel between the Soviet Bloc and the West was restricted and immigration forbidden.

Vilcek married and became a virology researcher.  When he was in his 20s, fed up with the Czech Communist government, he wanted to “relocate.”    In 1964 the couple received permission to cross the iron curtain for a three day vacation in Vienna. They traveled by auto.  It was October, still warm, and they brought their heavy winter coats.  When they reached the border and their car was being searched Jan worried that the coats would be a giveaway– that the inspectors would realize that Jan and his wife were trying to escape.  He waited while the border guards “hesitated for the longest minutes of his life before letting them pass.⁴”   Once across the line that divided the countries they, of course, didn’t go back.  After the couple reached Germany, life was rough, but within a year Vilcek was hired by NYU, New York University.

After spending a number of years studying interferon, one of the body’s cytokines, Vilceck attended a workshop on a poorly understood immune regulator called Tumor Necrosis Factor. 

In 1984 Genentech scientists determined and published the complete amino acid composition of TNF.  They purified the human TNF protein and they gave some of it to NYU.  Vilcek and his colleagues accepted the gift and “felt like kids in a candy store. –what should we try first?” 

The cytokine turned out to play a role in a body’s ability to fight viral infections.  It had so many actions that one of Vilcek’s graduate students quipped “TNF should stand for too numerous functions.” 

Cytokines are groups of special proteins.  They are discharged by immune cells and they act as chemical messengers.   After they are secreted by a cell, cytokines bind to receptors on the surface of other cells and they regulate the immune response.  They can work alone, work together, or they can work against one another.

In the 80s Centacor (still struggling) on a whim, a hope, produced a next generation monoclonal antibody that would block or inactivate TNF.  It was “chimeric”, a protein that was part human and part mouse.  The development took experts at Centacor 6 months and its patent was owned by NYU (an independent private research University) and Centacor.  The antibody didn’t (as Centacor had hoped) help people with sepsis.  But blocking TNF hindered one of the cascades of pro-inflammatory cytokines. It stopped or hindered inflammation.

When London doctors (Feldman and Maini) injected the medication into the swollen inflamed joint of a person with Rheumatoid Arthritis it usually helped.  The effect lasted three months.  A repeat injection was also successful.  In 1993 a physician from Holland used the antibody to treat a desperately ill 12 year old girl with a severe case of Crohn’s disease, a chronic inflammation of the small and sometimes large bowel.  The disease can cause diarrhea, pain, bowel blockage and fistulas, connections between the intestine and the skin or an organ.  The infusion was very effective for 3 months and it helped 8 of 10 additional people with severe Crohn’s. 

10 years after the original mouse antibody to TNF was generated in Jan Vilcek’s NYU lab, doctors had a tool that helped them treat a number of auto immune disorders.⁴

Part of the research was funded by the NIH (the taxpayer).  Part by Centacor. There was a lot of luck and serendipity along the way.⁵  Both Centacor and NYU were rewarded.  The FDA approved the drug for use in inflammatory bowel disease (for Crohn’s they say it has a positive effect 60 to 70 percent of the time),–and it can be used for ulcerative colitis, rheumatoid arthritis, ankylosying spondylitis and various manifestations of psoriasis.

In 1999 Johnson and Johnson bought Centacor for $4.9 billion.  Revenues from the drug (per J and J) rose annually between 2009 and 2016—from $4.3 billion in 2009 to $7 billion in 2016.⁶

Humira—adalimumab,  another antibody that blocks TNF, was created in mice that were genetically modified in embryo;  the animals make antibodies that human bodies think were made by a homo sapiens.  Some of the research on the drug was performed by researchers at the government funded Cambridge Antibody Technology, U.K.   The FDA licensed Humira at the end of 2002.  By 2005 AbbVie, the company that owned it, was selling more than a billion dollars worth a year, and by 2018 it was bringing in close to $20 billion.⁷

Scientists in many of the world’s labs knew how to make monoclonal antibodies to TNF, but they couldn’t market them until they performed placebo control studies that proved their drug was both safe and effective.  And that was costly, ethically questionable, and medically unnecessary.  Then a new law allowed companies to avoid double blind studies if they could prove their “new” antibody worked as well as the current one—that it was “biosimilar.”   A provision of the Affordable Care Act, gave the original antibody maker, in this case AbbVie, the exclusive right to sell the monoclonal antibody in the U.S. for 12 years.  At the time the FDA provided 5 years of exclusivity for new drugs that were not biosimilars.

At the end of the 12 years, as a result of a provision in the act, company lawyers were able to keep biosimilars—the biologic equivalent of generics–off the U.S. market for a few additional years if they claimed that one or several of the original drug’s 126 patents were fundamental.  (All the patents are presumably novel, non-obvious, and useful, but some merely protect a step in production or an inactive ingredient.)

Four companies produced effective biosimilars and wanted to steer clear of years of pointless litigation.  In an attempt to market their Humira-like medications, the manufacturers signed an agreement with AbbVie in 2017 and 2018.  It allowed them to market their medications outside the U.S.  AbbVie will retain their $10 billion a year U.S. Humira monopoly until 2023.⁸

Several cytokine families (including interferons) contain both pro and anti- inflammatory molecules.  Inhibitors are currently available to molecules that belong to one of two cytokine groups:  “TNF—tumor necrosis factor” and “interleukins”.

There are a number of situations where the  immune- system goes rogue.  A marked outpouring of cytokines can destroy joints and organs or bring on fatigue, fever, weight loss and an early death. 

An overly zealous “release” of these proteins, sometimes called “cytokine storm” may explain why

some treatments that rapidly destroy large numbers of malignant cells or severe cases of viral pneumonia kill. 

Huge numbers of cytokines have sickened people who received CAR-T treatment for cancer (discussed later in this chapter) and a four year old hospitalized at UCLA with a bad case of Coccidiomycosis, a soil born fungus infection.

High levels of a number of cytokines were found in the blood of  people with infiltrates in both lungs and low levels of blood oxygen caused by SaRS, MERS, AND COVID 19.³³

Some of the cytokine harm is mediated by one of more than 36 known interleukins–“hormones of the immune system”, and pharmaceutical researchers have developed, tested, and marketed humanized monoclonal antibodies that block some of them.²⁷

TRANSPLANTATION

On more than 34,000 occasions in 2017, organs from donors, dead and alive —livers, kidneys, hearts and lungs–were transplanted into the body of someone in the United States–and the immune system was challenged.

We learned organ transplant was possible in 1954 when an identical twin successfully gave his brother a kidney.  That’s as far as it went for decades because we weren’t very good at keeping a body from rejecting someone else’s organ.  Our original attempt to prevent the immune system from destroying foreign tissue, our “three drug anti rejection regimen”, according to Thomas Starzl, “wasn’t very effective or safe.”  

Starzl, the American who pioneered the effort to replace a failing liver with a healthy one, grew up in a small town in Iowa.  The son of the town’s newspaper editor he spent his teenage free time bulldozing giant rolls of paper into place, draining oil from the presses, and handsetting words letter by letter.  He went to medical school because that’s what his buddies on the football team did.  While attending Northwestern he lived in the Chicago ghetto and earned his keep tending the wounds and illnesses of local employees under the tutelage of a “very competent” physician. After graduating he started his surgical training at Johns Hopkins a programthat “ruthlessly” expected young men and women to be on call 24 hours a day, fifty one weeks a year, and the trainees were not compensated.  At age 26 he married Barbara and needing to earn money he became a surgical fellow at the University of Miami.  The program was new and they paid their doctors.  He cared for “vast numbers of patients”, became a competent surgeon, and on a theory (that he ended up disproving) he started operating on dogs in his garage.  He obtained the poor creatures from the pound and his wife, Barbara, “cared for the animals.”  While he was operating on the animals he figured out how to remove the liver without killing the canine, and he tried to transplant the organ. The blood from the small bowel was a problem.  Before it enters the main circulation it normally flows into the liver and is filtered and cleansed.  Newly transplanted livers couldn’t deal with the flow and they kept failing. Then Starzl learned how to detour the intestinal blood around the liver.  Once that problem was solved his transplanted dogs “were normal for almost a week; then began to reject their new liver.”

In 1961 Starzl became chief of surgery at the Denver VA hospital and used prednisone and immuran to prevent rejection of a few kidneys.  He had a modicum of success, but as late as 1978 “Graft survival was unsatisfactory and patient mortality high.¹⁰   Ambitious, focused, and perhaps a little too preoccupied by the rapid changes in his craft, Starzl remembered the day in 1976 when his wife of 22 years casually drove him to the airport in a snow storm.  He flew to London to present a research paper and while there received “ambiguous phone calls from his family, and he “knew” he could not return home.  After 22 years of marriage his wife Barbara’s “forbearance had run out.”   

Once effective anti rejection drugs were available, transplanted livers survived for many years and Starzl’s group in Denver led the way. 

In 1981 Starzl moved to the University of Pittsburg and brought liver transplantation east.  People who were dying of liver disease came to Pittsburg and were admitted to beds on the medical service where most spent their last days. Three of the first four people Starzl transplanted died and “54 residents and interns in the Department of medicine signed a resolution denouncing liver transplantation as unrealistic and potentially unethical.” In response Starzl admitted his patients with cirrhosis of the liver to the surgery service. (He couldn’t make the patients live longer but he could get the internists off his back.) Nineteen of the next 22 people transplanted survived and Starzl and others turned the Pittsburg transplant program into the largest in the world. 

In 1983 when the FDA approved cyclosporine for use in transplant patients, surgeons who performed the operations had successes and failures.  The procedure was far from standard or easy but some skilled doctors in the community apparently thought: if he can do it, I can too.  In the 1980s a California surgeon attempted a liver transplant and the patient bled to death.  In the process the operating physician transfused the person so aggressively that (hearsay) the blood supply of Southern California was threatened. 

Before the University of California at San Francisco started transplanting livers they agreed to make a major commitment to its support.    In addition to having access to a wide array of subspecialists the hospital needed kidney dialysis capability, respiratory therapy support, and an extensive blood bank.

 Surgeons had to be trained specifically for liver grafting.  A trained team had to be available to recover donor organs, keep them alive, and transport them quickly. Once transplant centers knew a liver was on the way they would call in two potential recipients whose blood type was the same as the liver.  They would start with the person at the top of their list and bring a back up into the hospital, just in case.  People with active infections could not be transplanted until the infection was gone. 

In 1990, having spent most of his life transplanting organs and teaching others, Starzl had a heart attack and wrote a memoir. In it he mused that every person who receives someone else’s organ starts seeing the world in a different way, and that medicine’s ability to save a life by transplanting an organ is a legitimate miracle.

In 1967 Christiaan Barnard in South Africa and Norman Shumway at Stanford each transplanted a human heart.  Neither recipient survived for three weeks.  In 1971 Life Magazine’s story of an “era of medical failure” told readers that subsequent to the first two “166 heart transplants were performed and 143 of the recipients died.²²” 

The son of a pastor and a church organist, Christiaan Barnard, the surgeon who performed the planet’s first heart transplant, was born in a sheep farming region of South Africa.  As a student at the University of Cape Town he was on scholarship, poor, and had to walk five miles to school each day.  After he graduated from medical school Barnard married, had two children, and practiced medicine for 2 years.  Then, deciding he wanted more from life, he accepted a scholarship to the University of Minnesota and spent 30 months (many without his family) working with some of the first surgeons who repaired heart defects in children.  He watched them work, learned techniques, and often operated the machine that oxygenated the bodies of the children whose hearts were not beating. After he returned to South Africa Barnard and his brother who was also a surgeon operated on 48 dogs, and they learned how to transplant a heart.  Then he was introduced to a 53 year old man who was bedridden, had severe heart disease, and was ready to resume his life or die.  The heart Barnard transplanted came from the body of a 25 year old woman who, as the result of a traffic accident, was brain dead.  The man who received the woman’s heart, survived surgery.  The operation became front page news, and the transplanted heart worked for 18 days before the patient developed pneumonia, and died.  Reflecting on the man’s decision Barnard later wrote, “For a dying man it is not a difficult decision because he knows he is at the end. If a lion chases you to the bank of a river filled with crocodiles, you will leap into the water convinced you have a chance to swim to the other side. But you would never accept such odds if there were no lion.”

A second heart transplant recipient lived 18 months.  A few years later effective anti rejection medications hit the market.  By 2001, the year Barnard died, doctors in the U.S. were performing 2,400 transplants each year.  Eighty seven percent lived for at least a year and ¾ more than five years.

Barnard became a celebrity, let his hair grow, started wearing suits made by an Italian tailor, dated movie stars, and ended his first marriage.  During his life he performed 75 more heart transplants, created a tissue heart valve, and was married two more times.  His rheumatoid arthritis eventually crippled his hands, and when he was 61 he stopped operating.

A month after Barnard performed the first heart transplant Norman Shumway, a California surgeon transplanted the second human heart.  At the time Shumway had been transplanting dog hearts for 10 years and knew technically what to do but his patient died within three weeks. 

A member of the high school debate team in Kalamazoo Michigan, Shumway originally planned to go to law school, but he was drafted during the Second World War.  When the government decided they needed more doctors and dentists Shumway was one of the soldiers tested.  He scored high and chose medicine over dentistry.  Assigned to a group of men who received pre-medical training at Baylor University, he was a hospital orderly for 6 months before he went to medical school at Vanderbilt.  During the Korean War he was an air force doctor.  When his service ended he joined the multitude at the University of Minnesota who were learning how to correct congenital heart defects.  Unable to get much hands-on training he decided to go into private practice and joined an older doctor.  It was not a fit.  Someone convinced him to come to Stanford University, an institution that didn’t have any doctors with heart surgery experience.  A modest man who was relieved when someone else performed the first heart transplant, Shumway became the chief of cardiothoracic surgery at Stanford in 1965.

In 1983, after the FDA sanctified the use of Cyclosporine, the first drug that allowed foreign organs to survive for years, the transplant scene changed.  In the subsequent decades over 700,000 people in this country lived part of their lives with someone else’s liver, kidney or heart.  Kidneys, on average, lasted 12 to 15 years; livers had a shorter lifespan.  That’s going to change now that hepatitis C (a frequent cause of liver destruction) can almost always be cured.  When a person with hepatitis C was transplanted, the new liver always became infected, and it had a relatively brief lifespan.

After a person receives a foreign organ, they (almost always) reject the newcomer if they don’t take an immunosuppressant daily for life.  A few anti rejection drugs are currently available.  There’s a marketplace and competition.

Cyclosporine, the first truly effective anti rejection drug, was developed by Sandoz, a Swiss chemical company that, in the 1800s, manufactured dyes and saccharine.  In 1917 the company hired a chemistry professor, and created a pharmaceutical department.  His group isolated ergot from a corn fungus and turned it into a drug used to treat migraine and to induce labor.

In 1958, the company asked employees to take a plastic bag with them when they went on vacation or business trips, and to periodically gather “soil samples that might contain unique microorganisms.”  They knew Penicillin was part of the juice produced by a mold, and they hoped one of their people would find the next great antibiotic.

John Francois-Borel was a company biologist, and reluctant scientist.  He said he originally wanted to make art and he was very gifted.  But, as he put it, “you know how art pays; I am not the Bohemian type.²¹He was the man who discovered cyclosporine, the drug that prevented the body from rejecting foreign tissue and that revolutionized the field of organ transplants.  Borel collected a handful of earth when visiting a desolate highland plateau in Southern Norway.¹⁸ A fungus in his sample of Norwegian dirt produced a metabolite (Cyclosporine) that lowered the immune response of lymphocytes.  It seemed to be relatively safe, and some thought it could potentially become an anti rejection drug.¹⁶

In 1976 Borel presented his findings to the British Society of Immunology.   “A small stocky surgeon with a mop of curly black hair (Starzl’s description) who had been working in transplantation since 1959,²⁰” Sir Roy Calne was one of several who “asked Borel for samples”.  Calne used the fungus juice to try to prevent the destruction of organs transplanted in rats and dogs.  The drug’s effect was dramatic. 

By 1973 the Sandoz supply of fungus derived cyclosporine was largely depleted.  Large sums of money (around $250 million,) would be needed to create more, evaluate its anti-rejection potential, develop a drug, and obtain approval from the FDA.  There wasn’t much of an organ transplant market, and the investment didn’t make much sense. But with Borel’s help, Calne presented his findings to decision makers at Sandoz.  “The pharmaceutical company agreed that the drug looked more promising now that there was evidence of its effectiveness.” Pharma scientists can produce great results.  But to create a truly innovative medication, in addition to money they need a modicum of serendipity, imagination, and stubborn determination.¹¹

Over time, in addition to performing surgery Calne became a well known artist.  He once wrote that art and surgery “Both require careful planning, skill and technique and familiarity.”

          In the early 1980s Starzl used Cyclosporine successfully on liver transplant recipients.  With his results in hand the FDA fast tracked approval of the medication and in 1983 it became available for use in the U.S.  Currently made generically by a number of countries Cyclosporine’s wholesale price is not outrageous.²⁴ $106.50 a month in the developing world– 121.25 pounds per month in the United Kingdom, and about $172.95 per month in the U.S. (if generic drugs are prescribed.)

The second major, now widely used, anti rejection drug was Tacrolimus (Prograf).  Originally isolated from the “fermented broth of a streptomyces bacteria”, it was discovered and developed in the 1980s by Japanese chemists screening “natural substances in the soil for their anti cancer and anti rejection properties.”   They performed their studies at Fujisawa Pharmaceutical, a company located at the foot of the Tsukuba Mountain, a green oasis with hiking trails, Shinto shrines, and a good view of Mt. Fuji.   

English scientists tried Tacrolimus in dogs and “declared it too hazardous to test in humans.”  Dr Starzl’s group kept at it.  They found the drug kept transplanted organs alive in some animals and “rescued some organs that, despite cyclosporine, were being rejected.” Additional clinical trials “suggested that tacrolimus might be safer and better tolerated than cyclosporine.¹²  ”  

In renal transplant recipients the drug led to improved graft and patient survival, and that lead to its routine use in U.S. renal and pancreas transplant recipients.  The FDA made it official in 1994.   Fujisawa later merged with and became Astellas, the world’s 14^th largest.¹⁷ The year before Prograf (its brand name) had a generic competitor, Astrellas sold up to $2.1 billion dollars worth of the medication.

Health care delivery:

There aren’t enough livers for everyone, and the people on the liver transplant list who are closest to death get the first organ of available for a person with the same blood type.  There are rules that limit the use of organs for people who are addicts, alcoholics, or obese.  If someone’s BMI (body mass index) is too high they can’t be transplanted with a “brain death” liver. 

One day I was asked to see a middle aged female who drove a fork lift in a warehouse.  She had never been sick before, was muscular and didn’t drink or have hepatitis.  But her liver was full of fat and she had developed hepato-renal syndrome.  Her liver disease had caused her kidneys to stop working. (I’m not going to explain what happens physiologically.  I’m just going to say it’s a well known, infrequent complication of advanced cirrhosis.)  When renal failure is caused by liver failure, dialysis doesn’t work.  She was in trouble and needed a liver transplant.  I explained the problem to the patient.  She said O.K., and I called the transplant intake doctor at the university.  It was Friday afternoon, time to go home, and the woman’s BMI (weight) was technically over the limit.  The university doctor was sorry but he had to turn the patient down.   I explained that part of the weight was caused by fluid retention. Her dry weight BMI (body mass index) didn’t exceed the threshold.  “No can do”, the University physician explained.

I told the patient.  She cried.  Her sister who was in her room cried, and the sister offered to donate part of her liver.  The patient refused.  She was given infusions of a few drugs and for some reasons during the next few days her kidney function didn’t get worse or better.  I visited her each day and we talked.  When Friday arrived she was still alive, and on a whim I called the hepatologist on call at the medical center.  The University of California had a group of liver specialists who accepted or refused referrals.  Each doctor was on call for a week; then a new physician took over.  I explained the situation to the new intake doctor and she said “no problem.  Send her over.”  The nurse called an ambulance.  The woman got a new liver and she did well. 

Currently, in addition to brain death, patients who have severe brain injuries but who are not “brain dead” can become organ donors if the patient consents by means of an advance directive, or the patient’s family decide that life support should be withdrawn. “To avoid obvious conflicts of interest, neither the surgeon who recovers the organs nor any other personnel involved in transplantation can participate in end-of-life decision or the declaration of death.”

Some countries have a system where an appropriate dead person’s organs can be transplanted in another unless the person explicitly objected while he or she was alive and competent.  The U.S. and a number of other countries require specific consent.

When someone “dies” and donates their organs teams of doctors come to their hospital.  Livers and kidneys are removed without dissection, without traumatizing blood vessels. The organs are cooled, and transported (sometime by plane or helicopter) to a hospital where surgeons and recipients are waiting.   

Once outside the body “The heart is most sensitive to lack of blood flow, “and needs to be planted in a body within 4 hours.   Lungs, with appropriate cooling “remain viable for 6 to 8 hours”, livers 12 hours and kidneys 24 to 36 hours. 

In 2011 an average transplant of one kidney had a price tag of $260,000.  Combined heart and lung transplants were costing $1.2 million dollars.   The first 180 days of post transplant medications was costing $18,000 to $30,000, and a number of generic immunosuppressive drugs have been marketed.  “Cellcept was approved in 1995.  Mycophenolate mofetil became available in 2008, Tacrolimus in 2009, and sirolimus in 2014,”

It’s claimed that the annual cost of U.S. transplant immunosuppressive therapy averages $10,000 to $14,000.  If true then the 33,000 transplant recipients in 2016 are (directly or indirectly) paying $330 million to $462 million a year.  That becomes $3.3 billion to $4.6 billion over ten years if drug prices don’t rise or fall.¹³  

In India (where the culture surrounding pharmaceutical prices is quite different from ours), the amount paid for Tacrolimus was slashed 65 percent in 2016.  The average recipient now pays $235 to $314 a month for anti rejection medications.

On October 30, 1972 chronic dialysis and kidney transplant became a Medicare ‘”right.”  If someone receives a kidney transplant (at a cost of hundreds of thousands of dollars) the operation and three years of anti rejection drugs are fully funded by the federal government.  At the end of those years the patient is removed from Medicare, and they have to pay for their own anti rejection drugs.  About 22 percent of people on anti rejection medications stop taking them because of side effects, high cost, or for other reasons.  When a kidney transplant recipient stops their immunosuppressive drugs they almost always reject their kidney, and they are forced to go back on dialysis or die. This is not theoretical.  It happens.  And it’s a problem.¹⁴

Founded in 1984, a private non- profit organ transplant organization (UNOS) under contract with the government, “oversees all organ procurement and transplant programs in the country and makes the rules about who can do transplants and how organs are to be allocated (given) to patients. “

People on dialysis wait their turn.  Managing the waiting list can be difficult.  My former employer tried to open their own renal transplant center in 2004, but closed the unit and paid a fine because they (allegedly) mismanaged the transfer of their patients’ records.      

A few years back our former neighbor’s son, learning he was a “match”, decided to donate half his liver to an uncle he didn’t know that well.  His mother was a mess.  Donors are screened.  They must be young and healthy.  But the operation is tricky.  The liver has a large and a small lobe.  The small lobe is adequate for a small child whose liver isn’t working.  An adult needs part of the large lobe.  The liver has to be “split” and a significant amount of tissue has to be removed.  Over time some liver will grow back, but it takes months.  If too much of the organ is removed the donor is in trouble.  There are occasional complications, mainly bile leaks.  And one in 200 donors dies.  There are only a few centers in the country that do at least 100 living donor liver transplants a year.  The young man’s mother is pretty cool.  She has a strong social conscience but this was hard.  Bottom line: he donated, and survived.  And mother and son are doing well.²⁵

• In the U.S. in 2019: 23,401 kidneys were transplanted as well as
• 8896 livers, 3551 hearts,  and 2714 lungs
• 11,900 of the donors were brain or heart dead.         
• 7397 of the organs came from living donors.      
• In 2019 over 112,000 Americans were on one of many transplant lists and “The wait for a deceased donor was often 5 or more years.²⁵”

Immunotherapy and Willie Nelson

Discovery consists of seeing what everybody has seen, and thinking what nobody has thought. Albert Szent-Gyorgyi

That’s what Jim Allison had to deal with when he learned how to use the immune system to attack and sometimes cure metastatic cancer.  Allison was from a small town in Texas.  His father was a country physician and his mother died of lymphoma when he was still a boy.  Initially planning to follow in his father’s footsteps, he got interested in research as a high school student. In an interview he said that he was reluctant to become a physician because doctors have to be right almost all the time.  Researchers, on the other hand, develop hypotheses and test them.  If they aren’t wrong most of the time “they’re not on the edge.” 

He wrote poetry, liked to read, loved country music and later in his career played harmonica on the stage with Willie Nelson.  At the University of Texas he studied biochemistry and earned a PhD.   After his post doc year he got a job in a small lab that the University of Texas/M.D. Anderson Cancer Center was operating in Smithville… close to Austin.⁶

While in Texas he worked out the structure of the T cell antigen receptor and gained some notoriety.  T cells, one of the white blood cells that float in our blood, are part of the immune system.  They aren’t very good at recognizing abnormal proteins but they are efficient destroyers.  When a dendritic or other watchdog cell spots a virus it processes the “stranger” and “presents” it to the antigen receptor on the T lymphocyte. Then the T lymphocyte recognizes and deals with it.  At one time early in Allison’s education he recalls a professor who doubted there was such a thing as a T cell.   

After his “receptor” accomplishment Allison took a year sabbatical and became a professor at the University of California, Berkeley.  He considered himself an immunologist and his lab tried to work out the relationship between the T cell and cancer.  In animal studies T cells seemed to recognize and attack cancer cells.  They latched on and released a poison, a protein called CD28 that should have destroyed the malignant cell.  But the cancer somehow survived.

Another protein, CTLA-4, showed up after the CD28 was released.  What was it doing there?  A large pharmaceutical company had concluded it was another cell poison, and the company patented it as a poison.

Allison wasn’t so sure.  So he developed an antibody to CTLA-4 and one of his fellows gave it to a mouse with cancer.  A few days later the cancer was gone.

The results surprised Allison.  Blocking a cancer poison should not have contributed to the death of the tumor.  Allison asked his fellow to repeat the experiment.  Since it was Christmas, the fellow went on vacation.  Allison manned the lab and watched the mouse as the tumors grew for a few days.  Then they faded away. 

Allison immediately realized he might have something big, but he had to be sure.  His group injected antibody that blocked CTLA-4 into the bodies of many different strains of mice.  In the absence of CTLA-4 the poison produced by the T lymphocyte– the CD28– was able to destroy one tumor after another.

Allison realized his success meant our understanding of cancer and the immune system was wrong.  “The biology was backwards”.  T lymphocytes, he hypothesized, recognized cancer cells, and they latched on.  They injected a “poison” (CD-28) that should have killed the malignant cell.  But cancer cells made an “antidote” (CTLA-4).  It stopped the poison from working.   His antibody blocked the antidote and it ALLOWED the poison to keep killing the bad cells.

Bristol Myers Squibb had patented CTLA-4.  Their patent claimed CTLA-4 was the poison not the antidote.  It was wrong—backwards.  But the company had a patent and lawyers and money.

Allison was a valued scientist.  His identification of the T cell antigen receptor was important.  People in the field respected him.  He was a full professor of Immunology at Cal Berkeley.  Bright ambitious students studied with him.  But he wasn’t an M.D.  His only interaction with sick people had occurred when he was a boy in a small Texas town.  He had gone on house calls with his father, the town doctor.  Allison wanted to try his antibody on patients, but he didn’t think he could take the next step without Pharma’s help.  He “spent the following close to two years going around and talking to a number of large and a few small biotech firms trying to interest them in his idea.  There was a lot of skepticism.  And the fact that Bristol Myers Squibb had a patent put people off.  They claimed the intellectual property was ‘dirty.’

Eventually a small firm, Medarex, decided to give his antibody a shot.  It was a big investment.  Niels Lonborg a scientist at GenPharm, a company that was purchased by Medarex (in 1997), had mice that had made fully human antibodies.   Lonborg created the antibody to CTLA-4 that later became the drug, Ipilimumab.

A trial of the drug on patients was arranged.  As Allison explained in an interview, he “was totally committed” to the endeavor.    He moved to New York, to be near Sloan Kettering Cancer Center “to make sure nobody hurt his baby– Nobody screwed up.”   He moved to be a nuisance.  The biology of Ipilimumab (the drugs generic name) was different than that of most cancer drugs.  “Usually you treat patients.  If the tumor grows in the face of treatment the drug is a failure.”  But in the treated mice the cancer grew for a while, then it withered.  The tumor didn’t always regress but “there was overall survival.”

As shown in Breakthrough, a film that documented Allison’s subsequent struggle, his discovery came face to face with the people who ran big Pharma. Immunotherapy had failed in the past and to the conservative corporate money men Allison’s drug seemed like a long shot, not worth the risk.  The doctor coordinating the trials, Rachel Humphrey, believed in the product and she was its chief advocate.   When she faced the Pharma company’s board she emphasized the fact that the drug had been effective in one person.  That made it worth pursuing.  Men yelled at her and she took it. 

A competitor, Pfizer, had an immunotherapy drug trial running at the same time.  They halted their effort when the tumors in the patients they treated didn’t shrink 30 percent in 12 weeks.  That was the FDA Standard. 

With Allison’s drug the tumors kept enlarging but the patients felt well.  Allison explained that’s how the drug works.  The T cell gets into the tumor and starts killing cancer cells.  It takes a long time before the tumor stops getting larger.  As the trial progressed some of the people who were treated, went home and their doctor gave them a drug that had not previously worked—and this time it seemed to work and they got well.  The recent drug got the credit for the improvement.  Allison knew it wasn’t the recent medication.  The T cells had continued to methodically kill the tumor. 

Bristol Myers Squibb, his company, eventually agreed the end point of their study would not be the number of people who were alive at one year or two years.  They agreed to see if there was an improvement in total survival.  The study kept going for years.  After three years the patients who hadn’t received immunotherapy were all dead.  Three, four and five years after they were treated over 20 percent of the people who received Allison’s drug were alive and well.  The company couldn’t call it a cure.  The tumor might someday start to grow. You never know.  But the people who responded stayed well and the treatment sure acted like a cure. 

Allison went to New York in 2004 but the drug wasn’t approved by the FDA until 2011.  During the 7 years Allison lived in an apartment 3 blocks from the hospital.  He gained weight.  He knew the drug cured cancer and was frustrated by his need to keep explaining why the tumor was still present.  At times he became angry. On one occasion he went into a tirade.  He’d come so far and he was afraid they would conclude the drug failed.  He became single minded and obsessed, and it affected his relationship with his wife.  Malinda, the woman he met when he was a college student, the coed who always felt he was the only person she ever loved—the most amazing human she ever saw– left. 

In 1997 Medarex acquired GenPharm.  In 2009 Bristol-Myers Squibb paid Medarex $2.4 billion and the companies merged.  

Squibb charged $30,000 for an ipilimumab injection or $120,000 for a course of therapy.  During Ipilimumab’s first year on the market, Squibb sold $706 million worth; they took in $462 million through the first half of 2013, and they thought they would sell$1.54 billion worth of the drug in 2018.

In 1992 a few Japanese scientists found another poison/antibody combination.  The antidotes were called PD-L1 and PD-1.  Drugs that block them were created by Pharma researchers, tested, approved by the FDA, and sell for about $150,000 a treatment.

In 2017 close to 1300 people with advanced melanoma were assessed 3 years post treatment.  They lived in 21 countries.  All had received a combination of two drugs nivolumab-plus-ipilimumab.  58% were alive and in 39% the disease had not progressed¹.  In another study: 5 years after the trial was started, Dr. James Larkin of the Royal Marsden in England and others assessed 300 plus people who had metastatic melanoma and who had been treated with two drugs that blocked the antidotes produced by melanoma cell.  Marsden reflected that “Historically, 5-year survival rates among patients with metastatic melanoma were dismal.”  The treatment had been hard on the bodies of the sufferers; only 58 percent seemed to have had a favorable response.  But 52 percent of the 300+ were alive at five years. The median progression-free survival was 11.5 months.  More than half the people treated, most of whom would have died without treatment, were still alive at 60 months.² Doctors evaluating new treatments for advanced cancer are reluctant to use the word cure.  It’s always possible that the tumor will, at some point, start growing again. 

In 2018 the PD-1 inhibor, nivolumab “showed a clinically meaningful survival benefit in some people who had advanced lung cancer.³

The clinical trials, hospital days, and advertising cost a lot of money and the companies that tweeked, developed and manufactured the drugs are working hard to recoup their outlay.  In 2015 Dr Saltz of Sloan Kettering estimated the price tag for the two drugs used to treat melanoma was about $300,000 per person, and the copay, the “out-of-pocket charge was usually $60,000.⁴” 

In 2018 Bristol-Myers Squibb sold $7.5 billion worth of Opdivo/nivolumab and Merck sold $7.1 billion worth of Keytruda/pembrolizumab

In 2018 Jim Allison was awarded the Nobel Prize

CAR-T

A T-cell is capable of eradicating a cancerous cell, but it’s not good at identifying the target. B lymphocytes are experts in identifying and marking targets, but they have no killer mechanism. What if the capabilities are combined?   

    Paraphrased words of Zelig Eshar, Weizmann Institute, Israel

The man who envisioned inserting a seeing-eye gene into T-cells, was raised in Rehovot, Israel, at a time when “the fragrance of orange blossoms and the sounds of crowing roosters” filled the air¹.” He was earning a PhD in Boston, when he “decoded” the T cell receptor. That’s the molecule on the “skin” of T-lymphocytes that spots the remnants of viruses that are displayed on the surface of sentry cells.  During his 20 years at the Weizmann institute in Israel, Eshar and his team developed and refined a special gene (a chimeric antigen receptor) that can be planted in the cytoplasm of a T cell. When it’s up and running it gives the T-cell the ability to both recognize and destroy targets. 

In another part of the world a surgeon at the NIH, Steve Rosenberg, led a team that assembled a similar gene.  Their CAR-T, however, specifically targeted cells that have the protein CD 19 on their outer membranes. They targeted B lymphocytes.

          A compulsive researcher Rosenberg once wrote that he enjoyed “working through the night in the lab, drinking thick pasty coffee that had been on the burner for hours, walking out into the sunrise, and watching the city come to life.”   During his 40 NIH years “there were probably only 40 days when I wasn’t in the hospital, checking on research or seeing patients.” Over the years he wrote a book about his efforts, was interviewed on T.V. by Charlie Rose, and was featured in a Siddhartha Mukherjee’s cancer documentary.

When young, Rosenberg was present when his father, a Jewish immigrant from Poland, received one post card after another telling of relatives who had died in the death camps.  The notes evoked a depth of silence and Rosenberg tasted pain.  His desire to stop everyone’s ache was not the sole reason he wanted to become a doctor, but it played a major role. 

Steve was married to Alice, an emergency room nurse who disliked doctors egos and was determined she would not marry one.  They met when he was on call in the ER.  It was a slow night—not much business, and she called him over and led him outside to gaze at the moon filled sky.  They dated for 5 years, then he told her “we can’t see each other anymore.  Otherwise it will be too difficult to break it off.”  She answered “It’s already too late.” After they married and had children he was a surgical resident.  His sleep deprivation was brutal.  He once fell asleep at a patient’s bed side and he routinely dozed when he encountered a red light when driving home. 

In 1968, as surgical resident he recalls admitting a man with a gall bladder attack who, 12 years earlier had undergone a cancer operation.  The primary malignancy in the stomach was cut out but metastatic implants in the liver could not be resected.  The man should have died but he didn’t.  His immune system had apparently overcome the cancer.  It happens rarely, but the event made an impression on Rosenberg

In 1974 Rosenberg started working at the National Cancer Institute and began his search for a way to help the body’s immune defenses fight cancer.

In 2010 he and his colleague James Kochenderfer told their medical colleagues about a patient with lymphoma whose tumors shrank after they gathered his T cells, added a gene that recognized CD 19, an antigen that is only found on the surface of the healthy and malignant B cells.  They allowed the T cells to multiply, then poured them back into the person’s bloodstream.⁸ The patient became and remained cancer free.  Rosenberg subsequently treated an occasional patient, and sent a copy of their gene in a plasmid to Addgene, the non-profit that makes genes available to interested researchers.  By 2010 researchers could buy one of their plasmids for $75.

The following year Dr. June, at the University of Pennsylvania, wrote about two of three patients with chronic lymphocytic leukemia who were similarly treated and went into complete remission.  At the time he didn’t think the infusion was ready for general use.  As Dr June explained “Some of these responses don’t last—there’s resistance. “We still have to run rigorous randomized studies to determine if the therapies are effective, and whether they are cost-effective, and whether they can be delivered at scale.”

          CAR-T infusion often takes a month to prepare.  After an appropriate person, someone with a difficult to treat lymphoma, is identified, a large bore needle is inserted into a vein.  It’s hooked to an apheresis machine and blood is drawn into a sophisticated instrument.  The gadget’s centrifuge spins the blood, picks out the T cells, and returns the rest of the blood to the patient.  The collection is then “prepared, frozen, and sent to the facility where CAR-T genes had already been inserted into a number of harmless viruses.  The viruses are co-mingled with the T cells. They enter the “killers” and deposit the Car-T gene in its cytoplasm. The T cells are given time to reproduce, to increase in number.  A month later, now modified, the T lymphocytes are returned to the treating facility.  The patient is sometimes given intensive chemotherapy before the modified T-cells are dripped into his or her body.  The person who received the modified T cells is watched carefully for up to 35 days because killing a large numbers of tumor cells can cause the body to release a large number of cytokines and they can make the patient very sick.

In the years after the process was developed a few desperate individuals without other options were treated.  The approach was a new, expensive, and time consuming process.  There were risks.  Short term improvements might or might not mean a person’s life would be prolonged.  

In 2009 a UCLA urologist and a businessman, Arie Bellgundrun, founded Kite pharmaceuticals in Santa Monica.  He searched the academic market to see who if anyone knew how to use the immune system to fight cancer.  Years before, as a young doctor he had briefly worked with Steve Rosenberg on cancer immunology. He eventually contacted his old boss, Dr. Rosenberg.  Rosenberg showed him the x-rays of several patients he had successfully treated with CAR-T. It’s a onetime treatment.  When gene therapy works the cancer is gone in three to four weeks. Rosenberg had tried to get interest from J and J and other companies but the approach was too new and different. 

          Bellgundrun was impressed. 

          “In 2012, Kite pharmaceuticals, partnered with Dr. Rosenberg and the NCI (National Cancer Institute) to further the research and development of multiple chimeric antigen receptor (CAR) and T cell receptor (TCR) based products.”

In 2018 the FDA gave two companies permission to sell a new, unproven, type of immunotherapy that treats lymphoma.  When used in kids, in one study, CAR-T cells had eliminated malignant cells 83% of the time for at least three months.

To get FDA approval Kite had to prove their approach was effective.  Since it’s unethical to run a study where some qualified patients are not treated—where they are “controls”, the FDA is allowing the company to use historical controls to prove their approach is effective.   By the end of February 2020, 108 people had been followed long enough.  Kite can now say they have proven the approach prolongs the life of at least some people.

Kite, Novartis, and other companies are starting to offer CAR-T treatment.  Kite charges $375,000 for processing a person’s lymphocytes.  In 2017 Gilead purchased Kite for $11.9 billion. Three years thereafter Medicare said they would pay for the process.

Chapter 8- GENE THERAPY

Each year 100 American babies are born with Pompe’s disease.  The children are floppy, their muscles barely work, and their heart is enlarged.  Few survive infancy.   A genetic, recessive condition, the disease is only seen when both parents carry the defective gene.

The malady is the result of an enzyme deficiency.  The kids’ cells don’t make enough lysosomal acid alpha-glucosidase, a protein that’s used to convert stored glycogen into glucose—energy.

We eat carbohydrates and sugar, and we turn what we don’t use into a storage polysaccharide called glycogen.  We stockpile the excess fuel in our muscles and liver.   Between meals, when we need sugar to keep going, we use enzymes like lysosomal acid alpha glucosidase to turn glycogen back into glucose.  Babies who lack the enzyme won’t stay alive long.

The condition was “characterized” by and named for a Dutch pathologist–Joannes Pompe.  A member of the Dutch resistance, he was executed by the Nazis in 1945.   The absent enzyme, Lysozyme, was isolated in Belgium in 1955, and the responsible GAA gene was identified in 1979.  (It differs a little from one family to another.)

The needed enzyme was first made at Duke University by a dedicated team of researchers.  Their leader, Dr. Chen, the chief pediatrician, started his quest after he went to the funeral of an infant who died of the disease.  The pastor said God must have given the child life for some reason.  Chen took the message to heart, and decided to assemble a team of Duke University researchers and go to work.

The inspiration came at the right time.  Researchers knew how to clone genes, how to isolate the fragment of DNA that is the gene and make large numbers of identical copies.  Scientists with genetic engineering training could plant the genes into plasmids, collections of DNA in the cytoplasm.  After an investigator spends years isolating and characterizing a gene and is ready to move on, most want to preserve and immortalize the fruits of his or her endeavor. So they send one of the genes in a plasmid to Addgene.  It’s a Massachusetts based non-profit that, since 2004, has collected and stored genes in plasmids from investigators all over the world.  For a nominal fee (like $75) they then supply genes to researchers.    

In mammals most of the DNA is found in the nucleus.  Bacteria and certain other microscopic organisms also have circular fragments of DNA—plasmids—floating in their cytoplasm.  Scientists have learned how to plant plasmids into viruses.  They, in turn, infect cells and deposit the DNA.  If everything goes well the deposited genes start telling the “infected” cell to make the desired protein. 

 I don’t know where or how the Duke researchers acquired the plasmid that contained the gene that’s defective in Pompe’s disease, but they made their therapeutic protein by inserting the gene/DNA into cells derived from the ovaries of Chinese Hamsters.  They are currently the most common mammalian cell line that is used for mass production of therapeutic proteins¹.  It took the researchers three years to make enough Lysozyme for their early tests.  The produced enzyme was injected into a quail that had been bred to be Lysozyme deficient.   The poor bird was in bad shape.  It couldn’t get off its back, much less fly.  Post injection the creature stood and even flew a little.

After 6 years of successful research, the Duke scientists got some manufacturing help.  Production rights were licensed to Synpac, a British/Taiwanese company with a presence in Durham, Dukes home.  Synpac, in turn “used experienced contractors to manufacture the enzyme.”  (Having done the heavy lifting, the Duke scientists gave a lot away, but they retained some royalty rights.)

Once the company had produced enough enzyme, physicians at Duke infused the protein into three kids with Pompe’s disease.  Lysozyme replacement worked.

In 2006 Synpac made a deal with Genzyme.  It was a “15 year royalty sharing agreement that was potentially worth $821 million.”  At the time Genzyme was huge.  Based in Boston, their 2010 revenue was $4 billion.  The company planned to spend more than $500 million dollars creating production facilities for Myozyme (their name for the enzyme).

The following year Genzyme was acquired by the French Pharmaceutical giant, Sanofi for $20 billion.  As part of the process Duke University was paid $90 million, and relinquished its royalty rights.   In 2016 Sanofi sold $800 million worth of the needed enzyme.

Now called Lumizyme, the enzyme is currently made in large sterile factories.  Babies with the disorder get an injection of the protein every two weeks.

In this country “according to Sanofi, the average annual cost of treatment is $298,000.”   If it works the first year it’s needed the second and third year.  By the time a child is 10 years old—if no one develops a less expensive generic product, the system (insurance companies and Medicaid) will have shelled out $1 to $3 million dollars per child and big Pharma will have been handsomely compensated.

For those who feel health care is too expensive:  You ain’t seen nothin’ yet. Scientists have started to effectively attack and control an increasing number of genetic diseases.  Insurers are not allowed to deny coverage to anyone who has a pre existing condition nor can they impose lifetime or annual coverage limits.  Given the way our economy works, the treatments and cures that create so much hope, will cost a bundle.  And no one knows how we’re going to control their price tags.   

During my early days as a Kaiser doc a young neurologist named Frank asked me to care for ”B” a 40 year old woman who had uncontrollable diarrhea and incontinence.  She was in a wheel chair, couldn’t walk due to weakness and numbness caused by nerve damage, and she was slowly getting worse.  A close cousin of hers had the same problem and would develop each new disability a few weeks before “B” did.  The “disease”, amyloidosis was genetic and affected many of B’s relatives. The afflicted started deteriorating in their 30s and died young.  The defective gene told the liver to make a mutant protein.  It accumulated in parts of the body and damaged hearts, kidneys, and a person’s small bowel. 

Frank (the doctor) contacted a researcher at Boston University who had an unproven diagnostic tool that could predict who among the offspring had the gene.  Carriers could choose to avoid bearing children. 

B’s relatives from all over the country were invited to a funded reunion.  I didn’t go, but I was told the get-together was a disaster.  Family members met distant cousins who were in different stages of deterioration.  Everyone was visibly shaken by the clear picture of what was going to happen to their bodies. 

B’s daughter didn’t want to be tested and I didn’t see her for more than a decade.  Then one day she called.  She had chronic diarrhea and knew what that meant.  Liver transplants had stopped the progression of familial amyloidosis in some and she wanted to give it a shot.  Getting her transplanted was tricky.  She was initially disqualified on the basis of a technicality.  Then a 32- year-old ex-convict died in an accident.  My patient was given his liver and a 67 year old grandmother with liver cancer received my patient’s liver. The organ was normal except for its secretion of one toxic protein and it helped the grandmother a period of time.   It was San Francisco’s first domino transplant.³⁰

The daughter was stable for a while, then became septic.  The drugs that kept her from rejecting the new liver were suppressing her immune system, and the disease had weakened her. She somehow accepted what was happening to her body but she worried about her sons.  She wanted the boys to be tested before they considered having children, but she knew that if they had the genetic disease they wouldn’t be able to get health insurance. 

Decades later the FDA approved two therapies that keep cells from making the harmful protein by interfering with the expression of the gene. (The DNA sends the instructions to make a protein to the cell’s factory, the ribosome.   The directions are carried by RNA.  If the RNA, the courier, is blocked the instructions won’t reach the factory– the protein won’t be made– and the gene will not be “expressed.”)

In 1983 researchers found the first genetic disease marker.  It was linked to Huntington’s, a dominant malady that strikes in midlife.  The disorder became well known after Woody Guthrie, the Oklahoma folksinger who wrote “This Land is Your Land” learned, at age 40, that his jerky movements, rigidity, clumsiness and inability to think clearly were caused by the disease.  Abandoned at age 14 by his mother, who was hospitalized with Huntington’s, and his father, who moved to nearby town for a job, Guthrie spent his teenage years sleeping at various friend’s homes.  He was able to rejoin his dad after a few years, but was more interested in his guitar than he was in high school.  Guthrie married when he was 19 and the couple had three children.  During the dust bowl Woody was living near the Oklahoma panhandle.  Giant clouds of dust periodically blew in, filled lungs and killed cattle and a few children.  The clouds were the result of decades of farming in an ecosystem that had adapted to long droughts. Farmers had pulled out the deep seeded grass that had covered and protected the dirt for over a century. During the wet years the crops were bountiful.  Then came years when it barely rained.    The soil became hard and the winds were fierce.  Called the center of the dust bowl the area was now barely habitable and people were pulling up stakes and heading to California.  Woody decided to join them.  He left his family and headed west.  Two of Woody’s first three children developed Huntington’s in their early 40s. During his 55 years Woody served in the merchant marines, lived in California and New York and was a popular entertainer.  He married two more times and wrote 1000 songs, one of which turned out to be his final message: “so long it’s been good to know yuh.”

The nucleus of each cell in our body contains 23 strands of DNA, 23 chromosomes.  That’s where the 20,000 genes that are unique to each person are found.  These genes account, at most, for 3 percent of the DNA in each nucleus.

Over several decades researchers identified the nucleotide sequences responsible for one genetic disease, then another.  In 1990 scientists started mapping the entire human genome; the task was “declared completed” in April 1993, and genetic research got a huge boost. . We also learned that after a cell makes a protein it has to coil and fold into a specific three-dimensional shape.  Misfolding produces inactive or toxic proteins and causes a number of genetic diseases.²⁴

Every so often a child is born with one of over 2000 really bad genetic diseases, and his or her family has to raise a disabled infant who will die young. Researchers working on the problems, have developed treatments that supply or teach the body to replace a vital protein. The number of children currently alive with each disorder is increasing.    

Companies that market these life saving products charge a lot, too much for most people.  It’s estimated that “orphan drugs will make up one fifth of worldwide prescription sales, amounting to $242 billion in 2024.  Much of the money will go to either big Pharma or big biotech.²”  “The cost per patient per year of the top 100 orphan products was $150,854 in 2018.”  Insurance companies that stay in the market and ultimately the taxpayers will have a new flood of costs they will increasingly have to deal with.   

In the U.S. 49% of our health dollar is spent on 5% of the people.  The total cost of care in the 2 ½ decades between 1980 and 2004,”has gone from $1,106 per person ($255 billion overall) to $6,280 per person ($1900 billion overall).” 

There was a time when drugs for uncommon diseases had a difficult time getting FDA approval.  Tests involving large numbers of affected people were needed before the FDA would conclude a new drug was safe and effective.  That usually wasn’t possible when relatively few people were afflicted. 

Then parents got together, pressured members of Congress, and the legislature acted.  In 1983 Congress passed and the president signed the Orphan Drug Act. 

          Companies that manufactured drugs for less than 200,000 Americans got a lot of rewards:  Their FDA monopoly lasted seven, not five years.  Companies got tax credits—they could write off half of the development costs.  If the disease was rare, developers skipped the usual wait and joined the “fast-track” line.

 The law worked better than anyone could have predicted.  There are 7,000 rare diseases affecting 25 million to 30 million Americans. In the first 20 years 249 orphan drugs were marketed. 

The FDA has approved 3 drugs that help people with cystic fibrosis.  They were developed using seed funding from the Cystic Fibrosis Foundation –$47 million over 5 years; and $20 million from the Gates foundation. 

The condition is genetic, and recessive.  If both parents are carriers, one of four offspring is afflicted. 

In kids with Cystic Fibrosis the mucous that collects bacteria and foreign particles is not watery, not easily swept out of the lungs and swallowed or coughed up.  It’s thick, “glue like”, and people with the disease have a hard time getting rid of it.  They periodically develop pneumonia, and over time they lose lung function.  A century ago most of the afflicted weren’t aggressively treated like they are now with inhaled bronchodilators, physical therapy, postural drainage, and appropriate antibiotics.  Few survived childhood.

The Cystic Fibrosis Foundation has established 117 centers of excellence.  They are manned by experienced health care professionals and have guidelines, “best” practices, and public monitoring. As a result of their aggressive approach the average person with Cystic Fibrosis now lives an average of 35 years, though getting kids through their teen age years is typically tough. 

Vertex, a biochemical startup that spent $4 billion during its first 22 years without developing an approved drug was not anxious to get into the Cystic Fibrosis business.  There were only 30,000 Americans with the condition.  If the company found a potential drug, it would cost $100,000 to test each person. In the company’s mind the expense of getting involved was “prohibitive.” Richard Aldrich, a deal maker and advisor, thought Vertex should only work with the CF (cystic fibrosis) foundation “if the foundation agreed to fund some of the early stage (drug) development.”

The Vertex research team was headed by Eric Olson.  An experienced research biologist, he was interested in CF.  A Colleague/friend’s daughter had the disease.

The faulty piece of DNA, the cause of the disease, was located in 1989 by a group of Canadians geneticists working with Hong Kong born Lap-Chee Tsui.  The mutation responsible for most cases of cystic fibrosis occurs when three nucleotides are deleted from a gene on chromosome 7.  Called Cystic fibrosis trans-membrane conductance regulator (CFTR), the abnormal gene causes the cell to make a defective membrane protein, one that doesn’t “fold” normally.  Appropriately folded protein regulates the amount of chloride, salt and water that flows in and out, of the cell. The fluid travels through “channels” in the cell’s outer wall or membrane.  In people with Cystic Fibrosis, salt accumulates outside the cell and secretions are thick. Sweat is salty. 

By June of 2011 Vertex had two drugs that dropped the salt content of sweat.  They decreased the exacerbation rate, and the unexplained “worsenings” that contributed to a more rapid decline in pulmonary function.  In the early 2000s Vertex added a third drug.  It had an effect on people who have a “Phe508del  CFTR  mutation.” It’s the most common abnormal gene.  90 percent of people with cystic fibrosis have at least one copy of the mutated DNA.  One analyst felt the triple-drug combo will rake in close to $4.3 billion by 2024.

——————————————————————————————-

The most common genetic cause of death in infancy, Spinal Muscular Atrophy “causes severe weakness by 6 months of age and inability to breathe by the age of two.”  The gene that directs cells to make an essential protein is deleted or mutated.  In the absence of the protein the nerves that send signals to muscles die. 

We all have a second gene that’s similar and that isn’t genetically affected.  But it doesn’t work.  It’s not able to make the needed protein.  And that’s OK because most of us don’t need it.

Scientists at Cold Harbor Laboratory, a large nonprofit research center on the north shore of Long Island developed a “segment of RNA” that, when injected into the spinal fluid, allowed the second gene to make the needed protein. It was a great accomplishment and it wasn’t easy.  The chemical, called nusinersen, was developed with the assistance of researchers at Isis pharmaceuticals, and another for-profit firm, Biogen Pharma paid for the testing.  Once nusinersen was shown to be effective Biogen paid millions and bought everyone else out. When the drug was approved by the FDA its owner decided to charge $125,000 for each dose, or $750,000 the first year and half as much each subsequent year.²⁷ 

          A physician at the University of Utah who cares for “about 150 patients with the disease, complained in an article that if each child was treated with nusinersen, the cost would be $113 million the first year and $56 million thereafter.¹⁰”

In November 2017 an Ohio company developed alternative approach to the problem.  Their therapy was based on research performed at Nationwide, a Columbus Ohio children’s hospital, by Brian Kasper.  An employed researcher, he studied adeno-associated viruses (AAVs).  One day his team discovered a serotype that penetrated the blood brain barrier. There are 50 serotypes of adenoviruses, they don’t usually make people sick, and most can’t get into the brain.

Kaspar and team believed they had “a new way of delivering genes to widespread regions of the central nervous system.  The drug companies they approached allegedly weren’t interested.  So in 2013 with the help of a biotech entrepreneur, Kasper formed a startup, AveXis.  They raised $75 million and licensed the therapy from the Columbus hospital.  To this point all research and development was paid for by the U.S. government and charitable funds.

Researchers placed a gene that promoted the production of the needed protein into an adenovirus.  Then they infused a high dose of the virus that contained the gene into the bloodstream of 12 affected children who were about 6 months old. 

After 1 ½ to two years 11 of the children were able to speak, 9 could sit unassisted for at least 30 seconds, 11 achieved head control, 9 could roll over, and 2 were able to crawl, pull to stand, stand independently, and walk independently.

The startup spent some of its $75 million. I presume that the SMN1 and SMN2 genes in plasmid form were available and could be purchased from Addgene for $65. The scientists had spent years learning how to use a modified virus to transfer genes. Injecting infants and running trials, they gave kids very high doses of a virus that contained the gene they lacked; and the results were pretty good. ¹²

In April 2018 Novartis bought Avexis for $8.7 billion.  After the FDA approved the therapeutic approach, Novartis named the treatment Zolgensma.  In an attempt to recover their multi-billion dollar investment, and make a profit the Swiss set a high price for a treatment.  Novartis will charge each child or their insurer $2.125 Million.²⁹

Currently “there are more than 800 cell- and gene-therapy programs in clinical development; several of these therapies have been approved by the FDA.”—And the science is in its infancy. Some of the treatments on the market are owned by Biomarin, a company headquartered in San Rafael California.  Founded in 1997 the company has acquired 6 biomedical startups in the last 15 years.  In 2016 were marketing 5 orphan drugs.

When a tear occurs in a blood vessel people bleed, platelets plug the hole, and a sequence of proteins pile on.   A clot won’t form if the person’s serum doesn’t contain enough clotting factor 8 or clotting factor 9.  People who genetically don’t make sufficient amounts of either of these proteins have hemophilia.

A genetic condition that “occurs in approximately one in 5000 live births,” hemophilia is sex linked– which means that women carry the gene and their sons get the disease.  When an affected male is injured and his factor 8 or 9 is low he won’t stop bleeding. Joints of men with hemophilia periodically and very painfully fill up with blood.  Over time they develop deformities. 

Victoria, the queen of Great Britain from 1837 to 2001 was a carrier of the hemophilia B gene.  She passed the condition through her daughter Alexandra to her grandson Alexei, the only son of Russian Tsar Nicholas. The couple had 4 daughters.  The boy’s painful and frightening bleeds seemed to be helped by a self proclaimed holy man named Rasputin. 

During the First World War Tsar Nicholas spent a lot of time at the front, and his wife was in charge.  Much to the chagrin of the Moscow elite she seemed to be “under the spell” of the holy man. 

The war went badly for Russia.  Over 5 million soldiers were killed or wounded.  After two years the Russian people had enough and they rebelled.  They deposed the Tsar and Russia withdrew from the conflict.  Hemophilia and the power of the mystic played a big role in 1917 fall of the empire.²⁶

Men whose blood level of clotting factor 8 is at or below one percent have a severe condition.  Those whose blood levels are 5 to 40 percent have a moderate problem and mainly receive factor 8 infusions before surgery or if there is a need.¹⁴ 

In the 1980s, during the height of the AIDS epidemic, small amounts of the factor that stopped hemophiliacs from bleeding was collected from each of hundreds of units of plasma that was obtained from donors.   One usually came from a person who had HIV but didn’t know it.  The young men who received the contaminated factor were given AIDS, a disease that, at the time, was lethal.

Researchers at the University College London recently put a portion of the factor 8 gene into an adeno-associated virus and “infected” a number of men.  With the gene floating in their cytoplasm, cells in the liver made the missing protein. In 6 of 7 patients receiving high doses of genes “factor 8 increased to a normal level and stayed there for a year.  None of the 7 bled during that time.”   After 2 to 3 years the treatment was still providing a clinically relevant benefit.²¹”

10 men with hemophilia B whose blood had less than 2% of the needed clotting factor were infused with an adeno virus containing a replacement gene.  During the subsequent year their clotting levels rose and stayed at a mean level of 33 %, bleeding virtually stopped, and only 2 patients needed a factor infusion. 

Scientists seem to be getting close to solving hemophilia.

As explained on 60 minutes, “Francis Collins of the NIH thinks we can cure sickle cell anemia by using CRISPR gene editing to increase blood levels of fetal hemoglobin (HbF).   Hemoglobin F is the form of hemoglobin that fetuses use to efficiently extract oxygen from the placenta and deliver it to their bodies. Shortly after birth a gene causes most children stop producing Hemoblobin F, and adult hemoglobin takes over.   

People with Sickle Cell disease have a genetic abnormality that affects adult hemoglobin. Red cells that should be round and flexible start looking like sickles or crescent moons.  They clump, stick in small blood vessels, and cause severe pain, anemia, stroke, pulmonary hypertension, organ failure, and far too often, early death.

Researchers at Vertex and CRISPR Therapeutics collected stem cells from a person with severe Sickle cell disease.  In the lab they used CRISPR to destroy the gene in the stem cells that shuts down production of fetal hemoglobin. Then they destroyed the remaining bone marrow with chemotherapy and infused the edited cells into the patient.²³ It seemed to be working.¹⁸

CRISPR derived gene therapy is new, exciting and not fully developed, but will be widely used in future gene editing. The investigators who did many of the studies and developed the concept were publically funded and were—at the time—trying to learn how bacteria defend themselves from assaulting viruses.  They were trying to understand CRISPR.

The following theory of how CRISPR came into being helped me understand the process: When a virus assaults a bacteria, the invader enters the cell, takes over its DNA, and directs the bacteria to make billions of viral particles. 

Most bacteria are enslaved, then destroyed.  A few mount a defense and survive.  Some of the survivors create a “DNA memory file.”  The identifying characteristics of the bad viruses are stored in the DNA’s CRISPR area, and the memory–sequence becomes a “gene” that is passed on to future bacteria.  In subsequent generations the memory DNA creates strands of RNA that float around inside the bacteria.  When a segment of RNA recognizes an invading virus it latches on.  Then it cuts the virus apart with an enzyme called Cas9.

After they understood how bacteria identify and destroy unwanted viruses, researchers tried to use the system to edit genes.  They chose a target–a “twenty-letter DNA sequence” that was part of the gene they wanted to delete. Then they “converted” a collection of nucleotides “into a matching 20 letter strand of RNA.”  This RNA was an exact replica of the DNA.  It would guide the Cas-9 past the cell’s 3 billion pairs of DNA nucleotides and it would eventually identify the desired strand of DNA.

They planted the genetic instructions for making Cas9—the knife—into one plasmid. They put the genetic instructions for “guide RNA” –-into a second plasmid.

Their concoction was able to search a cell’s DNA—3 Billion pairs of nucleotides—and find the desired segment of DNA–and unwind the DNA –and use Cas 9 to cut apart the strand of nucleotides.  In other words they could irreparably damage a chosen gene. 

Cells know how to repair a break in their DNA. The cut ends either come together on their own.– Or the gap can be bridged by a segment of DNA.

The study group was led by UC Professor Jennifer Doudna and Emmanuelle Charpentier.  Doudna, the daughter of a professor of English, grew up in Hawaii and spent the summer that followed her college freshman year in a lab studying a fungus that was invading papayas.  “It turned out to be a lot of fun”, she hungered for more, worked in a few labs, made a few discoveries.  After a decade she became the head of a research lab at the University of California in Berkeley, a campus that was often blanketed in fog, but on clear days provided a spectacular view of the Golden Gate Bridge and the Pacific.

Doudna met Emmanuel Charpenier, a French professor who was working in Sweden, at a 2011 conference in Puerto Rico.  Described as “Small and slight, with eyes so dark that they seem black” Charpentier was a PhD student at the Pasteur Institute in Paris when she “realized she had found her environment.” Once hooked on the life she spent more than 20 years performing research in 9 different institutes in 5 different countries.²⁹

The two women discussed possibly collaborating while they explored the narrow cobbled lanes of old San Juan.   

In June 2012 Doudna and Charpentier published a study that showed how RNA and Cas9 could be used for “site-specific DNA cleavage and RNA-programmable genome editing”.  Investigators around the world took notice and got busy.

Scientists already knew how to add a new, good gene.  Mario Capecchi, years back learned that genes intuitively know where, amidst the 3 billion pairs of DNA nucleotides, they belong.  If good genes are developed and put into cells, they migrate and attach to “their place.²².” 

After Doudna’s paper was published Kevin Esvelt (currently at MIT) explained how using CRISPR + selfish genes in the germ line can create changes that will be inherited by future generations of cells.

Sensing that there wasn’t time to write grants and get government funding, Doudna and other scientists formed a venture capital company– Editas Medicine.  Charpentier and others founded CRISPR therapeutics.  Both firms, according to their web sites, are trying to cure Sickle Cell disease, cystic fibrosis, and a few other genetic conditions.¹⁹

Medical thinkers have argued that:  given our current experience with the price of drugs we should start thinking about how we’re going to pay for “future success in gene therapy.”²⁰

Chapter 4 penicillin, TB, Syphilis and smallpox

Penicillin became available during the Second World War.  It was discovered in the 1920s by Alexander Fleming, a Professor of Bacteriology at the University of London who was a medical officer in World War I.   “Not known for fastidious laboratory organization,” he once had a cold, dropped mucous into a petri dish full of bacteria, placed the dish amidst the clutter at his desk,²⁶” and left it there forgotten, for two weeks. When he came back he noticed that his bugs were gone.  He investigated and discovered lysozyme, the enzyme in tears and saliva that was responsible.  He wrote up his finding, his account was published, and people in the field learned who he was. 

On another occasion he noted that fluid coming from a penicillium mold killed the bacteria growing in the Petri dishes.  He called the juice penicillin after the mold that produced it.  Collecting a small amount, he wrote an article that was published in a medical journal and largely forgotten.

          A decade later a group of Brits led by Howard Florey (a pathology professor) and Norman Heatley got interested in Fleming’s fluid.  They got hold of the Penicillium mold and extracted enough to treat a few lab animals.  In May of 1940 “they infected eight mice with a fatal dose of streptococcus.  Four of the creatures were then injected with penicillin.  Hours later “the untreated mice were dead and the penicillin-treated mice were still alive…. Penicillin’s spectacular possibilities were obvious.”  More needed to be done, but Britain was at war and Florey’s research could not proceed.   That’s why he and Heatley brought some of the mould to the U.S.  They convinced scientists at the agricultural research lab in Peoria Illinois to help them search for a Penicillium mold that would produce more than a trickle of the magic juice.  One of the labs mycologists, Kenneth Raper, found the super mold growing on a cantaloupe in a nearby store.  It was “50 times more potent than anything previously tested, and it became the primogenitor for almost all of the world’s penicillin.”  The group then looked for companies that could generate large amounts of the antibiotic and Pfizer stepped up big time. Their engineers knew had learned how to ferment gluconic acid in deep tanks and Pfizer purchased an old ice plant in Brooklyn that contained fourteen 7,500-gallon tanks.  Then they converted the building into a highly productive penicillin factory.⁶⁵ After the war the company manufactured a second antibiotic, streptomycin, and later a third antibiotic, Terramycin. 

In the decades before I entered the profession, students spent a lot of time learning about two of mankind’s chronic transmissible diseases:  Syphilis and Tuberculosis.  Scientists still aren’t sure if Syphilis arrived in the New World in the body of one of Columbus’ sailors or whether the bacilli was acquired from inhabitants of the Americas and, along with maize and potatoes, was brought to Europe.  Some are still periodically examining the remains of ancient humans and looking for evidence.    

In my days as a doctor syphilis was called the great imitator.  If someone got sick and syphilis was the possible cause of the problem we were taught to always rule it out. 

 By the 1950s a blood test for its presence, the VDRL was drawn every time a person entered a hospital or obtained a marriage license.  The test was invented before the World War I in a US public health service “venereal disease research lab”, hence its name.  The test detects the antibody a person started making when they were infected by syphilis.  Once penicillin, became available we could cure the disease and its incidence in the U.S. dropped.  But it didn’t go away and “Syphilis still occasionally presents with non-typical features in a person who has another sexually transmitted disease, HIV.  

The bacillus that causes the other chronic infection that has tormented mankind for thousands of years, tuberculosis, was identified in 1882 by the German physician, Robert Koch.  Many seemed to cure their disease by spending a year in a sanatorium, breathing clean air and leading a healthy life.  In the 1950s doctors were able to successfully treat most TB infections with a combination of antibiotics:  streptomycin, discovered in 1943, INH in 1952, and Rifampin in 1963.  Between 1954 and 1985 the number of infected people in the U.S. dropped from 80,000 to 20,000, and experts predicted that within a few decades TB would disappear.  They were wrong.  Poverty, HIV, and bacterial resistance reversed the trend, and the incidence of T.B. started to rise.

One of 4 people alive today, at some point in their lives was infected by the cough of a person with tuberculosis. 90 percent didn’t get sick.  They mounted a cell mediated immune response and their body encased and imprisoned the bug, but didn’t kill it.  It sometimes escapes.  10 million people currently have an active infection and a million and a half die each year.¹⁹ 

When I started medical school (1958), tuition was $600 a semester. By 2019 my school was charging $65,000 per year. With housing, food, and travel a student’s “estimated annual expenses were over $87,000.”  They don’t say why they are selectively lowering tuition, but in 2019 the school plans to decrease fees by an average of $20,000 per student per year.⁷

The planet wide eradication of smallpox wasn’t the result of a new drug.  It was the consequence of the expansive use of the century old vaccine that prevented people from developing the infection.  A viral disease that plagued the human race for at least 10 centuries, Smallpox caused high fevers, severe headaches, vomiting, exhaustion, and a papular rash.  It killed as many as three in 10 of those who were afflicted, and the people who survived were sometimes permanently scarred.  George Washington got the disease when at age19 he was visiting Barbados.  He was sick for a month and the disease left him with lifelong facial pock-marks.⁹ 

In1853 and 1867 the British Parliament made vaccination with modified cowpox compulsory. Much as cats and tigers are members of the same species, the viruses that cause cowpox and small pox are members of the same family.  Each can cause pustular lesions. People who develop cowpox sometimes run a fever and are sick for a week.  When a person recovers (or is vaccinated) their body is protected from the oft lethal disease.

Widespread vaccination in the U.S. contained the illness in the early 19^th century.  Then people in the U.S. stopped vaccinating.  There were outbreaks, and states attempted to enforce existing vaccination laws or pass new ones.  The disease disappeared from North America in 1952 and from Europe in 1953.  As recently as 1967 (according to the CDC) 10 to 15 million people in Africa, Asia, Indonesia, and Brazil were contracting Smallpox each year. That year 2 million died, many were scarred for life, and the World Health Organization started a program of worldwide vaccinations.  They hoped to eliminate the terrible disease and seem to have succeeded.  The bug’s last known “natural” victim was infected in 1977.⁵ 

Chapter 5 – narcotics, syphilis, TB, Vaccines

In 1935 a German physician and chemist discovered the first antibiotic, sulfa. (See chapter on FDA)  Chloral hydrate, the first synthetic hypnotic was introduced in 1869, and in 1860 Albert Niemann, a German chemistry student “extracted cocaine from coca leaves and found and wrote that “when applied to the tongue it left a peculiar numbness.” 

In the 1930s German chemists almost accidentally discovered the first synthetic pain relieving and addicting drug, meperidine—Demerol.  In the subsequent century chemists developed a number of additional synthetic narcotics.  One was created in 1953 by a group of European chemists led by Paul Janssen of Belgium.  They added carbons, benzene and other chemicals to the part of meperidine that causes sedation and analgesia and in 1960 came up with fentanyl.  The drug is 100 to 200 times more potent than morphine. I used it on patients when I performed colonoscopies.  Doctors like it.  Owned by Johnson and Johnson, it has recently been the cause of a number of over dose deaths. 

In June 1971 President Nixon declared the U.S. war on drugs.  Over the subsequent decades the Federal Drug Enforcement Agency grew to a force of over 10,000.   In 2016 about 200,000 Americans were incarcerated for Drug offenses.  And In 2018, over 67,000 people in the U.S. died from a narcotic overdose. 

In the decades before I entered the profession, students spent a lot of time learning about two of mankind’s chronic transmissible diseases:  Syphilis and Tuberculosis.  Scientists still aren’t sure if Syphilis arrived in the New World in the body of one of Columbus’ sailors or whether the bacilli was acquired from inhabitants of the Americas and, along with maize and potatoes, was brought to Europe.  Some are still periodically examining the remains of ancient humans and looking for evidence.    

In my days as a doctor syphilis was called the great imitator.  If someone got sick and syphilis was the possible cause of the problem we were taught to always rule it out. 

          By the 1950s a blood test for its presence, the VDRL was drawn every time a person entered a hospital or obtained a marriage license.  The test was invented before the World War I in a US public health service “venereal disease research lab”, hence its name.  The test detects the antibody a person started making when they were infected by syphilis.  Once penicillin, became available we could cure the disease and its incidence in the U.S. dropped.  But it didn’t go away and “Syphilis still occasionally presents with non-typical features in a person who has another sexually transmitted disease, HIV.  

The bacillus that causes the other chronic infection that has tormented mankind for thousands of years, tuberculosis, was identified in 1882 by the German physician, Robert Koch.  Many seemed to cure their disease by spending a year in a sanatorium, breathing clean air and leading a healthy life.  In the 1950s doctors were able to successfully treat most TB infections with a combination of antibiotics:  streptomycin, discovered in 1943, INH in 1952, and Rifampin in 1963.  Between 1954 and 1985 the number of infected people in the U.S. dropped from 80,000 to 20,000, and experts predicted that within a few decades TB would disappear.  They were wrong.  Poverty, HIV, and bacterial resistance reversed the trend, and the incidence of T.B. started to rise.

One of 4 people alive today, at some point in their lives was infected by the cough of a person with tuberculosis. 90 percent didn’t get sick.  They mounted a cell mediated immune response and their body encased and imprisoned the bug, but didn’t kill it.  It sometimes escapes.  10 million people currently have an active infection and a million and a half die each year.¹⁹ 

When I started medical school (1958), tuition was $600 a semester. By 2019 my school was charging $65,000 per year. With housing, food, and travel a student’s “estimated annual expenses were over $87,000.”  They don’t say why they are selectively lowering tuition, but in 2019 the school plans to decrease fees by an average of $20,000 per student per year.⁷

Mid Century

In 1962, aside from antibiotics doctors had (in retrospect) relatively few medications to work with.  We had aspirin, barbiturates, and a number of treatments that were largely the derivatives of plants, minerals and animals.  (Colchicine, for example, was extracted from Colchicum autumnal…the meadow saffron and was used to treat gout and a few other maladies.)  We worked with glass syringes and hypodermic needles made of steel.  After they were utilized, the needles were washed, sharpened, sterilized and reused.   When I was an intern (in 1963) we treated people who were stricken by a myocardial infarctions with “quiet and rest.”  One fateful night I entered a room—the door was closed– to do an admission history and physical on a man who was having a heart attack.  The patient was in trouble.  He was confused, pale, sweating–dripping wet and barely had a blood pressure.  He was in cardio-genic shock.  I started an IV and infused the available drugs.  Nothing helped and he died.  Nowadays heart attack victims who don’t instantly die are rushed by ambulance to a nearby hospital where a cardiologist and team are waiting to catheterize their coronary arteries and to unblock and “stent” the occluded vessel. (Some of the improvements in care are not due to better drugs.)

By the 1950s physicians had digitalis, quinidine, nitrates for diseases of the heart. Excess fluid accumulation could be flushed by an injection of a mercury based diuretic; there was a new promising diuretic called chlorothiazide. 

By my first year in med school, doctors could slow the coagulation of blood – and prevent and treat venous blood clots–with the anticoagulant Warfarin–Coumadin.  Produced by certain fungi dicoumarol initially got people’s attention when it caused the death of a number of cows in the 1920s.  The animals had eaten moldy sweet clover, it kept their blood from clotting normally, and they bled to death.  Researchers spent decades trying to extract the responsible chemical and “in the dimness of dawn on June 28, 1939, after working all night, Harold Campbell at the University of Wisconsin (finally) saw crystalline dicoumarol on a microscope slide.”  A few years later, led by the son of a Lutheran minister, Wisconsin researchers synthesized the chemical’s long acting derivative, called it Coumadin, and marketed it as an effective rat poison.  On further thought the decided to use it as a medication for people.¹² 

VACCINES

Maurice Hilleman, the scientist who ultimately created 40 vaccines, was born on a hot summer Montana day on a farm near the banks of the Yellowstone and Tongue River. His mother had eclampsia and died when he was 2 days old, but before she died she gave her baby to the childless couple down the road.  Maurice claims he was put to work as soon as he was able to tell a weed from a seed.  “Everyone in Montana had to earn their keep. “.On the farm they sold what they grew, and he picked berries, and watered the animals.  As a teenager he worked at J.P. Penny’s in the nearby town and “helped cowpokes pick out chenille bathrobes for their girlfriends.” Deciding he didn’t want to go to the local college because he “didn’t want to be strapped down by the church dogma,” Maurice won a scholarship to Montana State University.  Graduating first in his class, he was admitted to the PhD program in microbiology at the University of Chicago.  “Despite receiving a scholarship, money was always in short supply. Hilleman lived in a squalid apartment and survived on a single meal each day.  At 6 feet 1 inch tall, he weighed less than 140 pounds.¹⁴”

The Chicago University system, as he described it, was one where professors didn’t want to be bothered unless “you discover something. “While in school he determined that the bug that infected three million Americans a year and scarred the fallopian tubes of many women was not a virus.  It was a bacterium, a Chlamydia that grew in cells and it could be killed with antibiotics.   After he graduated his professors wanted him to stay in academia “I was not allowed to look for a job in industry; but I came from a farm.  I wanted to do something—to make something³⁸.” 

In 1944 as a new employee of Squibb he developed a vaccine for Japanese Encephalitis Virus.  It normally can be found in pigs in parts of South East Asia and it is transmitted by mosquitoes.  Usually mild, the infection sometimes causes fever, seizures, and serious long term movement problems.  In 1944 World War Two was raging, the U.S. was getting ready to fight the Japanese, and the army wanted a vaccine that would protect soldiers.  Hilleman offered to make the vaccine for $3 a dose and he won the contract.  Squibb gave him a horse barn and an engineer.  An old farm boy, he bulldozed out the manure, painted the floor, and went to work.  From U. of Chicago days Hilleman knew the virus would grow in the brain of a mouse so he did some testing.  As he later explained to fellow “vaccinologist” Burt Dorman, making a vaccine is like getting the old tractor working.  You fiddle with it.  If that doesn’t work you fiddle with it some more. Once Hilleman figured out how to make the vaccine he assembled a crew of 30 women.  They injected the virus into the skulls of mice and waited for it to grow.  After a few days they killed the rodents with ether and “harvested 30,000 brains a day.”  The organs were homogenized with a blender, washed, centrifuged, and washed again and again.  The process was repeated until the solution contained pure viruses.  The life forms were then inactivated with formaldehyde.  Three months later Squibb had enough vaccine to immunize 200,000 troops.³⁸

After the Second World War the U.S. military and the World Health Organization were on the lookout for the next influenza pandemic.  In 1957 Hilleman was working at Walter Reed military hospital when he read about a flu outbreak in Hong Kong that infected ten percent of the population–250,000 people.   He contacted an army physician in Japan who got an infected navy serviceman to gargle and spit into a cup.  A month later Hilleman put the spit into a fertilized egg and a flu virus grew.  He then checked the serum of hundreds of people and found that no one had antibodies to that strain of flu.  Most of the humans alive had never been exposed to the virus.  The only people who had antibodies were a few 70 and 80 year olds who had survived the flu epidemic of 1889-90.

 Hilleman figured that a virus would arrive in the fall and it would be devastating.  No one alive had ever experienced anything like it.  He “sent out a press release and warned the world” but no one seemed to believe him.  “Joe Bell” a prominent U.S. Public Health service epidemiologist, known for his attention to detail commented “what pandemic?  What Influenza?”  “How,” Hilleman wondered, “could people live in this world and be so stupid.”  Eventually Hilleman went to a restaurant where the head of the U.S. influenza commission was eating.  He interrupted the man’s meal, showed him the information, and told him that ignoring his findings was “a big mistake.”  The commissioner checked the data and agreed; it was a pandemic virus.

Hilleman contacted 6 companies that produced flu vaccine.  He cut the red tape, side stepped a few rules, and told chicken growers to NOT kill roosters.  As a farmer he knew roosters were usually killed late in the hatching season and companies would need a lot of fertilized eggs.  By late fall 40 million doses of vaccine were available and many people were immunized.  The disease arrived in the U.S. that September in the body of a girl who attended a church conference in Grinnell Iowa and in the lungs of Boy Scouts from Hawaii who attended a jamboree at Valley Forge Pennsylvania.   The 1957 flu killed 70,000 Americans and 4 million worldwide, but thousands of lives were saved.

In the 1950s Hilleman moved to the Merck Company and started a revolution of sorts.  Over the years his group turned out products that prevented a staggering 40 animal and human diseases.

His vaccine for Hepatitis B was made using killed virus.  To convince the public it was safe he asked Merck mid level executives to be the first to be injected. No one volunteered the first time so he brought the execs back and explained that “No” was not an option.  Fearing the vaccine might have been contaminated with HIV some of the injected execs later admitted they took the shot but were “scared to death.”

When he later learned the vaccine production was being accelerated Hilleman met with the people making it.  He had killed the viruses with formaldehyde, pepsin and urea.  The process was effective but it was slow.  When he heard the company was making it faster Hilleman assumed steps were being skipped.  No one knew if it affected the vaccine’s safety.  He gathered the production crew and told them someone was “changing the fucking process so he can get more yield and earn a bonus.  Meatheads are everywhere.³⁸”  

In 2005, 3 years before he died Hilleman famously told his colleagues that  “the most apt description of me was as a man who appeared to be a bastard, but if you looked deeper inside you still saw a bastard.”

The vaccines for measles mumps and chicken pox became available in the late 60s and early 70s. In 1957, the year before I graduated from med school, the people I interviewed all remembered their childhood illnesses, staying home for a week, fevers, rash, and a swollen jaw.⁸

          In the 1950s Jonas Salk and Albert Sabin developed immunizations for polio.   The studious son of immigrants, young Jonas Salk was “a perfectionist” and a good student.  He went to medical school, became a research bacteriologist, and, instead of joining the army, assisted Thomas Francis, the man who developed a flu vaccine for the army. The son of a steel worker, Francis—they called him Tommy, was 41 when the U.S. entered the war.  The nation remembered how the flu had killed more soldiers than the enemy during the prior conflict and the government didn’t want a repeat.  Salk was military age but discovering a vaccine for flu was more important than another soldier with a gun. 

In 1947, at age 33 Salk was given a laboratory at the University of Pittsburg and was funded by the March of Dimes.  The official charity that supported the development of a vaccine was created and promoted by Franklin Roosevelt.  He was the U.S. president during the depression of the 1930s and led the country during most of the Second World War years.  Unable to walk without help after he developed paralytic polio at age 39, he had a disability that was public knowledge.  The virus was feared.  1952 there was an outbreak of Polio in the United States and over 57,000 infections and 3145 deaths.

Salk’s vaccine used live virus that was chemically inactivated and injected. In the early ‘50s it was given as part of a placebo controlled trial to 2 million school children.  In 1955 the study proved it was safe and effective, Salk became an instant icon, and his life changed.  His celebrity status troubled his medical colleagues and affected his marriage of 28 years.  He ended up divorcing his first wife and he married Francoise Gilot, a woman who had once been the “longtime lover of Pablo Picasso.”  He founded a research institute in San Diego, was interviewed, and in a book was psychologically picked apart.  His interviewer wrote that the man “movie stars came to visit and babies were named after” was “conceited but vulnerable–mild-mannered, but often arrogant and combative.³⁹” 

The other developer of a polio vaccine was born in Poland and was15 when he and his parents came to the United States. Albert Bruce Sabin eventually went to medical school and graduated in 1931.  While studying Polio at the Children’s Hospital Research Foundation in Cincinnati, Ohio, he discovered that polio viruses lived in the small intestines before they attacked nerves. During the Second World War Sabin developed a number of vaccines for the army. When the war ended he returned to Ohio and he isolated a polio mutant that grew in the intestines and prevented infections with the wild virus.  The U.S. at the time was committed to Salk and wouldn’t allow Sabin to test, produce, or administer his creation.

In 1955 the Russians founded a Polio Research Institute in Moscow, and in 1956 its head virologist Mikhail Chumakov visited Salk in Pittsburgh and Sabin in Cincinnati.  Sabin spoke a little Russian, Chumakov a little English, and they became friends.   The following year Sabin spent a month giving lectures in Russia, meeting with researchers, and promoting his vaccine. When he returned home the Salk vaccine was being widely used and an American researcher advised Sabin to toss his vaccine “in the sewer.” In 1958 Chumakov tested a vaccine made with Sabin’s seed virus on 20,000 Russian children. It was safe, easy to administer, and effective. Chumakov got permission from the public health chief of the Politburo and distributed the oral vaccine to more than 15 million Soviets and later to 23 million children in East Germany, Czechoslovakia, Hungary, Romania, and Bulgaria.  An expert sent by the WHO agreed the vaccine seemed to be working but “definitive results would take time.”

Sabin refused to patent the Oral vaccine, and it is currently widely used in the poorer countries of the world. 

On April 26, 1955 half of the 760,000 doses of Salk vaccine made by Cutter in Berkeley California, were recalled when the nation learned the vaccine was making some kids sick and was causing paralysis and a few deaths.

Thousands of kids developed a stiff neck and fever, 51 were permanently paralyzed, and 5 died. The formaldehyde in the vats had failed to inactivate the virus completely and the vaccine was pulled from the market.  In 1961 the Sabin vaccine became available in the U.S. and was widely used.  26 years later the Salk, injectable vaccine was reintroduced.  This time it was safe. Since 2000 the Salk product has been the only vaccine used in the U.S. and Europe.  In the rest of the world “more than 10 billion doses of oral vaccine were given to 3 billion kids during the last 20 years. The World Health Organization thinks they have prevented 13 million cases of polio, but it’s also caused a few problems.  Mutatants of the oral vaccine occasionally occur in a person’s intestine, and they have caused 760 cases of polio and can cause paralysis.⁴⁰”

During the last half of the 20^th century states started requiring kids who attended public schools to be immunized. Most families complied; the rest were usually shielded by “herd” immunity.  If all or most kids in a community are protected, those who have not been immunized are unlikely to be exposed to the disease.  The shots sometimes caused fever and joint aches, and one in a million kids developed encephalitis, a serious brain inflammation.  The complications led to law suits and Pharma wanted to stop producing vaccines. In response, Congress passed the 1986 National Childhood Vaccine Injury Act, and the government started compensating the families of people who were harmed.

In 2020 a novel, sometimes lethal Coronavirus kicked off a terrible epidemic.

Chapter 6 HIV

One morning in the 1980s I attended a conference at the medical center, and heard about a tumor, Kaposi’s sarcoma, a cancer of old Italian men. It was affecting members of the gay community.  Pneumocystis, a microbe that had lived harmlessly in most lungs for a millennium, was causing pneumonia in young men. Similar infections had previously attacked the lungs of kidney transplant recipients whose immune system was suppressed.  Some had trouble swallowing and white dots of yeast covered their esophagus.  Previously healthy young men and women developed a bizarre assortment of diseases. Many were quite ill, occupied many of our hospital beds, and were receiving multiple medications.  For almost a decade everyone who contracted HIV eventually died.

In 1983 scientists in France and in the U.S. at almost the same time isolated the responsible virus.   The microbe was colonizing, taking over, and ultimately destroying T lymphocytes, a vital constituent of the system that keeps a lid on many of the organisms that live in the body.  As the virus destroys more and more of our defenders, the immune system loses its ability to control the indigenous microbes. 

We soon learned of cases of the disease in 33 countries.   Actor Rock Hudson died with AIDS and the Hollywood community rallied.  Our blood supply was tainted. Ryan White, a kid with hemophilia had the condition and was not allowed to attend classes.  A journalist who worked for the San Francisco Chronicle published a book called: “And the Band Played On.” The Gay community was particularly afflicted and decimated, and the book told of their struggle and “governmental indifference and political infighting”. Condoms were encouraged and needle exchange programs were initiated.  Gay bath houses were attacked by the police in many cities. Laws were passed that forbade physicians from testing people for HIV without permission.

After the HIV virus wiped out most of a person’s T lymphocytes, their immune system was unable to control the bugs that normally inhabit a body and their disease had morphed into the full blown acquired immunodeficiency syndrome—AIDS.

The HIV virus, we later learned, is not highly contagious.  You could shake hands or hug someone who had the virus growing in their body. Two principles of medicine, however, were turned on their head:  In otherwise healthy people, infectious illnesses were usually caused by a single microscopic organism.  When it was eradicated the person could stop taking antibiotics.  In people with AIDS antibiotics often suppressed but failed to eliminate the creatures responsible for a disease.  These individuals commonly required lifelong low doses of antibiotics to prevent a recurrence. 

 Also, when we identified the organism causing an infection (like Pneumocystis) we weren’t out of the woods.  The creature had attacked the body because the immune system reached a low point.  Additional problems were brewing.

Within a few years medical detectives in the Cameroon found chimp feces that contained Simian Immune Virus (SIV) with DNA that was identical to the DNA of the most common type of Human Immune Virus (HIV).  The source of the epidemic was a chimpanzee infected with the simian immune virus. 

In the early 20^th century chimps were wild game– “bush meat” in parts of Africa.  When wounded, the animals struggled. Presumably on one occasion a human was injured by a chimp he was killing.  Blood containing the Simian Virus entered the hunter’s body and the virus survived and thrived.  Later the pathogen was sexually passed to one person after another.  Sometime in the early decades of the century an infected individual moved to Leopoldville, (now Kinshasa).  In 1920 the town was the capitol of the Belgian Congo and was full of migrants. Scientists figure that by the time the colony became an independent country (1960) an estimated 1,000 to 2,000 people were living with HIV.  A physician of the day probably encountered many sick souls who had developed diarrhea, fever and wasting.  There’s no reason to believe that anyone at the time suspected their symptoms were the result of a new virus.

As the Congo, now a new country, was getting started, UN aid workers and volunteers from Haiti were flown in to provide medical care and assistance.  One of them presumably caught HIV, eventually went home, and the virus spread quietly in Haiti for a few years.  Then unknowing carriers visited the U.S. and Europe and passed it on.¹ 

After they identified the cause of the disease, scientists learned how the RNA virus methodically infects a cell and, use a special enzyme it brought with it, (reverse transcriptase), to make a DNA version of itself.  The DNA then integrates–becomes part of the host chromosome–becomes a gene.

• BRIEF GENETIC TUTORIAL (again–sorry)
• Our alphabet has 26 letters and we use them to make words.
• The DNA of living organisms uses 4 letter alphabet.   They “letters” are molecules called nucleotides. 
• Genes are strands of nucleotides.  They tell a cell what to do and make and they occupy up to 3 percent of a body’s DNA. We aren’t sure what the other 97 percent of the DNA is there for.
• Every cell in a person’s body has 3 billion pairs of DNA nucleotides. 
• They exist in groups called chromosomes.  Each cell has 23 pairs of chromosomes.
• The nucleus of every cell in the body contains all 20,000 genes. Some are turned on and some aren’t.
• To summarize:  The HIV virus knows how to create a DNA version of itself.  That DNA becomes a gene and it commands the cell to make more HIV viruses.

R., a gay 35 year old carpenter, was renting an apartment I owned in the SF Bay area.  I came by one afternoon and heard coughing from the house.  R. let me in and told me he didn’t feel well and was having trouble breathing.  His condition worried me and I suggested he visit a hospital.  He went and the doctors made a diagnosis of Pneumocystis Pneumonia.  He had AIDS.  Treatment was started but he got worse and needed to be intubated.  A tube was inserted through his mouth, passed his vocal cord, and into the main breathing tube. A respirator kept him alive for a week.  It took a few weeks before R. recovered and was able to leave the hospital, but he knew AIDS was a death sentence.  After he came home he moved out of the apartment, bought a house, fixed it up for his family and invited my wife and me over for Sunday afternoon Tea. He told us that he had long wanted have a home of his own before he died.   He looked good, seemed relaxed, and was proud of what he had recently accomplished.  We never saw him again.

The counter attack against HIV started when scientists at Burroughs-Wellcome synthesized compounds that might hinder the activity of the reverse transcriptase enzyme.  In 1985 they sent eleven promising compounds to researchers at the National Cancer Institute, and people at the NCI identified a chemical that worked in the test tube. The drug, AZT, was given to people with HIV, and their lives were prolonged.

25 months later the FDA approved the drug, and it was marketed by GlaxoSmithKline.  The company sold 225 million dollars worth in 1989.

In the late 1980s and in the 1990s manufacturers started cranking out (and selling) anti HIV drugs.  Some of the agents targeted protease, an enzyme that plays a role in the production of more viruses.  The first Protease inhibitors became available in 1996.

Drugs that work against the enzyme that turns HIV RNA into DNA, (like turning a photograph into a negative) were created by Emory university professors.    They discovered 2 important drugs (emtricitabine and lamivudine.) “Everyone was intrigued but skeptical about our work—no one realized the importance of what we had found,” Schinazi (the physician who developed the drug) said. He “pushed Emory University to file patent applications.”  They did and less than ten years later the University was paid $540 million…a lot of money but considerably less than big Pharma often pays to control a significant medication.     .

Two of the drugs that most effectively prevent and suppress the HIV virus were created in Prague Czechoslovakia by Anotonin Holy.  An intuitive researcher, Holy had been sneaking promising chemical creations through the iron curtain to a colleague in Belgium named Erik De Clercq for 20 years.  At the time a number of rules and regulations restricted trade between the Communist countries and the West.  But Czechs were able to export the hops that Belgians used to make beer and they could import powdered Belgian milk.  Somehow the chemicals got through.  In 1981 De Clercq visited Prague.  Holy took his friend to dinner and stuffed his coat with vials of newly developed compounds. 

In the mid 1980’s the Bristol Myers head of virology was John Martin. A respected researcher, he had developed the cytomegalovirus fighting drug, guancyclovir when he was in his 20s and was working for Searle.  Pharmaceutical leaders were starting to pay attention to HIV and researchers were developing compounds.  At one point Martin heard about a promising new group of antivirals that were discovered by a researcher in Czechoslovakia.  Called “acyclic nucleotide phosphonates” they were just chemicals in a test tube.  No one knew if they were safe or effective.  But for some reason De Clercq in Belgium thought they were special.  So Martin visited Prague and met Holy.  As the two strolled through the city’s narrow streets and cobblestone alleys they got to know and like one another.  Holy wasn’t a complainer.  His lab facilities were limited but he managed to do his work and he had no desire to leave the country of his birth. When Martin returned to the U.S., a CIA officer tried to convince Martin to turn Holy into an “asset” and Martin declined. 

In July 1989 Gorbachev allowed the nation’s of the Soviet Bloc to break away from Russia.  The iron curtain fell, and commerce and travel between the East and the West became relatively easy.  About that time Bristol Myers merged with Squibb and the company’s leadership and goals changed.  The following year Michael Riordan the long suffering, optimistic CEO of Gilead, a failing startup, convinced Martin to jump ship and become one of his company’s new leaders.  Martin (perhaps a little uncertain about his role in the new mega company) agreed and brought two of his best researchers with him.  At the time a number of pharmaceutical manufacturers were trying to fabricate drugs that suppressed the HIV virus, but Gilead was not one of them.  The chemicals Holy had created had been tested in Belgium and they effectively neutralized the HIV virus.  But they needed tweeking before they would be ready for human consumption.  Bristol Myers had planned to license and modify them.  Gilead wasn’t a player.

Then in mid 1991, with the head of Squibb calling the shots, the newly formed mega company decided they weren’t interested in Holy’s chemicals.  They didn’t want to take the risks and make the investment necessary to perhaps develop another HIV medication.  Realizing Squibb’s error, Martin phoned Holy and convinced him to sign a licensing agreement with Gilead.  In July 1991 Holy, Martin, and De Clercq met in a restaurant near the Eiffel Tower and signed a deal on a napkin. Holy’s nucleotide became the basis of several of the most potent medications that are currently used to prevent and treat HIV, and Gilead was finally an important player. 

In 1995, influenced in part by well healed pharmaceutical companies, the World Trade Organization was formed.  It required members “to honor 20 year patents on drugs”.   Poor countries were given until 2005 to comply with the mandate.  (Half the big drug makers are headquartered outside the U.S.).

In 1996 a three drug regimen was shown to successfully suppress the HIV virus. The disease could be controlled in advanced nations. But the companies that owned each drug’s patent charged what they thought they could get away with. The medications were too pricy for most people in the developing world. 

As Nobel Prize winner Joseph Stiglitz explained:  Patents are created for each nation’s needs.  They give the inventor a monopoly for a number of years. When they are appropriately designed they promote innovation and societal well being.  When they are not appropriately designed people die and innovation is suppressed. 

Most nations allow people and companies to patent unique, non obvious inventions.  When it came to medications, India had a different approach.  The country gained its independence from England in 1947.  In 1966 Nehru’s daughter, Indira Gandhi became prime minister. At some point she met with the head of the Indian drug maker—Cipla. He convinced her to allow inventors to patent the process –the way they manufactured a drug.  But the drug itself could NOT be patented in India.  That was the law in India before the country joined the WTO—the World Trade Organization. After India joined they changed their patent law.  Drugs could now be patented.

In  September 2000 Yusuf Hamied, the CEO of Cipla, was invited to the European Commission in Brussels for high level talks with health ministers and heads of large pharmaceutical companies.  The meeting was supposed to discuss access to medicines, especially those that suppressed AIDS, in the developing world.  At the large gathering, after the leaders of various companies made their remarks, Hamied spoke.  Saying he represented the developing world and an opportunity, he offered to provide the three anti retroviral drugs that suppressed HIV at a cost of $800 a year; and/or to set up factories in other nations; and to provide needed medicines to pregnant women so they would not infect their unborn child. Founded in 1935 by Hamied’s father, Cipla is a major pharmaceutical company. His proposal was serious and significant. But his offer was ignored. 

In the early 2000’s, according to Denis Broun M.D. of Unitaid, the powers- -that–be believed “Treatment for AIDS was something for the rich.  It was unthinkable for Africans.” Yusuf Hamied felt the whole of Africa was being taken for a ride.¹  

A year after the Brussels meeting James Love, an AIDS activist called Hamied and asked how cheaply he could produce the three drugs that suppressed the virus.  The key to pricing in medicine (according to Hamied) is the cost of the active pharmaceutical ingredients.  If you can get them cheaply, the end product is cheap.  Hamied told Love that Cipla would pay the cost of manufacturing a generic regimen.  He would only charge for the material.  Nevirapine would cost 65 cents a day.  3TC, lamivudine, 35 cents.  And there would be no charge for d4T, Stavudine.  The materials were too cheap.  In other words the three drug regimen would cost $350 a year. 

Donald McNeill of the New York Times felt the offer “was a watershed event.” He put the price of generics on the front page of the NY times, and papers around the world spread the news.

Shortly thereafter Peter Mugyenyi, a Uganda physician and director of the continent’s largest research and treatment center, decided to take matters into his own hands.  “I knew where drugs were, and as a doctor it was my job to save my patients lives.” He contacted Cipla in India, and in defiance of patent laws ordered the drugs. 

When the medications arrived at the airport they were impounded and the doctor was arrested. He refused to leave the airport without his medications.  Eventually the authorities relented. Other nations acted. To many it seemed like the blockade for inexpensive drugs in Africa was broken. 

In 2002 Kofi Annan, the diplomat from Ghana who was the Secretary-General of the United Nations, proposed a Global Fund to buy the drugs. The U.S. insisted that the fund could only buy branded medications or they would pull out. 

Poor countries couldn’t and wouldn’t comply with the WHO directive.  HIV was a killing their people.  143 countries favored relaxation of patent protection. 

“In 2003 South Africa’s competition commission ruled that Glaxo Smith Kline and another company had violated the country’s anti competitive act.  Glaxo was charging excessively high prices and was refusing to license their patents to generic manufacturers in return for reasonable royalties.  The company eventually agreed to allow three generic manufacturers to make and sell three of its AIDS drugs,³  and the company took a 5% fee.

Prior to 2003, the U.S hung tough. Then the Irish singer Bono got together with one of the day’s more influential Republican senators, Jesse Helms, and attitudes changed.  When they met the Senator was 80 and walked with a four-pronged cane.  He was a rightwing evangelical Christian who had exploited racial prejudices in his election campaigns and had called homosexuals “weak, morally sick wretches”.

Bono, by contrast, had publically supported Greenpeace, Amnesty International, and had joined Jubilee 2000, a 40 country movement that advocated cancelling third world debt for the millennium.  At one point the Jubilee campaign asked Bono to get the Baptist Nigerian President to write a letter to Baptist churches across southern US states.  He was supposed to explain the Biblical principles behind debt cancellation.

The Baptist leaders listened, and Bono suddenly had access to a lot of strongly Christian Republicans.  That’s why he was able to meet and speak with Jesse Helms.  Helms had been very tough on the concept of foreign HIV drug assistance.  “He’s a religious man”, Bono said, “so I told him that 2103 verses of scripture pertain to the poor, and Jesus speaks of judgment only once – It’s not about being gay or sexual morality, but about poverty. I quoted that verse of Matthew chapter 25: ‘I was naked and you clothed me.’ He was in tears. And later publicly acknowledged that he was ashamed…”

After the meeting vice president “Dick Cheney walked into the Oval office, and told President Bush that, ‘Jesse Helms wants us to listen to Bono’s idea.”  That led to negotiations and Bush’s 2003 plan.

That January in his State of the Union message President Bush announced his policy towards HIV had changed.  His words:  “Today on the continent of Africa nearly 30 million people have the AIDS virus, and across that continent only 50,000 are receiving the medicine they need.  Many hospitals tell people: “you have AIDS.  Go home and die.”  In an age of miraculous medicines no person should have to hear those words.”– “Anti retroviral drugs can extend life for many years.  And the cost of those drugs has dropped from $12,000 a year to under $300 a year.  Seldom has history offered a greater opportunity to do so much for so many. “

Bush would ask congress to spend $15 billion dollars over 5 years to combat the disease.  Since its creation in 2003, the “President’s Emergency Plan for AIDS Relief (PEPFAR)” received more than $70 billion in congressional funds …$6.56 billion in fiscal 2017.  The Trump budget plans to cut the amount the government contributes in 2019 by a billion dollars.

The under $300 number caught the drug industry by surprise, and they fought back.  Within days the administration changed its approach.  Rather than generic anti retro-virals the U.S. government money would be used to buy high priced branded drugs, and fewer lives would be saved.

As Bill Clinton later put it, “If you ran the numbers there was no way the money was enough to save the number who had to be saved in a hurry… it would never be enough unless they bought generics.” 

Many of the drug manufacturers are headquartered outside the U.S.  One hundred and twenty three nations (probably goaded by large corporations) signed an intellectual property rights agreement.-TRIPS, that “came into effect” in January 1995.  It allows members “to promote access to medicines for all.”   

Clinton decided to ignore the politics of the situation and do the right thing.   At the time India was a member of the World Trade Organization but patents issued before 2005 were still valid.⁹ 

In late November 2006 Bill Clinton announced an agreement between his foundation, two Indian drug makers: Cipla and Ranbaxy; Aspen Pharmacare, of South Africa, and Matrix Laboratories of Dubai.   The companies agreed to make pills for children that combined three HIV drugs and cost $60 a year.  Two million children in Africa had been infected by their mother and only 10 percent were receiving drugs.  Without treatment 80% would be dead by age 5.

The companies also apparently agreed that “The cost of anti-retroviral drugs (in general) was going to drop to $140 a year, and pills would cost 36 to 38 cents a day.”  The cost of making the medicines would be paid for by a $35 million grant from an international drug-buying consortium and $15 million from the Clinton Foundation.  The funds guaranteed the volume of drugs purchased would be “high enough to justify the lower prices.”  “The large quantity orders for generics was critical to bringing prices for anti retroviral treatment in Africa below $100 per person per year.” 

“After that the difference between branded and generic anti-retro-virals, and the scale of human tragedy in Africa made it impossible for donor funds to spend vast sums of money on expensive drugs.  The global fund and Pepfar eventually committed themselves to buying generics, and the number of people treated exploded.”¹

In 2017, per the U.N., 19.5 million people, more than half those infected, were being treated, but 2 million additional people had acquired the disease. Over 25 million HIV carriers lived in Sub Sahara Africa. That year worldwide 75% of people who carried the virus knew they were infected.⁴ 

The UN thinks they can end the epidemic if 90% of those infected know they are infected.  Then 90% of those infected would need to take anti retroviral drugs that effectively lower the measurable blood level of HIV 90 percent of the time.  Seven countries have achieved the 90/90/90 goal.

In 2019 the U.S. is still pretty far from getting HIV under control.  One in six men who has sex with other men will eventually acquire HIV.  Half are Latino or black.  In 2015 there were about 6500 AIDS-related deaths in the U.S.

The CDC (Center for Disease Control) thinks that 1.1 million people are currently infected and 40,000 inhabitants will acquire HIV each year.  83-88% of those infected have been diagnosed, and 85% of the people regularly take medicine that controls the virus; only half take enough pills in the right dose.

People with “decent” health insurance are commonly required to pay two thirds of the cost.⁵ The estimated average annual cost of HIV drugs is about $20,000 ($360,000 lifetime.)  In the appropriate age and income situations Medicare and Medicaid supply the meds.  The non-profit Ryan White Foundation helps when people can’t afford the drugs. And there are federal programs for some populations.

Pharmaceutical companies have managed to keep the price of drug combinations relatively high by combining one or two relatively cheap anti-retro-virals with an expensive newer drug that is still patented.  Some contend that people are more likely to take one pill that contains several drugs than they are to take a few capsules. 

Most new infections can be prevented with a daily pill that contains two of the more effective anti-viral drugs, but it is not always covered by insurance.⁸

Anthony Fauci of the NIH is quoted as saying:  “if we had a vaccine this effective-wow”. He was talking about a drug containing polymer that is implanted in a person’s body and slowly elutes significant quantities of a medication that suppresses HIV. 

We haven’t learned how to eliminate the HIV virus from a body.  The HIV DNA has become one of the genes of too many T cells. But genetic engineering is new and developing.   Que sera.

The 200 year history of medicine and the delivery of health care.

 A montage* in three acts: Section one: people, insights, drugs, devices, money.

Section two: the struggle to deliver care.  Section 3: problems looming on the horizon.

Section I: man discovers how the body works and learns how to heal.   

1.  The 1800s. the discovery of germs, sanitation, misquitos, and the first war on drugs.
2.  The transformative effect of anesthesia and transfusions
3. tetanus, parasites, ticks, cortisone and insulin
4. Penicillin TB; Syphilis, and the planet wide eradication of small pox.
5. the mid 20^th century and vaccines
6. HIV
7. Understanding and controlling the immune system

Cytokines and monoclonal antibodies 

Transplantation

T cells and cancer

Car-T 

• Gene Therapy
• Medical Devices.
• Surgery
• Childbirth
• Vision

Section II.  delivery of health care

1.  The right  to affordable quality care is given by the government to people:
2.  Over 65 and the very poor (Medicare and Medicaid)
3. With advanced renal disease
4. In distress who arrive in an Emergency Room
5. Native Americans, veterans, employees of the federal government and others
6. Private insurers take control and operate health care as a for-profit business.
7. The FDA and the government create the rules of the roads.
8.  Hospitals and the care they provide.
9. Obamacare—The Affordable Care Act  –the attempt to provide care to most

Section III:  looming problems

CHAPTER 1. UNDERSTANDING WHY AND HOW DRUGS BECAME EXPENSIVE.

1. SETTING THE PRICE
2. DONATED AND TAX DOLLARS
3. SWISS MOVE IN 
4.  DOMINATING THE MARKET
5.  SENATE HEARINGS

CHAP 2    ARE GENERIC DRUGS SAFE AND EFFECTIVE?

CHAP 3    SHORTAGES

CHAP 4    NEGOTIATING

CHAP 5     CANADIAN PHARMACIES

CHAP 6    MALPRACTICE

CHAP 7.    GOUGING

In our 200 year journey to the world of healing that our ancestors dreamed of and prayed for, we have also created a land where health care, like any other private industry, has in large part become a means of creating profit for the few.

*Montage:  the process of selecting, editing, and piecing together events and people and forming a continuous whole.

Chapter 1:  the 1800s

“It always seems impossible until it’s done.” – Nelson Mandela   

Prior to the last two centuries physicians in the West often relied on the teachings of the ancients, like the Greek physician Hippocrates, who concluded that illness, was “due to an imbalance of blood, phlegm, black bile, and yellow bile²;” the Roman Galen who dissected monkeys and wrote about their anatomy. 

Over millions of years the creatures that populate our planet developed defenses against microscopic invaders.  Our immune systems became powerful, and our bodies learned how to heal fractures, limit blood loss, and much, much more.  

Gurus and religious leaders employed prayer, meditation, and positive thinking to improve the lot of sufferers.  People with trained hands detected and corrected displaced bones. Expert knew how to turn certain plants and herbs into balms and how certain foods affect some ailments.  Some healers could therapeutically massage muscles or stimulate acupressure points.  And there have always been individuals with a seemingly lethal disease who inexplicably got well.

For most of man’s time on earth, our doctors often served the ill best when they stepped aside or heeded the dictum:  “first do no harm.”  Even today they aren’t needed very often. 

In the late 1700s most of the treatments used by the doctors of the day were pretty awful.  Consider—the December morning in 1799 when 67 year old George Washington awoke desperately ill.  He was retired, living at Mt. Vernon.  The previous day Washington felt well and went out in the snow to “mark trees that were to be cut down.”  Upon awakening the day in question he couldn’t talk and had trouble breathing.  His wife sent for one doctor, then another.  George and his wife Martha were two of the country’s richest people.  They didn’t need subsidized care.

During the day three prominent physicians came to their home and plied their trade.  The doctors were among the country’s best and they worked hard.  On 4 occasions they bled the sick man and removed a lot of blood.  His throat was swabbed, he gargled, his feet were covered with wheat bran, and he was given an emetic to induce vomiting.  Nothing worked and Washington’s breathing got worse, so he dressed, thanked his 3 doctors, and made arrangements for his burial.  That night he died. (As related by his secretary Tobias Lear¹)

At the time of his death, 1799, we didn’t know bacteria and viruses caused infections.  Antibiotics didn’t exist.  There were no blood banks.  Doctors (and barbers) were skilled at cutting off wounded or infected limbs, but surgery was risky and painful. 

The development of the health care that people in all corners of the world (to a greater or lesser extent) currently enjoy was triggered by discoveries made by a Dutch man named Leeuwenhoek.  A contemporary of Rembrandt and Vermeer, he was born in 17^th century Delft, a town in Western Holland known for cool foggy summer mornings, numerous boat filled canals, and wide streets connected by wooden bridges.  In his day horses and carts clattered across the stones in front of a large open air market.  Food and wood were weighed before it was sold.  Narrow rows of houses surrounded the town square.  Leeuwenhoek’s mother came from a well-to-do brewer’s family, and he started his work life as a draper’s apprentice.  He used lenses, such as they were, to check the quality of a fabric’s thread.  Over time he became politically active, and he spent 40 years as the chamberlain of a city hall assembly chamber.  At age 40 he invented a totally new technique for making lenses.  His microscopes were tiny, powerful and revealed a world man had never before seen or suspected.  He was the earliest man who ever observed tiny bacteria and the first person that visualized and described red blood cells.   As he watched this previously unknown world, he drew pictures and sent them to the Royal Society.  They published his letters. ⁴ He kept the process for developing his lens a secret, and when he wrote about the microscopic world some who worked with ordinary polished and ground glass didn’t believe him.

In 1796 Edward Jenner, a British doc and a contemporary of Leeuwenhoek, proved an old wives tale true.  He took material from the pussy scabs on a milkmaid’s hand and injected it into the skin of another person.  The illness it caused was mild, and the “treated” person was now immune to the highly lethal viral disease, smallpox.  Thomas Jefferson and Madison read about Jenner’s findings and Congress passed the Vaccine act in 1813.

During the centuries that preceded Jenner’s revelations, some in parts of Africa, Asia, and later Europe were intentionally infected with live small pox (or technically the variola virus.)   Material from “scabs were blown into a person’s nose” or Variola rich pus was dried and scratched into skin.  When done right it caused a milder form of the disease. 

Twenty years before Jenner published his cowpox observations, George Washington watched his defeated troops enter the high, flat ground south of the Schuylkill River at Valley Forge. It was 6 days before Christmas. The skies were grey and foreboding, and a cold wind was most likely blowing off the river. Washington worried about a smallpox outbreak. The disease had recently “raged through Boston.” Most of the British troops were city boys who had been exposed when they were young, and they were immune.  Washington’s soldiers were commonly farmers and had not been present during the Smallpox outbreaks that periodically played havoc with the colonial cities.  Battlefield flare-ups had caused deaths, and had contributed to at least one defeat. The continental forces besieging Quebec in 1775 were weakened by a smallpox outbreak and had to withdraw.

The retreating men that Washington observed entering Valley Forge were “without clothes to cover their nakedness, without blankets to lay on, and without shoes.” They walked “through frost and snow without a murmur.” Shelters were just being erected.  They had been defeated, would have to fight again, and Washington decided to act.  On his orders medical personnel gathered pus from active smallpox lesions and rubbed it into freshly created wounds in each soldier.  As Washington explained in his journal, “The need for secrecy was great, as the British would have had a significant advantage had they known of the debilitated condition of the American troops who were recovering from induced smallpox.”  The inoculations are said to have caused the deaths of 4 of every 500 soldiers.⁹

 I find the fatality numbers a little hard to believe.  Twenty five percent of the men who spent the winter in the valley died.  Before they were immunized they were already in a weakened state. People with smallpox are really sick.  In epidemics the disease often has a thirty percent mortality rate.      

In 1848, more than a century after Leeuwenhoek demonstrated the existence of microscopic creatures, no one (best I can tell) connected “germs” and sanitation with infectious illnesses.  Washing hands was little more than a cultural or religious ritual.  That year a Hungarian physician, Ignaz Semmelweis, was working at a hospital in Vienna and was troubled because the women whose babies were delivered by doctors and medical students developed a fever and died 4 times more often as babies who were delivered by midwives.⁴⁷ 

Semmelweis investigated and learned that the medical students who delivered babies came from the dissecting room to the maternity ward without washing their hands.  He introduced hand washing and the death rate plummeted.  Unfortunately his fellow physicians continued to believe that the high rate of childbed fever was due “miasmas”, clouds of invisible matter, and Semmelweis lost his job.  The son of a prosperous grocer he returned to his hometown, Budapest, and in 1881 published a book on “childbed fever.”  In his late 40s, overcome by paranoia and dementia, he was committed to a psychiatric institution.  It took a generation before his teachings were widely accepted.¹¹

1848 was also the year that Louis Pasteur, the Frenchman who would connect germs and disease, graduated and became a chemistry researcher.  An average student as a youth, Louis loved to draw and paint.  When he was a teenager he “won first prize in physics” and he went on to study chemistry and physics at the prestigious Ecole Normale.

Pasteur was 26 when he married 23 year old Marie Laurent. “According to legend he spent the morning of his wedding day in the lab and became so wrapped up in what he was doing that he had to be reminded to go to church.^23”

At 32 Pasteur became a professor of chemistry at the University in Lille, a market city near the Belgian border whose streets were paved with stones and whose skies were often grey and rainy. In Lille, and 3 years later in Paris, Pasteur showed his fellow scientists that living organisms, called bacteria caused fermentation.  We call it the germ theory. In 1863, working for the French emperor, Napoleon III, Pasteur learned that the contamination of wine could be prevented by heating fermented grape juice to 50–60 °C (120–140 °F).  The process of eradicating harmful bacteria at a temperature well below boiling, bears the scientist’s name, Pasteurization.   

In 1879 he and his assistants discovered that a culture of bacteria that had been sitting around for a month lost most of its virulence.  When injected into a chicken it created a mild infection, and the chicken was subsequently resistant to illness caused by the bug.  In the following years his group learned how to weaken a pathogen to the point where it wasn’t harmful, but triggered an immune response.  Pasteur exploited the phenomenon and developed vaccines for chicken cholera, and anthrax. 

In 1885 a rabid dog bit a 9 year old French child. After it enters the body, the Rabies virus infects an axon, the “long slender projections of nerve cells that conduct electrical impulses.”  Then it travels up the axon to the brain and is uniformly lethal.  

The oft repeated story says the young man was bitten 15 times and his mother was knocking at Pasteur’s door two days later.  Prior to this incident Pasteur had, for some time, been injecting the agent that caused rabies into a series of animals.  When the first infected animal died, dried extracts of its spinal cord were harvested and injected into a second, and later a third animal.  With each passage the agent became less virulent.  Using this technique Pasteur injected the boy with a series of 14 increasingly virulent fragments of dried homogenized rabbit spinal cord.  The boy survived, and Pasteur’s fame grew.  For decades thereafter doctors used similar extracts to treat people who were bitten by a rabid creature. . 

          The Rabies virus is still responsible for the deaths of 59,000 humans a year. 90 percent of the cases in Africa and Asia are caused by dogs.  In this country we worry about bats and wild animals, but the U.S. has less than 5 confirmed cases a year.  In his later years Pasteur had a series of strokes and he died when he was in his 70s.¹

Born 21 years after Pasteur, the other “father” of the germ theory, Robert Koch, seemed destined for greatness since his childhood.  He was a star student, and it is said he was reading newspapers at the age of 5.  In Germany he simultaneously ran a medical practice, was a district medical officer, and spent hours peering into a microscope. 

As a district medical officer he investigated a pasture where the cows that ate grass got sick and died.  He found rod shaped microscopic creatures in the soil and in the blood of a sheep that grazed in the pasture.  When the sheep died he collected some of the dead animal’s blood and injected it into a mouse.  The rodent promptly died and its blood killed a second mouse.  Koch was later able to grow bacilli that killed the mouse in a rabbit’s eye.  He dried the rod shape microscopic bacilli and they appeared to be innocuous, but they weren’t.  They still caused a lethal disease.  In the current century anthrax spores have been used as agents of bioterrorism. 

Once doctors had good microscopes they learned that when they dried and dyed objects before they viewed them, it was easier to identify bacteria.  Koch colored tissue infected with human and bovine (cow) tuberculosis with his special stains and was able to identify the bacillus that caused the disease.  “A plodding worker and a careful seeker of facts, Koch dazzled a group of colleagues one Friday evening in 1882 by proving that the tubercle bacillus was transmissible and that it was the cause of TB in man.  Later he isolated a glycerine extract of the bacillus that, when injected into the skin of a person with active disease, caused chills, fever and aggressive skin reaction.  Koch believed the byproduct that we now call tuberculin would “slow or halt” the deadly disease.  He announced his “cure” in a Berlin auditorium that seated 8000.   Some of “the rich and famous sought the treatment.  The mystery writer Conan Doyle noted a pile of letters four feet wide and two feet deep on the floor of Koch’s office.  All contained pleas for the miracle cure.” 

When his “cure” failed and he faced public scorn, he wrote his young lover: “as long as you love me I cannot be beaten down.”⁵⁶ At age 47 he left his wife and married the 18 year old woman who was fascinated with his studies.”  (In the German television drama Charite, Koch’s woman, Hedwig, is a “vivacious debutante actress who “comes on to the shy scientist, and he falls in love with her.”) https://www.sciencedirect.com/science/article/pii/S1201971210023143#bib2

“When Koch inoculated himself with tuberculin, she volunteered to be injected too.” 

Before 1870 Germany was a group of kingdoms, and they had been humiliated by Napoleon.  In 1870 Germany became a nation and invaded and defeated the once proud French.  A few years later the two germ theory “fathers”, Koch and Pasteur were introduced to one another in London.  Koch was 47 years old and Pasteur 68 and partially paralyzed.  The meeting was cordial, tense, and controversial.  Later, in part due a mistranslation of what one said or wrote, each started criticizing the work of the other.²⁴ 

In 1848, the year Pasteur was a novice chemist, Joseph Lister, the father of modern antisepsis began his medical studies.  ” A humble Scotsman with an athletic build he became the surgical apprentice of James Syme, “the greatest surgical teacher of the day.”  Lister later married Syme’s eldest daughter and adopted her religion.  Born a Quaker, he became a Scottish Episcopalian.  A few years after he completed his training, he was the surgeon for the Glasgow infirmary and he noticed that half the people who had a limb amputated became septic and died.  He’d been reading about Pasteur and germs, and he started treating raw wounds with carbolic acid, a foul-smelling antiseptic that was used to clean sewers.  The infection rate dropped to 15%, and the Scots were impressed.  They started cleaning and sterilizing the tools they used at the time of surgery. English doctors weren’t convinced until Lister went to London and operated on a fractured kneecap.  He wired the bone together, closed the incision, and the wound didn’t become infected.²⁹ At age 56 Lister was named a Baron.²⁰

Florence Nightingale took our awareness of cleanliness up a notch.  Born in Florence Italy, hence her name, she was the rebellious daughter of wealthy Brits who didn’t want her to become a nurse.  During the disastrous Crimean War between Britain and Russia, (1853-6), she worked at a small hospital in London.  A world away in Turkey a muckraking reporter visiting the front lines stopped at a British Military hospital.  He found the conditions “appalling”, which no doubt meant poor sanitation, gaping wounds, and bad smells.  His newspaper articles detailed what he saw and his fellow countrymen were incensed.  Then a high official made it possible for Florence to get involved, and she and 38 other nurses sailed to Turkey.

At the military hospital in Scutari, sanitation was “neglected and infections were rampant.” There was no clean linen.  The clothes of the soldiers were swarming with bugs, lice, and fleas.  The floors, walls, and ceilings were filthy, and rats were hiding under the beds. There were no soap, towels, nor basins, and there were only 14 baths for approximately 2000 soldiers. Nightingale purchased towels and provided clean shirts and plenty of soap. She brought food from England, scoured the kitchens, and set her nurses to cleaning up the hospital wards.” A sanitary commission, set up by the British government, arrived to flush out the sewers. She may not have had the drugs, blood, or modern day ‘tools’ that can turn an illness around, but she showed that diseased bodies have a remarkable ability to mend themselves.  As Florence saw it, “Sufferings were the result of too little “fresh air, light, warmth, quiet, or cleanliness.”¹

In the early part of the 19th century objects seen through the microscopes of the day were sometimes blurry or distorted.  A century earlier Van Leeuwenhoek had learned how to magnify objects 250 fold with a single tiny lens.  He produced 500 gadgets but didn’t teach others how to produce them and no one knew how to make “his kind” of lens.   Robert Hooker, his British contemporary used a different type of magnifying device when he studied plants.  Looking through a pair of lined up pieces of glass, his ability to see tiny objects depended on the quality of his lenses.  A jack of many trades, Hooke was also a surveyor and, as an architect, helped design the buildings that replaced those destroyed by the Great Fire of London in 1666. 

The quality of the microscopes produced during the early 1800s was variable.  Then two German mechanics independently started to manufacture really good lenses and microscopes.  One of them, Carl Zeiss, came from a German family of artisans and apprenticed with a maker of fine tools.  In 1846 he opened a mechanical workshop in Jena, a river valley town in the “green heart” region of eastern Germany.  His microscopes were simple.  Lenses were the result of trial and error.  Poor quality scopes were destroyed.  20 years later a mathematics professor, Ernest Abbe joined the company.  He introduced mathematical modeling (whatever that is) and the company started regularly producing microscopes that allowed observers to see tiny objects clearly.  A number of parasites that had not, previously, been visible were identified. After Zeiss died in 1888, Abbe became the head of the company and, ahead of his time, he introduced an 8 hour work day, pensions and holiday and sick pay.

In the late 1880s Charles Laveran was gazing through a powerful microscope and saw pigment and motionless bodies in the red blood cells of some people with Malaria.  A French military doctor, Laveran was the son of a physician, and spent part of his childhood in Algeria.  During the 1870 Franco Prussian War he was in charge of a number of ambulances and was trapped along with his fellow French troops in the besieged fortress of Metz.  At age 40 he married and he was stationed in Bone Algeria, a colonial city on the Mediterranean coast, when he saw the red cell abnormalities. Realizing what he saw might be significant he “meticulously examined the blood of 200 patients and observed crescent bodies in all cases of malaria” but never in the blood of people who didn’t have malaria.  Laveran presented his findings to his fellow doctors, and many thought he was seeing disintegrating red blood cells.  By 1884 Italian researchers looking through advanced microscopes were also able to “observe amoeboid movement of the organisms” and Laveran’s findings were validated.   

The parasite that causes Malaria lives in the liver and attacks oxygen carrying red blood cells.  Historically a major cause of death and disability, the disease has been around for hundreds of years.  In 1898 the Italian, Giovanni Grassi proved that “mosquitoes that fed on infected patients transmitted the parasite to uninfected individuals.  About the same time Richard Ross performed similar studies in India.  A British physician who preferred to spend his time writing novels and poetry, Ross didn’t believe in the mosquito theory, but he kept receiving bothersome letters that promoted the mosquito hypothesis from Patrick Manson, a Scottish physician he met in London.  In 1898 Ross finally did the research, and failed because he used the wrong mosquito. Eventually Ross proved that mosquitos carry the infection from one person to another and he received the Nobel Prize.  The Italians who made a similar finding weren’t honored.  And there were doubters.  To convince nonbelievers Manson shipped a number of infected mosquitos from Rome to the middle of London.  The trip by ship took 48 hours and some of the mosquitos died en route.  When they arrived Manson allowed one of the mosquitos to infect his son.  The young man got sick, but was cured with quinine. 

Malaria remains a huge worldwide problem.  In 2019, 228 million people were infected with the parasite.  400,000 of them, two thirds of which were children died. That year there were only 2000 cases in the U.S.  Most occurred in immigrants or people returning from an at-risk area. 

Over the last century and a half we’ve learned a lot about the illness.  Many generations of drugs have been developed.  But the disease is mainly absent from countries that are able to control the vectors that spread it.   

When the French tried to build a canal between the Atlantic and Pacific Oceans at Panama in the late 1800s no one knew that Malaria and another tropical disease, Yellow Fever, were transmitted from one person to another by mosquitos. A few years later an American military doctor had a theory and performed a study. 

The research was conducted in 1900 in Cuba. At the time the island was occupied by U.S. soldiers.  America had won a war with Spain in 1898, and had freed the island from the European colonizer.  Cuba was scheduled to become independent in 1902.   In 1898 there was an outbreak of Yellow Fever among American soldiers who were stationed on the island.

          Doctors currently believe the virus that causes the infection originally came from the rain forests of Africa, was around for centuries, and was brought to the New World by slave traders. Infected people develop headaches, fever, and bleed easily.  Many develop shock and die.  The doctors who cared for the sick soldiers in Cuba apparently thought the illness was caused by mysterious “fomites.” 

The U.S. government sent Major Walter Reed to the island of rum and cigars to investigate.  A military physician who had spent 17 years in the arid American West, Reed suspected Yellow Fever was transmitted by mosquitos.  He met with the doctors caring for the ill, and they were willing to check out his theory.  Volunteers, some of whom were ill and others who were well, were housed in a barracks. Mosquitos were collected and the insects were allowed to use the tip of their straw-like mouth to pierce each person’s skin.

One of the apparently skeptical doctors conducting the investigation “submitted to the bite of a creature that had fed on an infected soldier.”  He joked “if there is anything to the mosquito theory, I should have had a good dose.”   A week later his life was in the balance for three days. 

A fellow doctor who brought the mosquitoes from one soldier to another noticed a bug on his hand.  He allowed it to suck his blood.  A week later he became febrile, delirious, started vomiting, had seizures and died.  As one of the infected who survived put it: “such is yellow fever.” 

We now know the illness is caused by a virus and there is an effective vaccine.  But Yellow Fever still annually causes 200,000 infections and 30,000 deaths in central Africa and South America. 

As mentioned earlier, the role of mosquitoes was unknown when the French decided to build a canal at Panama.  They were encouraged when the Suez Canal opened in 1869, and they believed an ocean to ocean passage way in Panama wouldn’t be very expensive or difficult.  They raised money from over 200,000 investors.  Twenty thousand workers from the West Indies were recruited, and a Frenchman named Jules Dingler was put in charge.  When he went to Panama, Dingler brought his family.  He “is credited with having said that “only drunkards and the dissipated contract yellow fever and die.” During his early years on the job Dingler’s son, daughter and wife each contracted the infection.  None of them survived.  Dingler returned to France a man broken in mind and body.  Unlike Suez, the Panama terrain turned out to be challenging. Between 1881 and 1889 over 20,000 laborers who toiled in the thick rain forests died.  That year the company funding the project declared bankruptcy and the French abandoned the project.⁴²

In 1904, when the U.S. started building the Panama Canal, the people in charge knew that the mosquito transmitted Malaria and Yellow Fever.  Engineers “drained pools of water, cut all the brush and grass near villages, and constructed drainage ditches.  Larvae were oiled and killed with an insecticide. Screens were placed on windows and doors, and “collectors were hired to gather the adult mosquitoes that remained in the houses and tents during the daytime.”

It took ten years to build the canal that linked the two oceans.

Cholera has only been a problem in the western world for a little over 200 years.  It first came to our attention in 1817 when an epidemic started in the Ganges Delta of India.  It was spread by ships trading goods in Thailand, China, and Japan. Millions got sick. 

Three decades later when the third world wide cholera pandemic struck there were outbreaks in Europe and the Americas.   The epidemic of 1854 started in the Soho district of London.  Cities in Western Europe and the U.S. didn’t have running water until sometime in the 1800s.  Initially there was only one tap per neighborhood or large apartment building.²²  Most people got their water from communal pumps.  Sewage and untreated human waste was dumped in the Thames and the river smelled. 

John Snow a physician living in London suspected the source of the infection was contaminated water.  A vegetarian and teetotaler who liked to swim, Snow mapped the location of the people who got sick and convinced town officials that the Broad Street pump was the source of the epidemic.  They removed the pump handle and the epidemic “almost immediately” trickled to a stop.  Snow, not surprisingly, was subsequently disbelieved and denounced.

Some claim that the chlorination of our drinking water may be “the most significant public health advance of the millennium.” The practice was prompted by the realization, in the late 1800s, that bacteria were the cause waterborne infections like typhoid fever, dysentery, and cholera.  About the same time scientists learned that the element chlorine kills bugs.  When a municipal water sand filter failed in a city in England in 1905 there was a typhoid outbreak, and the city started adding chlorine to their municipal water. Three years later Jersey City, New Jersey started chlorinating city water.  Chlorine is currently added to “over 98 percent of all U.S. municipal water,” and outbreaks of typhoid fever have been virtually eliminated.  (Chlorine does not kill parasites like Giardia and Cryptosporidium.)

In the last century we’ve learned a lot about diarrheal diseases and their treatment.  But the slums of many third world cities don’t have good plumbing.  Much of the world’s fresh water is contaminated.  For half of the world’s people governments haven’t been able to solve the problem.⁴⁴   One in 9 childhood deaths are the result of diarrhea and the culprits responsible include bacteria like E. coli, salmonella, shigella, and cholera.

When I was a freshman med student a biochemistry professor who looked like the movie star Robert Wagner was trying to prove that water didn’t just passively flow into our bodies through the wall of the small intestine.  Salt and water are sometimes pushed in by a glucose fueled biochemical pump.⁶³

I took notes when he lectured and I passed the exam, but I didn’t know why it mattered.  Why would a person spend years of his life learning how salt and water moves across a membrane.  ?

          I later learned that when the cholera bacteria infect the small bowel the bug causes a large amount of liquid to leak into the intestines and those infected develop watery diarrhea. At the same time their small bowels don’t absorb much fluid and many die of dehydration.

Our lecturer, Robert Crane showed that if a teaspoon of salt and two tablespoons of sugar are added to a liter of clean water, a biochemical “force” drives liquid into the body and the person can be rehydrated.  His simple formula has saved more lives than most of the $100,000 a year drugs being advertised on television.  Somebody bottled it and called it Pedialyte. 

Self described as a problem solver, Crane was born in New Jersey and didn’t develop an interest in science until he was a freshman in college.  During the Second World War he was a deck officer on a navy destroyer that “took a bomb” at the battle of Leyte Gulf and was later part of the screen of ships that carried Douglas MacArthur back to the Philippines.  Crane got his PhD in chemistry at Harvard, married a biochemist, and spent more than a decade performing research in St Louis.  In 1978 he was awarded the Nobel Prize .

In 1991 a massive Hurricane blew across Hispanola, the Caribbean island that is shared by the Dominican Republic and Haiti.  At the time there hadn’t been cases of cholera in Haiti for more than a hundred years.  The U.N. brought in relief workers from Bangladesh and they lived with the people.  70% of Haitian households had either rudimentary toilets or none at all.  A few months after the volunteers arrived, the water people drank was spreading the kind of Cholera bacteria that infects people in Bangladesh.  665,000 Haitians were infected and over 8000 died.  15 years later a non-profit called SOIL is supplying compostable toilets and trying to help solve the island’s waste problem.⁶²  

In addition to the drinking water we’re sometimes impacted by the water that flows from our cattle feeding lots.  E.coli was recently found in Romaine lettuce grown downstream from an area where cattle were confined.  In 1987 sewage from farm animals infected with the parasite cryptosporidium overflowed in Georgia and 13,000 people developed diarrhea.⁴³

Hormones are chemical messengers. They are created in an “endocrine gland” then travel by blood and other mechanisms to parts of the body where they do their thing.  If a man is given estrogens he grows breasts.  If a woman is given male hormones she grows a beard. 

One of the endocrine glands, the thyroid gland is located in the middle of the neck, just below the voice box and above the chest.  The story of the gland and the hormones it produces is both old and new.  It’s complex enough to deserve a chapter or a book, and that’s not what I’m currently writing. 

Mankind has dealt with the thyroid gland for thousands of years, in large part because when it gets big it’s hard to ignore.  In parts of the world benign growths called goiters once commonly protruded from the front of many necks. We now know that the condition is caused by a deficiency in Iodide.  Thousands of years ago Chinese doctors knew that seaweed helped.

The mass is currently gone from much of the world because most countries require salt to contain iodide and it’s routinely added.  In the U.S., the land of freedom of speech and religion, our salt is often free of iodide.  Fortification, putting iodide into salt is voluntary and often not done.  Companies don’t have to mention the iodide content of a product on the label, and processed foods commonly use non iodinated salt.^64,65 

In the absence of enough iodide newborns don’t make enough thyroid hormone, their growth can be stunted, and they can develop physical deformities and neurologic impairment.” The condition is called cretinism and it was recognized over the years by a number of physicians. 

Once we had adequate anesthesia, a few surgeons started removing thyroid glands that were too big or were cancerous.  The operation was bloody, we didn’t know how to transfuse blood, and before Theodore Kocher started performing the surgery many died.

One of the brightest students at his Swiss university, Kocher was not, best I can tell, formally surgically trained.  One of the talented and intuitive few, he apparently developed his skills by observing a few British surgeons and by trial and error.  Born, raised, and a lifelong resident of Bern, a centuries old Swiss city encircled on three sides by the Aare River, he was once described as “a slight, rather cadaverous little man with a close cropped beard and very large, prominent upper teeth made his smile rather ghostly.”  Aside from work he had few interests His vacations were mostly trips to medical meetings.  Deeply religious and adamant about sterility, he told students whose patients had developed an infection to stand, beat their breasts and say “I sinned.”

He learned that the thyroid was a vital organ the hard way.  In 1882 a physician in Geneva reported on the changes that occurred to 10 patients whose thyroids were totally removed a few years earlier.  Kocher heard the paper and asked a few people he had operated on to come in for an evaluation.  One woman in particular bothered him.  She “had changed from a pretty young girl to a small woman who was overweight, and slow of intellect and speech. She had lost hair and had a thick tongue.” Realizing the lack of thyroid was the cause her changes Kocher “vowed to never again to remove the entire gland.”

He was a colonel in the Swiss militia and spent some of his non medical time trying to get the makers of weapons to create missiles that didn’t deform and were “intentionally less lethal.”

His operations were meticulous.  Large goiters and cancer of the thyroid were removed slowly and with little or no blood loss.  Surgery took a long time and the slow pace irritated many of the spectators who gathered for the show. 

By 1912, Kocher had removed approximately 5000 thyroid glands and the mortality rate in his hands was less than one percent.  For this accomplishment and for his studies on the gland and how hormones function he received the Nobel Prize in 1909. 

I don’t know when or if Kocher started treating people with animal extract after surgery.  The books give the credit to George R. Murray, a 26 year old physician who didn’t have a hospital or medical school appointment.  In 1891 he obtained fresh sheep’s thyroid from a slaughterhouse, prepared an extract, and injected it under the skin of a woman who looked like she was markedly deficient in thyroid.  When she improved he published his experience.  Though others have probably used similar treatments for decades or centuries, Murray was the first rooster to crow and the books claim he was the first doctor in recent centuries who extracted and administered the hormone.^60,61 

https://www.surgjournal.com/article/0039-6060(69)90069-5/pdf

By the time I became a physician narcotics had long been used for pain control and had an age-old disreputable history.  Mentioned 4000 years ago by Aristotle’s buddy Theophratus, the extract of the poppy plant, was long known as a drug that relieved pain, affected moods, and created a craving and an addiction.

          In the 1700s the British developed a love for tea grown in China and the UK was shelling out a lot of silver for the leaves.  Needing a commodity the Chinese would buy, the Brits grew poppies in India and peddled its extract, opium, in China.  It sold well.  Many got addicted and silver started flowing back to England.   By the 1800s Chinese leaders, troubled by the way the drug affected the people and upset because so much silver was leaving the country, started the world’s first war on drugs.  They forbade the British from trafficking opium.  The Brits responded by sending 16 warships.  They “arrived at Guangzhou, bombarded forts, fought battles,” and won the first opium war.  As spoils of their victory, the English gained control of the island of Hong Kong and access to 5 Chinese ports.

In the early 1800s at a time when purified plant extracts were used as medicines, Wilhelm Serturner was an apprentice apothecary in Paderhorn.  The town bordered Germany’s shortest river and was founded by Charlemagne in the eighth century.  After separating “morphine crystals from tarry poppy seed juice,” Serturner learned the crystals put stray dogs and rats to sleep.  Taking “a small quantity” for a tooth ache, he “experienced tremendous relief.”  A low dose made three volunteers “happy and light headed.” A higher dose caused “confusion.⁵⁸” Over time Serturner became an addict.  He was once described as a person with “aggravated hypochondriacal alterations in his frame of mind and quiet disturbances of mood.⁵⁹”

In 1844 Francis Rynd, a Dublin physician who hunted foxes and was “in much demand at “fashionable dinner parties”, invented the hollow metal needle.  A decade later a physician in Edinburg and another in France independently invented the syringe.  In the process they helped people in pain and created an instrument that would lead to countless infections and the addiction of many.

In 1897 two traveling salesmen from North Carolina met at a train station in Texas and learned they had the same birthday.  A decade later, now entrepreneurs, Beckton and Dickinson started the first U.S. facility that produced hypodermic needles and syringes.

Chapter 2 Anesthesia and transfusions

In 1900, 76 million people lived in the U.S., 200,000 miles of railroad tracks criss-crossed the continent and people traveled in horse drawn carriages and wagons on narrow dirt and gravel roads.  Trains dominated commerce, the modern internal combustion engine was 15 years old and 1575 electric and 900 gasoline powered vehicles were produced each year.

Electricity was new and scarce.  Thomas Edison’s incandescent light bulb was 20 years old and an American city, Cleveland had started using electric lamps to illuminate some of its streets.    

Sixty seven years had passed since drinking water was first pumped into the White House from a nearby reservoir; Chicago’s “comprehensive sewer system” had been up and running for 15 years, and a revolutionary toilet made by Thomas Crapper’s was 9 years old.⁸

House calls were common.  People who had suffered heart attacks, strokes, or major trauma were often cared for at home.  Adequate anesthesia was made elective surgery painless. But in the decades that preceded blood banking and antibiotics, cutting a body open was risky. 

My wife had two uncles who died in the 1930s from a strep throat, an infection that’s currently rapidly cured with a few doses of an antibiotic. A family member who had a severe asthma attack and who was getting exhausted responded to medications and didn’t need to be intubated and placed on a breathing machine. Another who was stung by a bee and developed anaphylactic shock was treated aggressively and was well enough to go home the next day.  Either relative could have died a century ago.

The 20^th and 21^st centuries were filled with transformative medical advances and I chose a few that I think were game changers. 

1.  Anesthesia, the first “game changer” got its start in 1846.  A monument in the Boston Public Garden commemorates the day that William Morton proved to the world that “the inhalation of ether causes insensibility to pain.”
2.  The second:  Early in the 20^th century we learned how to collect, store, and “safely” transfuse blood.

ANESTHESIA

The Tombstone in the Boston Cemetery marks the site of the “Inventor and Revealer of Inhalation Anesthesia: Before Whom, in All Time, Surgery was Agony; By Whom Pain in Surgery was Averted and Annulled; Since Whom, Science has Control of Pain.” 

The demonstration of Ether’s effect occurred in a Boston Hospital in October 1846.⁴   One of the nation’s most active, Boston’s Mass General Hospital was, at the time, hosting up to two surgeries a week.  They were performed in an operating room that was, in essence, a stage.  It was surrounded by a steep amphitheater.  People filled the seats and watched.  One October day the doctor in charge, Dr. Warren told the onlookers “there is a gentleman who claims his inhalation will make a person insensitive to pain.  I decided to permit him to perform his experiment.”

The dentist who administered the anesthetic, Dr. Morton, was described as being strikingly attractive and alternately optimistic and pessimistic.”  He arrived 25 minutes late, took out his narrow neck flask, and filled its bottom with two liquids:  Sulfuric ether and oil of orange. The second chemical was supposed to mask the ether odor.

The man who was about to undergo surgery inhaled “gas” through a mouth piece, and in 3 to 4 minutes he became “insensible and fell into a deep sleep.” He had a mass in his neck and the doctor quickly cut it out. When the operation ended Dr. Warren, the man’s surgeon, spoke to the rapt onlookers. Gentlemen, this is no humbug.  People cheered, and the public took notice.²⁶

          During the Civil War battle of Fredericksburg, Morton decided to help. When a wounded soldier was about to undergo a limb amputation Warren “prepared the man for the knife, producing perfect anesthesia in an average time of three minutes.⁹”

Once operations could be performed without pain surgeons started performing them and a number of hospitals were built or expanded.  Elective surgery became the cash cow that supported one institution after another.

In July 1868 William Morton was agitated because another doctor was trying to claim credit for his invention.  He was in New York, the city was in the midst of a grueling heat wave, and Morton took his wife on a wild carriage ride through Central Park.  Then he abruptly stopped the buggy, got out, and died. He was 48 years old.⁵

During the next century doctors and dentists used diethyl ether and later chloroform to put people to sleep.  Over the decades drugs changed, but the overall effect has largely remained the same.  One of the current anesthetics of choice is propofol, the drug that killed Michael Jackson.  It’s administered as an intravenous drip.  It starts and stops working rapidly and has a “low incidence of side effects like postoperative nausea and vomiting and cognitive impairment.¹ ”  Operations are also performed using spinal anesthesia, a nerve block or a local infusion of lidocaine. 

One hundred years to the month after Morton made his presentation I was asked to see a sick patient with jaundice.  At the time I was the assistant chief medical resident at the San Francisco VA hospital, a collection of buildings on the edge of the Pacific that were usually blanketed in fog and cooled by a breeze from the ocean. The man I examined had yellow eyes, was weak, had no appetite and was lying in his bed.   He recently had a hair transplant and otherwise had been well.  He’d been put to sleep with halothane, the anesthesia of the day. Plugs of his hair were harvested from the back of his head, and planted up front.

The patient told me this had been his second transplant.  He turned yellow the first time and thought he knew what was happening.  He had witnessed fellow service men that got hepatitis when he was stationed in the South Pacific.  He decided to not tell his doctor because he was afraid the physician wouldn’t perform the second set of hair transfers.

This was a few years before liver transplants were being done, so people with failing livers could not be rescued. The patient’s condition got worse, his abdomen filled with fluid, he sank into a coma, and he died. — And it happened because of a hair transplant.

Most anesthesiologists back then didn’t believe “so called” halothane hepatitis was a real entity and wouldn’t accept that the anesthetic they used could cause the problem.  They had “never seen” a case of liver failure that they couldn’t pin on one of their patient’s underlying medical conditions.  Halothane was a smooth, well tolerated anesthetic.  I was a budding gastroenterologist and I knew they were wrong.  Turns out that halothane causes liver failure and death in one of 35,000 patients. 

Anesthesiologists needed proof and they got it in 1969 after an MD anesthesiologist visited the Yale hepatologist, Gerald Klatskin.  The anesthesiologist said he turned yellow every time he administered halothane to a patient. Klatskin decided to test his theory.  He biopsied the man’s liver.  It was normal.  Then the anesthesiologist inhaled halothane and his eyes and skin turned yellow.  A second biopsy showed an injured liver.  Klatskin published a report of the case, and U.S. anesthesiologists stopped administering halothane.  It is still “widely used in developing countries.³”

Fast forward 40 years and I’m interviewing the chief of anesthesia at a local hospital.  He’s telling that nowadays general anesthesia is safer than crossing the street.  During the 50 years when the rest of medicine was inventing new operations and trying to cure more diseases, the top anesthesia thinkers were obsessed with safety.

They had long since learned how to put a person into a state where the patient heard and saw nothing, was impervious to pain, and had muscles that were totally relaxed.  When aroused some people had painful wounds, sensitive areas, inactive bowels, and bodily parts that didn’t function normally.  Grogginess could last a while.  But the recipients of general anesthesia had no memory of the trauma their body had endured. 

The anesthesiologist whose insights I’m channeling credits the emphasis on safety to the skyrocketing cost of malpractice insurance.  It became the focus of a number of physicians who “passed gas” for a living in the 1980s.  I’m sure doctors in the field thought their care was excellent and wondered why they were being singled out.  But the numbers said it all.  In 1974 three percent of all American doctors who bought malpractice insurance were anesthesiologists, and these were the very doctors who were responsible for 10% of all malpractice pay outs.  Outsiders concluded that the care they provided was “below the standard”.

          Malpractice is not a good way to judge medical quality.  Doctors are sued when something major goes wrong and when the responsible physician is arrogant or seems to be hiding something.  It’s also is easier to sue someone you have never consciously spoken to or interacted with, someone who has never become a real person with feelings and regrets.

Nonetheless rates were rising and something had to be done.  The anesthesia societies embarked on something they called the “closed claim project.”  They reviewed malpractice suits that had run their course, that had been litigated, settled or just dropped by the plaintiff.  Discovering what went wrong did not create a legal or other risk for the involved doctor.

Data for events prior to 1990 revealed that in a third of the cases, the person whose families sued had died or had suffered brain damage.  In 45 percent of these people the harm was caused by a “respiratory event”.  When anesthesiologists induce coma they become responsible for the movement of air into and out of the lungs.  They slide a tube through the mouth and pharynx, between the vocal cords, and into the bronchus.  Then they aerate the lungs and the body.  In 7 percent of the respiratory cases the anesthesiologist mistakenly slipped the breathing tube into the esophagus, the tube that transports food and drink to the intestinal system.  It is located above the vocal chords at the lower end of pharynx.  A sphincter at its top end keeps air from entering the gut and helps prevent regurgitation of esophageal contents.

In 12 percent intubation was difficult, and the body was deprived of air for a period of time.  In another 7 percent the doctor got the tube in the right place but didn’t ventilate the lungs adequately.

25% of the law suits were the result of cardiovascular events, arrhythmias of the heart, a drop in blood pressure, and heart attacks.

Nerve damage due to poor positioning and compression of nerves caused 21 percent of the problems.   

Anesthesiologists sometimes instill Novocain or alcohol into nerves in an attempt to mitigate chronic pain.  If they injected a person who was taking blood thinners they sometimes precipitated bleeding; damage caused by the leaking blood prompted some of the legal action. 

Six percent of the cases were prompted by burns caused by electrical cautery or by IV bags of fluid that were overly warmed.   

There were people whose blood pressure dropped and they lost vision, individuals whose airways had been damaged during a difficult intubation, and a few who had back pain, emotional distress, or eye injuries. (Anesthesiologists work close to the eyes.)

Seventy nine percent of the problems were attributed to lack of vigilance.  The specialty’s has an old saying:  putting someone to sleep starts with seconds of panic, (intubation) and is followed by hours of boredom.

 After the anesthesiologists learned what they were doing wrong they disseminated their findings, made recommendations, and general anesthesia became safer.

Anesthesiologists now have tools that make it possible to intubate almost everyone.  Small flexible instruments containing long fiberoptic bundles allow the anesthesiologist to see into dark corners.  Some scopes have chips on their tips and send images to a TV screen.  Anesthesiologists and anesthetists confirm the endotracheal tube is in the right place with a beside ultrasound examination and by measuring and monitoring the carbon dioxide level of air that exits the lungs.  If the level gets too high ventilation may be inadequate.  Since the blood of anesthetized people is enriched with oxygen, a high carbon dioxide concentration is more sensitive to air movement problems than a low level of oxygen. Complex machines that ventilate the patient regulate and monitor the movement of the gases.  Sophisticated gear has valves and gauges that are routinely checked.  Bells ring and beeps sound when something is amiss. 

In addition to physicians, 43,000 nurses administer much of the anesthesia in this country.  These nurses are educated, trained, licensed, and competent. In all but 15 states they are required to “work under a physician’s supervision”.

TRANSFUSIONS

Blood the liquid that carries nutrition and oxygen to every corner of our body is a mixture of cells and protein rich fluid.   Most of the cells are “erythrocytes” –red cells.  As they flow through the arteries of the lung the tiny discs discard carbon dioxide and acquire oxygen.  When they are propelled through the rest of the body the cells deliver oxygen and collect carbon dioxide.

We didn’t really start to understand the value and danger of transfusing the red solution until 1900 when a Viennese Physician and researcher, Karl Landsteiner, separated blood into its two components: Cells and serum.  “Many but not all normal sera will agglutinate the red cells of other normal persons. 

Landsteiner separated human beings into groups.  People in the same group could safely give blood to one another.⁸.”

A physician researcher, Landsteiner was six when his father died.  Raised by his mother Fanny, he was “so devoted to the woman that her death mask hung on his wall until he died.”  An esteemed professor, Karl was living in Vienna, the capital of the vast Austro-Hungarian Empire when the First World War ended.  His country had been on the losing side and the imperial lands were carved into many of the nations of modern day Europe.  That winter there were shortages and Landsteiner’s laboratory wasn’t heated.  One day “the Viennese poor cut down the trees around his house for firewood and tore away his fences.”  Feeling personally threatened, Landsteiner moved with his wife and children, to Holland.  During the next three years he lived and performed experiments in a “little cottage with a rose garden” in the seaside town, Scheveningen.  He was assisted by a man-servant and a nun who was “very devout and frequently quit the lab for prayers or to serve as an organist in the chapel.”  After accepting a position at the Rockefeller Institute, Landsteiner moved his family to New York and lived “on the floor above a butcher shop on a street with trolley cars.”  Avoiding social activities, he spent his days in the lab, and read and thought at night “until the late hour.”  “His energy was continuous and compelling, and no moment of idleness in the lab was tolerable to him.⁸”   He was living in New York in 1930 when he received the Nobel Prize.⁶

In the early 1900s, while still in Vienna, Landsteiner identified three blood types: A, B, and O. They were based on the antigens on the surface of red blood cells,  We now, of course, know that:                                                             

• A person with Type B blood has “B” antigens on the surface of his or her red cells.  Their serum contains antibodies to A blood—antibodies that cause type A red cells to stick together. 
• A person with Type A blood has “A” antigens on the surface of his or her red cells– and antibodies to B red cells in their serum
• If a blood type B person is transfused with Type “A” blood, the infused red cells will agglutinate—stick to one another and form a clump.   . 
• If B cells are transfused into someone with type A blood, the new cells will adhere to one another.
• People who are transfused with incompatible blood got quite ill and can die.  
• Individuals whose red cells have both A and B surface antigens on the surface of their red cells don’t have serum antibodies to either B or A.  They can receive–be safely transfused with A, B, AB OR O blood.
• Type O red cells don’t have antigens on their surface.  The serum of Individuals with type O blood contains B and A antibodies. They can’t safely receive–be transfused with A, B or AB cells, but their red cells can be instilled into people with any blood type. 
• In 1937 Alexander Wiener added another red cell surface antigen, the RH, Rhesus factor to the equation.

During the First World War years (1914-1918) a series of doctors learned that when they added sodium citrate to blood it didn’t clot.  With additional additives it could be stored for 2 weeks. 

The notion that blood circulates and that it can be transfused was “based” on the observations of a Brit named William Harvey. In the 1600s he cut open a few living fish and snakes, and learned (and wrote) that the ancients were wrong.  Blood didn’t come from the liver and slowly ebb through the body.  Its flow was “propelled by the heart” and the red stuff traveled through tubes called arteries.  In the 1800s a few doctors used a syringe to remove blood from one person and directly inject it into the vein of another.¹ It helped some and harmed others.

The first blood bank was set up by the Russians in 1932. Doctors at Chicago’s Cook County Hospital are given the credit for opening the first American facility. It started to “save and store” donated blood in 1937.  San Francisco’s Irwin Memorial blood bank was established 3 years later.  

When blood, plus a chemical that prevents clotting is put in a test tube, the cells settle to the bottom and the plasma floats to the top.  For blood loss or significant anemia packed red cells or erythrocytes can be transfused. Each tiny disc lives for 120 days.  In transfused blood half the red cells are new and half old, so the average cell in a unit of blood should last 60 days. 

In the test tube full of blood, immediately above the red cells there’s a thin layer of white cells and a stratum of platelets.  The cells and particles only live a few days.  White cells are an important contributor to our defense against infection.  In transfused blood they can cause adverse reactions.  When chemotherapy suppresses the bone marrow white cell levels can get quite low.

Platelets are particles that plug holes and help stop bleeding. Some chemotherapy drugs can significantly suppress their blood levels for a number of days.  When the risk of bleeding is high enough platelets are collected from others and infused.   Blood banks have machines that separate and collect platelets, then reinfuse the platelet poor blood back into the donor.  

In 1940, a year and a half before the U.S. became combatants in the Second World War, London was being bombarded by Nazi planes.  Many in the U.S. wanted to aid the wounded, and an effort to provide the cell free portion of the blood, the plasma, to the Brits was started in New York.  Called Blood for Britain, the organizers attempted to collect thousands of units of blood, separate the cells from the plasma, and under sterile conditions ship the fluid across the Atlantic.  It was a huge undertaking and the man in charge had previously only organized a group of people once.  As a young man, he coordinated the paper routes of ten childhood friends who were delivering 2,000 newspapers a day. 

When he was still a trainee the doctor who was chosen to coordinate the effort, Charles Drew, studied the preservation of blood products.  He wrote a doctoral thesis titled “banked blood”, and he knew how to produce plasma that had a two month shelf life.  Gathering, transporting and processing thousands of units of blood was a complex undertaking but Drew pulled it off and was able to send close to 15,000 pints of the precious fluid to the Brits.  A black man, Drew was born in Washington D.C. and was an outstanding high school athlete. He was Amherst University’s most valuable football player in 1926, went to medical school at McGill University in Canada, and graduated in 1933. In 1941 he became the director of the first U.S. Red Cross blood bank. It was a big honor but he didn’t stay very long.  He resigned because the organization labeled each unit of blood with the donor’s race and didn’t give blood from a black donor to a white patient. He’s credited with saying “No official department of the Federal Government should willfully humiliate its citizens; there is no scientific basis for the practice; and people need the blood.”  Drew returned to Howard University and became the chief surgeon at Freedmen’s Hospital.⁷

By the time I entered med school (1958) blood drives had come to my campus annually, and I had been a donor twice.  The Red Cross proudly boasted that it saved the lives of wounded service men and women.  People who were hemorrhaging or very anemic often needed transfusions.   When I graduated in 1962 there were already 4400 hospital blood banks and 178 Red Cross and community facilities.  I never knew what medicine was like before transferable blood was readily available. 

In 1997 several San Francisco Bay area blood banks merged and called themselves Blood Centers of the Pacific.  The non -profit corporations collected huge amounts of blood (200,000 units a year) from willing voluntary donors.  They then checked it for blood type and for disease, fractionated the fluid into its various components, and sold– supplied it to more than 60 hospitals.  Their annual budget exceeded $40 million.

The blood supply is relatively safe in part because of the outrage of an angry man.  In the 70s a California legislator named Paul Gann capped our property taxes.  That made him famous.   But the legislation that bears his name, the Gann Act, has nothing to do with taxes.  It deals with transfusions.   It seems that around 1982 Gann had heart surgery and was transfused.  5 years later he discovered he had HIV.  The blood he received came from someone who was infected with the AIDS virus.  Either the blood donor had not been adequately screened or the blood Gann received was not tested carefully enough.  Gann was furious and apparently felt:  “there oughta be a law.”  So he wrote one. 

Prior to elective surgery California doctors must tell patients that they can store their own blood and have it available should they require a transfusion.  Stock piling blood prior to planned surgery can be tedious and costly.  But it’s intuitively better to get your own blood back than it is to receive that of another.  It’s also the law, so if the patient wants it we do it.  The act also says people can refuse blood from the “bank” and, instead get it from a donor they designate.  The idea makes sense, but the blood from a friend or loved one is no longer safer than banked fluid. Before a unit of blood is given it must be tested for the usual suspects, and it’s logistically near impossible to collect, check, and process designated blood in an acute or urgent situation. 

Before Gann’s outrage some blood bank executives argued that if they looked at blood too carefully they would have to reject many donors, throw away too many units.  Doctors wouldn’t be able to treat the ill.  People would die.  After the Gann incident blood banks (which were pretty good at questioning people about risk factors) got serious about screening blood for HIV, HTLV, Hepatitis B, Hepatitis C, (and a few other illnesses such as mosquito born West Nile virus, Zika, Cytomegalovirus, Chagas, a parasitic disease whose normal habitat is Central and parts of South America, and Babesia, a parasite found in New England that is transmitted by ticks.)

We’re apparently NOT yet testing the 11 million units of blood Americans use each year for dengue, a disease transmitted by mosquitoes that’s common in South East Asia— or for Chikungunya, a West Africa disease that was responsible (between 2014 and 2016) for the fever and joint pain of 4000 American travelers.  Most of them had recently visited a Caribbean island.⁵. And we don’t test for Hepatitis E, the most common type of hepatitis in India and parts of Asia.² 

Before 1996 blood banks identified viral diseases by checking for the presence or absence of specific antibodies in the serum.  When a virus invades a body, the immune system reacts and makes detectable antibodies.  It was believed that blood that did not contain certain antibodies should not be infectious.  To prove their blood was safe blood banks participated in studies on people who were transfused with blood whose antibody levels had been tested.  2.3 million transfusions were given during the study period and people were subsequently evaluated to see if they remained disease free.  One in every 493,000 infused units caused HIV; Hepatitis C was seen after one in a hundred thousand transfusions, and Hepatitis B one in 63,000.³ Screening was good but imperfect.  During the early weeks after a person is infected, the virus incubates and its number grow.  It takes a while before measurable antibodies develop.  So blood can be contagious when the antibody tests are negative. 

Over time PCR technology improved and we were able to directly detect and measure miniscule amounts of virus. (PCR is like a Xerox machine for DNA.  It allows technicians to make millions of copies of the original, to turn a tiny amount of stuff into a wad large enough to analyze and learn what we are dealing with.)   In 1999 blood banks started using the technique to screen all 66 million units of blood that were transfused.  Between 2006 and 2008, with PCR testing being used, the recipients of 3.5 million Units of blood were checked to see if they had been infected with any of three common chronic viral diseases.  One in 1.85 million units of blood that were free of “measurable” viral particles caused an HIV infection; one in 246,000 transmitted hepatitis C, and one in 410,000 gave the recipient Hepatitis B. We’re not perfect yet.⁴ 

While blood is donated freely, screening the donor, and acquiring, testing and distributing the red stuff is expensive.  A recent survey put the cost of a unit of transfused blood at $522 to $1,183.  In most hospitals much of the blood is used at the time of surgery.   Hospitals vary in size and in the numbers and the types of operations performed.  So it’s not surprising that, in the same survey, acquired blood cost $1.6 million to $6 million per hospital annually. 

Chapter 3 –20^th century tetanus, parasites, hormones

Early in the First World War, 8 of every thousand wounded British troops in France developed tetanus, also known as lockjaw.  When dirt got into their wound and the skin healed, bacteria were trapped and the germs that didn’t require oxygen thrived.  One of the organisms that commonly live in the soil, clostridium tetani, doesn’t usually cause a terrible infection but the germ produces a lethal toxin.  An average of eight days after a soldier was wounded, enough of the poison had often entered his body.  Jaws tightened, muscles became rigid, and breathing and swallowing became difficult. 

The development of a toxoid, an antibody that blocks the venom and prevents “lockjaw” was the result of research performed by 2 men.  One, a physician named Shibasaburo Kitasato, was born in a mountainous village on the southern Japanese island, Kyushu.  He became a microbiologist and the Japanese government sent him to Berlin, to Koch’s lab.  He was the first to grow a pure culture of the tetanus bacillus.  In 1890 he and another researcher “injected sub-lethal doses of tetanus toxin into rabbits.” They produced an antitoxin that, when injected, blocked the poison.  They did not, however, develop the vaccine that prevents the disease.      

The vaccine was created in 1924 by a French veterinarian, Gaston Ramon. He inactivated the deadly poison with formaldehyde.  Then he added an “adjuvant”, a chemical that boosts the immune response to the now weak and no longer lethal toxin.¹⁵ His creation, which also led to the development of the vaccine that prevents diphtheria, saved countless lives, and he was nominated for the Nobel Prize 155 times.  He never won.

By the time the U.S. entered the Second World War the army was routinely using the vaccine for tetanus.  Though there were over 2.5 million wounded soldiers during the conflict, and only 12 developed cases of lockjaw–tetanus.  Four of those individuals probably didn’t get all three shots. 

PARASITES

As a freshman med student, I attended a weekly class and was introduced to a large number of bizarre appearing microscopic creatures. I don’t recall many of the details I crammed into my brain for the final exam, but I’ll never forget the take home message.  It was written on the chalk board by the good natured Japanese professor and is probably the only thing that most of the giggling medical students remember to this day.  DES.  Don’t Eat Shit. 

By the time I entered school, the discoveries of Pasteur, Koch, and Lister were ancient history and a whole new class of invaders called parasites had been identified.   Dozens of scientists had isolated and studied the life cycle of one creature after another.  We learned that when people defecate in the open (and half a billion people in India still do) bacteria and parasites are deposited in the dirt and they get into our rivers.  Some of the organisms can enter the bodies of the animals and fish that we sometimes eat raw.  When we walk barefoot on ground where someone previously defecated, parasites can penetrate the soles of our feet.

Humans currently co-exist with 90 common species of parasites.  Most are mainly found in the tropics.  Some were apparently inherited from our primate ancestors in Africa.  The tape worms and round worms that live in our intestines and thus share our meals were visible to the naked eyes of Hippocrates and physicians of Rome, China, and of the Arab Empire during the first millennium.

Most of the parasite life cycles were worked out by researchers all over the globe before the Second World War.  There are a number of drugs with a variety of toxicities that have been developed and can kill the creatures. We don’t need them much in the developed world because parasites are not a major problem in most places that have good sewage, vector control, and clean water.  But a problem may be brewing.  Close to 200,000 Americans sleep outside most nights and the government doesn’t provide adequate facilities to protect them and, in turn. protect us from the microscopic creatures. 

The chief drug that’s used to kill intestinal parasites was patented in 1975 by Smith Kline.  It was created by Robert J. Gyurik and Vassilios J.Theodorides, after Vassilios read an article, had a sudden insight, and sketched the chemical structure of the future medication.  Raised in a small Greek village near the Macedonian border, the drug’s inventor, Vassilios, starts the tale of his youth by telling of the morning in 1941 when 400 German soldiers surrounded his town and marched its 1600 occupants to the village center.  He was 10 years old.  The soldiers told everyone to bring out their guns.  Then they searched the houses.  Finding shotguns in two homes they tied the owners of the weapons to a tree and publicly shot them.  Later that day a German soldier was searching Vassilios house. He saw a shotgun behind a door and motioned to Vassilios–hide it. When he left Vassilios threw the gun in the bushes and was grateful.

To attend school the young man had to walk an hour and a half to another village.  He was in that nearby town the day in 1947 that Communist soldiers burned his village and killed 48 people.  Some were relatives. A good student, Vassilios found school to be easy and interesting.  After he finished high school, planning to become a mathematician, he visited the university office and asked where the mathematics school was.  The clerk asked: what’s wrong with the Veterinary school?  And Vassilios decided to give it a shot.  As a veterinary student he developed an interest in research and decided he needed a PhD.  His future wife’s family had emigrated to Boston and Vassilios decided to follow her.  He came to the U.S., married the girl, earned a PhD, and worked for Pfizer in Terra Haute Indiana for two years.  There were only two Greek families in town.  The other Greek was the mayor.  Vassilios’ wife was unhappy and they moved to Pennsylvania where he got a research job at Smith Kline and French laboratories. 

A few years later he read an article, and had an “aha” moment.  Unexplainably he somehow “knew” the steps he would have to take to create the chemical that became Albendazole. (Quoting Pasteur he explained “God helps the minds that are prepared.”)  Introduced in 1977, the medication was initially given to animals in Australia and New Zealand, but it was not approved for people in the U.S.  Someone at the FDA decided it was carcinogenic.  Vassilios met with scientists at the agency and showed them that their “mathematical approach in evaluating the drug’s potential carcinogenicity was incorrect.”  The officials at the FDA agreed and humans started using it in 1982.  

Twenty eight years later the company that owned the drug had merged with two other pharmaceutical giants and was called GlaxoSmithKline, (GSK).  It had offices in over 100 countries, and was headquartered in Brenford, a “town” in greater London where Julius Caesar crossed the Thames River during his 54 BC invasion of Britain.  By October 2010, the drug had become a financial loser and the company dumped/sold it.  The marketing rights for the major anti-parasitic drug, was picked up by Amedra pharmaceuticals, a small American drug company.  The details of the deal were not disclosed (or at least I couldn’t find them on the web.)  As part of the agreement GSK agreed to continue manufacturing the medication for Amedra in the short run.   They also renewed their pledge to the World Health Organization.  They would continue to give the organization 600 million tablets per year as their contribution to the struggle to free the world from Lymphatic Filiariasis. 

As explained by the CDC: “Lymphatic Filiariasis (LF) is a mosquito-borne parasitic disease caused by microscopic, thread-like worms.  They “inhabit the lymphatic and subcutaneous tissues” and prevent liquid from flowing through the lymphatic vessels.  The country roads of the body, lymphatic vessels flow in an upward direction and empty into the large subclavian (under the collar bone) veins.  On their way they pass through lymph nodes that filter toxins.  The fluid within them transports infection fighting white cells.   

Filiariasis affects 120 million people in 80 countries.  People with the condition develop swollen limbs, breasts and scrotums and their skin becomes thick and hard.”  The Global Alliance is trying to rid the planet of the parasitic disease by annually giving albendazole and Ivermectin to all of the occupants of communities that are at risk.³

The year after Amedra bought Albendazole, generic medication manufacturer Teva, stopped manufacturing the drug’s only U.S. competitor, Mebendazole (brand name-Vermox), and Amedra became the only U.S. player in the intestinal parasite business. With the U.S. rights in their pocket, its new owner dramatically increased the amount they charged for the medication.   In late 2010, the average wholesale price was “$5.92 per typical daily dose”.  By 2013 it had jumped to $119.58. 

In India Albendazole commonly sells for $18.  According to Wiki, in some countries it costs a penny to 6 cents a dose. 

The parasites albendazole targets, helminthes, live in the intestines of a billion people. Usually acquired in childhood, the creatures are sometimes ingested with tainted food and water.  When mature, some worms can penetrate the skin of a child or adult who walks “barefoot on contaminated soil.”  Much as a butterfly spends part of its existence as a caterpillar, the parasites who camp in our bodies have a life cycle.  Some spend part of their existence in a cow, pig or fish and gain entrance to a person’s body when people eat raw meat or uncooked fish.  As Giovanni Grassi, an almost world famous Italian researcher (he should have shared the Nobel Prize for Malaria) demonstrated in 1881, the worms can go directly from man to man. He started an experiment to prove his point by examining his feces to prove he wasn’t infected. Then he ate ascaris eggs.  (Ascaris is a round worm that travels through the lungs on its way to its home in the intestines.) A bit later he found the parasite in his feces. In 1922 a Japanese pediatrician, Shimesu Koino one-upped Grassi when he ingested ascaris eggs and found worms in his sputum.  Such, as they say, is how research on parasites was performed.

Medicaid spent less than $100,000 per year on Albendazole in 2008, and more than $7.5 million in 2013.  Doctors in this country are prescribing it more often because the CDC (center for disease control) thinks we should presume that refugees that come here from poor countries have parasites in their intestines, and we should treat them. 

One day when my grandson, who had never lived in a third world country, was 3 or 4, he passed a worm.  My daughter checked the internet, identified the creature and put it in a jar.  When she showed it to her doctor he was taken aback– amazed.  His nurse, on the other hand, merely shrugged. No big deal.   She had grown up in a village in the Philippines.  We still have no clue as to where or how the worm got in the kid’s body.

A totally different kind of parasite lives in the bodies of millions of people in sub-Saharan Africa, some South American countries, a few countries in Asia and is common in parts of South Africa.  Called Shistosomiasis or bilharzias it “affects close to 240 million people in the world and it’s found in the fresh water ponds of Puerto Rico.  In 1960 the U.S. Army had a research facility that studied the creature.  It was situated on a bluff overlooking the balmy Caribbean, and I spent one med school summer working in the lab. A fellow student and I would drive to an inland body of water, put on protective hip boots and trudge into the ponds. The snails of Puerto Rico are part of the life cycle of a parasite.  An intermediate life form of the creature exits a snail, enters the water, and penetrates the skin of people who wade in the island’s fresh water ponds.  Once inside a person’s body the parasites make their way to the liver or urinary tract and lay eggs.  Our body’s reaction to them can cause significant damage. 

We scooped the snails up with a net, carried them back to the lab, and placed them in sunlight.  The snails discharged– “shed” miniscule worms.  We gathered the tiny parasites, they are called cercareiae. And we put them into test tubes.  Then we dipped the tails of mice into the liquid.  Weeks later we studied the infected mice.

In the 20^th century we learned of at least one malaria like parasite that is transmitted by a tick.  Called Babesiosis, it enters a person’s body when an infected tick bites and it invades red cells, causing chills and fever.  It can be lethal. 

The most common infection that ticks spread is caused by a bacterium that’s technically a spirochete. Called Lyme disease it is named for the town in Connecticut where it was identified.  In the mid 1970s Mrs. Murray, an artist who had been living in a house near a picture post card rural country road for 15 years, developed rashes, painful swollen joints,  and numbness and weakness.  Over the years she got worse.  She was hospitalized three times and unable to paint.  Some thought she was a hypochondriac.  Then her son developed joint pain and he couldn’t smile.  He had Bell’s palsy and his facial muscles didn’t work.  Another son developed a rash behind his knee and others in the town got ill.  It took a while before a young Yale physician and others discovered that some ticks carry a bacteria– a spirochete.  When the ticks bite the spirochetes are injected into a person’s body.  It often takes decades before the creatures causing Lyme have done their worst. 

During the last century we’ve learned, one by one, about the diseases that are transmitted by the bites of a ticks hiding in the long grass we hike through, the nearby woodlands, or the fur of a four legged companion.  The brown dog tick can carry the bacteria responsible for Rocky Mountain spotted fever.  It’s an infection that makes people quite ill but thanks to doxycycline is only lethal one time in 200. The bite of black legged ticks of the North East and Great Lakes area can introduce our bodies to Anaplasmosis, a bacterium that causes chills and fever and responds to antibiotic.  And there are others.  

In recent decades the Center for Disease control has been informing those who care about common and rare conditions with concise, disease specific posts on the internet.  They have a free newsletter, the Morbidity and Mortality Weekly report. Located in Atlanta Georgia, the federal agency was created a little over 70 years ago.  In its early days it concentrated on mini epidemics.  I recall a hepatitis outbreak in 1963.  It affected a number of the doctors and nurses who worked at the hospital where I was an intern.  The CDC sent a young sleuth.  He checked our plumbing, drew our blood, and inspected our kitchens.  It took a month but he figured out where and how the illness started.  When I was in the military a friend who was sent to help immunize a tribe of Native Americans in the state of Washington came through town.  My brother-in-law was sent overseas to help determine the dose of gamma globulin that would keep soldiers in Viet Nam from getting hepatitis.  Currently a $6.6 billion a year department of the public health service, the agency collects data on acute and chronic diseases and makes recommendations.  Their epidemiologists investigate outbreaks, and they provide the laboratory and pharmacy of last resort for rare infectious diseases.  According to the Kaiser Health news, some experts are saying that “under President Donald Trump, the CDC has become a non-entity in the battle against the coronavirus.“⁵⁹

In the late 19th and early 20th centuries a number of hormones were discovered and isolated.  We learned what endocrine glands do and how they go wrong. 

Hormones are chemical messengers. They are created in an “endocrine gland” then travel by blood and other mechanisms to parts of the body where they do their thing.  If a man is given estrogens he grows breasts.  If a woman is given male hormones she grows a beard. 

Thyroid and adrenal hormones help regulate many of the body’s metabolic and other functions. When either is totally absent people wither and die. They are “vital.”

Adrenal glands sit atop the kidney and produce cortisone and a number of other hormones.  In 1940 war seemed likely and the government funded cortisone research allegedly because they believed the hormone would allow pilots to fly up to 40,000 feet without oxygen. .

Three people got the Nobel Prize for cortisone.  The first, Phillip Hench was a Mayo Clinic rheumatologist who loved Sherlock Holmes and had “one of the more remarkable Sherlockian libraries ever assembled.”  He liked mysteries and wanted to understand why his patient with jaundice suddenly got well or a woman he was caring for who had severe rheumatoid arthritis improved dramatically when she was pregnant.  Some hormone had to be responsible. 

His “Watson” was Edward Kendall, Mayo’s chief of Biochemistry.  Described as a charismatic man with a generous personality, by one writer—and as a person who “often didn’t get along well with his colleagues” by another, he spent the greater part of his professional life standing before a lab bench.  Working with 150 tons of adrenal glands, he extracted 9 million dollars worth of epinephrine for Parke Davis and he kept the material the company didn’t want.  Later he separated 5 cortical compounds from the organs.¹³

Collaborating with Hench, Kendall checked the urine of the people who unexpectedly got well and found adrenal compounds in both of the patients.   Kendall gave Hench minute amounts of one his adrenal extracts and Hench gave it to volunteers with arthritis.  It didn’t help.  

About that time they met Tadeus Reichstein.  He was a Swiss researcher who was born in Poland and had been named for Tadeusz Kościuszko, the Polish national hero who fought in the continental army during the American Revolution.  Tadeusz had learned how to extract adrenal hormones from bile.  I’m not sure what happened next but Dr Kendall and biochemists from Merck & Company produced 9 grams of adrenal “extract E.”  In 1948 it was given to a patient with rheumatoid arthritis and “The resulting improvement was amazing,” and all three researchers were given the Nobel Prize

Before Merck Sharpe and Dome learned how to manufacture commercial quantities of the hormone turned medication, “the New York Times published sensational stories and pictures.”  Many wanted to try the medication.  Scientists using cattle and sheep bile were only able to produce a limited quantity, and for a few years there was a cortisone black market, doctors didn’t know how to use the drug, and when it was used there were serious side effects.

.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1113923/

Cortisone and hydrocortisone became available after the Second World War:  The hormone saved Jack Kennedy’s life.⁷ Kennedy was the 35^th U.S. president and the son of a wealthy Irish immigrant.  In the 1940s he was diagnosed as having Addison’s disease, of having adrenal glands that didn’t make enough cortisone.  People with the condition are anemic, have abdominal pain, and lose weight.  Some have weak muscles and get dizzy when they stand.  The disease is usually the result of an immune system disorder.  20% of time Tuberculosis is the offender. When young Jack fought with his older brother he was always on the short end. As an adult Kennedy collapsed twice: once on a congressional visit to Britain and a second time at the end of an election campaign parade. That time “the diagnosing physician told one of Kennedy’s friends: “That young American friend of yours, he hasn’t got a year to live.³⁵”  

Over the last century pharmaceutical researchers have developed many oral, injectable, or topical cortisone derivatives.  Some are a little more potent or have fewer side effects, but they’re basically the same hormone. Most doctors who care for patients have used them for conditions as unrelated as swelling of the brain, joint inflammation, severe asthma, and poison oak.  I, like most doctors, developed an introductory pitch. This is a medicine but it’s also a hormone.  That means depending on the dose and the amount of time it’s taken, everyone who uses it has side effects.  They range from feeling good, hungry and having trouble sleeping to decreased immunity, thin bones, muscle weakness, and diabetes.

The body makes insulin in the islets of Langerhans, groups of cells that are scattered throughout the pancreas.  The hormone allows sugar to enter muscles and fat.  When sugar can’t get into the cells, the level of glucose in the blood rises.  People with juvenile diabetes have, over months to years, lost the ability to make insulin because their immune system has destroyed their beta, insulin producing cells. 

Prior to 1920 scientists knew where the hormone was made, but they didn’t know how to extract it intact.  Most of the pancreas makes digestive enzymes that enter the small intestine through the pancreatic duct.  The activated enzymes break food into small absorbable pieces–they divide the bonds that link the amino acids together to form proteins.  The insulin inside the pancreas can’t be extracted because it is “digested “when the pancreatic enzymes become functional.

In the early 1920s it was known that when the pancreatic duct of a dog was tied off the enzymes were activated.  They digested the dog’s pancreas but the animal didn’t develop diabetes. 

Two Canadian scientists, Banting and Best took the knowledge and ran with it.  Fred Banting, a Canadian surgeon had been a battalion medical officer during the First World War and his arm had been wounded by shrapnel.  After the war he had trouble finding work and needed the research job. His colleague, Best had just graduated from college. 

They tied off a dog’s pancreatic ducts and managed to keep the dog alive long enough for the pancreas to destroy itself. Then they removed the organ, chopped it into pieces, mixed it with saline, and filtered an extract.  As they hoped, the activated enzymes had digested most of the pancreas, but they hadn’t destroyed insulin.³ 

The discovery was momentous. A fatal disease could be controlled. For complex reasons the Nobel Prize for the breakthrough was only awarded to Fred Banting, but Charles Best, according to Banting, “was never credited with proposals that advanced the research.” The other half of the Nobel Prize for insulin was given to the head of the department, J.R. Macleod.

That bothered Best.  He had done most of the work.  He “developed a deep psychological hunger for recognition as a discoverer of insulin.” During the subsequent decades he and Banting worked together and “Banting developed an intense dislike of Best.” In 1940 Best was invited to come to London.  When he suddenly backed out Banting, now the head of the department, decided he would go.  Before boarding the plane and setting out for the distant world, before flying to war torn London, Banting’s last words were: “If they ever give that chair of mine to that son of a bitch, Best, I’ll roll over in my grave.” His plane crashed in Newfoundland, and he died.²⁵