the rest of the story

this is the story youyoutu told when she received the award:

“I was born on December 30, 1930 in Ningbo, a city on the east coast of China with a rich culture and over seven thousand years of history.

My father worked in a bank while my mother looked after my four brothers and me, the only girl in our family. Our family’s long history of highly valuing children’s education and always considering this as the family’s top priority allowed me to have good opportunities for attending the best schools in the region –I unfortunately contracted tuberculosis at the age of sixteen and had to take a two-year break and receive treatment at home.  Then I resumed my study at the private Ningbo High School (1948–1950) This experience, being ill and cured, led me to make a decision to choose medical research for my advanced education and career After graduation from high school, I attended the university entrance examination and fortunately I was accepted by the Department of Pharmacy and became a student at the Medical School of Peking University.

Most pharmacy courses were designed and taught by returnees such as Professors Lin Qishou (林启寿) and Lou Zhicen (楼之岑) who had received educations and advanced degrees in Western countries. Professor Lin Qishou gave a comprehensive introduction and hands-on training on how to extract active ingredients from the plants, how to select proper extraction solvents, how to carry out chemistry studies and determine the structures of the chemicals isolated from the plants etc. These courses provided scientific insights into the herbs and plants and more importantly.  They explained how these herbal medicines work, in a way different from traditional Chinese medicine.

China lacked medical resources in the early 1950s. There were only around twenty thousand physicians and several tens of thousands of traditional Chinese medical practitioners in the country   The Ministry of Health of China organized a number of full-time training courses in the late 1950s . In my two and a half year training program, I learned traditional Chinese medical theory and gained experience from clinical practice. Another training program I attended was on the processing (炮制) of Chinese Materia Medica.. Knowledge of such processing, in combination with the scientific explanation, benefited my work enormously.

Malaria is a life-threatening epidemic disease. It was, however, effectively treated and controlled by chloroquine and quinolines for a long period of time. Then most of the plasmodium parasites became drug resistant. 

In the late 1960s following the catastrophic failure of a global attempt to eradicate malaria. Resurgence rapidly increased mortality posed a significant global challenge, especially in the South East Asian countries.

 In the 1960s, the Division of Experimental Therapeutics at the Walter Reed Army Institute of Research (WRAIR) in Washington, DC launched programs to search for novel therapies to support the US military presence in South East Asia. US military force involved in the Vietnam War suffered massive casualties due to disability caused by malaria infection. Up to 1972, over 214,000 compounds were screened with no positive outcomes.”

https://www.nobelprize.org/prizes/medicine/2015/tu/facts/

China was in the middle of the great cultural revolution. “According to Wikipedia the cultural revolution wasa violent movement launched by Mao Zedong that lasted from 1966 until 1976.  Its stated goal was to preserve Chinese Communism by purging remnants of capitalist and traditional elements.  Mao called on the young people to rebel and insisted that revisionists who formed red guards to grab power.

The Cultural Revolution damaged China’s economy and traditional culture, with an estimated death toll ranging from hundreds of thousands to 20 million. There were a number of massacres.  Red Guards destroyed historical relics and artifacts and ransacked cultural and religious sites. Tens of millions of people were persecuted, purged, exiled and imprisoned. Notable scholars and scientists were killed or committed suicide. Schools and universities were closed and over 10 million urban youths were sent to the countryside.

According to Wikipedia the Cultural Revolution wasa violent movement launched by Mao Zedong that lasted from 1966 until 1976.  Its stated goal was to preserve Chinese Communism by purging remnants of capitalist and traditional elements.  Mao called on the young people to rebel and insisted that revisionists who formed red guards to grab power.

The Cultural Revolution damaged China’s economy and traditional culture, with an estimated death toll ranging from hundreds of thousands to 20 million. There were a number of massacres.  Red Guards destroyed historical relics and artifacts and ransacked cultural and religious sites. Tens of millions of people were persecuted, purged, exiled and imprisoned. Notable scholars and scientists were killed or committed suicide. Schools and universities were closed and over 10 million urban youths were sent to the countryside.”

 Youyou:  “Almost every institute was impacted and all research projects were stalled. A lot of experienced experts were sidelined. After thoughtful consideration, the academy’s leadership team appointed Youyou Tu to head and build “Project 523 research group” at the Institute of Chinese Materia Medica. My task was to search for ant malarial drugs among traditional Chinese medicines.

As a young scientist, I was so overwhelmed and motivated by this trust and responsibility. I also felt huge pressure from the high visibility, priority, challenges as well as the tight schedule of the task. The other challenge was the impact on my family life. By the time I accepted the task, my elder daughter was four years old and my younger daughter was only one. My husband had to be away from home attending a training campus. To focus on research, I left my younger daughter with my parents in Ningbo and sent my elder daughter to a full-time nursery where she had to live with her teacher’s family while I was away from home for the project. This continued for several years. My younger daughter couldn’t recognize me when I visited my parents three years later, and my elder daughter hid behind her teacher when I picked her up upon returning to Beijing after a clinical investigation.

Our long journey searching for anti malarial drugs began with collection of relevant information and recipes from traditional Chinese medicine.

Malaria was one of the epidemic diseases with the most comprehensive records in traditional Chinese medical literature, such as Zhou Li (周礼), a classical book in ancient China published in the Zhou Dynasty (1046–256 B.C.).

After thoroughly reviewing the traditional Chinese medical literature and folk recipes and interviewing experienced Chinese medical practitioners, I collected over two thousand herbal, animal and mineral prescriptions within three months after initiation of the project. From these two thousand recipes, I summarized 640 prescriptions

After multiple experiments and failures, I re-focused on reviewing the traditional Chinese medical literature. One of the herbs, Qinghao (青蒿) (the Chinese name for the herbs in the Artemisia family), showed some effects in inhibiting malaria parasites during initial screening, but the result was inconsistent and not reproducible. I repeatedly read relevant paragraphs in the literature where the use of Qinghao was recorded as relieving malaria symptoms.

In Ge Hong’s A Handbook of Prescriptions for Emergencies (肘后备急方), I noticed one sentence “A handful of Qinghao immersed in two liters of water, wring out the juice and drink it all” (青蒿一握, 以水二升渍, 绞取汁, 尽服之) when Qinghao was mentioned for alleviating malaria fevers. Most herbs were typically boiled in water and made into a decoction before taken by the patients.

This unique way of using Qinghao gave me the idea that heating during extraction might have destroyed the active components and the high temperature might need to be avoided in order to preserve the herb’s activity. Ge Hong’s handbook also mentioned “wring out the juice.” This reminded me that the leaf of Qinghao might be one of the main components prescribed. I redesigned experiments in which the stems and leaves of Qinghao were extracted separately at a reduced temperature using water, ethanol and ethyl ether.

Sample no. 191 was a symbolic breakthrough in artemisinin discovery.  We produced extracts from different herbs including Qinghao using the modified process and subsequently tested those ethyl ether, ethanol and aqueous extracts on rodent malaria. On October 4, 1971, we observed that sample number 191 of the Qinghao ethyl ether extract showed 100% effectiveness in inhibiting malaria parasites in rodent malaria. In subsequent experiments, we separated the extracts into a neutral portion and a toxic acidic portion. The neutral portion showed the same effect when tested in malaria-infected monkeys between December 1971 and January 1972.

Starting in March 1972, the team started to produce large quantities of Qinghao extract in preparation for clinical studies. Most pharmaceutical workshops were shut down during the great cultural revolution. Without manufacturing support, we had to extract herbs ourselves using household vats etc. The team worked very long hours every day including the weekends. Due to lack of proper equipment and ventilation, and long-term exposure to the organic solvents, some of my team members included myself started to show unhealthy symptoms. This, however, did not stop our efforts.

Some conflicting information was seen from the animal toxicological studies. It was already in the middle of the summer and very limited time was available to us before the malaria epidemic season would end. We would have to delay the study for at least a year if we continued our debate on toxicity. To expedite the safety evaluation, I got permission to take the extracts voluntarily. In July 1972, two other team members and myself took the extracts under close monitoring in the hospital. No side effect was observed in the one-week test window. Following the trial, another five members volunteered in the dose escalation study. This safety evaluation won us precious time and allowed us to start and complete the clinical trial in time.

Traditional Chinese medicine started with a story: “Shen Nong tasted a hundred herbs.” Shen Nong was an ancient Chinese medical practitioner. To understand the efficacy and toxicity of the herbs, he tasted over a hundred herbs himself and recorded all the details, which left us with a lot of precious information. Although Qinghao was prescribed as an herbal medicine for thousands of years, the dose of the active ingredients in these prescriptions was much lower than that in the Qinghao extract we tested. Our desire to get the clinical trial completed and have the medicine for our patients as soon as possible was the real driving force behind our action.

The first clinical trial on the Qinghao extract was carried out in Hainan province between August and October 1972. We treated a total of twenty-one local and migrant malaria patients, nine infected by Plasmodium falciparum, eleven infected by Plasmodium vivax and one with mixed malaria infections. The trial was successful: all patients recovered from the fevers and no malaria parasites were detected

We started isolation and purification of neutral Qinghao ethyl ether extract parallel with the clinical trial in 1972. We carried out a clinical trial of artemisinin between August and October 1973 using artemisinin tablets, which however did not yield the desired results. We examined the tablets returned from the clinical center and found that the tablets were too hard to disintegrate. We resumed the study using artemisinin capsules at the end of September 1973. Dihydroartemisinin was found in September 1973 in an experiment where I tried to derivatize artemisinin for a structural activity relationship evaluation. In a subsequent test in rodent malaria, we noticed that a significantly reduced dose was sufficient to achieve the same efficacy as artemisinin when dihydroartemisinin was administered.

Dihydroartemisinin is ten times more potent than artemisinin clinically, again demonstrating the “high efficacy, rapid action and low toxicity” of the drugs in the artemisinin category.  “Bench to bedside” – collaboration expedited translation from a discovery to a medicine. 

The herb Qinghao was frequently mentioned in the traditional Chinese medical literature for various clinical applications besides alleviating malaria symptoms. These applications include relieving itches caused by scabies and scabs, treating malignant sores, killing lice, retaining warmth in joints, improving visual acuity, etc. However, little explanation was given on either the species or effective parts of the plant in the traditional Chinese medical literature.

We carried out a thorough investigation and confirmed that only Artemisia annua L. (sweet wormwood) contains artemisinin. In addition to identification of the right species, we also verified the best regions for growing Qinghao, the best collection season and the officinal part of the plant.”

https://www.nobelprize.org/prizes/medicine/2015/tu/biographical/

China and Vietnam provide 70% and East Africa 20% of the raw plant material. Seedlings are grown in nurseries and then transplanted into fields. It takes about 8 months for them to reach full size. The plants are harvested, the leaves are dried and sent to facilities where the artemisinin is extracted using a solvent, typically hexane a straight-chain alkaline with six 6 atoms that is a colorless liquid, odorless and is widely used as a cheap, relatively safe, largely unreactive, and easily evaporated solvent.  Alternative extraction methods have been proposed. The market price for artemisinin has fluctuated widely, between US$120 and $1,200 per kilogram from 2005 to 2008. It also works on Shistosomiasis.

Artemisinin wiki https://en.wikipedia.org/wiki/Artemisinin

By the beginning of the 1980’s, China started to open up to the rest of the world and the Chinese scientists, including Li Guoqiao contacted professors David Warrel and Nicholas White from the Wellcome Trust and gave them access to data related to the use of artemisinin in the treatment of malaria. These data were first mentioned in a Wellcome Trust publication entitled A present from Chairman Mao (Gardner, 2002), which made these compounds known internationally. After this first encounter Nicholas White became a great advocate of artemisinin and through intense lobbying managed to convince the scientific community to take an active interest in these drugs This is also how a first Western company, Rhône- Poulenc Rorer (RPR, now Sanofi-Aventis), decided to study the potential of these drugs and license one of them, injectable artemether, from Kunming Pharmaceuticals. It took four years from the time of the first meeting in September 1989 to the launch in 1993. Negotiations were difficult as the manufacturer could not conduct direct discussions with a foreign company and had to go via a state organisation (Citic Group), which did not necessarily follow the same goals. Moreover, the Chinese government suddenly decided to promote its relationship with other emerging countries and all the negotiators found themselves having to pursue their talks in Brazil! Nevertheless, a contract was finally signed in July 1990 in the presence of Deng Zhifang, Deng Xiaoping’s youngest son (Fig. 1). But work only started: the technical dossier was not receivable and had to be totally re-written. New studies were requested, including animal toxicity studies though the product had already been widely used in man! Two major clinical trials were conducted, one in Vietnam (Hien et al., 1996) and one multi-centre in different African countries (Bougnoux & Ancelle, 1993Danis et al., 1996). Finally an approval for a limited use in French hospitals was granted, which allowed RPR to market this product in endemic areas.

These data were first mentioned in a Wellcome Trust publication  intense lobbying convinced the scientific community to take an active interest in these drugs (White et al., 1999). This is also how a first Western company, Rhône- Poulenc Rorer (RPR, now Sanofi-Aventis), decided to study the potential of these drugs and license one of them.  . It took four years from the time of the first meeting in September 1989 to the launch in 1993. Negotiations were difficult as the manufacturer could not conduct direct discussions with a foreign company and had to go via a state organisation (Citic Group), which did not necessarily follow the same goals. Moreover, the Chinese government suddenly decided to promote its relationship with other emerging countries and all the negotiators found themselves having to pursue their talks in Brazil! Nevertheless, a contract was finally signed in July 1990 in the presence of Deng Zhifang, Deng Xiaoping’s youngest son (Fig. 1). But work only started: the technical dossier was not receivable and had to be totally re-written. New studies were requested, including animal toxicity studies though the product had already been widely used in man! Two major clinical trials were conducted, one in Vietnam (Hien et al., 1996) and one multi-centre in different African countries (Bougnoux & Ancelle, 1993Danis et al., 1996). Finally an approval for a limited use in French hospitals was granted, which allowed RPR to market this product in endemic areas.  Not in 2010 washington u. manual

it was found that the artemisinin do not only affect the malaria parasites, but are also active against juvenile schistosomes, which was first shown by Chen et al. [25] at the end of the golden decade of antiparasitic drug discovery in the 1970s. In fact, this discovery predates that of scholarly articles on qinghaosu’s use against malaria, which remains its main application. From the New England Journal of Medicine. 

“Artemisinin derivatives, used in carefully developed combinations, have recently served as the first-line drugs against most uncomplicated malaria infections. Artemisinins are combined with other drugs so that the fast-acting artemisinin can immediately reduce parasitemia, allowing remaining parasites to be removed by a long-acting partner drug. Monotherapy with the artemisinin compound artesunate is used for initial management of severe disease.A slowdown in the clearance of parasites in patients treated with artesunate sounded alarms when it was first reported from Cambodia. Subsequently, similar delays in parasite clearance were noted in countries in Asian territories, including Myanmar, Thailand, Laos, and China, collectively referred to as the Greater Mekong Subregion.1 It was determined that parasites that were cleared more slowly after artemisinin treatment carried mutations in the propeller domain of the malarial kelch13 (K13) gene. Although K13 mutations are not reliably associated with increased risk of treatment failure, parasites bearing these mutations are now called “artemisinin-resistant.” Phenotypically, “artemisinin resistance” is defined as a delay in parasite clearance. These parasites recrudesce more frequently than artemisinin-sensitive parasites after standard 3-day therapeutic courses with artemisinin combination treatments (ACTs).

However, 3-day courses do not contain the full treatment doses of artemisinins needed to cure infections, which last 7 to 10 days, according clinical studies conducted in China. When a 7-day treatment course of artesunate is used, it is effective even when early parasite clearance is delayed.2 The same is not true of resistance to other classes of antimalarials, which results in a failure to cure the infection after a full treatment course.

Should a delay in parasite clearance with artemisinin treatments be defined as drug “resistance” or “tolerance”? Either way, 3-day therapeutic courses are losing their efficacy against malarial parasites in the Greater Mekong Subregion. So what matters most to patients and populations at risk is how we handle this emerging threat.

The history of artemisinin—from bark to weed  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671478/

Treatment failures with artemisinin combination therapy can be directly attributed to the partner drug, despite delayed-parasite-clearance phenotypes.2 For example, if piperaquine–dihydroartemisinin treatment is failing in a given region, another combination, such as mefloquine plus artesunate, may prove very effective.

NEJM   May 30, 2019

120 years later Malaria no longer affects people who live in countries that are able to control the vectors that spread it, but 40 percent of the world remains at risk.  According to Nicholas White, the Brit who is a professor of tropical medicine in Thailand, “Malaria is currently the most important parasitic disease of humans.  It has a huge humanitarian and an enormous economic impact, mainly in Africa where it causes the death of 2000 people each day.  Most who die are children. 

https://pubmed.ncbi.nlm.nih.gov/30954453/

The health care systems of our world have drugs that can be used to treat or prevent the disease. Centuries before western man learned what causes malaria and how it’s transmitted, natives in South America were using the quinine rich bark of the cinchona tree to treat the “shivers” that are a symptom of the infection. 

In the 1930s, Hans Andersag, a Tyrolian born researcher who worked at the Bayer facility in Western Germany deconstructed quinine and developed chloroquine,  an extremely effective anti-malarial medication.  It was used all over the world during the mid 20th century.  Brazil and a few other countries added chloroquine to salt and the USAID, the “humanitarian” agency created by U.S. president Kennedy, distributed over a hundred million of the pills.  In the 1960s the malaria parasites gradually became resistant to our drugs and the disease started re emerging.  A few decades later scientists started controlling the condition with derivatives of artemisinin, the extract of a plant that was used by Chinese healers as long ago as the 4th century.  The Gates foundation got involved in the 21st century, and the Swiss company Novartis packaged and sold Coartem, a medicine that is part artemisinin and part a weaker drug. Combinations of two or more medicines slow down the development of drug resistance.

The Novartis drug was too expensive for most of the people who lived in Africa and parts of Asia and was mainly taken by Westerners who worked in or visited countries whose mosquitos carry the parasite. I suspect the medication never contributed much to the company’s bottom line.   Over time Novartis lowered the price of Coartem twice, and in 2011 the company decided to spend $200 million, one 37th of its $7.5 billion annual research budget on Malaria.

The Development of Drugs against Chloroquine-Resistant Malaria

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393441/

The books Tu studied included:

-Zhou Li (周礼), published in the Zhou Dynasty (1046–256 B.C.).

-Inner Canon of the Yellow Emperor (黄帝内经)

from the Chun Qiu and Qin Dynasties (770–207 B.C.),

-Synopsis of Prescriptions of the Golden Chamber (金匮要略)

the Han Dynasty (206 B.C–220 A.D.),

General Treatise on the Causes and Symptoms of Diseases (诸病源候论) from the Sui Dynasty (581–618 A.D.)

-Qian Jin Fang–Prescriptions Worth a Thousand Pieces of Gold (千金方)

-Wai Tai Mi Yao = Secret Medical Essentials of a Provincial Governor (外台密要) from the Tang Dynasty (618–907 A.D.),

-Malaria (痎疟论疏) from the Ming Dynasty (1368–1644 A.D.)

-The Malignant Malaria Guide (瘴疟指南) from the Qing Dynasty (1644–1911 A.D.),

Prescription for Universal Relief (普济方) from in the Ming Dynasty, 1368–1644 A.D.)

She summarized 640 prescriptions in a brochure entitled “Antimalarial Collections of Recipes and Prescriptions” (抗疟单秘验方集).

From May 1969, extracts of over hundred herbs were prepared and tested in rodent malaria.  Up to June 1971 she found few promising results, and she re-focused on the traditional Chinese medical literature. One of the herbs, Qinghao (青蒿) an extract of sweet wormwood, was the Chinese name for the herbs in the Artemisia family.  It had shown some effects in inhibiting malaria parasites during initial screening, but the result was inconsistent and not reproducible. In Ge Hong’s A Handbook of Prescriptions for Emergencies (肘后备急方), Tu noticed one sentence “A handful of Qinghao immersed in two liters of water, wring out the juice and drink it all” (青蒿一握, 以水二升渍, 绞取汁, 尽服之)  Qinghao was used for alleviating malaria fevers. Traditionally most herbs were boiled in water and made into a decoction before taken by the patients.  In 1971 sample number 191 of the Qinghao ethyl ether extract showed 100% effectiveness in inhibiting malaria parasites in rodent malaria.

Traditional Chinese medicine started with a story: “Shen Nong tasted a hundred herbs.” Shen Nong 2696 BCE tasted over a hundred herbs himself and recorded all the details.  The internet said one of the herbs killed him. Youyou Tu’s talk.

Bib: chapters 32-33

Chapter Thirty-Two: The For-Profit Insurance Companies Take Over

The American Medical Association https://www.referenceforbusiness.com/history2/76/American-Medical-Association.html

Is health care a commodity?

https://www.theberylinstitute.org/blogpost/947424/215160/Thoughts-from-a-Commodity

https://www.enttoday.org/article/health-care-as-a-commodity-competition-should-be-focus-of-health-reform-lecturer-says/  https://journals.lww.com/annalsplasticsurgery/Citation/2009/01000/Is_Health_Care_a_Commodity_.1.aspx

The British NHS 

https://www.historic-uk.com/HistoryUK/HistoryofBritain/Birth-of-the-NHS/

https://www.newyorker.com/magazine/2009/01/26/getting-there-from-here

French health care

https://www.french-property.com/guides/france/public-services/health/system-overview

https://healthmanagement.org/c/it/issuearticle/overview-of-the-french-healthcare-system

Universal health care was almost part of the original Social Security Act of 1935

https://timeline.com/social-security-universal-health-care-efe875bbda93

khruschev meets castro 

https://www.wilsoncenter.org/publication/new-russian-evidence-soviet-cuban-relations-1960-61-when-nikita-met-fidel-the-bay-pigs

Medicae and hospitals are integrated  “The Power to Heal:  Civil Rights, Medicare, and the Struggle to transform America’s Health Care System” by David Barton Smith, Vanderbilt University Press, 2016

An American Sickness by Elizabeth Rosenthal. Penguin Press. 2017.

https://www.newyorker.com/magazine/2009/01/26/getting-there-from-here

Did Blue Cross’ Mission Stray When Plans Became For-Profit?

https://www.npr.org/templates/story/story.php?storyId=124807720

Deadly Spin, book by Wendell Potter, Bloomsbury Press, 2010

http://ushealthpolicygateway.com/vi-key-health-policy-issues-financing-and-delivery/health-financing/tax-expenditures/employer-tax-exclusion/

https://www.managedcaremag.com/archives/1996/6/what-profit-trend-health-care-really-means ——Managed Care Magazine June 1996: “In June 1994, a little-known event occurred behind closed doors in Washington, D.C., that opened the path for any of the 63 Blues plans to switch. The Blue Cross and Blue Shield Association’s board of directors gathered to discuss, among other things, changing the association’s bylaws to allow its affiliates to operate as for-profit companies. It wasn’t the first time the board discussed the hotly-debated issue, but this time the measure had enough supporters to enact the proposed reform by a narrow margin. Until then, the board only allowed its plans to operate for-profit subsidiaries, while the parent company using the Blue Cross and Blue Shield name had to remain nonprofit.”…”Whatever its implications for that “social value,” the market — employers, government and patients themselves — is clearly calling the shots in health care today. In most places, it seems to be saying that for-profit plans are the wave of the future.”

How the cost of care affects treatment

https://www.gsb.stanford.edu/insights/kate-bundorf-what-really-drives-medical-treatment-decisions

https://www.congress.gov/bill/103rd-congress/house-bill/3600/text

‘Hillary’ on Hulu 

The Hillary Clinton Health care proposal (abridged.) The health plans they proposed had to cover: hospital services;  health professionals;  emergency and ambulatory medical and surgical services; clinical preventive services; mental illness and substance abuse services; family planning and services for pregnant women; hospice and home health care.  extended care and ambulance services  outpatient laboratory, radiology, and diagnostic  services;  outpatient prescription drugs and biological; outpatient rehabilitation services  durable medical equipment;  prosthetic and orthotic devices; vision care; dental care; health education classes;  investigational treatments;

The items and services provided could not be subject to any duration, scope limitation, deductible, copayment, or coinsurance. 

The legislative proposal included a “low” cost sharing schedule:  no deductibles;  An annual individual out-of-pocket limit on cost sharing of $1500; and (B) an annual family out-of-pocket limit on cost sharing of $3000;

High cost packages which (with a few exceptions) had an annual individual general deductible of $200 and an annual family general deductible of $400.

Individuals had to pay for the first day of care for each episode of inpatient and residential mental illness and substance abuse, and for each episode of intensive nonresidential mental illness and substance abuse treatment. And patients were responsible for the first $250 for outpatient prescription drugs and biological.  Then the plan provided benefits.

To keep costs from going through the roof there was a regional target.  If the projected cost of care was exceeded there were: automatic, mandatory, nondiscretionary reductions in payments to health care providers.

For out of network emergency and urgent care, individuals had to pay “a percentage of fee set by the alliance.   

The items and services provided could not be subject to any duration, scope limitation, deductible, copayment, or coinsurance. 

The legislative proposal included a “low” cost sharing schedule:  no deductibles;  An annual individual out-of-pocket limit on cost sharing of $1500; and (B) an annual family out-of-pocket limit on cost sharing of $3000;

Balanced billing was prohibited:  A provider was not allowed to charge or collect money in excess of the fee schedule. And they couldn’t directly bill the patient.

They also recommended caps on health insurance premiums.  Companies who wanted to charge more would now have to come before a commission and explain where the money was going and why it was needed. 

Chapter Thirty-Three: Obamacare—the Affordable Care Act

Frontline TV

OBAMA’S ORGANIZING YEARS  https://www.nytimes.com/2008/07/07/us/politics/07community.html

McCain’s deciding vote on the Affordable Care Act

https://www.pbs.org/video/thumbs-down-6wiayp/

In 2014, as part of the Affordable Care Act, members of congress and their staff members lost the ability to purchase insurance through the FEHB.  So 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.    https://www.npr.org/sections/health-shots/2017/04/12/523335954/what-happens-to-a-congressmans-health-insurance-if-obamacare-goes-down

Why some dislike Obamacare

https://www.nytimes.com/2017/01/13/upshot/the-biggest-changes-obamacare-made-and-those-that-may-disappear.html

Bib: chap 28-31

Chapter Twenty-Eight: Gene Therapy and CRISPR

The first gene is found Woody Guthrie and Huntington’s Chorea

https://www.britannica.com/biography/Woody-Guthrie

http://news.mit.edu/1993/huntington-0331

https://www.genome.gov/25520322/online-education-kit-1983-first-disease-gene-mapped

Orphan Drug Report 2019 

https://info.evaluate.com/rs/607-YGS-364/images/EvaluatePharma%20Orphan%20Drug%20Report%202019.pdf?mkt_tok=eyJpIjoiWWpVMk1UVmtNRFpqT0dFeiIsInQiOiIrcmZ3QjNwamZWWVwvZ1ZkcU5XS2E3Rk5oNXA5MXZJVUVCRitMQXpQd0sxMGJPU0JhdGRWbVJQQkZrc0xZNDNPSXRNM09wMGh2OEFXNXFNN1wvb1plT

http://www.paradigmglobalevents.com/events/orphan-drugs-rare-diseases-2017-americas/

https://hbr.org/2017/04/the-cost-of-drugs-for-rare-diseases-is-threatening-the-u-s-health-care-system

Gene therapy Aug 2019

https://www.nejm.org/doi/full/10.1056/NEJMra1706910

Genetic blindness: Leber’s Congenital Amaurosis

https://www.nejm.org/doi/full/10.1056/NEJMoa1414221

http://www.cnn.com/2017/10/12/health/fda-gene-therapy-blindness-vote/index.html

 Cystic FibrosisThree drug treatment for cystic fibrosis  nejm  https://www.nejm.org/doi/full/10.1056/NEJMoa1908639

The Antidote by Barry Werth, Simon and Schuster, 2014 (see page 69–Victoria Sato, president of Vertex}

http://www.nejm.org/doi/full/10.1056/NEJMe1712335

https://www.nejm.org/doi/full/10.1056/NEJMoa1908639https://cysticfibrosisnewstoday.com/2020/08/24/vertex-triple-combo-kaftrio-approved-for-cf-patients-in-eu-with-f508del-mutation/

Europe approves triple therap.  August 2020 According to Vertex, as many as 10,000 people in Europe ages 12 years and older have CF characterized by one F508del mutation and one minimal function mutation, or a mutation in which the resulting CFTR protein works minimally. The newly approved triple combination is the first therapy that works on the underlying cause of CF to be approved for such individuals.ttps://cysticfibrosisnewstoday.com/2020/08/24/vertex-triple-combo-kaftrio-approved-for-cf-patients-in-eu-with-f508del-mutation/

Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL)

SMA spinal muscular atrophy and POMPE’S

https://smanewstoday.com/2015/02/23/exclusive-new-insight-into-sma-from-dr-adrian-krainer/

https://www.nejm.org/doi/full/10.1056/NEJMoa1706198

https://xconomy.com/national/2019/04/15/ho-an-ohio-kids-hospital-quietly-became-ground-zero-for-gene-therapy/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692727/

https://www.jci.org/articles/view/1722

https://doi.org/10.1002/14651858.CD011539.pub2

Hemophilia

Nicholas and Alexandra by Raymond Massie. Random House; 1967

hemophila B  N Engl J Med  2015

https://www.nejm.org/doi/full/10.1056/NEJMoa1708538

Gene transfer in severe hemophilia A https://www.nejm.org/doi/full/10.1056/NEJMoa1708483

https://www.forbes.com/sites/matthewherper/2017/12/11/spark-shadows-biomarin-in-hemophilia-gene-therapy-race/#7af39d156106

http://www.ucl.ac.uk/news/news-articles/1217/131217-UCL-research-leads-to-haemophilia-therapy-success

As of 2016, BioMarin has six products on the market, each of which is an orphan drughttps://en.wikipedia.org/wiki.BioMarin_Pharmaceutical

Buy a gene cheap:  Addgene

https://www.addgene.org/

Amyloidosis 

https://www.sfgate.com/health/article/The-Domino-Effect-Woman-gets-new-liver-gives-3238583.php

CRISPR

A Crack in Creation by Jennifer Doudna

Emmanuelle Charpentier co-discoverer of CRISPR

Charpentier rna https://embryo.asu.edu/pages/jennifer-doudna-and-emmanuelle-charpentiers-experiment-about-crisprcas-9-systems-role-adaptive

https://www.nytimes.com/2016/05/31/health/emmanuelle-charpentiers-crispr-dna-gene-editing.html https://www.nature.com/news/the-quiet-revolutionary-how-the-co-discovery-of-crispr-explosively-changed-emmanuelle-charpentier-s-life-1.19814

Sometimes, I then go to sleep again for an hour. I don’t have time to have a social life or even a cultural life.e.

https://www.nature.com/news/the-quiet-revolutionary-how-the-co-discovery-of-crispr-explosively-changed-emmanuelle-charpentier-s-life-1.19814

https://embryo.asu.edu/pages/jennifer-doudna-and-emmanuelle-charpentiers-experiment-about-crisprcas-9-systems-role-adaptive

In the early 1980s, Mario Capecchi discovered that sections of DNA that had been inserted into the cell nuclei of mammals could be incorporated into the cell’s genome. 

https://www.nobelprize.org/prizes/medicine/2007/capecchi/facts/

Chapter Twenty-Nine: Gaming the System

Martin Shkreli and Daraprim

Gertrude Elion

daraprim https://theoncologist.onlinelibrary.wiley.com/doi/full/10.1634/theoncologist.11-9-961

https://www.washingtonpost.com/archive/lifestyle/wellness/1988/10/25/pathway-to-the-prize/12924d14-d134-455b-aa9f-d7a494ddeb86/

Acthar ny times https://www.nytimes.com/2012/12/30/business/questcor-finds-profit-for-acthar-drug-at-28000-a-vial.html

https://www.britannica.com/biography/Gertrude-B-Elion https://www.nap.edu/read/9977/chapter/3#18   

The Curious Case of Colchicine NEJM June 2010 https://www.nejm.org/doi/full/10.1056/NEJMp1003126

Acthar

60 minutes May 12, 2019

Chapter Thirty: Are Generic Drugs Safe and Effective?

https://www.bloomberg.com/news/articles/2017-01-17/where-the-u-s-actually-gets-its-drug-supply-quicktake-q-a

Katherine Eban: NY Times May 12, 2019.

Bottle of Lies by Katherine Eban: Harper Collins 2019

https://www.fda.gov/news-events/congressional-testimony/securing-us-drug-supply-chain-

International regulations

https://www.ema.europa.eu/en/human-regulatory/research-development/compliance/good-manufacturing-practice

https://www.fda.gov/international-programs/international-arrangements/mutual-recognition-agreement-mra

https://www.panmobil.com/single-post/In-2019-pharmaceuticals-are-only-available-with-2D-Barcodes

https://www.gs1.org/docs/healthcare/events/17-10-17/8-_achieving_single_unit_pharmaceutical_traceability_-_van_der_schors.pdf

https://www.pharmamanufacturing.com/industrynews/2018/india-regulators-to-re-inspect-147-drug-plants/

Oversight of the FDA foreign inspection program Dec 10, 2019

https://www.fda.gov/news-events/congressional-testimony/securing-us-drug-supply-chain-oversight-fdas-foreign-inspection-program-12102019

Chapter Thirty-One: The FDA—The Fox That’s Guarding the Henhouse

Fastrack approval

https://www.accessdata.fda.gov/scripts/fdatrack/view/track.cfm?program=cber&id=CBER-All-IND-and-IDEs-recieved-and-actions/

Forbidden Cures. By Steven Fredman MD; Robert E Burger Stein and Day, 1976

The Rosiglitazone Story — Lessons from an FDA Advisory Committee Meeting. https://www.nejm.org/doi/full/10.1056/NEJMp078167 

The Kefauver–Harris Amendments at 50

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101807/

A Political History of Medicare and Prescription Drug Coverage

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690175/

This article examines the history of efforts to add prescription drug coverage to the Medicare program.

https://www.nejm.org/doi/full/10.1056/NEJMhle1800125 https://ipandtech.hillwallackblog.com/wp-content/uploads/2017/12/BPCIA_DoYouWannaDance_RichardCatalinaJr_-NewJerseyLawyer_August-2017.pdf

https://www.patentdocs.org/followon_biologics/\

Overview of FDA’s Expanded Access Program for Investigational Drugs

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443564/

https://www.ncbi.nlm.nih.gov/pubmed/27917324

Indian Patent act of 1970

https://www.lexology.com/library/detail.aspx?g=3f92413f-107c-4886-aca7-24633a341e22

https://www.business-standard.com/article/companies/40-years-ago-and-now-cipla-the-crusader-for-affordable-drugs-takes-the-patent-battle-to-mncs-114122400009_1.html

The Fate of FDA Postapproval Studies, by Steven Woloshin M.D. et al   N Engl J Med 2017; 377:1114-1117

FRANCES KELSEY AND THALIDOMIDE

https://www.fda.gov/media/89162/download

Kefauver

Crime in America, by Estes Kefauver; paper back 1951

Sulfa in ethylene glycol 

https://www.the-scientist.com/foundations/the-elixir-tragedy-1937-3

https://www.smithsonianmag.com/history/the-senator-and-the-gangsters-69770823/

Remdesivir 

https://www.nejm.org/doi/full/10.1056/NEJMoa2007764

https://www.reuters.com/article/us-health-coronavirus-india-gilead-scien/india-approves-gileads-remdesivir-to-treat-severe-covid-19-cases-idUSKBN2390VL

Bib: Chap 22-27

Chapter Twenty-Two: The Right to Emergency Care

The Emergency Medical Treatment and Active Labor Act (EMTALA) is an act of the United States Congress, passed in 1986 –Wikipedia

1986 Congress passed the Emergency Medical treatment and Active Labor Act, (EMTALA)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1305897/

Out-of-Network Emergency-Physician Bills — An Unwelcome Surprise.  Zack Cooper, Ph.D., and Fiona Scott Morton, Ph.D. November 17, 2016 N Engl J Med 2016; 375:1915-1918

surprise ER bills.

https://health-access.org/wp-content/uploads/2019/06/AB1611-Fact-Sheet_updated-6.28.19.pdf

Surprise medical bills https://washingtonmonthly.com/magazine/april-may-june-2020/why-congress-cant-stop-surprise-medical-bills/

Surprise ER bills.  https://health-access.org/wp-content/uploads/2019/06/AB1611-Fact-Sheet_updated-6.28.19.pdf

SURPRISE BILLING.  B N Engl J Med 2020; 382:1189-1191 

2020 Legislation that bans surprise bills

Balanced billing

https://www.commonwealthfund.org/blog/2019/state-efforts-protect-consumers-balance-billing

N Engl J Med 2020; 382:1189-1191 

2020 Legislation that bans surprise bills

https://www.nytimes.com/2020/12/20/upshot/surprise-medical-bills-congress-ban.html

a woman is charged $3000 for lab tests

https://www.npr.org/sections/health-shots/2020/12/23/949287668/retiree-living-the-rv-dream-fights-a-nightmare-12-387-lab-fee

Chapter Twenty-Three: Hospitals

(additional references at end of web chapter: hospitals)

Murder or Mercy? Hurricane Katrina and the Need for Disaster Training

https://www.nejm.org/doi/full/10.1056/NEJMp068196  

Market Place Medicine the rise of the for-profit hospital chains.  Book by Dave Lindorff

Hospital charges 

https://jrreport.wordandbrown.com/2019/01/10/hospitals-now-required-to-reveal-secret-prices-lists-online-for-every-medical-procedure-service/

SUTTER 

https://www.milbank.org/publications/californias-sutter-health-settlement-what-states-can-learn-about-protecting-residents-from-the-effects-of-health-care-provider-consolidation/anti trust suit for hospital charges

Khruschev meets Castro

https://www.wilsoncenter.org/publication/new-russian-evidence-soviet-cuban-relations-1960-61-when-nikita-met-fidel-the-bay-pigs

BLACK HOSPITALS https://guides.mclibrary.duke.edu/blackhistorymonth/hospitals#:~:text=It%20still%20exists%20today%20as,and%20other%20health%20care%20facilities.

Sick from Freedom: African-American Illness and Suffering during the Civil War and Reconstruction by Jim Downs
Desegregation: The Hidden Legacy of Medicare

https://www.usnews.com/news/articles/2015/07/30/desegregation-the-hidden-legacy-of-medicare

The Power to Heal: Civil Rights, Medicare, and the Struggle to Transform America’s Health Care System by David Barton Smith 

anti trust suit for hospital charges

Nurses strikes

https://fau.digital.flvc.org/islandora/object/fau:3598/datastream/OBJ/view/Nursing_and_national_healthcare_implications_with_the_rise_of_the_California_Nurses_Association_and_the_National_Nurse_Organizing_Committee.pdf

https://www.labornotes.org/2013/10/one-day-strikes-word-wise#:~:text=Workers%20can’t%20be%20legally%20fired%20for%20a%20ULP%20strike.&text=More%20and%20more%20unions%20are,safety%2C%20and%20to%20protest%20discharges

https://www.labornotes.org/2013/10/one-day-strikes-word-wise

The veteran’s administration builds hospitals

https://www.va.gov/about_va/vahistory.asp

statistics

https://www.aha.org/statistics/fast-facts-us-hospitals

Most of the nation’s facilities have fewer than 200 beds  https://www.forbes.com/2010/08/30/profitable-hospitals-hca-healthcare-business-mayo-clinic_slide.html

In 1995 around half of private hospitals were solo.  Then, over the decades for profit and non-profit hospitals have increasingly merged and/or joined systems with at least one other hospital partner in the same metropolitan statistical area (MSA). https://www.healthaffairs.org/doi/full/10.1377/hlthaff.22.6.77

What insurance companies pay for services by zip code

https://www.healthcarebluebook.com/

BLACK HOSPITALS  https://guides.mclibrary.duke.edu/blackhistorymonth/hospitals#:~:text=It%20still%20exists%20today%20as,and%20other%20health%20care%20facilities.

Hospital charges   https://jrreport.wordandbrown.com/2019/01/10/hospitals-now-required-to-reveal-secret-prices-lists-online-for-every-medical-procedure-service/

anti trust suit for hospital charges  https://californiahealthline.org/news/california-sues-sutter-health-alleging-excessive-pricing/

Surgery as a part of hospital revenue and costs  https://www.healthleadersmedia.com/clinical-care/ahrq-surgical-admissions-bring-48-hospital-revenue

https://www.beckershospitalreview.com/payer-issues/america-s-largest-health-insurers-in-2018.html

As Elisabeth Rosenthal of Kaiser Health News put it: “there’s money to be made by billing for everything and anything.” And hospitals currently intentionally submit amplified bills for their services.

Each hospital has an all inclusive list of “items billable to a person or a health insurance provider.”  Called “charge masters” they have long been secret in most states; but starting in 2019 they will be posted on line.  They do not include physician charges, and they are intentionally inflated–or in the “speak” of the University of California San Francisco Hospital:  “they are not the amount that either you or your insurer will actually pay. Out-of-pocket costs will be impacted by insurance plan coverage, co-pays and deductibles, if any, (etc.) – so our list should not be used to estimate the actual final cost you will incur.” 

Insurance companies like to flaunt them to demonstrate how much money they are saving their patrons.  And hospitals can claim that overstated prices are useful when they negotiate contracts with insurance companies.  The “fair” cost, the amount insurance companies (on average) really pay for most emergency and hospital visits, is accessible to anyone who has a smart phone. They merely have to open Healthcarebluebook.com or some similar service, and type in their zip code.  

Medicare strictly regulates the amount the government shells out to hospitals.  The agency is constantly updating what it pays for an illness or operation; 98% of American hospitals accept what the Feds dole out as payment in full. 

Exaggerated bills punish the ill and wounded who are cared for in a hospital that does not have a contract.  They hassle the person who is seen in an “out- of-network” facility or who was cared for by a doctor who was not covered by an agreement.  And they are especially harmful to people who don’t have health insurance. 

Paradoxically the people who try to collect the most exorbitant amounts of money commonly tend to blame the injured party. 

 I believe that once hospitals start charging people without insurance fairly, a form of BACK STOP INSURANCE makes sense.  As detailed in the “alternative approach” chapter, when corporations have a big stock offering, they obtain insurance.  If some of the stocks and bonds are not sold on the open market, the investment firm that is handling the transaction has to buy them.  

We need to take a similar approach to people who can afford insurance but don’t have a policy.  Health insurance is rarely used by some because they have a healthy life style, they’re young, and they are lucky.  And because bodies have an innate ability to fight off invaders and heal wounds.

If one of these people is in a “higher income” category,  and they haven’t purchased medical insurance, and they get sick or are injured, they would be best served if the system has “automatically enrolled them in a “backstop” insurance plan.”  If they are seen in an emergency room or are hospitalized the facility should be able to submit a claim and it should be paid by the government.  At tax time the IRS can then decide how much the person owes for a year’s worth of “backstop insurance.”  (As conceived by Matthew Fielder, NEJM:  May 2, 2019.)3

II. HEALTH INSURANCE: Some employer policies are unusable because the co-pays are so high.  In addition to taking care of the people with pre-existing conditions, we need a law or regulations that make health insurance affordably-useable.  There should be caps on premiums and co-pays; out of pocket payments should be based on income—should mirror earnings

Several of the Democratic candidates for president believe in Medicare for All.  Like all “rights” this form of care must be paid for.  That usually means taxes, and people who promise more taxes aren’t usually elected.  In addition to something like the current payroll tax– the government would have to collect the money employers contribute to a person’s insurance and the excess insurance company profits. 

 As an old retired M.D. and a socialist at heart I favor Medicare for all.  But as a realist I’m worried. 

In the 60s and 70s affordable health care was available to those who wanted it via Blue Cross and programs like Kaiser (my people.)   Then insurance companies entered the market and did what insurance companies do.  They risk adjusted.  People who live in the low lands near the Mississippi River pay more for flood insurance, and we in California pay more for earthquake insurance.  Private insurers didn’t sell affordable policies to people with pre existing conditions.  Premiums for the young and healthy were relatively cheap. 

Over the subsequent decades the young, healthy and employed started choosing private insurers; people with problems joined Blue Cross and Kaiser.  Year by year medical care improved and it also became increasingly costly:  CAT scans; MRI’s; organ transplants; angioplasties; artificial joints; and ICU’s aren’t cheap.

As their population increasingly had fewer healthy clients and more people with costly problems, Blue Cross and Kaiser started “hemorrhaging money.”  Ultimately they were on the verge.  After Hilary’s very reasonable Health Care adjustments were rejected, many Blue Cross companies and Kaiser said “uncle”.  They adopted a risk adjusted approach.

Over the subsequent decades people forgot that affordable health care, like the roads or schools, was once widely available.  The young, healthy, and employed grew up assuming they would be able to buy insurance that was good and affordable. It was their “right.”  Understandably, they don’t want to give it up.  And we need their votes. 

My approach:  lower the Medicare age, and keep dropping it. Make affordable Medicare purchasable for those who want it.   At the same time, over a few years–SUBSTANTIALLY LOWER THE MEDICAL LOSS RATIO.  Under the Affordable Care act companies get to keep 15 to 20 % of premiums for expenses, bonuses and stock holders.  The overhead of Medicare allegedly is 3%.  If insurance companies could keep 8% of the premiums, they should still be profitable.  If a yield of 5% isn’t enough, a company can leave the market. And some will. Over time healthy people will increasingly migrate to Medicare.  We may never get to Medicare for All but we’ll get close.  

As a result of the current medical loss ratio, the heads of the health insurance companies are doing quite well. In 2018 as a result of exercised stock options and stock awards, the one year compensation of the head of 49.5 million member UnitedHealth insurance, the nation’s largest, was over $18 million. The leader of Anthem, the 40.2 million policy, second largest was $14.2 million.4    

III. We should also extend some of the benefits of the Affordable Care Act (ACA) to traditional Medicare.  The ACA (Obamacare) created an annual lid on the amount people are forced to pay for their care.  In 2018 it was $7350.  By contrast, traditional Medicare, has no cap, no maximum amount a person can be charged.  When people see a doctor or are hospitalized, they are responsible for “copayments, coinsurance, and other gaps in coverage.”  If someone has a very serious illness and is hospitalized for months, the government stops paying the bill “after the 150th day in the hospital. 

People can buy an insurance policy that pays the bills that are not covered by Medicare. There are 10 levels of “Medigap” plans.  If a person doesn’t buy one of them when they enroll in Medicare, the policies are subsequently only available (most of the year) to people who pass an insurance physical.   

Medicare Advantage plugs a number of the holes in traditional Medicare.  Currently (according to AARP) 44 million Americans are insured by Medicare.  The number opting for Medicare Advantage rose to 20 million in 2018 and it’s going up.  Advantage plans are capitated.  The government gives the insurer a dollar amount per person per year, and “everything” is covered.  Plans may include limited dental care and gym memberships.  Out-of-pocket costs were capped at $5,215 per year in 2018.  (November 14, 2018, NEJM.org.)

According to Wiki “You cannot have both a Medicare supplement (Medigap plan) and a Medicare Advantage plan at the same time.”  It’s time to identify and close the Medicare gaps.

IV: Extra money for health care was supposed to come from a few additional sources.  Congress recently abolished the Medical Device tax, the health insurance tax , and the tax on Cadillac plans.

I suggest re-opening the question of what happens when university and nonprofit hospitals make hundreds of millions of dollars. Should they be taxed? Should they return some of the tax funds they received from the government for use elsewhere in the health care system? Or perhaps charitable and university hospitals should (like the for-profits) generate a bill for the service rendered. The amount charged would be similar to the sum Medicare or insurance companies would actually pay. (Inflated excessive charges should be treated as potential tax fraud.) The institution’s outlay could then be deducted from the hospital’s gross income.  If an institution performs a lot of charity work and has no net income they would owe no taxes.  If they generate a large profit, they, like for-profit corporations, could pay a tax.

Summary:   if our goal is to make quality health care affordable and available :

  1.  We need to fix the drug price problem.
  2. Pevent hospitals from generating outrageous inflated bills for their services.
  3. Eliminate out of network charges. 
  4. Eliminate balanced billing. 
  5. Allow the medical loss ratio (MLR) to whither. 
  6. Put a cap, an upper limit, on the out of pocket Medicare bills that unsuspecting seniors are sometimes forced to pay.
  7.  And we should allow people to buy into Medicare. 
  8. And perhaps tax the excess profits of University and Charitable hospitals.

Chapter Twenty-Four: Generic Drugs

HATCH WAXMAN

Overview of the Hatch-Waxman Act and Its Impact on the Drug Development Process

http://plg-group.com/wp-content/uploads/2014/03/Overview-of-the-Hatch-Waxman-act-its-impace-on-Drug-Develo.pdf

https://scholarship.shu.edu/cgi/viewcontent.cgi?article=1677&context=shlr

GENERIC DRUGS

Overview of the Hatch-Waxman Act and Its Impact on the Drug Development Process 

Pharmaceutical patents and the world trade organization

http://infojustice.org/archives/42129   India patent

https://books.openedition.org/obp/3094?lang=en  argument for WTO

Prior to the creation of the World Trade Organization in 1995, individual countries were free to determine their own patent laws. This position has now changed. All members of the WTO are required to adopt patent laws that comply with the Agreement on Trade-related Aspects of Intellectual Property Rights,1 including the implementation of patent protection for pharmaceuticals. The developed members of the WTO negotiated mandatory protection for pharmaceutical products and processes in the TRIPS Agreement on the basis that such mandatory protection will provide the necessary incentives for continued pharmaceutical innovation. In contrast, the developing countries and the Least Developed Countries argued that enacting patent laws that comply with TRIPS may restrict production and supply of low-cost generic medicines by their local pharmaceutical industries or by the pharmaceutical industries in other developing countries, and hence could increase the price of pharmaceuticals to the point that pharmaceuticals become inaccessible to their populations.

https://books.openedition.org/obp/3094?lang=en

https://www.thebalance.com/top-generic-drug-companies-266311

http://www.pewtrusts.org/en/research-and-analysis/reports/2017/01/drug-shortages

http://www.nejm.org/doi/full/10.1056/NEJMp1112633#t=article

https://www.fda.gov/media/132058/download

https://www.wisc-asc.org/news/382129/FDA-Approved-Drug-Extended-Use-Dates-List-.htm

https://www.health.harvard.edu/staying-healthy/drug-expiration-dates-do-they-mean-anything

https://www.aljazeera.com/indepth/features/2017/05/world-suffering-penicillin-shortage-170517075902840.html

https://www.nytimes.com/2019/12/25/health/antibiotics-new-resistance

Intellectual property

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217699/#ref1

Chapter Twenty-Five: The Price of Everyday Drugs

How companies price medications https://www.investopedia.com/articles/investing/020316/how-pharmaceutical-companies-price-their-drugs.asp

HIGH PRICES OF DRUGS  https://www.commonwealthfund.org/publications/newsletter-article/specialty-drug-costs-poised-skyrocket-many-employers-have-yet-take#:~:text=Specialty%20drugs%20are%20vastly%20more,upwards%20of%20%24100%2C000%20per%20year.

How companies’ price drugs  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866602/

https://medtech.pharmaintelligence.informa.com/PS017438/SENATE-MAJORITY-LEADER-WORKING-WITH-SEN-PRYOR-ON-MEDICAID-DRUG-PRICE-DISCOUNT-BILL-PRYOR-ACKNOWLEDGES-APPLICABILITY-OF-BILLampnbspBEYOND-MEDICAI THE MEDICARE CATASTROPHIC COVERAGE ACT OF 1988

https://www.cbo.gov/sites/default/files/100th-congress-1987-1988/reports/88doc140.pdf  Specialty drugs—a distinctly American phenomenon

https://www.nejm.org/doi/full/10.1056/NEJMp1909513

Patient and Plan Spending after State Specialty-Drug Out-of-Pocket Spending Caps

https://www.nejm.org/doi/full/10.1056/NEJMsa1910366

biologic account for 37 percent of drug costs  https://www.forbes.com/sites/theapothecary/2019/03/08/biologic-medicines-the-biggest-driver-of-rising-drug-prices/#547789dc18b0

how companies price drugs https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866602/

Chapter Twenty-Six: High-Priced Drugs

EXPENSIVE DRUGS https://www.pharmaceutical-technology.com/features/top-selling-prescription-drugs/

https://library.cqpress.com/cqalmanac/document.php?id=cqal84-1151745

drug prices in the 1970s to 1980s  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191468/http://plg-

HIGH PRICES OF DRUGS https://www.commonwealthfund.org/publications/newsletter-article/specialty-drug-costs-poised-skyrocket-many-employers-have-yet-take#:~:text=Specialty%20drugs%20are%20vastly%20more,upwards%20of%20%24100%2C000%20per%20year

http://plg-group.com/wp-content/uploads/2014/03/Overview-of-the-Hatch-Waxman-act-its-impace-on-Drug-Develo.pdf

https://scholarship.shu.edu/cgi/viewcontent.cgi?article=1677&context=shlr

DRUG COSTS

Biologics account for 37 percent of drug costs   https://www.forbes.com/sites/theapothecary/2019/03/08/biologic-medicines-the-biggest-driver-of-rising-drug-prices/#547789dc18b0

http://www.indiatogether.org/articles/lwcstman-health/print

A congressional committee questions heads of drug companies

https://www.c-span.org/video/?458198-1/lawmakers-press-pharma-ceos-rising-drug-prices

Vagelos great debate on drug pricing  https://www8.gsb.columbia.edu/leadership/ethicsofpricing

Chapter Twenty-Seven: Expensive Pharmaceuticals

https://www.pharmaceutical-technology.com/features/top-selling-prescription-drugs/

Drug prices in the 1970s to 1980s

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191468/

Gleevec

https://www.forbes.com/sites/joshuacohen/2018/09/12/the-curious-case-of-gleevec-pricing/#30e1487654a3

Treatment of chronic myelocytic leukemia UPTODATE.

Gleevec generics 

https://www.ascopost.com/issues/may-25-2016/the-arrival-of-generic-imatinib-into-the-us-market-an-educational-event/

Gleevec in other countries.  

https://www.statista.com/statistics/312011/prices-of-gleevec-by-country/

Out of pocket cost burden for certain drugs 

https://www.kff.org/medicare/issue-brief/the-out-of-pocket-cost-burden-for-specialty-drugs-in-medicare-part-d-in-2019/

The ethics of drug prices 

https://www8.gsb.columbia.edu/leadership/ethicsofpricingt

The Emperor of all Maladies, by Siddhartha Mukeherjee, Scribner 2011

https://www.seattletimes.com/business/technology/pharmacyclics-miracle-cure-a-cancer-drug-saves-a-biotech-company/

RoyVagelosTranscript.pdf

https://www.annualreviews.org/userimages/ContentEditor/1337783424709/P.

THE SWISS

http://fortune.com/2015/07/28/why-pharma-mergers-are-booming/

Post-Merger Integration: How Novartis Became No.

https://www.strategy-business.com/article/16383?gko=6321f

http://www.nytimes.com/2008/07/06/health/06avastin.html

Switzerland takes on its top drugmakers in price row  Reuters Sept 16, 2014.  

https://www.reuters.com/article/us-swiss-medicine-prices/switzerland-takes-on-its-top-drugmakers-in-price-row-idUSKBN0HB0XA20140916

Making of Herceptin

http://www.nytimes.com/books/first/b/bazell-her.html

Siddhartha Mukherjee, “The Emperor of All Maladies” Scribner 2010

avastin

https://tvst.arvojournals.org/article.aspx?articleid=2503070

Judah Folkman

https://www.scientificamerican.com/article/quiet-celebrity-interview

Tumor Angiogenesis by Judah Folkman, NEJM, 197112.

Genentech by Sally Smith Hughes, University of Chicago Press; 2011

Rituximab and Ivor Royston

https://libraries.ucsd.edu/sdta/histories/royston-ivor.html  https://libraries.ucsd.edu/sdta/companies/idec.html   https://libraries.ucsd.edu/sdta/transcripts/royston-ivor_20081014.html

THE SWISS:

Michael Houghton hepatitis C

MICHAEL HOUGHTON INTERVIEW  https://www.youtube.com/watch?v=Bc61-nzuZSo&list=PLkLWuDKntM8vMGKvKBC-gSGx6PO6V5S23&index=1

https://www.journal-of-hepatology.eu/article/S0168-8278(09)00535-2/fulltext

michael houghton hepatitis C https://www.youtube.com/watch?v=Z-JCT6ifmMA&list=PLkLWuDKntM8vMGKvKBC-gSGx6PO6V5S23&index=4https://www.youtube.com/watch?v=Bc61-nzuZSo&list=PLkLWuDKntM8vMGKvKBC-gSGx6PO6V5S23&index=1

Lipitor: 

Akira Endo moulds

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108295/

Atherosclerotic plaque 

https://www.nejm.org/doi/full/10.1056/NEJMra2000317

Monoclonal antibodies

https://whatisbiotechnology.org/index.php/exhibitions/milstein/monoclonals/The-making-of-monoclonal-antibodies

https://www.immunology.org/kohler-and-milsteins-hybridoma-technology-1975 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)72025-0/fulltext

Cytokines –“Love and Science” by Jan Vilcek

BIOSIMILARS AND CYTOKINE BLOCKERS

Abbvie and biosimilars

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008392/#:~:text=Exclusivity%20period,-One%20way%20that&text=During%20this%2012%2Dyear%20period,that%20references%20the%20innovator’s%20biologic.&text=Under%20the%20Biosimilars%20Act%2C%20the,12%20months%20and%2042%20months.

Transgenic mice

https://www.ncbi.nlm.nih.gov/books/NBK231336/

toclizumab for overzealous release of toclizumab  https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30173-9/fulltext

Richard Gonzalez AbbVie https://www.chicagobusiness.com/article/20150306/NEWS03/150309840/bored-by-golf-and-cancer-cured-abbvie-ceo-gonzalez-came-back-to-work

AbbVie and biosimilars

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008392/#:~:text=Exclusivity%20period,-One%20way%20that&text=During%20this%2012%2Dyear%20period,that%20references%20the%20innovator’s%20biologic.&text=Under%20the%20Biosimilars%20Act%2C%20the,12%20months%20and%2042%20months.

http://www.gabionline.net/Pharma-News/Boehringer-Ingelheim-finally-signs-licensing-deal-for-Humira-biosimilar#:~:text=Boehringer%20Ingelheim%20(Boehringer)%20has%20finally,adalimumab)%2C%20in%20the%20US.&text=Under%20the%20terms%20of%20the,to%20Humira%20in%20the%20US

pros and cons of 12 years exclusivity for biologics https://repository.library.northeastern.edu/files/neu:cj82rb53g/fulltext.pdf

European handling of biosimilars  

https://www.biosimilardevelopment.com/doc/how-the-eu-influences-u-s-thinking-on-biosimilar-interchangeability-other-policies-0001#:~:text=In%20the%20EU%2C%20almost%20from,the%20biosimilar%20or%20the%20originator

In much of Europe biosimilars can be marketed as soon as they have been shown to perform as well as the original drug, but they are usually not thought of as interchangeable or a generic version of an existing medication.  They are instead treated like a competitor or a therapeutic alternative, and outside of a small number of Eastern European countries pharmacists can’t substitute a biosimilar for a designated medication without permission from the prescribing physician. When the biosimilars begin to significantly price compete attitudes will probably change, but for now in France and Italy, at least, “biosimilar adoption rates have been low.”

Used in place of the some european hospitals In the hospital setting, however, there are also coordinated efforts to switch patients, with reports of U.K. hospitals switching >95 percent of their rituximab patients in just six weeks since the biosimilar for rituximab was introduced. All stakeholders in the hospital (including patients) realize how, by switching, they are able to generate savings  ion, and

 (e.g., Estonia, Latvia, Poland), while France recently introduced legislation allowing substitution in treatment-naive patients under specific conditions (although in practice, this is still uncommon). But in most other European markets, biosimilars have been treated as competitors of the originator products in much the same way blood products such as factor agents, immunoglobulins, and other high-cost treatments are handled.1 This is evidenced by the widespread use of tenders to drive procurement decisions across Europe, although these can take many guises ranging from exclusive to nonexclusive contracts.

Immunotherapy

Movie Jim Allison –Breakthrough

Tasuku Honjo nobel prize pd1 apan

https://japan-forward.com/cancer-can-be-conquered-says-2018-nobel-prize-laureate-tasuku-honjo/

https://www.kyoto-u.ac.jp/en/news/2018-12-11

CAR-T

https://pharmaboardroom.com/infocus/big-pharmas-quest-for-blockbuster-car-t/

https://www.nytimes.com/2011/09/13/health/13gene.html

Transformed Cell by Steve Rosenberg M.D.

Rosenberg  CAR-T

https://ascopost.com/issues/november-25-2018/steven-a-rosenberg-works-to-unmask-cancer-s-achilles-heel/

https://medicine.temple.edu/education/narrative-medicine-program/how-working-christmas-eve-hospital-became-familys-tradition

https://learningenglish.voanews.com/a/what-it-takes-steve-rosenberg/4226596.html

Zelig Eshhar CAR-T Israel

https://www.haaretz.com/science-and-health/.premium.MAGAZINE-the-scientist-who-paved-the-way-for-a-chimeric-cancer-therapy-1.5463978

The Scientist. The CAR T cell race. April 2015

https://www.the-scientist.com/bio-business/the-car-t-cell-race-35701

https://www.aceabio.com/video/webinar-optimization-chimeric-antigen-receptor-car-t-cell-design-guided-sensitive-assessment-b-cell-killing/

https://ww w.addgene.org/107226/

(CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. 

https://www.nejm.org/doi/full/10.1056/NEJMoa1910607

https://www.goldmansachs.com/insights/talks-at-gs/arie-belldegrun.html

https://blogs.timesofisrael.com/sugar-coated-memories-of-rehovot/

https://www.the-scientist.com/bio-business/the-car-t-cell-race-35701

https://www.weizmann-usa.org/news-media/in-the-news/t-cell-therapies-for-cancer-from-outsider-to-pharmaceutical-darling

https://boards.fool.com/macro-view-of-the-car-t-cell-sector-32661956.aspx?sort=wholeedit”car-t”

https://www.gilead.com/news-and-press/press-room/press-releases/2012/10/kite-pharma-partners-with-the-national-cancer-institute-to-develop-novel-cellular-immunotherapy-clinical-products

https://thewinnower.com/papers/2626-addgene-an-open-access-success-story

http://dx.doi.org/10.1257/aer.101.5.1933

www.addgene.org.

Bib: chap 18-21

Chapter Eighteen: Vision

In 2019, according to the NIH, the most common causes of blindness are:  Cataracts (51%); Glaucoma (8%); Age-related macular degeneration (5%);Corneal opacification (4%); Childhood blindness (4%; Refractive errors (3%); Trachoma (3%); Diabetic retinopathy (1%) 

https://www.who.int/apoc/onchocerciasis/en/

https://www.who.int/news-room/fact-sheets/detail/trachoma

Trachoma, is it history by H.R. Taylor 

https://www.nature.com/articles/eye2008432

https://www.who.int/news-room/detail/27-06-2019-eliminating-trachoma-who-announces-sustained-progress-with-hundreds-of-millions-of-people-no-longer-at-risk-of-infection

http://sped.wikidot.com/malnutrition-a-cause-for-visual-impairment

Blindness in India

https://www.devex.com/news/how-india-became-a-leader-in-low-cost-high-quality-eye-care-93749

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2580063/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612994/#:~:text=Cataract%20has%20been%20documented%20to,presentation%20is%20defined%20as%20blindness.&text=In%20India%20cataract%20has%20been,bilaterally%20blind%20in%20the%20country

David green Aurolab cataracts https://www.youtube.com/watch?v=90FenXnKlyo&list=PL4A704BBAFAC324F6&index=3

https://www.reviewofophthalmology.com/article/thoughts-on–cataract-surgery-2015

Harold Ridley and the Invention of the Intraocular Lens

https://rayner.com/wp-content/uploads/2019/02/Invention_of_the_IOL.pdf

https://www.seva.org/site/SPageServer/;jsessionid=00000000.app272a?NONCE_TOKEN=D331A52171C42E9234E1E43A336A29B0&pagename=25_Years_of_Aurolab 

https://www.mitpressjournals.org/doi/pdf/10.1162/itgg.2006.1.3.25

david green aurolab cataracts

https://www.youtube.com/watch?v=90FenXnKlyo&list=PL4A704BBAFAC324F6&index=3

http://www.indiatogether.org/articles/lwcstman-health/print

Cataract surgery

http://www.indiatogether.org/articles/lwcstman-health/print

Cataract lenses in India

.glaucoma india https://www.nhp.gov.in/world-glaucoma-week_pg#:~:text=In%20India%2C%20glaucoma%20is%20the,Glaucoma%20prevalence%20increases%20with%20age

Glaucoma
Lifetime visual prognosis for patients with primary open-angle glaucoma

https://www.nature.com/articles/6702284

India Glaucoma

Worldwide glaucoma is one of the leading causes of visual loss and it has blinded and estimated 4.5 million people in India alone. 

https://www.nhp.gov.in/world-glaucoma-week_pg#:~:text=In%20India%2C%20glaucoma%20is%20the,Glaucoma%20prevalence%20increases%20with%20age

https://www.hopkinsmedicine.org/wilmer/services/glaucoma/book/ch17s01.html

Soft contact lenses Otto Wichterle

\

soft lens https://www.mayoclinicproceedings.org/article/S0025-6196(16)00071-9/fulltext

Bausch and lomb contact https://www.prnewswire.com/news-releases/global-12-billion-contact-lenses-market-to-2024—major-vendors-are-johnson–johnson-novartis-the-cooper-companies–bausch–lomb-300834563.html

Wichterle soft contact lens file:///C:/Users/User/Documents/50_years_of_Soft%20….pdf

  http://www.aoafoundation.org/ohs/hindsight/how-soft-contact-lenses-came-to-the-usa/

http://www.aoafoundation.org/ohs/hindsight/how-soft-contact-lenses-came-to-the-usa/

http://www.aoafoundation.org/ohs/hindsight/how-soft-contact-lenses-came-to-the-usa/  

In all he wrote six books, over 100 publications in scientific journals and held over 150 patents.  He received a great many awards during and after his life.  In 1993, Asteroid 3899 was named Wichterle and a statue was erected outside the IMC in 2005.

Bausch and Lomb contact

https://www.prnewswire.com/news-releases/global-12-billion-contact-lenses-market-to-2024—major-vendors-are-johnson–johnson-novartis-the-cooper-companies–bausch–lomb-300834563.html

Wet macular degeneration

A Conversation with Napoleone Ferrara

https://www.jci.org/articles/view/77540

Lucentis 

https://www.businessinsider.com/price-difference-lucentis-and-avastin-2014-6

Diabetic Retinopathy

https://www.nejm.org/doi/full/10.1056/NEJMct0908432

NEJM 2011;365:1520-6

https://www.ncbi.nlm.nih.gov/books/NBK448182/ \

https://www.nejm.org/doi/exam/10.1056/NEJMcme1909637?ef=article

https://www.who.int/news-room/fact-sheets/detail/trachoma

Chapter Nineteen: Childbirth

https://www.npr.org/2017/05/12/528098789/u-s-has-the-worst-rate-of-maternal-deaths-in-the-developed-world .

https://www.npr.org/2018/05/10/607782992/for-every-woman-who-dies-in-childbirth-in-the-u-s-70-more-come-close

Ellison K, Martin N (December 22, 2017). “Severe Complications for Women During Childbirth Are Skyrocketing — and Could Often Be Prevented”. Lost mothers. ProPublica.

Li HT, et al. Geographic Variations and Temporal Trends in Cesarean Delivery Rates in China, 2008-2014. JAMA. 2017;317:69–76. doi: 10.1001/jama.2016.18663.

Assisted reproductive technology

 file:///C:/Users/User/Documents/ART-2013-Clinic-Report-Full.pdf

https://www.pennmedicine.org/updates/blogs/fertility-blog/2018/march/ivf-by-the-numbers

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593338/

Heavy Menstrual Bleeding in Women with Uterine Fibroids. William D. Schlaff, M.D., et al  NEJM January 23, 2020  

https://www.nejm.org/doi/full/10.1056/NEJMoa1904351?query=featured_home   “Half of women with Uterine fibroids (leiomyomas have symptoms:  heavy menstrual bleeding, which can lead to anemia, pelvic pain and pressure, urinary and gastrointestinal symptoms, infertility, and complications of pregnancy.”  They sometimes affect a woman’s  physical,  psychological, and social well-being.”

file:///C:/Users/User/Documents/policy-research-perspective-liability-insurance-premiums.pdf

Medical Professional Liability Insurance Premiums for $1M/$3M Policies, Selected Insurers.

George Papanicolaou (1883–1962): Discoverer of the Pap smear

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613936/

https://healthmatters.nyp.org/georgios-nikolaou-papanicolaou/

https://www.newscientist.com/article/2202635-georgios-papanikolaou-inventor-of-the-pap-smear-cervical-cancer-test/

Papilloma vaccine and cervical cancer

https://www.cancer.gov/news-events/cancer-currents-blog/2020/hpv-vaccine-prevents-cervical-cancer-sweden-study/

https://www.mediatheque.lindau-nobel.org/research-profile/laureate-hausen-zu

Chapter Twenty: Care of Kidney Failure Becomes a Right

Medicare’s end stage renal disease entitlement

N Engl J Med 2011; 364:596-598February 17, 2011

https://www.ncbi.nlm.nih.gov/books/NBK234191/

Scribner shunt 

Scribner shunt  https://www.asn50.org/anniversary/#!/watch*cat=Dialysis   https://pharm.ucsf.edu/kidney/need/statistics#:~:text=Medicare%20spending%20for%20kidney%20failure,a%20total%20of%20%2428%20billion.

Dialysis statistics  https://pharm.ucsf.edu/kidney/need/statistics#:~:text=Medicare%20spending%20for%20kidney%20failure,a%20total%20of%20%2428%20billionhttps://www.asn50.org/anniversary/#!/watch*cat=Dialysis 

https://www.asn50.org/anniversary/#!/watch*cat=Dialysis

http://www.aakp.org/aakp-library/Home-Dialysis/

Dr. Christopher Blagg

India faces acute shortage of dialysis units: Dr D S Rana Sunday, March 6, 2011  

http://www.aalatimes.com/2011/03/06/india-faces-acute-shortage-of-dialysis-units-dr-d-s-rana/

Medicare’s end stage renal disease entitlement

N Engl J Med 2011; 364:596-598February 17, 2011

Hemodialysis – 2011

Dialysis Therapy

N Engl J Med 1998; 338:1428-1437May 14, 1998

Art Buchwald, Whose Humor Poked the Powerful, Dies at 81 NY TIMES

By RICHARD SEVERO Published: January 19, 2007

Monday, Sep 28, 2009  salon.com  I love my socialist kidney

We already have a public option. How it saved my life — and my dad’s life — and how it may one day save yours.  By Jennifer Nix

https://pharm.ucsf.edu/kidney/need/statistics#:~:text=Medicare%20spending%20for%20kidney%20failure,a%20total%20of%20%2428%20billion.

https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease

https://catalyst.nejm.org/the-big-business-of-dialysis-care/

healthcare for people in prison became a right

In 1976 the U.S. Supreme court created a right for medical care to one group of Americans: People in Jail.  Eight of nine justices “acknowledged that the eight and fourteenth amendments required the Texas government to provide medical care for prisoners.”  Estelle vs. Gamble.

https://www.oyez.org/cases/1976/75-929

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. 

https://cchcs.ca.gov/wp-content/uploads/sites/60/2017/08/pr_070506.pdf

Chapter Twenty-One: HIV and the Plight of 23 Million Africans

Tinderbox By Craig Timberg and Daniel Halperin. Penguin Press. 2012—.

Fire in the Blood. Documentary Movie.  Written and directed by Dylan Mohan Gray.  2013.

And the band played on https://www.amazon.com/Band-Played-Politics-Epidemic-20th-Anniversary/dp/0312374631/ref=sr_1_3?dchild=1&keywords=and+the+band+played+on&qid=1597522204&sr=8-3

nucleoside phoshanate https://www.intmedpress.com/serveFile.cfm?sUID=7580f2bf-12b9-4a9c-840d-fb337dcb9873 https://en.wikipedia.org/wiki/Phosphonate

Schinazi compensation  https://www.military.com/daily-news/2016/02/05/former-va-scientist-responds-to-lawmakers-suspicions-drug-sale.html

Clinton brokers aids deal

https://www.nytimes.com/2006/11/30/world/asia/01aidscnd.html  http://www.cnn.com/2003/ALLPOLITICS/10/23/clinton / http://news.bbc.co.uk/2/hi/americas/3209741.stm

Treating and Preventing HIV with Generic Drugs–Barriers in the U.S. Erika G. Martin, Ph.D., M.P.H.,and Bruce R. Schackman, Ph.D.

https://www.nejm.org/doi/full/10.1056/NEJMp1710914

The Truth about Drug Companies by Marcia Angell. Random House. 2005

CDC website

 https://www.nejm.org/doi/full/10.1056/NEJMp1804306 . 

https://www.sciencemag.org/news/2019/07/simpler-hiv-treatment-and-prevention-strategies-/take-center-stage

Elimination of HIV-1 Genomes from Human T-lymphoid Cells by CRISPR/Cas9 Gene Editing

Kaminski et al  

https://www.nature.com/articles/srep22555

https://www.sciencedaily.com/releases/2019/07/190702112844.htm

Washington University 2010 therapeutic manual for doctors listed drugs that block the virus at several transitional sites.  We had more than 10 reverse transcriptase inhibitors, 9 protease inhibitors, 2 entry inhibitors and an integrase inhibitor.  All drugs had side effects.  People who couldn’t tolerate one reverse transcriptase inhibitor often had no problem taking a different one.   When a combination of medications was used, the viral biochemical assembly line was blocked in more than one location, and viral resistance was uncommon.  Refractory HIV however, commonly developed when a person stopped and started the medications.  That happens when people can’t afford their co-pay, when they live in a remote part of the world and don’t have access, or if they merely decide to take a “drug holiday”.

HIV– broadly neutralizing antibodies https://www.aidsmap.com/news/mar-2020/hiv-vaccine-generates-broadly-neutralising-antibodies-passes-first-safety-and-proof#:~:text=A%20broadly%20neutralising%20antibody%20(bNAb,from%20persons%20living%20with%20HIV

President Bush and HIV

https://www.cnn.com/2003/ALLPOLITICS/01/28/sotu.transcript/

“And the band played on” book by Randy Shilts

Bib: Chap 14-17

Chapter Fourteen: Minimally Invasive Surgery

Surgery as a part of hospital revenue and costs 

https://www.healthleadersmedia.com/clinical-care/ahrq-surgical-admissions-bring-48-hospital-revenue

Eddie Joe Reddick

https://journals.sagepub.com/doi/10.1177/1553350608325119

https://www.generalsurgerynews.com/Article/PrintArticle?articleID=24018

Complicated surgery through tiny incisions

operating room fees Akron general hospital

https://my.clevelandclinic.org/-/scassets/files/org/locations/price-lists/akron-general-patient-price-list.ashx

Military Care for the Wounded from Iraq and Afghanistan—Gawande

List of procedures performed in outpatient facilities

https://blog.definitivehc.com/top-10-outpatient-procedures-at-ascs-and-hospitals

Milestones Pioneered by Interventional Radiologists

1964 Angioplasty

1966 Embolization therapy to treat tumors and spinal cord vascular malformations by blocking the blood flow

1967 The Judkins technique of coronary angiography, the technique still most widely used around the world today

1967 Closure of the patent ductus arteriosis, a heart defect in newborns of a vascular opening between the pulmonary artery and the aorta

1967 Selective vasoconstriction infusions for hemorrhage, now commonly used for bleeding ulcers, GI bleeding and arterial bleeding

1969 The catheter-delivered stenting technique and prototype stent

1960-74 Tools for interventions such as heparinized guidewires, contrast injector, disposable catheter needles and see-through film changer

1970’s Percutaneous removal of common bile duct stones

1970’s Occlusive coils

1972 Selective arterial embolization for GI bleeding, which was adapted to treat massive bleeding in other arteries in the body and to block blood supply to tumors

1973 Embolization for pelvic trauma

1974 Selective arterial thrombolysis for arterial occlusions, now used to treat blood clots, stroke, DVT, etc.

1974 Transhepatic embolization for variceal bleeding

1977-78 Embolization technique for pulmonary arteriovenous malformations and varicoceles

1977-83 Bland- and chemo-embolization for treatment of hepatocellular cancer and disseminated liver metastases

1980 Cryoablation to freeze liver tumors

1980 Development of special tools and devices for biliary manipulation

1980’s Biliary stents to allow bile to flow from the liver saving patients from biliary bypass surgery

1981 Embolization technique for spleen trauma

1982 TIPS (transjugular intrahepatic portosystemic shunt) to improve blood flow in damaged livers from conditions such as cirrhosis and hepatitis C

1982 Dilators for interventional urology, percutaneous removal of kidney stones

1983 The balloon-expandable stent (peripheral) used today

1985 Self-expandable stents

1990 Percutaneous extraction of gallbladder stones

1990 Radiofrequency ablation (RFA) technique for liver tumors

1990’s Treatment of bone and kidney tumors by embolization

1990’s RFA for soft tissue tumors, i.e., bone, breast, kidney, lung and liver cancer

1991 Abdominal aortic stent grafts

1994 The balloon-expandable coronary stent used today

1997 Intra-arterial delivery of tumor-killing viruses and gene therapy vectors to the liver

1999 Percutaneous delivery of pancreatic islet cells to the liver for transplantation to treat diabetes

1999 Developed the endovenous laser ablation procedure to treat varicose veins and venous disease

https://www.hopkinsmedicine.org/interventional-radiology/mMilestones.html

https://www.nejm.org/doi/full/10.1056/nejmp048317

Chapter Fifteen: Transplantation

Puzzle People by Thomas Starzl

Cyclosporine history–Borel

https://www.washingtonpost.com/archive/lifestyle/wellness/1988/11/15/jean-francois-borels-transplanted-dream/f3a931b9-e1a1-4724-9f08-a85ec4d3e68f/

https://link.springer.com/chapter/10.1007/978-1-4615-9846-6_2

Christiaan Barnard the surgeon who dared

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062759/

Norman Shumway heart transplant

https://med.stanford.edu/news/all-news/2006/02/norman-shumway-heart-transplantation-pioneer-dies-at-83.html

Competition for organs for transplant  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644566/

Chinese organ transplant

https://www.bbc.com/news/world-asia-china-30324440

Chapter Sixteen: Taxpayer-Funded Research Is Privatized—Bayh-Dole

bayh dole https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063341/

Bayh Dole– DISCOVERIES MADE AT UNIVERSITIES AND THE NIH CAN BE SOLD TO DRUG COMPANIES

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063341/

https://cen.acs.org/articles/83/i39/Celebrating-Bayh-Dole-Act.html

https://core.ac.uk/download/pdf/149256924.pdf

https://autm.net/about-tech-transfer/advocacy/legislation/bayh-dole-act#:~:text=The%20Bayh%2DDole%20Act%20fundamentally,the%20Bayh%2DDole%20Act%20(P.L.

https://www.ipwatchdog.com/2010/11/28/the-enactment-of-bayh-dole-an-inside-perspective/id=13442/

Charles Huggins and hormonal control of prostate cancer

https://www.nobelprize.org/prizes/medicine/1966/huggins/facts/

enzalutamide

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551941/

Pfizer buys medivation for $14 billion and acquires enzalutamide

Abiraterone: a story of scientific innovation and commercial partnership

hormonal effect on Prostate cancer Larry Altman interview NY Timeshttps://www.nytimes.com/1997/01/15/us/c-b-huggins-dies-at-95-won-nobel-for-cancer-work.html

Chapter Seventeen: Medical Devices

Einthoven EKG

https://web.archive.org/web/20100707232722/http://www.ieeeghn.org/wiki/index.php/Willem_Einthoven

https://www.nobelprize.org/prizes/medicine/1924/einthoven/biographical/

Crooks tube

https://www.sciencedirect.com/sdfe/pdf/download/eid/1-s2.0-S0016003225911957/first-page-pdf

MRI cost

https://info.blockimaging.com/bid/92623/mri-machine-cost-and-price-guide

rebleeding https://jamanetwork.com/journals/jamaneurology/fullarticle/787971#:~:text=We%20found%20that%20rebleeding%20still,associated%20with%20a%20dismal%20prognosis.

Cerebral aneurysm wire

Cost of aneurysm wire https://thejns.org/view/journals/j-neurosurg/128/6/article-p1792.xml

https://thejns.org/view/journals/j-neurosurg/128/6/article-p1792.xmlhttps://www.lyfboat.com/cerebral-aneurysm-treatment-cost-hospitals-surgeons-in-india/

https://thejns.org/view/journals/j-neurosurg/128/6/article-p1792.xml

Heart valves

valve cost https://www.modernhealthcare.com/article/20140329/MAGAZINE/303299961/nonsurgical-heart-valve-procedure-spurs-cost-concerns#:~:text=TAVR%20devices%20typically%20cost%20about,of%20thoracic%20and%20cardiovascular%20surgery.

Trans catheter aortic valve replacement

https://www.mayoclinic.org/tests-procedures/transcatheter-aortic-valve-replacement/about/pac-20384698

John Charnley prosthetic hip

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1888784/

John Insall and knee prostheses

https://www.hss.edu/conditions_knee-surgery-research-chair-john-n-insall-md.asp

https://www.beckersspine.com/sports-medicine/item/21903-10-knee-surgeries-that-impact-history

John Holter brain shunt

https://www.uh.edu/engines/epi2582.htm https://www.tampabay.com/archive/1993/02/09/small-wonder/

Pill capsule evaluation of small intestine

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295178/

MRI cost

https://info.blockimaging.com/bid/92623/mri-machine-cost-and-price-guide

Proton beam 

COST OFF PROTON BEAM THERAPY  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351082/

https://www.astro.org/About-ASTRO/History/John-Archambeau

https://www.forbes.com/forbes/2009/0316/062_150mil_zapper.html#734ef3092068

https://www.healio.com/news/hematology-oncology/20160826/proton-beam-therapy-at-tipping-point-due-to-inconsistent-reimbursement-lack-of-comparative-data

https://www.sciencedirect.com/science/article/pii/S2405630819301077https://news.llu.edu/patient-care/memoriam-james-m-slater-pioneer-of-proton-therapy-transformed-cancer-treatment

surgical mesh

https://my.clevelandclinic.org/health/articles/16298-surgical-mesh-use-and-complications-in-women

Metal on metal hip prosthesis

https://www.nejm.org/doi/full/10.1056/NEJMp1206794

https://www.nejm.org/doi/full/10.1056/nejmp1211581

Price of devices

https://www.healthaffairs.org/doi/pdf/10.1377/hlthaff.27.6.1544

Medical device spending

https://www.advamed.org/sites/default/files/resource/estimates_of_medical_device_spending_in_the_united_states_november_2018.pdf

https://www.proclinical.com/blogs/2020-9/who-are-the-top-10-medical-device-companies-in-the-world

Medtronic to buy Covidien for $42.9 billion, rebase in Ireland

https://www.reuters.com/article/us-covidien-medtronic-inc/medtronic-to-buy-covidien-for-42-9-billion-rebase-in-ireland-idUSKBN0ER03420140616

In 2015 Medtronic bought a Tyco spinoff (Covidien) that was headquartered in Dublin for 42.9 billion and moved their home base to Ireland.  They made most of their money in the U.S. and avoided paying tax on $14 billion.  They called the maneuver a “tax inversion” and it was legal.  Between 1982 and the present 82 companies have shifted their headquarters to a foreign destination, usually Ireland or Bermuda “without changing the majority ownership”

https://www.bloomberg.com/graphics/tax-inversion-tracker/

bib: chap: 8-13

Chapter Eight: Surgery Becomes a Learned Craft

Halsted –America’s first residency program at John’s Hopkins https://www.researchgate.net/publication/12748668_The_training_of_the_surgeon_Dr_Halsted’s_greatest_legacy

https://embryo.asu.edu/pages/william-stewart-halsted-1852-1922#:~:text=At%20Johns%20Hopkins%20Hospital%2C%20Halsted,perform%20procedures%20under%20his%20guidance.&text=Private%20tutors%20educated%20Halsted%20at,ten%20years%20old%20in%201863

Harvey Cushing : A man of ambition, boundless, driving energy, and a fanatical work ethic

Harvey Cushing: A Life in Surgery Michael Bliss –522 pages published 2007

https://www.google.com/books/edition/Harvey_Cushing/zENRDAAAQBAJ?hl=en&gbpv=1&dq=a+man+of+ambition,+boundless,+driving+energy,+and+a+fanatical+work+ethic&pg=PA9&printsec=frontcover

https://www.healio.com/news/endocrinology/20120325/harvey-cushing-1869-1939

https://www.jstor.org/stable/44447846

https://www.medschool.lsuhsc.edu/neurosurgery/nervecenter/cushing.html

Evarts A.Graham–  book by C. Barber Mueller

Chapter Nine: Narcotics

Serturner morphine https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125194/  Serturner https://books.google.com/books?id=hzB9DwAAQBAJ&pg=PT196&lpg=PT196&dq=aggravated+hypochondriacal+alterations+in+his+frame+of+mind+and+quiet+disturbances+of+mood.&source=bl&ots=GkPrUkJ0ea&sig=ACfU3U2dtwCbjDzm4CQBOISY-cl8SH_zPQ&hl=en&sa=X&ved=2ahUKEwj_rNSR3q_qAhVDoZ4KHZNmAF0Q6AEwAHoECAoQAQ#v=onepage&q=aggravated%20hypochondriacal%20alterations%20in%20his%20frame%20of%20mind%20and%20quiet%20disturbances%20of%20mood.&f=false

OPIUM WARS 

https://asiapacificcurriculum.ca/learning-module/opium-wars-china

Fentanyl https://www.jpain.org/article/S1526-5900(14)00905-5/pdf

The Sackler’s and Oxycontin—an article in the New Yorker Magazine https://www.newyorker.com/magazine/2017/10/30/the-family-that-built-an-empire-of-pain

Patrick Rodden Okeefe.  The Family that Built an Empire of Pain. New Yorker Oct 30,2017

https://www.pharmaflowltd.com/exploding-penicillin-myth-way-disrupt-pharma/

Drug over doses. Drug over doses.   https://www.cdc.gov/nchs/products/databriefs/db356.htm

Chapter Ten: Penicillin

Fleming  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520913/

Florey Chain Heatley discovery of penicillin

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403050/

Pfizer penicillin

https://www.eurekalert.org/pub_releases/2008-06/acs-pwo061208.php#:~:text=They%20needed%20huge%20tanks%20that,opened%20on%20March%201%2C%201944

Penicillin patent 

https://www.mayoclinicproceedings.org/article/S0025-6196(15)00304-3/fulltext#:~:text=Chain%20strongly%20advised%20obtaining%20a,Fleming%20and%20Chain%20in%201945.

https://www.pharmaflowltd.com/exploding-penicillin-myth-way-disrupt-pharma/

Ernst Chain penicillin

https://www.nobelprize.org/prizes/medicine/1945/chain/biographical/

https://www.pharmaflowltd.com/exploding-penicillin-myth-way-disrupt-pharma/

Syphillis  https://pubmed.ncbi.nlm.nih.gov/15219556/

Streptomycin –Selman Waksman—Albert Schatz

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3911012/

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61202-1/fulltext https://www.nytimes.com/2012/06/12/science/notebooks-shed-light-on-an-antibiotic-discovery-and-a-mentors-betrayal.html

https://www.theguardian.com/education/2002/nov/02/research.highereducation

Chapter Eleven: Hormones—Cortisone and Epinephrine

The Tortured Path to the Cortisone Discovery February 17, 2019 • By Thomas R. Collins  

 

https://www.mayoclinicproceedings.org/article/S0025-6196(11)62920-0/pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1296908/pdf/jrsocmed00020-0011.pdf

https://www.the-rheumatologist.org/article/the-tortured-path-to-the-cortisone-discovery/ 

Cortisone by Edward C. Kendall. Charles Scribner’s Sons, 1971 

https://www.sciencedirect.com/topics/neuroscience/adrenocorticotropic-hormone

http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/kendall-edward.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1113923/

https://pdfs.semanticscholar.org/0419/f2e829172a3864f861a49cb75b0d905c8d42.pdf

https://www.semanticscholar.org/paper/Some-social-aspects-of-discovery%2C-synthesis-and-of-Jadre%C5%A1ki%C4%87/0419f2e829172a3864f861a49cb75b0d905c8d42?p2df

HENCH DISCOVERS CORTISONE

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1296908/pdf/jrsocmed00020-0011.pdf

Addison’s disease and President Kennedy

https://www.healio.com/rheumatology/practice-management/news/online/%7B74059ff3-579e-4540-b20f-d496eec0a7f0%7D/all-the-presidents-secrets-john-f-kennedy-and-addisons-disease\

Epipen –House of  Representatives: Cummings on Bresh http://www.digitaljournal.com/news/politics/epipen-ceo-raked-over-the-coals-during-hearing-on-price-gouging/article/475477#ixzz6bLqV6Hdh

Heather Bresch | C-SPAN.org

Cummings on Heather Bresh–epipen  http://www.digitaljournal.com/news/politics/epipen-ceo-raked-over-the-coals-during-hearing-on-price-gouging/article/475477#ixzz6bLqV6Hdh

Chapter Twelve: Surgery of the Heart and Blood Vessels

https://www.annalsthoracicsurgery.org/article/S0003-4975(05)00347-4/pdf

cost of cardiac birth defects  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657658/pdf/mm6602a1.pdf

Heart lung machine

http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/gibbon-john.pdf

https://www.annalsthoracicsurgery.org/article/S0003-4975(05)00347-4/pdf

Bigelow hypothermia

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC556354/

King of Hearts by Wayne Miller –Book

Cost of cardiac birth defects  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657658/pdf/mm6602a1.pdf

Heart valve:  Albert Starr meets Miles Edwards

https://www.ohsu.edu/historical-collections-archives/miles-lowell-edwards-1898-1982

valve cost 

https://www.modernhealthcare.com/article/20140329/MAGAZINE/303299961/nonsurgical-heart-valve-procedure-spurs-cost-concerns#:~:text=TAVR%20devices%20typically%20cost%20about,of%20thoracic%20and%20cardiovascular%20surgery.

vascular surgery

Debakey and the Archimedes pump for heart lung machine https://www.annalsthoracicsurgery.org/article/S0003-4975(03)01822-8/pdf

Michael Debakey YouTube interviews

https://debakeyfilm.com/

Gabe Mirkin on Debakey

Medgadget heart valves https://www.medgadget.com/2020/03/heart-valve-repair-and-replacement-market-size-share-global-industry-report-2019-2025.html

Vascular grafts  https://www.medgadget.com/2019/06/vascular-graft-market-size-acquire-4-14-billion-usd-grabbing-a-cagr-of-7-6-by-2023-top-key-players-triggering-advancing-technology-in-vascular-and-cardiovascular-surgeries.html

Chapter Thirteen: Safety: Anesthesia—Checklists—Malpractice

Hepatitis Attributable to Halothane–Gerald Klatskin

https://www.nejm.org/doi/full/10.1056/NEJM196903062801001

Anesthesia close claim project

http://www.healthwatchusa.org/conference2016/slides/07-Posner-HWUSA-2016.pdf

Military medicine malpractice and the Feres Doctrine

https://fas.org/sgp/crs/misc/IF11102.pdf

Bib: chap 3–7

Chapter Three: The 1900s

Chapter Four: Insulin

Banting and the discovery of insulin

http://www.uefap.com/reading/exercise/ess3/pringle.htm

Rewriting medical history: Charles Best and the Banting and Best Myth by Michael Bliss

https://www.nejm.org/doi/full/10.1056/NEJMms1411398

https://www.nobelprize.org/prizes/themes/august-krogh-and-the-nobel-prize-to-banting-and-macleod-2/

Nobel Prize insulin https://www.nobelprize.org/prizes/themes/august-krogh-and-the-nobel-prize-to-banting-and-macleod-2/

Cloning insulin by Lara Frazer https://www.gene.com/stories/cloning-insulin

Genentech insulin  https://www.gene.com/stories/cloning-insulin

https://www.nlm.nih.gov/exhibition/fromdnatobeer/exhibition-interactive/recombinant-DNA/recombinant-dna-technology-alternative.html

Genentech insulin  https://www.gene.com/stories/cloning-insulin

https://www.nlm.nih.gov/exhibition/fromdnatobeer/exhibition-interactive/recombinant-DNA/recombinant-dna-technology-alternative.html

Genentech insulin by Lara Frazer 

https://www.gene.com/stories/cloning-insulin

Herbert Boyer and Stan Cohen and Genentech

https://www.sciencehistory.org/historical-profile/herbert-w-boyer-and-stanley-n-cohen

Why Is There No Generic Insulin? Historical Origins of a Modern Problem 
Insulin patent sold for one dollar
March 19, 2015  N Engl J Med 2015; 372:1171-1175

https://www.nejm.org/doi/full/10.1056/NEJMms1411398

https://www.nejm.org/doi/full/10.1056/NEJMms1411398

Why insulin is so expensive

https://www.vox.com/2019/4/3/18293950/why-is-insulin-so-expensive

Why Americans are getting insulin from Mexico

https://www.vice.com/en/article/8xzyy4/why-americans-are-getting-their-insulin-from-mexico

Chapter Five: Transfusions

Karl Landsteiner

Landsteiner blood types 

https://www.uni-wuerzburg.de/en/uniarchiv/personalities/gelehrte/karl-landsteiner/

Early transfusions and blood banking Oswald Robertson

https://rdcr.org/wp-content/uploads/2014/01/robertsen-and-robertsen.pdf

https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1537-2995.2000.40010110.x

#:~:text=Blood%20transfusion%20is%20often%20cited,United%20States%20entered%20the%20war.&text=Blood%20transfusion%20had%20been%20attempted,to%20a%20variety%20of%20factors.

https://us.macmillan.com/books/9781627796378

http://www.kumc.edu/wwi/medicine/blood-transfusion.html#:~:text=Blood%20transfusion%20is%20often%20cited,United%20States%20entered%20the%20war.&text=

http://www.kumc.edu/wwi/medicine/blood-transfusion.html

Landsteiner blood types  https://www.uni-wuerzburg.de/en/uniarchiv/personalities/gelehrte/karl-landsteiner/

https://www.vice.com/en_us/article/9k74bz/america-is-selling-blood-for-big-profits-to-the-rest-of-the-worldblood as a commodity

book about blood https://us.macmillan.com/books/9781627796378    

Who Is Making Money From Bay Area Blood Donations?

OSWALD ROBERTSON THE FIRST BLOOD BANK   http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/robertson-oswald.pdf

Paid blood donations

https://factcheck.afp.com/it-not-illegal-pay-blood-donations-us-hospitals-choose-not-use-paid-donors-over-safety-concerns

The Risk of Transfusion-Transmitted Viral Infections 1996 study

https://www.nejm.org/doi/full/10.1056/nejm199606273342601

PCR study

https://pubmed.ncbi.nlm.nih.gov/20345570/

https://www.nejm.org/doi/full/10.1056/NEJM199107043250101

Chapter Six: Viruses

ELECTRON MICROSCOPE THE RUSKA BROTHERS https://www.sciencedirect.com/science/article/pii/S1076567008701551

https://www.nobelprize.org/prizes/physics/1986/perspectives/

Then, in 1981, Jacques Dubochet and Alasdair McDowall made a breakthrough in imaging macromolecular complexes with EM — introducing the rapid cryo-cooling of individual molecules in a thin layer of vitrified water –

Ruska electron microscope Ruska electron microscope

https://en.wikipedia.org/wiki/Ernst_Ruska https://authors.library.caltech.edu/5456/1/hrst.mit.edu/hrs/materials/public/ElectronMicroscope/EM_HistOverview.htm#:~:text=1.,the%20limitations%20of%20visible%20light.

Tobacco mosaic virus

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC408320/?page=6

Michael Riordan Wash U. magazine

https://riordangileadsciencesarticle.wordpress.com/

https://riordanclinic.org/books/

Schinazi –scientist who created two HIV drugs and was instrumental in finding cure for hepatitis C.

https://www.military.com/daily-news/2016/02/05/former-va-scientist-responds-to-lawmakers-suspicions-drug-sale.html

Schinazi compensation  https://www.military.com/daily-news/2016/02/05/former-va-scientist-responds-to-lawmakers-suspicions-drug-sale.html

https://joncohen.org/2015/05/08/king-of-the-pills/

King of the Pills by Jon Cohen, Science May 8, 2015 (Shinazi interview)

DRUGS THAT TREAT VIRAL INFECTIONS  Michael Riordan—the founder of Gilead.

Riordan Gilead  https://riordangileadsciencesarticle.wordpress.com/https://en.wikipedia.org/wiki/Gilead_Sciences

Gilead remdesivir

https://www.gilead.com/-/media/gilead-corporate/files/pdfs/covid-19/gilead_rdv-development-fact-sheet-2020.pdf

https://en.wikipedia.org/wiki/Gilead_Sciences

nucleoside phosphanate –

Antonin Holy Czech scientist created the powerful HIV durgs—the nucleoside phoshanates 

https://www.intmedpress.com/serveFile.cfm?sUID=7580f2bf-12b9-4a9c-840d-fb337dcb9873 

https://en.wikipedia.org/wiki/Phosphonate

Antonin Holy and nucleoside phoshanates https://www.intmedpress.com/serveFile.cfm?sUID=7580f2bf-12b9-4a9c-840d-fb337dcb9873 

Cold War Triangle: how scientists in east and west tamed HIV, by Renilde Loeckx;  Leuven University Press

Riordan Gilead https://riordangileadsciencesarticle.wordpress.com/

https://www.intmedpress.com/serveFile.cfm?sUID=7580f2bf-12b9-4a9c-840d-fb337dcb9873 https://en.wikipedia.org/wiki/Phosphonate

HIV prevention Gilead

https://www.statnews.com/2020/02/26/newest-prep-pill-hiv-prevention-fuel-progress-or-profits/

https://www.ibtimes.com/hiv-drug-truvada-costs-2000-us-only-8-australia-2792684

Schinazi  antivirals for hepatitis C and HIV

https://www.ft.com/content/e7925e46-fc86-11e3-86dc-00144feab7de

https://www.military.com/daily-news/2016/02/05/former-va-scientist-responds-to-lawmakers-suspicions-drug-sale.html

King of the pills by Jon Cohen. PUBLISHED MAY 8, 2015

https://joncohen.org/2015/05/08/king-of-the-pills/

Hepatitis C

https://www.scientificamerican.com/article/inventor-of-hepatitis-c-cure-wins-a-major-prize-and-turns-to-the-next-battle/

A Better Treatment for Hepatitis C (edited)   Dec 9, 2013 New Yorker  By Celine Gounder a physician, public-health specialist, and medical journalist

There are six genotypes of hepatitis C.  Using interferon some were more responsive to treatment than others. “Sofosbuvir changed everything.  One-pill-a-day therapy, very high cure rates, shorter treatment duration, and fewer side effects.” Sofosbuvir was invented by, and named after, Michael Sofia, the kind of person who daydreams about enzymes metabolizing drugs. Sofia was raised in a row house on the northeastern side of Baltimore. His parents, a barber and a payroll clerk, were both children of Italian immigrants, and born within a block of each other in Baltimore’s Little Italy. Although they instilled an immigrant’s appreciation for education in their three children, who would all go on to work in science, Sofia’s reading skills were so poor as a child that in the fourth grade he was put in a remedial reading class. Sofia credits the nun who taught him with transforming into a “completely different student.”  Sofia eventually enrolled at Cornell and went on to earn his Ph.D. from the University of Illinois.

When he arrived at Pharmasset, the company had already started moving away from the H.I.V.-drug development that it was initially known for, since the market had become saturated with “nucleoside” drugs that worked reliably with manageable side effects. Nucleosides are the building blocks of D.N.A. and R.N.A.; they can be chemically altered to terminate chains of genetic code early, producing something like a defective Lego that can’t be build onto, stopping the growth of the virus. Though this chemistry had been used successfully to treat H.I.V., only a few labs were trying this approach with hepatitis C. Sofia noted that one of the company’s test drugs, PSI-6130, showed activity against hepatitis C.  He realized that any effective hepatitis-C drug not only needed to get into the liver, where the virus was replicating, but stay there, to avoid unintended side effects elsewhere in the body. In their active form, nucleoside drugs don’t enter liver cells. Sofia hypothesized that if he could shroud a nucleoside with an “invisibility cloak” to get it into liver cells he could then count on the liver’s enzymes to break down the cloak and activate the drug. Once the cloak has been shed, the nucleoside would be trapped inside, protecting the rest of the body from exposure. “  He explicitly engineered sofosbuvir with this and a number of other goals in mind—that the drug would be taken orally, ten times more potent than PSI-6130, and effective against all six genotypes of hepatitis C. Beginning with a modified version PSI-6130, after three years of development, Sofia and his colleagues arrived at sofosbuvir in 2007. What’s remarkable, according to Sofia, is that it was not in fact a happy accident, but a product of explicit engineering. Following the Pharmasset acquisition in 2011, Sofia worked with Gilead for about a year to manage the transition process. 

https://www.npr.org/sections/health-shots/2020/06/29/884648842/remdesivir-priced-at-more-than-3-100-for-a-course-of-treatment

https://www.ibtimes.com/hiv-drug-truvada-costs-2000-us-only-8-australia-2792684

https://en.wikipedia.org/wiki/Gilead_Sciences

HIV: And the band played on https://www.amazon.com/Band-Played-Politics-Epidemic-20th-Anniversary/dp/0312374631/ref=sr_1_3?dchild=1&keywords=and+the+band+played+on&qid=1597522204&sr=8-3

FDA APPROVES REMDESIVIR https://www.remdesivir.com/us/?gclid=CjwKCAjwtNf6BRAwEiwAkt6UQpOs8ddJlLqD2i0gTt8oH4AQwYLvU6jjdMySaNkYW65er7MLrRKrnRoCEh0QAvD_BwE&gclsrc=aw.ds

Remdesivir Covid 19

https://www.gilead.com/-/media/gilead-corporate/files/pdfs/covid-19/gilead_rdv-development-fact-sheet-2020.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202249/

Chapter Seven: Vaccines

Vaccines –2020 WHO

https://www.cdc.gov/vaccines/hcp/acip-recs/index.html

https://academic.oup.com/cid/article/38/10/1440/346900

WHO https://www.cms.gov/CCIIO/Resources/Fact-Sheets-and-FAQs/preventive-care-background

https://www.cdc.gov/vaccines/hcp/acip-recs/index.html

https://academic.oup.com/cid/article/38/10/1440/346900

Anti venom in India https://insa.nic.in/writereaddata/UpLoadedFiles/IJHS/Vol53_4_2018__Art18.pdf

http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/francis-thomas.pdf

Sabin https://www.sciencehistory.org/historical-profile/jonas-salk-and-albert-bruce-sabin

Anti snake venom in India  https://insa.nic.in/writereaddata/UpLoadedFiles/IJHS/Vol53_4_2018__Art18.pdf

Sabin the man who developed an oral vaccine for polio

Human papilloma virus CAPSID PROTEIN   https://www.google.com/search?q=what+is+a+capsid+protein&rlz=1C1CHBF_enUS730US736&oq=what+is+a+capsid+protein&aqs=chrome..69i57j0l4.4510j0j7&sourceid=chrome&ie=UTF-8

WHO https://www.cms.gov/CCIIO/Resources/Fact-Sheets-and-FAQs/preventive-care-background

https://www.cms.gov/CCIIO/Resources/Fact-Sheets-and-FAQs/preventive-care-background

https://www.cdc.gov/vaccines/hcp/acip-recs/index.html

https://academic.oup.com/cid/article/38/10/1440/346900

Anti venom in India https://insa.nic.in/writereaddata/UpLoadedFiles/IJHS/Vol53_4_2018__Art18.pdf 

Pasteur

https://www.famousscientists.org/louis-pasteur/https://www.vbivaccines.com/wire/louis-pasteur-attenuated-vaccine/

Tetanus– diphtheria

https://www.weforum.org/agenda/2019/04/gaston-ramon-vaccination-secret-weapon-adjuvanted/

https://academic.oup.com/cid/article/38/10/1440/346900

Tetanus anti-serum  https://prism.ucalgary.ca/bitstream/handle/1880/51826/9781552388655_chapter06.pdf;jsessionid=6B018FEE77F343A6F601D0AF647F4DF1?sequence=9

https://www.terumo.com/story/terumostory/1921_2001/cat1_1_3.html#:~:text=Kitasato%20succeeded%20in%20growing%20the,toxins%20that%20can%20cause%20convulsions.

Maurice Hilleman–Book:  Vaccinated by Paul Offit

Thomas Francis jr. influenza vaccine

http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/francis-thomas.pdf

https://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(15)00317-3.pdf

Book:  Jonas Salk a life by Charlotte DeCroes Jacobs, Oxford press 2015

Sabin

https://www.sciencehistory.org/historical-profile/jonas-salk-and-albert-bruce-sabinh

ttps://www.notablebiographies.com/Ro-Sc/Sabin-Albert.html

https://www.sciencehistory.org/distillations/political-ills

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2589490/pdf/yjbm00059-0074.pdf

Heloisa Sabin

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1383764/

Polio Cutter Berkley 

https://www.nejm.org/doi/full/10.1056/NEJMp048180

Ending use of oral polio https://www.nejm.org/doi/full/10.1056/NEJMp1808903

Dengue vaccine https://www.nejm.org/doi/full/10.1056/NEJMoa1903869

Hepatitis B surface antigen and Baruch Blumberg

https://www.theguardian.com/science/2011/apr/07/baruch-blumberg-obituary

https://www.webofstories.com/play/baruch.blumberg/14;jsessionid=AA25332CCC8A1CBADC3504F21A7B32B8

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541201/

https://www.nature.com/articles/nbt0184-28.pdf?origin=ppub

hepatitis B vaccine 

https://virologyj.biomedcentral.com/articles/10.1186/s12985-019-1182-0 Margaret mead Adlai Stevenson hepatitis B vaccine

https://oac.cdlib.org/view?docId=kt7q2nb2hm&chunk.id=d0e5843&brand=oac4&doc.view=entire_text

Hepatitis b vaccine  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541201/

Rutter uses yeast  https://caselaw.findlaw.com/us-federal-circuit/1421143.html

Vaccine for hepatitis E  https://www.nejm.org/doi/full/10.1056/NEJMoa1406011

Interviews with William Rutter

https://update.lib.berkeley.edu/2015/12/15/william-j-rutter-oral-history-now-online/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804231/

Rutter uses yeast to make viral antigen

Hepatitis B vaccine  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541201/

Rutter uses yeast  https://caselaw.findlaw.com/us-federal-circuit/1421143.html

https://caselaw.findlaw.com/us-federal-circuit/1421143.html

Vaccine for hepatitis B

https://www.nejm.org/doi/full/10.1056/NEJMoa1406011\

Novartis acquires rest of Chiron

https://www.latimes.com/archives/la-xpm-2005-sep-02-fi-chiron2-story.html

Human papilloma virus casid protein  https://www.google.com/search?q=what+is+a+capsid+protein&rlz=1C1CHBF_enUS730US736&oq=what+is+a+capsid+protein&aqs=chrome..69i57j0l4.4510j0j7&sourceid=chrome&ie=UTF-8

SARS  the first corona epidemic

https://onlinelibrary.wiley.com/doi/full/10.1046/j.1440-1843.2003.00518.x?sid=nlm%3Apubmes https://www.who.int/csr/sars/country/table2004_04_21/en/ https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30129-8/fulltext  

MERS the second corona virus epidemic

Yaseen M. Arabi, M.D., February 9, 2017; N Engl J Med 2017; 376:584-594 DOI: 10.1056/NEJMsr1408795

CHINESE COVID VACCINE  https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31605-6/fulltext

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31605-6/fulltext

Coronavirus envelope protein: current knowledge

https://virologyj.biomedcentral.com/articles/10.1186/s12985-019-1182-0

CHINESE COVID VACCINE https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31605-6/fulltext

BIB: CHAP. ONE AND TWO

Introduction

Introduction

A little over a century ago, my six-year-old dad and his family lived in a small, wooden, dirt-floored cottage in a shtetl that straddled one of the main Ukrainian-Russian east-west highways. In 1914, the First World War started. The Russian army attacked Germany and fell into a trap. The Russian Second Army was virtually destroyed at the Battle of Tannenberg, and 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 war 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, 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, tear their skin, and bacteria enter their bodies. One to two weeks later, the aching starts. Many become quite ill.  They have chills, high fevers, an unremitting headache, and exhaustion. When my grandmother became feverish, she was also confused. A Russian army nurse who was making the rounds came by. The family was unable to hide the sick woman and the nurse summoned a wagon. It took my grandmother 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 years between 1917 and 1925, more than 25 million people living in Russia developed epidemic typhus, and three million died.” Some claim epidemic typhus has caused more deaths than all the wars in history.  My father always remembered his boyhood, and when I chose to go to medical school, he shrugged. Based on what he witnessed, he believed doctors know how to recognize and diagnose illness, but that’s all they can do. (In the 21stcentury, typhus is easily cured and prevented with the antibiotic Doxycycline.)

The human body knows how to mend itself and fight off infections, and there have always been healers and helpers. The first sign of civilization, according to anthropologist Margaret Mead, was a femur (thighbone) that had been fractured and healed. Repair and restoration takes time.  Without help creatures with broken legs can’t escape danger and don’t survive.

Prior to the 1900s, mankind didn’t have the ability and tools needed to cure the lame and blind, turn around a lethal infection, remove a cancer, or give someone a new heart or kidney. The needed drugs, devices, and skills—“health care”—were created (or transformed) during the last 120 years. It’s a gift we received because we were born in the 20th and 21st centuries. It may be as common as the iPhone, the airplane, or the internet. We may take it for granted and feel like it has always been and always will be available when we need it.

But it has become expensive. In the last 50 years, some of us have had to deal with costly insurance, obscenely priced medications, and outrageous hospital bills. Many of the people in charge don’t believe health care is or should be a shared responsibility.

—————————–

The authors of the Declaration of Independence didn’t think health care was an “unalienable right that was endowed by our creator” and health care wasn’t one of the many rights that were added to the nation’s Constitution in 1791.

Back then, nursing care supported the ill and sped their recovery. Amputations prevented some deaths. But most of the treatments doctors employed were pretty awful. Consider—the December morning in 1799 when 67-year-old George Washington awoke desperately ill. He was retired and lived 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 on the day in question, he couldn’t talk and had trouble breathing. His wife, Martha, sent for one doctor, then another. She and her husband were two of the country’s richest people and obviously 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 four 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. When Washington’s breathing got worse, he dressed, thanked his three doctors, and made arrangements for his burial. That night, he died. (As related by his secretary Tobias Lear)

Before 1800, the educated elites relied on the teachings of the ancients, like the Greek physician Hippocrates, who believed that illness was “due to an imbalance of blood, phlegm, black bile, and yellow bile,” and the Roman Galen who dissected monkeys and wrote about their anatomy.

Mankind was not aware of the microscopic creatures who lived in, around, and on us until the late 1700s.

During the 1800s we gradually learned about their existence. We started believing and understanding that they were the source of many of our maladies, and we began to take precautions.

In the 1900s our abilities exploded: We learned how to safely transfuse blood. Hormones were isolated. Antibiotics and drugs that fought viruses and parasites were developed. Experts learned and taught others how to replace eye lenses that were opaque. Vaccines were crafted. Thousands of medical gadgets were devised. Surgeons were taught how to proceed after they cut a person open, and a large number of effective drugs became available.

In 1965, over 100 million Americans were introduced to socialized medicine—Medicare and Medicaid. Most loved it.

In 2003, the entire human genome was “sequenced.” Scientists determined the exact order, the way the 3 billion pairs of human DNA nucleotides (building blocks) lined up, and our ability to attack and “cure” genetic conditions got a big boost. The push and pull between medical care as a shared endeavor or a wealth-producing commodity started in the 1900s. It intensified over time. In the last half of the 20th century, “health care” increasingly became a major part of the U.S. economy and obstacles and inequalities were created.  This book seeks to make sense of the wonders that were developed and the challenges we face. 

In the pages that follow, I’d like you to accompany me up the miraculous, tortuous road medicine has traveled during the last 200 years, and get a more detailed understanding of what I’m talking about.

The typhus epidemic in a shtetl during the First World War.

www.ferdmanfredman.com      0.11 TYPHUS.pdf

The death of George Washington. 

https://www.mountvernon.org/library/digitalhistory/digital-encyclopedia/article/the-death-of-george-washington/

Morens DM. Death of a President. New Engl J Med. 1999:341;1845-1849. Pubmed: 10588974https://www.nejm.org/doi/full/10.1056/NEJM199912093412413 https://doctorzebra.com/prez/z_x01death_lear_g.htm

Is Health Care a Right?  By Atul Gawande.  The New Yorker Oct 2, 2017

MEDICINE BEFORE 1800

Margaret mead 

https://medium.com/@ismailalimanik/the-first-sign-of-civilization-95bc3f44f956#:~:text=Anthropologist%20Margaret%20Mead%20was%20asked,been%20broken%20and%20then%20healed

Hippocrates:  https://www.ncbi.nlm.nih.gov/pubmed/10361669 

Blood letting history
http://www.pbs.org/kqed/demonbarber/bloodletting/

Chapter One: Awakening to the Microscopic World

Van Leeuwenhoek

https://interestingengineering.com/the-father-of-microbiology-an-antonie-van-leeuwenhoek-biography

http://www.brianjford.com/a-avl01.htm

Edward Jenner and the first vaccination: 

cowpox –smallpox

https://emedicine.medscape.com/article/1131886-clinical

https://online.ucpress.edu/abt/article/39/7/440/11436/Edward-Jenner-and-the-First-Vaccination

http://sitn.hms.harvard.edu/flash/special-edition-on-infectious-disease/2014/the-fight-over-inoculation-during-the-1721-boston-smallpox-epidemic/

https://www.nlm.nih.gov/exhibition/smallpox/sp_variolation.html

http://www.sjsu.edu/people/ruma.chopra/courses/h174_MW_F11/s3/smallpox_GWarmy.pdf

https://www.nlm.nih.gov/exhibition/smallpox/sp_variolation.html http://www.sjsu.edu/people/ruma.chopra/courses/h174_MW_F11/s3/smallpox_GWarmy.pdfhttp://sitn.hms.harvard.edu/flash/special-edition-on-infectious-disease/2014/the-fight-over-inoculation-during-the-1721-boston-smallpox-epidemic/

Semmelweiss and hand washing

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)60062-3.pdf

Microscopes—Zeiss

https://www.zeiss.com/content/dam/corporate-new/about-zeiss/history/downloads/the_companys_history_of_zeiss-at_a_glance.pdf

https://royalsocietypublishing.org/doi/10.1098/rsob.150019

https://www.zeiss.com/microscopy/us/solutions/reference/basic-microscopy/microscopy-historical-perspective.html

https://www.zeiss.com/microscopy/us/solutions/reference/basic-microscopy/microscopy-historical-perspective.html

https://www.zeiss.com/microscopy/us/about-us.html

https://www.zeiss.com/corporate/int/about-zeiss/history/carl-zeisshtml

Abbe took over for Zeiss.

According to Abbe’s calculations the wavelength of light determines the light microscope’s ability to see tiny objects and the magnification factor can’t be much more than 1,000. 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.

Ruska developed the electorn microscope and one the nobel prize in 1986

https://www.nobelprize.org/prizes/physics/1986/perspectives/

Pasteur

https://books.google.com/books?id=YNBjDwAAQBAJ&pg=PA25&lpg=PA25&dq=pasteurs+wedding+day&source=bl&ots=0lwF4g53mX&sig=ACfU3U1G-UjPjYi4kBzEI_lieShlRCztYQ&hl=en&sa=X&ved=2ahUKEwiquNS0vanoAhUFup4KHbjqBJ4Q6AEwFHoECBkQAQ#v=onepage&q=pasteurs%20wedding%2

https://www.famousscientists.org/louis-pasteur/https://www.vbivaccines.com/wire/louis-pasteur-attenuated-vaccine/

LILLE

https://www.thelocal.fr/20171017/lille-why-would-anyone-want-to-live-there

KOCH

https://www.britannica.com/biography/Robert-Koch

Koch and tuberculin  https://www.sciencedirect.com/science/article/pii/S1201971210023143#bib2

.https://www.sciencedirect.com/science/article/pii/S1201971210023143#bib23 

https://books.google.com/books?id=el2LDwAAQBAJ&pg=PT130&lpg=PT130&dq=was+robert+koch+a+showman&source=bl&ots=5vLQTaTbaU&sig=ACfU3U0h3exSZu02YnkjDQbKAY41K6jQJw&hl=en&sa=X&ved=2ahUKEwiwp6nB26LqAhVBMH0KHfYVCSUQ6AEwCnoECAYQAQ#v=onepage&q=was%20robert%20koch%20a%20showman&f=false

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916274/

https://www.sciencedirect.com/science/article/pii/S1201971210023143#bib23

https://www.nobelprize.org/prizes/medicine/1905/koch/biographical /

https://www.who.int/news-room/fact-sheets/detail/tuberculosis

Dzintars GothamFaculty of Medicine, Imperial College London, London, UK; et al.   Estimated generic prices for novel treatments for drug-resistant tuberculosis Journal of Antimicrobial Chemotherapy, Volume 72, Issue 4, April 2017, Pages 1243–1252

https://www.downtoearth.org.in/news/health/fda-approves-new-oral-three-drug-regimen-for-extensively-drug-resistant-tb-66179

Joseph Lister

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468637/

Florence Nightingale

Eminent Victorians by Lytton Strachey https://www.ncbi.nlm.nih.gov/pmc/articles/PMC292098/

Chapter Two: The Late-19th Century

John Snow and diarrhea in 1854 

The son of a York farmer, Snow had moved to Newcastle, a northern English city located on the Tyne River when he was 14 and was an apprentice to an Apothecary- surgeon for 9 years.  He then moved to London where he studied medicine.  He became a member of the Royal College of Surgeons ten years before “the first case of Asiatic cholera” came to “the great city.” The illness arrived in the body of a seaman who died a few hours after the illness “seized” him.  The sailor had been working on a steamer where “the disease was prevailing.” Shortly after the man’s death his body was removed from the room he had been renting and another man moved in.  Eight days later the newcomer developed severe diarrhea and fever—cholera.  Snow discussed their illness in a medical paper and argued cholera was not airborne.  “He also wrote about the neighborhood keeper of a coffee shop who served glasses of water from the Broad Street pump along with meals.  She knew of nine of her customers who had contracted cholera.”

Mostly a vegetarian Snow “occasionally” drank wine when he was older, but he continued to have “faith in the temperance cause.”  He dressed plainly, never married, “and found every amusement in scientific books, and simple exercise.”  He was “full of humorous anecdotes” and told them in an irresistibly droll style.  His husky voice “rendered first hearings from him painful,” but when he guffawed “his good natured face laughed in every feature.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150208/#:~:text=The%20epidemic%20caused%20violent%20diarrhea,one%20week%20during%20September%201854.

http://www.johnsnowsociety.org/john-snow.htm

On the Mode of Communication of Cholera
by John Snow, M.D.
London: John Churchill, New Burlington Street, England, 1855

https://collections.nlm.nih.gov/ext/cholera/PDF/0050707.pdf

http://www.bbc.co.uk/history/historic_figures/snow_john.shtml

http://www.ph.ucla.edu/epi/snow/snowbook.html https://johnsnow.matrix.msu.edu/work.php?id=15-78-43

The Origin of the Haitian Cholera Outbreak Strain | NEJM

https://www.nejm.org/doi/full/10.1056/nejmoa1012928

Water

https://scadata.net/brief-history-clean-drinking-water/

Robert Crane biochemist

https://iubmb.onlinelibrary.wiley.com/doi/full/10.1002/iub.366

Cholera and Ganges delta

https://www.passporthealthusa.com/2018/02/the-history-of-cholera-and-the-ganges-delta/

Koch and cholera https://www.sciencedirect.com/science/article/pii/S1198743X14608557

Cholera in Haiti

https://www.nejm.org/doi/full/10.1056/NEJMp1012997

See one do one teach one

Morton demonstrates anesthesia in 1846 and Dr. Warren proclaimed “This is no humbug”

https://pubs.asahq.org/anesthesiology/article/124/3/553/14273/Gentlemen-This-Is-No-Humbug-Did-John-Collins

https://www.pbs.org/newshour/health/the-painful-story-behind-modern-anesthesia

Thyroid removal surgically Kocher .

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206627/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824781/

Thyroid extract 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046199/

Iodine in food. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509517/#B17-nutrients-04-01740

Murray thyroid replacement

https://www.jameslindlibrary.org/articles/the-discovery-of-thyroid-replacement-therapyappendicitis 

https://www.oumedicine.com/docs/ad-surgery-workfiles/williams_history-of-appendicitis-with-anecdotes-illustrating-its-importance.pdf

https://pubmed.ncbi.nlm.nih.gov/20391748/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1353017/

The first cholecstectomy https://jamanetwork.com/journals/jamasurgery/article-abstract/589001

Anesthesia and amputation civil war http://www.pbs.org/mercy-street/uncover-history/behind-lens/surgery-civil-war/ Appendicitis- history

https://www.oumedicine.com/docs/ad-surgery-workfiles/williams_history-of-appendicitis-with-anecdotes-illustrating-its-importance.pdf

Anesthesia and amputation civil war

http://www.pbs.org/mercy-street/uncover-history/behind-lens/surgery-civil-war/

Horsley brain surgery England  https://www.neurosurgeryblog.org/2016/08/17/faces-of-neurosurgerys-founders-victor-horsley/

PARASITES AND VECTORS

Patrick Manson-vector parasitology

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3630944/

https://www.rcpe.ac.uk/sites/default/files/jrcpe_49_1_hussey.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2463920/?page=1

Malaria 

https://malariajournal.biomedcentral.com/articles/10.1186/1475-2875-10-144

https://www.encyclopedia.com/people/medicine/medicine-biographies/alphonse-laveran

https://www.nobelprize.org/prizes/medicine/1907/laveran/biographical/https://www.nobelprize.org/prizes/medicine/1907/laveran/lecture/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2825508/ https://malariajournal.biomedcentral.com/articles/10.1186/1475-2875-10-144

https://www.nobelprize.org/prizes/medicine/1907/laveran/biographical/

https://www.nobelprize.org/prizes/medicine/1907/laveran/lecture/

Richard Ross and mosquito transmission

https://www.cdc.gov/malaria/about/history/ross.html

https://www.britannica.com/biography/Ronald-Ross

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62019-3/fulltext

Patrick manson in london  https://www.rcpe.ac.uk/sites/default/files/jrcpe_49_1_hussey.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2463920/?page=1

Chloroquine and malaria.  https://blogs.sciencemag.org/pipeline/archives/2020/03/20/chloroquine-past-and-present

https://web.stanford.edu/group/parasites/ParaSites2005/Chloroquine/history.html

Artimisinen  https://www.who.int/malaria/position_statement_herbal_remedy_artemisia_annua_l.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966551/#:~:text=The%202015%20Nobel%20Prize%20in,of%20China%20to%20global%20health.

https://www.nobelprize.org/womenwhochangedscience/stories/tu-youyou

Artemesian combination therapy malaria 

https://www.nobelprize.org/prizes/medicine/2015/tu/lecture/ https://www.nobelprize.org/womenwhochangedscience/stories/tu-youyou

https://www.kit.nl/wp-content/uploads/2018/08/879_The-world-of-Artemisia-in-44-questions.pdf

https://www.novartis.com/news/media-releases/novartis-malaria-treatment-coartem-80480mg-receives-who-prequalification-enabling-greater-access-patients

https://www.forbes.com/sites/helencoster/2011/02/07/novartis-institute-tackles-unprofitable-drugs/#164e9f5c3d89

https://www.mmv.org/newsroom/news/price-coartem-reduced-third-time-8-years

Yellow Fever

Dingler Suez canal http://www.kumc.edu/school-of-medicine/history-and-philosophy-of-medicine/panama-canal/french-panama-canal-failure.html

https://watermark.silverchair.com/milmed.170.10.881.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAArcwggKzBgkqhkiG9w0BBwagggKkMIICoAIBADCCApkGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMHnjScnqNYqfNRpvQAgEQgIICahMUjnyPzEdYmCBOMkXoqOdhCzGXtEf3ccBb7Uqd53T1thD4rcueqf8Uo4voGj3ewfPM_PZNJTNmVOOj9vRW35ROWy0kJVgKgAYeOz4u-nrcEHXqMVjXW_P5uEiFA73tpwF2Rxt-xoFbt_MrXVsYl41CT-6KUbVQx0JBVl2GinLV4BSb38KmwmDTiDuJHTDHN4tbOMKKKftSIN25QbRLWII0fSADatoNRoeTOH6nJUAZOW7xZxyrayunvqgrdv-TWpo-hdJbVeFLt9yGtQJMqFAovObbswudBieg3DLQlvih41ZNknpUlluj-dgO0hzXXxAD_8QQW6xl66x22tuoEymE-Eg2bx7nL21eESh-jS6YwH3d9T2fb0lOQV_SY-QRSD4fqD0WCRy51Q6iM3ohaLm4a9WxA089WrEyoeDvnaIupnQ64-xBYSuOqszGyogqtuekFMskzhBX-57A7JaMPqKO3J2HDtAtUIErYJ4fILvB4QR8dm1UPyHGfrBR2hQ0bRSxEWOTaosKuVFfTQrCrfYsPGLQUh7JxU1uhc3_CwQvG2gW4bkUqK6Lh0lvAkn_5si3pOoEoi6kT5AWMgGBuREGbnNXeLm6PlUlBscmvhLHvSzlWz3fV-pnZT79I0t7G2Jx1rWBIJZgD2L1sbgOlnZFqlSVr2Rt9crgVIbeFN6M63jQfCQGLRUSUWKr55WhdJLYT22i59CKY5Yy5eJQ7WLlzNlSRkq9TsjhU26dcI48r9w39dDJsr-NHDfgEtDCDyP3Lbcz7q0aJMI9MKbEC-KZxBjp5S7Q4KfETPTWo3QTdI-mLMSXpCC9fw

dingler suez canal http://www.kumc.edu/school-of-medicine/history-and-philosophy-of-medicine/panama-canal/french-panama-canal-failure.html

Walter Reed and Jesse Lazear– yellow fever

https://www.forbes.com/sites/kionasmith/2017/09/25/the-epidemiologist-who-killed-himself-for-science/?sh=7db1e0b8b664

https://www.jstor.org/stable/6065?seq=16#metadata_info_tab_contents

https://www.medicalmuseum.mil/index.cfm?p=visit.directors.reed

https://onlinelibrary.wiley.com/doi/full/10.1111/jvec.12261 https://www.jstor.org/stable/6065?seq=4#metadata_info_tab_contents

https://www.historyofvaccines.org/content/us-army-researchers-discover-cause-yellow-fever

Mosquito eradication

“Lien Jih-ching (連日清) is a specialist in mosquito-borne diseases and helped eradicate malaria in Taiwan by reducing the number of endemic cases from more than 1 million to zero within a decade,” Chen said, adding that Lien helped Taiwan become the first nation in the world to be declared “malaria-free” by the WHO in 1965.

“People call me the ‘mosquito man,’” said Lien, who is nearly 90 years old.

Lien also helped to significantly reduce the prevalence of malaria in Sao Tome and Principe — an island nation in western Africa — as depicted in the second part of the documentary.

“The prevalence of malaria was about 40 percent in 2000 … after we applied mosquito prevention measures, the numbers of patients hospitalized for malaria in Sao Tome and Principe dropped to zero in 2003,” Lien said in the documentary.

The use of an insecticide called dichlorodiphenyltrichloroethane is credited with the eradication of malaria in Taiwan, but it was not as effective in Sao Tome and Principe, Lien said, adding that he instead used alpha-cypermethrin, which had proven effective in southern Taiwan against dengue fever.

http://www.taipeitimes.com/News/taiwan/archives/2016/07/14/2003651008 https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011539.pub2/full

Schistosomiasis

Schistosomiasis — Assessing Progress toward the 2020 and 2025 Global Goals. 

Schistosomiasis–assessing progress toward the 2020 and 2025 global goals

https://www.nejm.org/doi/full/10.1056/NEJMoa1812165

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964474/

Praziquantel for Shistosomiasis-bilharzia

https://www.nejm.org/doi/full/10.1056/NEJMra012396

https://www.emdgroup.com/en/news/ivory-coast-19-10-2016.html

who.int/news-room/fact-sheets/detail/schistosomiasis#:~:text=Praziquantel%20is%20the%20recommended%20treatment,initiated%20and%20repeated%20in%20childhood.

https://www.nejm.org/doi/full/10.1056/NEJMoa1812165

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964474

Praziquantel  https://cdn1.sph.harvard.edu/wp-content/uploads/sites/480/2013/01/praziquantel.pdf

https://www.nejm.org/doi/full/10.1056/NEJMoa1812165

https://www.nejm.org/doi/full/10.1056/NEJMra012396

https://www.emdgroup.com/en/news/ivory-coast-19-10-2016.html

who.int/news-room/fact-sheets/detail/schistosomiasis

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3780935/

https://cdn1.sph.harvard.edu/wp-content/uploads/sites/480/2013/01/praziquantel.pd

https://www.nejm.org/doi/full/10.1056/NEJMoa1812165

The story of Lice and ticks is on the web site but not in the book.

LICE

In the 1800s some claimed the river flowing past Rouen smelled bad when too many in Paris flushed at the same time.  Rouen borders the Seine River and is 80 miles closer to the ocean than the city of lights.  It is the capital of Normandy, is known for the Monet paintings of its Gothic cathedral, and is the home of the ancient marketplace where Joan of Arc was burned at the stake. 

It’s also the town where Jules Noelle was born in 1866.  At age 29, after he studied in Paris and became a doctor.  Then he moved back home and married 21 year old Alice Louise Avice.  He got a job at the local medical school, but his position was not tenured, his colleagues were reluctant to accept his “wonky” Parisian belief that germs caused disease, and he was unable to hear well enough to use a stethoscope.  His career was going nowhere when the French government came looking for doctors for Tunisia, their recently conquered colony.  Jules’ brother was offered a job in north Africa and he declined, but 36 year old Jules applied for the position and was hired. 

In Tunisia an illness called Typhus was a problem each winter. (The name comes from the Greek word tuphos or stupor.)  People in the “overcrowded prisons, asylums, and tent villages” ran fevers, became confused, and sometimes died. When Jules arrived an outbreak “was raging in a native prison 80 kilometers south of Tunis/” The doctor in charge of health care was planning to visit the area and Jules asked if he could accompany him.”  The night before the trip Nicolle coughed up blood and he decided to stay behind.  The chief doctor and his servant, visited the prison, spent the night, contracted typhus and both died.

As one of the now senior physicians, Nicolle decided to learn more about the illness.  He visited a hospital, and recalled stepping over the bodies of typhus patients who were awaiting admission to the hospital and had fallen exhausted at the door.”  He noticed that sick people “spread the contagion “to others in the hospital waiting room but stopped contaminating others as soon as they bathed and dressed in a hospital uniform.”  Nicole figured the clothes—more specifically the lice that lived in the clothes, had to be the vector that spread the disease.

He injected a chimpanzee with blood from an ill patient and a day later the chimpanzee was running a fever and was prostrate. “Nicolle then injected a toque macaque (Macaca sinica) with blood from the ill chimpanzee and two weeks later the macaque got sick.  He transferred the lice that were feeding on sick macaques to other macaques and they got sick.  Nicolle was unable to culture the offending organism in agar or broth, but he published his findings in 2009 and remained in Tunis where he became an important bacteriologist.  As he aged Nicolle became philosophical and a nature lover.  His deafness got worse, it was hard to be social, and he spent much of his non research time writing and publishing three novels:  The Two ThievesThe Pleasures of Boredom, and Marmouse and his Guests. He was “Captivated by the town of Carthage” built near the ruins of a once influential and affluent city.  Noelle was known to hold court and sip mint tea in the village of Sidi Bou at a café that overlooked the town.  Carthage had once been the home of Hannibal the general who marched his troops and elephants across the Alps and almost reached Rome.  Between 264 and 146 BC the ancient city-state fought three bloody wars with Rome. During the third war the Carthaginian troops were defeated and the town was thoroughly destroyed.     At age 62 Noelle was awarded a Nobel Prize. 

The germ that causes typhus belongs to a “type” of bacteria that replicates inside other cells but doesn’t grow on agar.  Called Rickettsia, this type of bacillus enters the body through a skin scratch, gets into the blood stream, and infects the cells that line the arterial walls.  The first illness proved to be caused by this type of bacteria was Rocky Mountain spotted fever.  Infected people have headaches, fever, and a rash.  Some become quite ill, and a few die.  The name—Rocky Mountain fever–is a bit misleading because the disease affects people in many parts of the U.S.  The groups of bacteria that only replicates inside cells are called Rickettsia after Thomas Rickets, a small town Illinois boy who showed how Rocky Mountain spotted fever is spread.  As a young researcher Rickets spent four years working mostly alone and separated from his young family.  He pitched a 10 by 10 foot tent in a hospital yard in the Bitter Root Valley of Montana, in a location where the population of ticks increased when the snow melted in spring.  Rickets spent much of the research years catching and studying the vector that he thought probably spread the disease.  One of the human families Rickets studied lived on a farm where large number of ticks thrived around the house, on trees, and on the ground.  At one point, Rickets stained a sample of blood from a sick boy who had been bitten multiple times.  Examining the slide Rickets saw the gram-negative bacillus that caused the illness.    He was the first to identify the organism, and in 1910 he wrote a medical paper describing his findings.  His discovery made him famous and later that year he went to Mexico to look for the organism that caused typhus.  In the process of his research he developed typhus–and he died.

https://web.archive.org/web/20110722231400/http://www.asm.org/asm/files/ccLibraryFiles/Filename/000000001350/znw00205000065.pdf

https://academic.oup.com/jid/article/189/5/938/810819

In 1930, the year after Nicolle won the Nobel Prize, Paul Müller, a Swiss biochemist working for the pharmaceutical company Geigy, discovered that dichlorodiphenyltrichloroethane (DDT) was highly effective for killing lice and other insects and seemed to be safe for man.   Muller had become interested in chemistry when he was a high school student.  As a teenager he “was often mocked by his peers and called, “The Ghost,” due to his thin and pale appearance”  In later life he owned “a home in the alps, tended a small fruit farm, and took the children on  early morning nature walks. In 1948 Muller was awarded a Nobel Prize.  After it was discovered DDT was widely used in Europe and elsewhere and Typhus stopped being a major problem.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819868/

Ticks and tickborne diseases

https://www.nejm.org/doi/full/10.1056/NEJMp1911661

lyme

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117402/

https://www.bayarealyme.org/about-lyme/history-lyme-disease/

Babesia

https://www.lymedisease.org/lyme-basics/co-infections/babesia/

https://www.nejm.org/doi/full/10.1056/NEJMp1911661

Enteric worms. 

https://aeon.co/essays/medieval-people-were-surprisingly-clean-apart-from-the-clergy

Albendazole—high cost generic drugs

https://www.nejm.org/doi/full/10.1056/NEJMp1408376

Albendazole — Interview with Dr. Vassilios J. Theodorides

THE MICROSCOPIC WORLD

Modern health care’s creation was triggered by the observations of a Dutch man named Van Leeuwenhoek.  Like the fictional Gulliver he became the first to make the voyage, the first to gaze at the unknown world through a powerful lens.

  A contemporary of Rembrandt and Vermeer, Leeuwenhoek was born in 17th century Delft.  It’s a town in Western Holland known for cool, foggy summer mornings, numerous boat filled canals, wide streets connected by wooden bridges, and blue and white pottery.  In his day horses and carts clattered across the stones in front of a large open air market, narrow rows of houses surrounded the town square, and food and wood were weighed before it was sold.  Leeuwenhoek’s mother came from a well-to-do brewer’s family and Van Leeuwenhoek first worked as a draper’s apprentice.  While there he used the lenses of the day to check the quality of a fabric’s thread.  Later in life he was politically active.  He became a civil servant and was a chamberlain of one of the assembly chambers at city hall.  At age 40 he made one, and later many incredibly powerful, tiny magnifying lenses. Once he had created the devices he started exploring the microscopic world, and he saw sights that had never before been seen or suspected.  He drew pictures and sent them to the National Geographic of his day, the Royal Society.  His images of bacteria, red blood cells and sperm seemed fictional to some contemporaries who looked through ordinary polished and ground glass lenses.  Others believed.  During his life Leeuwenhoek made an additional 500 magnifiers.  One person, then another became aware of a microscopic world and learned it was often unfriendly. To this day no one really knows how he made his lenses.  His process died with him. 

 Back then people had long known that when someone develops smallpox and survives they don’t get it again.  That’s why some in ancient China and Africa blew crusts of a diseased person’s scab up the nose of an uninfected person.  They hoped the illness they were causing would be mild, or at worst it wouldn’t be deadly.

In 1796 Edward Jenner, a British doc proved there was a safer way to prevent the disease.  He heard that milkmaids who were infected by cowpox didn’t’ develop small pox, and he checked it out.  He took material from the pussy scabs on a young woman’s hand and “inserted it into small incisions he made in a boy’s skin.”  Much as cats and tigers are members of the same species, the viruses that cause cowpox and small pox are related.  Each can cause pustular lesions.  People who develop cowpox sometimes run a fever and are sick for a week, but the illness is mild and when a person recovers (or is vaccinated) their body is protected from the oft lethal disease

Jenner submitted his findings to the Royal Society and they were rejected, so he self published and became famous. Thomas Jefferson and James Madison read about his findings, and in 1813 Congress passed the Vaccine act.

In1853 the British Parliament made childhood vaccination with modified cowpox compulsory. 

After widespread immunization contained the illness, people in the U.S. stopped vaccinating.  In the19th century there were outbreaks, and states attempted to enforce existing laws or pass new ones.  The disease finally 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 and many were scarred for life.  The World Health Organization started a program of worldwide vaccinations.  Their efforts to eliminate the terrible disease seem to have succeeded.  The bug’s last known “natural” victim was infected in 1977.

In 1848 hand washing was little more than a cultural or religious ritual.  No one (best I can tell) connected “germs” and sanitation with infectious illnesses.  That year a Hungarian physician, Ignaz Semmelweis, was working at a hospital in Vienna and was troubled.  Women whose babies were delivered by doctors and medical students developed a fever and died 4 times more often than women whose babies who were delivered by midwives.

Semmelweis investigated and learned that the medical students in question came from the dissecting room to the maternity ward without cleaning 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 Budapest, his hometown.  In 1881 he published a book on “childbed fever.”  When he was in his late 40s he was overcome by paranoia and dementia and he was committed to a psychiatric institution.  It took a generation before his teachings were widely accepted.

While Semmelweis was investigating sanitation in Vienna, Louis Pasteur, a French chemist was graduating and becoming a researcher.  When he was young Pasteur was an average student who loved to draw and paint.  Then he got his act together and “won first prize in physics.”  He eventually studied chemistry and physics at the prestigious Ecole Normale.

At age 26 Louis 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.

Pasteur was 32 when he 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, bacteria, caused fermentation.  We call it the germ theory. In 1863, working for the French emperor, Napoleon III, Pasteur proved it was possible to eradicate harmful bacteria at a temperature well below boiling.  He prevented wine from contamination by heating fermented grape juice to 50–60 °C (120–140 °F). .  We call the process Pasteurization.   

In 1879 he and his assistants injected chicken cholera bacteria into some of his birds.  The germs had been sitting on the shelf for a while, the infections they caused were mild, and the infected chickens were subsequently resistant to the bug.  Pasteur realized it was possible to weaken a pathogen to the point where it wasn’t harmful but it still triggered an immune response.  He exploited the phenomenon to develop vaccines for chicken cholera, and anthrax. 

In 1885 a rabid dog bit a 9 year old French child. We now know that after it enters a person’s body, the virus that causes Rabies infects an axon, the “long slender projections of nerve cells that conduct electrical impulses.”  The infectious agent then travels up the axon to the brain and eventually kills the person or animal.    

The oft repeated story says the young man was bitten 15 times and two days later his mother came knocking.  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 animal.  Upon the second creature’s death, part of its spinal cord was injected into a third animal.  With each passage the agent became less virulent.  Using the technique in reverse 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.  Doctors started using similar extracts to treat people who were bitten by a rabid creature. The vaccines of the twenty first century contain inactivated virus that was grown in human or chick embryo cells.

          The Rabies virus is still responsible for the deaths of 59,000 humans a year. Ninety percent of the cases in Africa and Asia are caused by dogs. In this country we worry about bats and wild animals, and 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.

In the early 1800s the quality of microscopes was variable.  Then a few craftsmen started making clear, powerful magnifying lenses.  One of them, Carl Zeiss, came from a German family of artisans and he apprenticed with a maker of fine tools.  In 1846 he opened a workshop in Jena, a river valley town in the “green heart” region of eastern Germany.  The first dozen years his technicians under the supervision of a short tempered, authoritarian foreman, made single lens precision microscopes.  Eleven years later Zeiss introduced scopes with two lenses.  Scientists could now look into the upper curved glass, peer down a tube and view an object that was just below a second lens.  With the help of Ernst Abbe, a mathematician, the company used calculations to determine the optical characteristics of their lenses, and it improved the illumination system. Smaller and smaller objects came into view.  Doctors from Germany and beyond bought one of their scopes.  Carl’s first wife died shortly after she gave birth to their first son.  She was 22 at the time.  Carl married two more times and out lived one of the women.  All three of them were, in his words, “spiritually very much country folk.”

Robert Koch the German “father” of the germ theory, once wrote that his Zeiss scope was responsible for a large part of his success.  Koch was born 21 years after Pasteur.  He was a gifted child and could read a newspaper when he was 5.  In Germany he ran a medical practice and spent hours peering into a microscope.  When he was a district medical officer he investigated a pasture where the cows that ate the grass got sick and died. He collected blood from one of the dead animals, injected it into a mouse, and the rodent died.  Koch found rod shaped microscopic creatures in the soil, grew them in a rabbit’s eye, and allowed them to dry out.  They looked innocuous, but they were just dormant. When their survival was threatened the bacteria surrounded themselves with a protein coat, become spores, and vegetated.  They were able to endure harsh conditions, and when and if conditions permitted they emerged.  In the twentieth century these spores—anthrax—became one of the agents bioterrorists use. 

Koch’s life as a researcher started after he returned from the 1870 war with France.  When the conflict started Koch, “a 5 and a half foot tall man with a stern face and thin high voice,” tried to become an army physician.  He was rejected because he was nearsighted.  As the conflict wore on he re-applied and became a military doctor. He was with the German troops that besieged Orleans.  It’s the city on the Loire River where, in 1429, Joan of Arc famously fought the English.  Koch was troubled by the damaged bodies he had to deal with.  He once observed that in war time human life becomes “worthless.”

Years later Koch was a famed researcher.  When he was 47years old he met the other “germ theory father” in London.  At the time Pasteur was 68 and partially paralyzed.  The encounter was cordial, tense, and controversial.  Both men were doing research on anthrax.  After Pasteur presented the results of his research Koch was judgmental.   Neither man spoke the other’s language.  Letters were exchanged, and one of Pasteur’s remarks was translated as a comment on “German arrogance.” After the apparent insult each man started criticizing the work of the other.24  

Once doctors had good microscopes they learned how to categorize bacteria by drying and dyeing tissue and sputum that contained germs.  Koch used special stains on infected human and bovine (cow) tuberculosis and identified the bacillus that caused the disease.  “A plodding worker and a careful seeker of facts”, Koch dazzled a group of colleagues on a Friday evening in 1882.  He proved that the tubercle bacillus was transmissible and that it was the cause of TB in man. 

Much as people in 2020 are investing our hopes and fortunes into vaccine that will force our immune systems to reject the coronavirus– Koch tried to energize the (poorly understood) immune systems of people with tuberculosis.  He isolated a glycerine extract of the TB bacillus and injected it into the skin of a person with an active TB infection.  The fluid caused chills, fever and an aggressive skin reaction.  When it was instilled into infected guinea pigs it seemed to “completely cure animals in the late stage of the disease.” 

Koch unveiled his new treatment when he addressed the crowd at a Berlin auditorium.  “I have at last hit upon a substance which has the power of preventing the growth of the tubercle bacilli not only in a test tube but in the body of an animal.” In the subsequent months he began giving regular tuberculin injections to a number of patients with advanced disease who were in Berlin’s Charite hospital. 

Conan Doyle, the Scottish physician who created Sherlock Holmes admired Koch and wanted to meet and hear the great man.  On November 16th he arrived in Berlin by train.  When the British Embassy was unable to get him a seat at one of Koch’s demonstrations he went to Koch’s house.  He knocked on the door, and the butler showed him into the living room.  While Doyle was waiting, letters were dumped on a nearby desk and on the floor.  Doyle would later characterize them as pleas for help from people with “sad broken lives and wearied hearts who were turning in hope to Berlin.”  The next day Doyle visited the clinic where the infected were being treated.  He saw people who were febrile, quite ill, and suffering as a result of the injections.  Disappointed and dubious he wrote about his visit and misgivings and returned to Scotland. 

Koch’s supply of his “remedy” was “scarce”, but by the end of 1890 over two thousand people with advanced disease had been treated. Most of the people who received tuberculin were not improved and only 28 were cured. 

Facing public scorn because his treatment failed, the now 47 year old Koch left his wife and married Hedwig, an 18 year old art student who was “fascinated with his studies.”  He traveled to Egypt and wrote his 18 year old lover, “If you love me I can put up with anything, even failure.  Don’t leave me now.”  When Koch inoculated himself with tuberculin, she volunteered to be injected too.” 

During his later years, his reputation now diminished, Koch traveled the globe with Hedwig and weighed in on various issues– often to his detriment.  He, for example, didn’t believe milk that contained bovine (cow) TB was harmful and opposed the pasteurization of milk.  He also promoted the use of an arsenic containing medicine to treat sleeping sickness.  When he was 67 he had a massive heart attack.

During Koch’s lifetime many who had Tuberculosis spent a year in a sanatorium.  Breathing clean air and leading a healthy life helped some of them go into a remission.  The first antibiotic that killed TB, Streptomycin was discovered in 1943.  Like penicillin it was being used by a soil organism to defend itself from the bacteria that surrounded it.  Over time streptomycin resistant bacteria started to emerge.  In 1953 it was joined by INH –isoniazid.  The medication was a chemical that a PhD student in Prague synthesized in 1912.  It was probably sitting on a shelf somewhere when, in the 1940s industry researchers decided to test hundreds of random chemicals on mice with Tuberculosis. The third powerhouse, Rifampin, became available in 1963.  It was a chemical that was produced by a soil organism, and it was isolated and modified by Italian researchers.

.  By the 1950s and 60s doctors were able to successfully treat most TB infections with a combination of the medications.  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 tuberculosis would disappear.  Unfortunately poverty, HIV, and bacterial resistance reversed the trend, and the incidence of T.B. started to rise.

At some point in their lives one of 4 people alive today, was or will be infected by the cough of a person with tuberculosis. 90 percent mount a cell mediated immune response.  Their body encases and imprisons the bug, but doesn’t always kill it.  Years later the bacillus sometimes escapes, grows, and spreads.  In 2019 ten million people worldwide developed an active infection and 1.4 million died.  

Koch and Pasteur had challenged the belief that diseases were the result of some mysterious force in the miasma.  They used live organisms to energize the immune system and with others demonstrated that germs cause disease and cleanliness matters.  

In the mid 1800s Joseph Lister, the man who was called 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.” In time he 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, Lister was the surgeon for the Glasgow infirmary.  He noticed that half the people who had a limb amputated became septic and died.  By that time he had read about Pasteur and germs, and he started treating raw wounds with carbolic acid, a foul-smelling antiseptic that was used to clean sewers.  His surgical infection rate dropped to 15%, and the Scots were impressed.  Their doctors started cleaning and sterilizing the tools they used.  Doctors in England 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 Over time he wrote articles and influenced his peers.  At age 56 he was named a Baron.

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, or 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.” Then a sanitary commission, set up by the British government arrived and they flushed 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 once wrote: “Sufferings were the result of too little “fresh air, light, warmth, quiet, or cleanliness.”