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, 1993; Danis 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, 1993; Danis 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.
