Tu Youyou, Researcher of Chinese Materia Medica, Is China's First Nobel Laureate in Physiology or Medicine

Today, the most exciting news for Chinese people is that the pharmacologist of Chinese materia medica Tu Youyou has won the Nobel Prize in Physiology or Medicine. This is the first time a scientist based in China has won a Nobel science prize. The Nobel Prize in Physiology or Medicine has gone to a researcher of Chinese materia medica—an affirmation of Chinese scientists and also of traditional Chinese medicine and pharmacology.

Chinese medicine and pharmacology is a vast treasure house from which many resources beneficial to human health can be developed. From Ge Hong's Zhouhou Beiji Fang, written over 1,700 years ago, Tu Youyou discovered that Qinghao (Artemisiae Annuae Herba) could counter malaria; she then studied its antimalarial action and discovered artemisinin. The discovery of artemisinin has brought good news to malaria patients worldwide.

Tu Youyou's research is of major significance in two respects. First, it affirms the practical value of Chinese medicine/pharmacology and of ancient TCM texts. In recent years, TCM has been dismissed in China as a fraud or pseudoscience, and those who study TCM have been questioned like rats crossing the street. Her award is a great encouragement to the many researchers in Chinese medicine. Second, she has advanced the cause of Chinese medicine against the background of modern science and technology, greatly enhancing the value of traditional TCM with modern means. Developing new drugs through modern science not only enriches the content of traditional TCM but also expands TCM's ways of thinking.

Within TCM there have always been many factions, and many TCM students are trapped in their mutual disputes. Tu Youyou devoted herself to the combination of Chinese medicine and modern science, greatly raising its clinical efficacy and showing practitioners, in practice, a correct path for TCM development. If TCM wants to advance, it must progress—not revert to the past.

Seeing Tu Youyou win the Nobel Prize in Physiology or Medicine, I feel deeply moved. As someone devoted to researching Chinese medicine, I have grieved over the cold reception and rejection TCM suffers in this era and have felt the future bleak; but seeing this affirmation by scientists worldwide, my confidence has grown.

Below are media reports on Tu Youyou.

【Chinese pharmacologist Tu Youyou shares this year's Nobel Prize in Physiology or Medicine with two overseas scientists.】The Karolinska Institute of Sweden has just announced that Tu Youyou shares this year's Nobel Prize in Physiology or Medicine with two overseas scientists. Tu Youyou has long worked on Chinese materia medica and integrated Chinese-Western pharmacology; her outstanding contribution is the creation of new antimalarial drugs—artemisinin and dihydroartemisinin. (CCTV reporter Wang Weiwei)

Tu Youyou becomes the 12th woman in the history of the Nobel Prize in Physiology or Medicine to receive this honor.

【The reason for the award to the Chinese woman scientist Tu Youyou.】The Nobel Committee said that the three laureates—Tu Youyou, William C. Campbell, and Satoshi Ōmura—developed therapies that have had a revolutionary effect on the treatment of some of the most devastating parasitic diseases.

【Tu Youyou will receive half of the Nobel Prize award.】According to the Nobel Prize website, the prize in Physiology or Medicine will be split in two: William C. Campbell and Satoshi Ōmura together share one half, while the other half goes to Tu Youyou.

Extended reading:

Who is Tu Youyou?

September 23, 2011, New York. This year's Lasker Award ceremony was held at a cocktail reception. In this relaxed Western social setting, Tu Youyou's slight awkwardness seemed to have its own charm. She lifted the trophy, smiled for photographers, and then read her acceptance speech from notes: 'In the course of discovering artemisinin, ancient texts gave me inspiration at the most critical moment of the research.' The 80-year-old woman scientist's voice was clear, with a strong Jiangzhe accent. 'I believe that striving to develop traditional medicine will surely bring more therapeutic drugs to the world.'

Inspired by a TCM text over 1,600 years old, Tu Youyou's initial discovery made artemisinin the WHO-recommended first-line antimalarial, saving millions of lives worldwide; the Lasker Foundation awarded her $250,000 for this.

Silence

As a science prize with a 66-year history, the Lasker Award is not very famous in China. Yet the phrase 'the weather vane of the Nobel Prize' easily arouses interest. Understandably, after the Lasker Award, Tu Youyou's name quickly became widely known in China, and people felt great expectation for this 'Chinese person closest to the Nobel Prize.' Later she was described as 'the Chinese person who passed by the Nobel Prize.'

Tu Youyou seemed prepared for her sudden fame and maintained extraordinary, stubborn resistance to the intense public attention that followed. After receiving the award in New York, she consistently refused to speak to the media; her only public appearance was at the '2011 Science and Technology Workers' Congress' held by her institute on November 15. The ordinary-sounding meeting had in fact a single theme—honoring Tu Youyou. She was given the 'China Academy of Chinese Medical Sciences Outstanding Contribution Award,' and her artemisinin research team was awarded 1 million RMB.

'The achievement of artemisinin belongs to everyone in the research team and to the Chinese scientific community as a whole. It is also an honor marking TCM's going out to the world.' Tu Youyou's tone stayed consistent; she said the same at the New York ceremony and at the Beijing commendation meeting.

Yet regarding Tu Youyou's 'low profile,' some insiders noted, 'She has never acknowledged others' work, and the present acknowledgments are regarded as insincere.' Whether facing today's 'popularity' or the disputes among peers over the years, Tu Youyou does only one thing—stay silent.

For Tu Youyou, the long-delayed Lasker Award is not only a great honor; its other meaning may be even more important—a footnote to the silence she has kept for decades. Even so, after the award, she still responded to everything with silence. In the China News Weekly reporter's only phone conversation with her, Tu Youyou did not answer any question directly. She said it was enough to read her book: 'This is a key national publication of the 11th Five-Year Plan, published by Chemical Industry Press, green cover, preface by Wu Jieping, inscription by Song Jian.'

Qinghao and Artemisinin-Type Drugs—this 260-page academic work—was the only way the scientist Tu Youyou was willing to converse with the world; of everything else, she seemed to have nothing to say.

Tu Youyou's own name is not 'silent': 'Youyou' is the cry of a deer, from the Book of Songs. Opening Qinghao and Artemisinin-Type Drugs, the first page bears that poem: 'Youyou cry the deer, eating the artemiste of the fields.' This name and this plant were linked in a strange way over 2,000 years ago, lending poetic mystery to a scientist's story. Yet the story's beginning was connected with war.

The battle to crack the problem

In 1969, during the Cultural Revolution, when all scientific work had stopped, the China Academy of Traditional Chinese Medicine (now the China Academy of Chinese Medical Sciences) received a special task—to join a military-codenamed project '523.' It was the time of the Vietnam War; drug-resistant falciparum malaria was rampant in Vietnam, causing severe non-combat losses to both sides. At the request of the North Vietnamese, China began antimalarial drug research within the military and established the 'National Leading Group Office for Malaria Prevention and Control Research' (code-named the '523 Office'). Tu Youyou, a graduate of the Pharmacy Department of Beijing Medical College with experience in TCM research, was—in an era when most academic authorities had been overthrown—at 38 appointed team leader, responsible for focused research on antimalarial Chinese herbs.

Over three months, from more than 2,000 formulas (including various plants, animals, and minerals), she compiled 640 and then screened over 100 samples. The finally selected pepper, 'although 84% inhibitory against the malaria parasite, was not ideal in its killing effect'; while Qinghao, which had once shown 68% inhibition, was abandoned in re-screening because the results were poor.

Later, re-studying Ge Hong's Eastern-Zhou-era Zhouhou Beiji Fang, Tu Youyou noticed that Qinghao was used against malaria by 'squeezing the juice,' not by the traditional Chinese method of 'water decoction.' She realized this special method might be 'because high temperature destroys the drug's effect.' Accordingly, she 'switched to low-boiling-point solvents, and the efficacy indeed improved markedly.' After repeated trials, the finally isolated neutral artemisia extract sample No. 191 showed the surprising result of 100% inhibition against the rodent malaria parasite.

In that special era, let alone intellectual property rights, even publishing results under one's own name carried great political risk. In March 1972, as arranged by the 523 Office, Tu Youyou reported as the representative of her research group the experimental results of the neutral artemisia extract; her report was titled 'Guiding antimalarial Chinese-herb work with Mao Zedong Thought.' The whole room was inspired. In the subsequent clinical observation, Tu Youyou not only led the way in testing the drug on herself but personally carried the medicine to the malarious Changjiang county of Hainan to verify efficacy. After she reported the summary that 'all 30 cases of artemisia antimalarial treatment were effective,' a national tide of artemisinin antimalarial research was launched.

The Institute of Chinese Materia Medica where Tu Youyou worked continued the research into the active constituents of Qinghao, finally isolating and purifying the active antimalarial monomer and naming it artemisinin. Among the artemisia extracts from across the country, artemisinin extracted by the Yunnan Institute of Materia Medica with petroleum ether from the local variant Dadang Huanghao showed excellent antimalarial efficacy in clinical trials. Later, Zhou Weishan's group at the Shanghai Institute of Organic Chemistry determined the chemical structure of artemisinin and discovered its antimalarial mechanism.

In the book Qinghao and Artemisinin-Type Drugs, there is a crudely printed copy of a new-drug certificate—the first new-drug certificate issued after China implemented its new-drug approval measures: (86) Wei Yao Zheng Zi X-01. This certificate, applied for and approved by the China Academy of Traditional Chinese Medicine, does not bear Tu Youyou's name.

Controversy

The question raised by the Lasker Award is: why did artemisinin not first win a major national science prize in China, but instead an overseas one?

The mainstream scientific answer is that the attribution could not be determined. In 1978, the appraisal meeting of the '523' project finally concluded that the successful development of artemisinin was 'a collective honor of China's science and technology workers, with each of the six inventor units making its own inventions.' In this conclusion, several pages long, the discoverer's name was not mentioned once. The great-cooperative '523' project ended in 'victorious completion,' yet over the following decades the controversy never stopped; Tu Youyou was considered by many to be 'not indifferent enough to fame and gain' and 'stubborn in personality.'

In 2009, the publication of Tu Youyou's Qinghao and Artemisinin-Type Drugs immediately drew criticism over the details of citation and attribution: it did not adequately acknowledge the role of other research groups and members. Opponents held that Tu Youyou exaggerated her own role in the '523' project.

Rao Yi, dean of the School of Life Sciences at Peking University, had highly praised Tu Youyou's work even before the Lasker Award. He mentioned: 'As an undisputed party, we had some difficulty communicating with Tu Youyou; we did not understand why she kept the academy's original materials at her home for at least some period and would not show them to us.' But after checking certain non-public materials, he still concluded that Tu Youyou played a key role in the discovery, because her group was the first to extract Qinghao with ether and to confirm the highly effective antimalarial action of the crude artemisia extract.

Science magazine's online report said: 'The Lasker Award has reignited a controversy over whether the development of a powerful antimalarial drug—the product of a massive government project during the Cultural Revolution—should be credited to one person.'

Su Xinzhuan, a researcher in the Malaria Laboratory of the U.S. National Institutes of Health who accompanied Tu Youyou during the Lasker period, believes that contributions of many people were indispensable along the way from artemisia to the antimalarial drug, but the Lasker Award did not go to the whole organization because 'as a prize encouraging scientific discovery, the Lasker Award tends to go only to the original discoverer.'

In the Lasker jury's description, Tu Youyou is the Chinese woman who discovered artemisinin through 'insight, vision, and stubborn conviction.'

Seven contributions of Tu Youyou

1. The first inventor of the new antimalarial drug artemisinin.

Malaria is a serious worldwide epidemic; over 300 million people are infected annually in more than 100 countries. From the 1960s, chloroquine and other existing antimalarials failed as the parasite developed resistance. During the Vietnam War, the world urgently needed new-structural antimalarials. When massive work at home (the '523' office once organized screening of over 3,200 Chinese herbs in seven provinces and cities; some had tested Qinghao, thought it ineffective, and abandoned it) and abroad (the U.S., tied to the Vietnam War, screened up to 300,000 compounds) had failed, she led her group, guided by inheriting and developing China's pharmaceutical legacy with modern science, to systematically compile historical medical texts and bencao works, collecting over 2,000 formulas and compiling them into the Kangnue Fangyao Ji (Collection of Antimalarial Formulas), then selecting 200-plus for screening. After developing over 380 samples and, in particular, drawing on ancient dosing experience—from Ge Hong's Eastern-Jin account in Zhouhou Beiji Fang that Qinghao was taken by 'squeezing the juice' to stop malaria—she, considering temperature and enzymatic factors, continuously improved the extraction method and finally, in 1971, succeeded in the antimalarial development of Qinghao! The active fraction and active monomer she discovered—artemisinin—showed 100% antimalarial action against both rodent and simian malaria. After extensive extraction, safety experiments, and self-testing, in 1972 and 1973 she conducted the first clinical studies of the active fraction and the artemisinin monomer in the malarious Changjiang region of Hainan, confirming satisfactory efficacy superior to chloroquine; the new antimalarial drug artemisinin was thus born! Tu Youyou and her group, after isolating the artemisinin monomer in 1972, began studying its chemical structure, collaborating successively with the Shanghai Institute of Organic Chemistry and the Institute of Biophysics, and finally determined the stereostructure of artemisinin by X-ray diffraction. Artemisinin is a new sesquiterpene lactone bearing a peroxide group—a new antimalarial with a structure completely different from past drugs, breaking the old claim that 'antimalarials must contain a nitrogen heterocycle.' Thus the discovery not only found a new drug to solve resistant malaria but also opened a new route to finding new antimalarials. Through national collaboration, over 2,000 cases were verified, confirming it as a 'highly effective, rapid-acting, low-toxicity' antimalarial, especially effective against chloroquine-resistant falciparum malaria. After the 1978 artemisinin appraisal meeting, her group's work continued; artemisinin received in 1985 the first New Drug Certificate issued after the Ministry of Health implemented its new-drug approval measures (No. 86-X-01). The invention drew attention from experts at home and abroad; in 1981, at WHO's request, China agreed to hold an international symposium on artemisinin in Beijing, where Tu Youyou gave the first report, titled 'Chemical research on artemisinin,' and was highly praised: 'The discovery of artemisinin not only adds a new antimalarial; its greater significance lies in the unique chemical structure of this new compound, which will point the way to designing new drugs.' This drove new progress in international antimalarial work and prompted many countries to pursue further research. Artemisinin is currently the only Chinese innovative drug recognized internationally; it is now widely used in many countries, producing great social and economic benefit.

2. The first to discover dihydroartemisinin.

In studying the chemical structure of artemisinin, Tu Youyou in 1973 created its reduced derivative—dihydroartemisinin. This is of major significance for artemisinin-type drug research: (1) it confirmed the existence of the carbonyl group in the artemisinin structure; (2) the hydroxyl group in dihydroartemisinin allows preparation of various artemisinin derivatives, enhancing efficacy and expanding biological activity, driving the ongoing in-depth study of artemisinin-type drugs at home and abroad for better human health; (3) after seven years of effort by her group, a new-generation antimalarial was created with clinical efficacy ten times that of artemisinin and a recrudescence rate as low as 1.95%. Its tablets have outstanding advantages of 'high efficacy, rapid action, safety, small dose, convenient oral use, low recrudescence rate, and simple, low-cost development.' Pharmacodynamic and clinical research confirmed that the tablets—most convenient for oral use by patients—are, in 'safety and efficacy,' superior to currently injectable derivatives of the same class and are regarded as the preferred artemisinin-type drug. In 1992 it received the national 'Class One New Drug Certificate' (92 Wei Yao Zheng Zi X-66, 67), has been mass-produced and marketed internationally with good reception, and is regarded as 'a relatively ideal oral treatment for all types of malaria internationally.'

3. Completing 'Systematization of Qinghao varieties and quality research.'

During the 7th Five-Year Plan period, she participated in the national key project 'Quality Research on Commonly Used Chinese Materia Medica,' leading the subproject 'Systematization of Qinghao varieties and quality research,' conducting systematic study of Qinghao, isolating and identifying 17 compounds (five new), and correcting long-standing errors in the Chinese Pharmacopoeia.

4. Further research on mechanism.

To prevent the emergence of artemisinin resistance, protect the clinical life of artemisinin, and avoid abuse, she collaborated with the Capital Medical University on 'The effect of dihydroartemisinin on the development of Plasmodium yoelii within the mosquito.' She found that artemisinin affects the infectivity of P. yoelii gametocytes but does not inhibit sporogony in the mosquito—i.e., it failed to inhibit oocysts from developing into sporozoites. This suggests artemisinin-type drugs cannot be used for malaria prophylaxis, warning against those who now use them for prevention.

5. Developing 'compound dihydroartemisinin' combining artemisinin-type and acridine-type antimalarials.

To address the worldwide spread of multidrug-resistant falciparum malaria, foreign countries have in recent years paid great attention to combination research. Dihydroartemisinin is currently the preferred artemisinin-type drug and has no cross-resistance with multidrug-resistant falciparum. The acridine-type antimalarial malaridine (pyronaridine) has no cross-resistance with 4-aminoquinolines, pyrimidines, biguanides, or sulfonamides. She therefore designed a combination of dihydroartemisinin and pyronaridine. Supported by the Academy of Military Medical Sciences, experimental research confirmed the two drugs have significant synergistic potentiation with a synergy index of 7.6 (higher than the widely used compound artemether-lumefantrine, whose index is 6), multiple sites of action, and a short course. Ten cases of falciparum malaria treated with the two-drug combination, taken in two doses over 12–24 hours, achieved high efficacy with no parasitemia recurrence for 40 days. A patent has been granted (ZL 99109669.X).

6. Developing multiple dosage forms according to clinical needs.

According to WHO data, about 3,000 infants and young children die of malaria every day. She therefore developed 'dihydroartemisinin suppositories' for convenient rectal administration to children. She also made oral tablets from artemisinin obtained directly from Qinghao—simple to make, cheap, and less prone to resistance. Both received New Drug Certificates in 2003, No. Guo Yao Zheng Zi H20030341 and H20030144 respectively.

7. Extending efficacy into the immunological field.

Research found that dihydroartemisinin has a good bidirectional regulatory effect in the immune field: it can lower B-cell hyperreactivity to reduce autoimmune disease caused by immune-complex deposition, and can also raise T-cell immune function. With support from Peking University Health Science Center, she has used dihydroartemisinin to treat lupus erythematosus and photosensitivity diseases. It has now received the SFDA 'Drug Clinical Research Approval' (2004L02089) and a Chinese invention patent (ZL 99103346.9). Preliminary observation of 100 clinical cases gives a total effective rate of 94% and a marked-effect rate of 44%.