New Drugs from Ancient Chinese Remedies: Unsung heroes in Unusual Times

Yi Rao^{1, *}, Runhong Li² and Daqing Zhang²

¹School of Life Sciences and

²Health Sciences Center

Peking University

Beijing 100871

China

^*To whom correspondence should be addressed: yrao@pku.edu.cn

Summary

In the early 1970s, while most Chinese scientists struggled to survive the Cultural Revolution with no chance for research, two junior researchers, Youyou Tu and Tingdong Zhang, played key roles in discovering artemisinin as a novel antimalaria drug and arsenic trioxide as a new drug for leukemia, respectively. There is no shortage of twists and ironies in the history of these discoveries. One began with China’s efforts to help the North Vietnamese defend against the Americans, and the other with observing, modifying and improving the recipe of a countryside practitioner. Although their drugs have now saved many lives across the globe, Tu is considered controversial and Zhang essentially unknown. Relevant literature has been buried in internal files and obscure journals. Based on original documents, articles and interviews, we outline here the history of these discoveries. It has not escaped our attention that ancient and current Chinese literature as well as Chinese medical practices may contain jewels that remain to be re-discovered to benefit the rest of the world.

Chinese medicines have been used for a long time in China, but have not been a major source of drugs for general use in other countries. Are Chinese medicines still helpful today or in the future? There are two opposite views, one believing that Chinese medicines are of little, if any, use today； the other believing that Chinese medicines are useful, but they have to be used only as complex combinations whose effects should be judged by special criteria for Chinese medicines, but no by conventional science.

These questions and debates can be addressed by our studies of the history of two lines of research: one on artemisinin and the other on arsenic trioxide. We show here that both drugs were uncovered by modern scientific approaches and tested by generally acceptable scientific standards. Furthermore, these drugs, by standing the test of time and saving human lives, have proven the value of chemically defined drugs from traditional remedies. We conclude that the discoveries of artemisinin and arsenic trioxide have established that Chinese medicines are still beneficial today and an ancient tradition has largely untapped potential to improve human health.

Artemisinin and arsenic trioxide can be viewed as the most important discoveries from Chinese medicines in the last century. Although the Chinese government is investing heavily today in drug discoveries and many Chinese pharmaceutical companies are profiting from selling Chinese medicines, artemisinin and arsenic trioxide remain unsurpassed by chemicals from other Chinese medicines in their benefits to human health.

Uncovering the history of these discoveries and recognizing Youyou Tu and Tingdong Zhang will not only do justice to the scientists, but also stimulate international interests in using traditional medicines to find chemically novel drugs and new applications of known chemicals. At a time when many Chinese pharmaceutical companies profit from chemically undefined combinations with vague disease targets and have not actively taken the proven track of artemisinin and arsenic trioxide to reveal the truly effective components for specific diseases, it will be a wakening call for them to put real efforts in understanding the relationships between chemical components in Chinese medicines and specific diseases. National and international efforts may take Chinese medicines to a new era and save more lives.

Leading Characters

Artemisinin was discovered in a large project called “Task 523” to find anti-malaria strategies and its major representative is Youyou Tu from the Institute of Chinese Meteria Medica at the China Academy of Traditional Chinese Medicine (now known as China Academy of Chinese Medical Sciences) in Beijing. The anti-leukemia effect of arsenic trioxide was discovered during research by individual scientists in a small group, with the major contribution from Tingdong Zhang of the First Affiliated Hospital of Harbin Medical University.

Youyou Tu was born in 1930 and studied from 1951 to 1955 at the School of Pharmacy of Beijing Medical University (known now as Peking University Health Sciences Center). According to the practice of that time she was assigned a job upon graduation, to the China Academy of Traditional Chinese Medicine. With only an undergraduate degree, she was drafted in 1969 into the “Task 523” with colleagues from her institute.

Tingdong Zhang was born in 1932 and graduated in the 1950s from Harbin Medical University, after studying the regular (Western) medicine. He took classes of traditional Chinese medicine in the 1960s.

Their most important research was carried out in the early 1970s, under conditions unimaginable by today’s graduate students.

Cultural Milieu of China in the Early 1970s

Knowledge of the cultural milieu and working conditions in the early 1970s is necessary before we can understand the peculiar significance of discoveries related to artemisinin and arsenic trioxide.

Social background is required so that one can understand why Youyou Tu and Tingdong Zhang, rather than senior scientists with Western training, were the ones who made the discoveries.

This article will use Chinese Medical Theories （CMT）to describe what is generally called Traditional Chinese Medicine (TCM) and use Chinese Medicines （CM) to describe drugs from traditional Chinese sources. These are different from the conventional translation because we believe that TCM has combined CMT and CM. It is much clearer to discuss drugs from CM, whereas controversies about CMTs will remain unresolved for a while.

The best known early studies of CMs were carried out by K. K. Chen. During the early 1920s while he worked at Peking Union Medical College (PUMC) funded by the Rockefeller foundation, Chen studied the pharmacology of chemical components from CMs, and his work on the function of ephedrine became well known. Before Chen worked at PUMC, he was trained in the US, where he would return after a few years at PUMC. He was internationally well recognized in academia (especially by pharmacologists) as well as in the pharmaceutical industry.

From the 1950s, China was isolated from the West for more than two decades. It was not possible for Youyou Tu in Beijing and Tingdong Zhang in Harbin to obtain training comparable to that of Chen.

In the mid- to late- 1960s, China went through the peak of “the Great Proletarian Cultural Revolution”, a strange period in Chinese history, pursuing leftist ideology and tramping knowledge and civilization. Some Chinese were involved in fierce infighting. Most scholars with Western education were affected, being suspected of being spies, viewed as “reactionary academic authorities” or “elements interested only in their research and not in the society”. Some died during attacks and some committed suicide after being humiliated. CS Jang (or Changshao Zhang) of Shanghai First Medical College, the father of the advisor of one of the authors (YR), was a pioneer of antimalaria drugs from Chinese sources with a 1946 Science paper and 1948 Nature paper on the anti-malaria effects of the herb Changshan and its active chemical. He committed suicide in 1967 after political criticism of him. More researchers were put into “cow pens” (either local rooms or far away farm fields where scholars were isolated from their families), and more were set aside. For example, the grandfather of one of the authors (YR), a Professor of Geometry without Western experience and insensitive to politics or ideologies, was isolated in a “cow pen”. The same author’s father was sent to the countryside to work on farm fields. Farmers and peasants, who wanted a doctor more than a farmhand, immediately reinstalled him as a doctor.

In the early 1970s, many in Chinese universities and research institutes were still idle. The major daily activity for some was to read People’s Daily, a newspaper with a single sheet with four pages. During working hours, some male researchers played chess while some female researchers knitted sweaters. Many books and journals were sent to paper recycling stations. In most middle schools, there were no regular biology classes. “Basic Knowledge of Agriculture” was a close proximity, with the goal of teaching how to grow chickens, fish, pigs and cows, which was all biology taken by one of the authors (YR) in middle school.

Funding for science was little until at least the 1980s. From the late 1950s to the mid-1960s, China has supported and successfully made Two Bombs and One Star (the atomic and the hydrogen bombs, and the artificial satellite; the satellite project continued in the 1970s and expanded to date as the missiles program and the space program of today). In the late 1960s and 1970s, there were few such projects and the support was much smaller. Among them was “Task 523” to deal with malaria, which led to the discovery of artemisinin. In the 1970s, projects supported nationally included Bronchitis, which collected recipes for treating bronchitis of Mao Zedong, although it was unclear whether he knew the existence of offices across the country for bronchitis. The father of the same author left the countryside to work in a major city because he was called to the local Bronchitis Office, though he had little patience for sitting in offices and soon went to work directly with common patients in a hospital.

It should be noted that publications of a significant fraction of scientific journals were halted for a few years during in the Cultural Revolution. Furthermore, in the leftist atmosphere, for quite a few years, with the exception of Mao Zedong and Marxism classics, publications (books, magazines, or journals) did not encourage authorship (so that no one should fight for or get credits). There was either no authorship, or group authorship, leading to collective authorships such as Qinghaosu Cooperative Research Group or China Cooperative Group on Insulin. This created debates about credits that remain unresolved today. It is ironic that the egalitarian idea of no credit increased the fighting for credits later.

In what seems now the ridiculous leftist era, some measures were not futile. For example, a friend of the same author felt that he would never have had the same quality of education, if his teachers had not been those sent to his village from big cities. This person later went to the US and was the mentor of a current editor at Cell. In a separate order, Mao Zedong asked doctors in big cities to serve patients in the countryside. “Circulating Medical Teams” were thus formed to send doctors to the countryside on a regular basis. These teams indeed improved the quality of medical care for farmers. Incidentally, a Circulating Medical Team from Harbin Medical University actually contributed to the beginning of the second part of our article, because it led to the finding of the effect of arsenic oxide to treat leukemia. If these measures are applied more voluntarily today, they can still be beneficial.

It is only a small exaggeration to call important discoveries made under such circumstances miracles.

Artemisinin (aka Qinghaosu) and Youyou Tu

By now, artemisinin is relatively well known. It is a fast acting anti-malaria drug, which can be used as a frontline drug or when resistance develops for other drugs such as chloroquinine. It has treated a large number of patients and has saved lives. Chemically, it is novel and efforts are still under way to find derivatives with higher efficacy and less resistance. Scientifically, its mechanisms are still under investigation.

       Much have been written about the discoveries of artemisinin, but debates, sometimes heated debates, still rage today. A major problem is whether Youyou Tu can be considered a representative.

 “Task 523”, the national program to design strategies to fight malaria, is believed to be initiated with the instructions of the then Chinese president Chairman Mao Zedong and Premier Chou Enlai, when they responded to requests from North Vietnamese leaders for help to fight malaria, taking into the consideration that malaria was also a problem for the southern China. It is now also an open secret that several hundred thousands of Chinese soldiers went to Vietnam to help them defend against Americans, though in supportive roles such as artilleries and engineering. Among the documents, files and publications, we found the responsible officials to be below the rank of ministers, with no direct evidence for Mao and Chou’s involvement. The national organization was formed after a week-long meeting beginning on May 23, 1967, in the height of the Cultural Revolution when the organizers had a hard time to find a location for meeting in the middle of social upheavals. The leaders were from the Chinese Military, the Ministry of Health and the National Commission on Science and Technology) with the coordinating office always located in the Military Academy of Medical Sciences. Participating institutions were spread across China, involving hundreds of individuals, from Beijing, Shanghai, Yunnan, Shangdong to Guangdong and Guangxi, which borders Vietnam. It was undoubtedly a large collaborative project, with contributions from administrators, scientists and soldiers who volunteered for tests of the early treatments.

Was there a representative contributor? If so, who would that be?

In 1969, Youyou Tu was called into the “Task 523”, at a time when most senior scientists could barely survived the “struggles” against them.

“Task 523” had several parts, one for copying known Western drugs or making their derivatives, one for finding antimalaria drugs from Chinese medicines, and one for producing mosquito repellents. Among the CMs, different research groups had tried many different ones, including Changshan (from the herb Dichroa febrifuga). Changshan has been studied in the 1940s by Changshao Zhang (CS Jang) and coworkers, who reported antimalaria effect of a crude extract of Changshan on humans in 1943, the effect of Changshan and three alkaloids from Changshan on a chicken model of malaria in 1945, and the antimalaria effect of dichroine b in the chicken model in 1946, and the antimalaria effect of dichroine g, dichroine b , dichroidine and quinazolone isolated from Changshan in 1948, and determined the molecular formula of all the alkaloids in 1947 and 1948. Changshan was considered again by Task 523, but it run into the same problem: although it was powerful against malaria, it had strong side effects. Changshan was abandoned but the approach used for Changshan was basically the same as that for artemisinin.

The plant Qinghao (Artemisia annua) was not only recorded in ancient Chinese books, but also was used in the 1950s and 1960s among Chinese farmers to treat malaria. In the early 1970s, Yagang Yu in Youyou Tu’s group went through the Chinese literature of anti-malaria recipes and came up with a list of 808 CMs. The Military Academy of Medical Sciences tested nearly a hundred of them on a rodent model of malaria, and found Qinghao to have an efficacy of 60% to 80%, but it was unstable. Youyou Tu gave her group a list of CMs including minerals (such as arsenic disulfate), animal products (such as snake skin) and herbs. Qinghao was among the last category on this list. Yagang Yu was asked by superiors to move onto the bronchitis project and left the Tu group in early 1971. Youyou Tu’s group observed the effect of Qinghao: on the rodent model, water extract of Qinghao was ineffective but 95% ethanol extract of Qinghao showed an efficacy of 30% to 40%. It should not be ignored that several ancient books recorded water boiling of Qinghao, which would not result in much artemisinin. Similar mistakes can hamper modern efforts to discover the effects of CMs.

In late 1971, Youyou Tu played a key role by proposing the use of ether to extract Qinghao, which resulted in an efficacy of 95 to 100%. This was an important step in recognizing the efficacy of Qinghao. In March 1972, Tu reported her findings on a meeting organized by Task 523 in Nanjing. It attracted immediate attention, but did not make Qinghao the only or the top candidate. In the meeting summary, the organizers listed two other medicines (a chemical from a Chinese herb and the other with a candidate chemical) before Qinghao. The goal for Qinghao was listed as “to confirm its clinical efficacy and purify its effective chemical components”.

The work of Tu group was then focused on Qinghao. Muyun Ni of the group tried to purify active components of Qinghao. Yurong Zhong of the group succeeded in purifying “Qinghao Su II” in crystal forms (later called Qinghaosu or artemisinin). In February 1974, Tu reported the molecular formula of artemisinin at a meeting at the China Academy of Traditional Chinese Medicine, which was attended by researchers from her own institute, as well as those from Shandong Institute of Chinese Materia Medica and Yunnan Institute of Materia Medica.

Other groups collaborated with the Tu group to determine the structure of artemisinin. Major roles were played by the Institute of Organic Chemistry and the Institute of Biophysics of the Chinese Academy of Sciences (CAS).

Upon learning the results of Qinghao extracts reported by Tu in March 1972, Shangdong Institute of Parasitology in collaboration with Shangdong Institute of Chinese Medicine, and Yunnan Institute of Materia Medica, independently purified active chemicals from similar (though not identical) plants. They named their chemicals Huanghuahaosu and Huanghaosu, respectively. Qinghaosu (aka artemisinin) of Beijing, Huanghuahaosu of Shangdong and Huanghaosu of Yunnan were believed to be the same molecule in 1974.

It is important that our analysis of the history of artemisinin research has led to the conclusion that, although there are debates about the discovery of artemisinin, there is no dispute that: 1) Youyou Tu proposed the idea of ether extraction of Qinghao, which immediately led to the discovery of its powerful effects and raised the priority of Qinghao among hundreds of recipes; 2) Yurong Zhong, who first succeeded in purifying the active molecule, was a member of the Tu group; 3) Other groups that also succeeded in purifying the active molecule did so after learning Tu’s March 1972 report and after the Tu group had purified the same molecule.

There are numerous reports mentioning artemisinin discovery. The work of Tu group was based on previous. Other groups have played important roles. Tu and colleagues only tested on a rodent model of malaria, whereas the clinical efficacy on humans was carried out by others, some on soldiers and some on patients. When the crystals of the Tu group were not very effective and had toxic side effects, Zeyuan Luo of Yunnan provided their crystals which Guoqiao Li of Guangdong used effectively on humans. Since 1976, Powerful derivatives of artemisinin have been developed, including artemether by Ying Li of the CAS Institute of Materia Medica and artesunate by Xu Liu of Guilin Pharmaceutical Company in Guilin, Guangxi.

The present article is focused on clarifying one question: that Youyou Tu has indeed played a key role.

We can only hope that more detailed research will show the roles of others involved in “Task 523”, with contributions from its organizers, researchers and volunteers.

Arsenic Trioxide and Tingdong Zhang

Arsenic has been used for a long time, both in China and in the West. There are several traditional Chinese medical recipes that contain arsenic (trioxide or disulfide), with Chinese names of Pishuang, Pishi, Xionghuang and Cihuang. Treatment of leukemia by arsenic was reported in the 1930s in the West, but was not generally accepted.

In a Circulating Medical Team, Taiyun Han, a pharmacist of the First Affiliated Hospital of Harbin Medical University, learned that a countryside practitioner of traditional Chinese medicine used a combination of arsenic, mercury and toad venom to treat lymphatic tuberculosis and cancers. In March 1971, Han dissolved the three components in a solution, which he called “713” or “Ailin (literally meaning cancer sensitive)”. This was injected intramuscularly into patients, showing effects in some cancer patients. It was hotly sought after locally for a while but abandoned because of its toxicity.

Tingdong Zhang, a doctor in the same hospital, collaborated with Han and continued on this line of work. After 1972, Tingdong Zhang and colleagues focused on leukemia. They also separated the components of “Ailin” and discovered that arsenic was solely responsible for the therapeutic effect, whereas mercury had kidney toxicity and toad venom caused hypertension. Neither of the latter two was therapeutically useful for leukemia.

Their first paper on this line was published in 1973, when Tingdong Zhang, Pengfei Zhang, Shouren Wang and Taiyun Han reported in a local journal that they had used “Ailin solution” (also known as “Ailin No.1”) to treat six cases of chronic granulocytic leukemia. They explicitly stated that the components of the solution were arsenic trioxide and a trace amount of mercury chloride. All six improved after the treatment. They also mentioned that they were working on acute leukemia patients.

In 1974, using the authorship of The Departments of Traditional Chinese Medicine and Laboratory Medicine of their institution, they published a report in their university journal, summarizing their treatment of 17 cases of leukemia patients from January 1973 to April 1974. After going through different types of leukemia, they reported that Ailin No.1 was effective in treating multiple types of leukemia, leading to complete remission (CR) in acute leukemia patients. In 1976, they used institutional authorship to publish a report on five cases of acute leukemia in which they had achieved CR.

In 1979, Fuxiang Rong and Tingdong Zhang published two acute granulocytic leukemia cases, one with CR for 4 and half and the other for 3 years.

In a second paper in 1979, Tingdong Zhang and Fuxiang Rong published a summary of 55 cases of acute leukemia. Among those, 23 were treated with Ailin No.1 alone (from 1973 to 1974), 20 were treated with Ailin No.1 in combination with Western chemotherapy and other CMs from 1975 to 1976, and 12 cases treated with Ailin No.1 plus other CMs and chemotherapy from 1977 to 1978. For each patient, they presented the subtyping of leukemia and the clinical observations. All 55 cases improved to some extent, with a remission rate of 70% and with CR in 12 cases. The side effect was small with the doses they used. They then applied 10 times the equivalent of what they used for adult human patients into 12 rabbits. No toxicity was observed in the heart, the liver, the spleen or the kidney of the rabbits. While the 1973 paper reported their pioneering findings, the second 1979 paper represents their understanding of the therapeutic effect.

There are three important questions: 1) Had Tingdong Zhang and colleagues shown that the therapeutic effect came from arsenic trioxide, but not from other Western chemicals or Chinese medicines? 2) Did they realize that the effect of Ailin No1 came from arsenic trioxide but not from mercury in the solution? 3）did they know the effect of arsenic trioxide on acute promyelocytic leukemia (APL)?

Answers for all three questions can be found in Zhang and Rong (1979) which explicitly stated：1）Significant improvement was observed in three patients（one adult and two children） used only Ailin No.1, but no other Western or Chinese drugs. At the time of publication, the children had survived for more than 4 years and the adult more than 9 months. When using other Chinese medicines, Zhang and Rong pointed out that those were not used for treating leukemia, but for supporting the general health of the patients so that they could tolerate more treatment; 2）on page 11 of their paper, they pointed out that the effective component of Ailin No.1 was arsenic trioxide; 3）on pages 10 and 11, they reiterated that acute granulocytic leukemia (M3 type) was the most sensitive to the treatment.

We can conclude that, by 1979, Tingdong Zhang and his collaborators had clearly achieved our current understanding: that arsenic trioxide could treat leukemia, especially acute promyelocytic leukemia (APL, also known as M3 type of the French-American British FAB classification).

In 1981, an institutional authorship with a footnote indicating Tingdong Zhang as the supervisor (with 8 other authors) reported 73 cases of acute granulocytic leukemia patients, with a CR of 24% and remission rate of 86%。In 1982, Tingdong Zhang and Yuanshang Li presented a report to a national meeting on 22 cases of CR by Ailin No.1 and on 98 cases of non-lymphatic leukemia.

In 1984, Tingdong Zhang and Yuanshang Li published a summary of 81 cases whom they had treated since 1971. Among the 22 cases of CR, they pointed out that 7 were of the M2 type and 15 were of the M3 type. They again stated that the effect on M3 type were particularly obvious. In 1985, Tingdong Zhang and colleagues published another paper on the effect of Ailin No.1 on non-lymphatic acute leukemia.

In 1991, Hongde Sun, Lin Ma, Xiaocheng Hu, Tingdong Zhang, Fuxiang Rong, Qinghua Wang, Jinmei Li and Xiuqing Hong reported 16 cases of APL, which should be a continuation of Zhang and Li (1984). They reported that Ailin No1 had been used to treat 32 APL cases from 1974 to 1985, with CR in 19 cases and that 16 cases had survived for more than 5 years.

In 1992, Hongde Sun, Ling Ma, Xiaocheng Hu and Tingdong Zhang published a short “Sharing Experience”, reviewing materials identical to the 1991 paper. Strangely, most English papers cite this 1992 paper for the discovery of arsenic trioxide treatment of APL. Both the 1991 and the 1992 papers were in Chinese. But as we documented, the key findings were published in 1973 and the effect on APL was clear by Zhang and Rong (1979). The often cited 1992 paper of Sun et al was not substantially different from that of 1979, in either what chemicals were applied or the subtype of leukemia treated.

Questions Related to the Research of Tingdong Zhang

There were no simultaneous controls for Zhang’s clinical research. Was it because he did not know? In 1982, Zhang published a commentary, which showed that he was aware of the standards in medical research, but he followed by stating “ it is not permissible to set up ‘blank controls’ for patients with severe diseases, and one can only compare new therapies to existing therapies that are conventionally considered good. For some ‘absolute’ therapies, one can also choose not to use controls, such as with acute leukemia or other malignant cancers”. Clearly not everyone will accept his argument, but his reasoning was clear.

Zhang’s research should be compared to similar work in the West in the same period. When Bernard et al (1973) in France established the effect of daunorubicin on APL, the comparison was made between patients before the availability of daunorubicin treatment and those after it. From 1983 to 1986, case studies in the West on APL were all published without controls: Flynn et al (1982) in the US, Nilsson (1984) in Sweden, Daenen et al (1986) in the Netherland and Fontana et al (1986) in the US. The 1988 report from the group of Zhen-Yi Wang, which is widely known, also did not have simultaneous controls. Thus, work of Tingdong Zhang from 1973 to 1979 was not below the international standards of the time.

Are CMTs helpful for using arsenic trioxide to treat leukemia? We can not find evidence that CMTs have helped defining or refining the treatment. For example, when they discussed five types of leukemia based on CMT classification, there was no difference of arsenic trioxide on different CMT types. It was Western classification of leukemia which was helpful. When they completely gave up the CMT classification, the effect was more obvious. Interestingly, their first paper in 1973 did not mention CMTs, while their latter papers did. It is odd that they never dropped the trace amount of mercury until 1996, although they already stated that only arsenic trioxide was therapeutically effective on leukemia. Was it due to their considerations of CMTs or their unwillingness to change a therapeutically proven recipe?

Lack of evidence for the utility of CMTs does not disprove CMTs, but it is so far unclear whether CMTs are important or essential for scientific studies of CMs.

Chinese Contributions to APL Treatment

APL was one of the most aggressive and fatal type of leukemia. In 1973, Bernard et al. of Paris reported their use of daunorubin in treating APL since 1967. It has since become the mainstream treatment for APL to use anthracyclines (including daunorubin) and cytosine arabinoside (Ara-C). In 1973, Tingdong Zhang and colleagues of China reported the therapeutic effect of arsenic trioxide（As₂O₃） on leukemia, and Zhang and Rong (1979) reported that APL was particularly sensitive to As₂O₃.

In 1983, Koeffler summarized the effect of multiple chemicals including retinoic acid (RA) on differentiating human leukemic cells cultured in vitro. A single case of APL treatment by 13-cis RA was reported in 1983 by Flynn et al of Minnesota, USA, in 1984 by Nilsson of Lund, Sweden, in 1986 by Daenen of the Netherland and in 1986 by Fontana et al of West Virginia USA.

In 1985, Zhen-Yi Wang of Shanghai Second Medical College used all trans-RA (ATRA) to treat a five year old girl. In 1987, his group published a paper in the English edition of the Chinese Medical Journal, reporting the use of ATRA (alone or in combination) to treat six APL patients. In 1988, Wang’s group published in Blood their use of ATRA in treating 24 APL patients, with CR. This English paper published in the US certainly drew the attention of the world. The findings were soon replicated and the application became the convention. This paper, but not the 1987 one (also in English), was widely cited.

In 1995, Huang and coworkers from Dalian China reported that a tablet with multiple components derived from CMs (herbs and minerals) led to 98% CR in 60 APL patients. One of the components contained arsenic disulfide.

In February 1996, Peng Zhang et al from the same hospital as Tingdong Zhang published their use of As₂O₃ in treating 72 APL cases. This summarized their experience of using As₂O₃ alone (without the trace amount of mercury) in 130 APL cases from 1992 to 1995, among which 72 went through one ore more course of treatment. A CR of 73% was reported for patients undergoing initial treatments and 52% in recurrent patients. No cross-resistance was observed between As₂O₃ and ASTRA.

In August, 1996,  Guoqiang Chen and 18 other authors (including Tingdong Zhang in the middle and Saijuan Chen, Zhen-Yi Wang and Zhu Chen as the last authors) reported work in Shanghai Hematology Institute that used in vitro culture leukemic cells to pioneer mechanistic studies of the therapeutic effect of As₂O₃ on leukemia at the molecular level.

In 1997, Jingshu Xu, Jingxiu Duan, Ying Xu, Xiaomin Xin, Xiaohong Song and Tingdong Zhang reported in the Chinese Journal of Hematology a case of who had recurrent APL three times. The patient was treated with Ailin No1 every time and had survived for 20 years.

In 1997, Shen et al from Shanghai reported in Blood that they used pure As₂O₃ to treat 15 APL patients, among which 10 cases with only As₂O₃. CR was achieved in 90%.

In 1998, Soignet et al from the Memorial Sloan-Kettering Cancer Hospital and Cornell Medical College reported in the New England Journal of Medicine (NEJM) that they had treated 12 recurrent APL cases with As₂O₃ and observed CR in 11 cases. The mechanisms were thought to be partial cellular differentiation and apoptosis.

This NEJM paper led to general international acceptance of As₂O₃ as a treatment of APL, achieving what could not be achieved by many papers published in China by Chinese doctors over the previous 2 decades.

Belated, or Lack of, Recognitions

The findings of Tu and Zhang have been well accepted (and generally used) nationally and internationally, saving lives in China and other countries.

       However, neither scientist has been duly recognized nationally or internationally, for different reasons.

       While artemisinin is well known, the contribution of Youyou Tu has been controversial. The reasons remain to be investigated by other historians. A major cultural problem is that, while facing such an important discovery, Chinese authorities did not try to find out where credits are due when they saw controversies and conflicts. The authorities opted to stay out of the controversies, leading to scarcity of recognition for all of those involved in the discovery. The international community have difficulties in understanding or even reading internal circulations and meeting reports in Chinese and inaccessible to the outside.

During our research of the history of artemisinin, we have examined materials that no Chinese authorities had spent time on. Unlike the best known large projects such as the Two Bombs and One Star, the collaborative atmosphere of Task 523 has not been the same, with fighting for credits between different groups, as well as among members of the same group. Group leaders were relatively junior and were not always highly respected by group members.

Publication of articles did not follow the usual convention.    Here the shadow of the Cultural Revolution is obvious. In conventional science, instead of presenting unpublished work on the March 1972 meeting, Tu could have hold onto her data about ether extraction before publication. Her group could also have published the purification of artemisinin when Yurong Zhong in her group obtained the crystals. These two papers would have established their priorities. In real life, they only presented reports in closed door meetings, before the first paper was published in Chinese in 1977 under the collective authorship of Qinghaosu Coordinating Research Group. English articles were in 1982, under the collective authorship of China Cooperative Research Group on Qinghaosu and Its Derivatives as Antimalarials. These left ample room for controversies.

Now, while sharing of information without publication did not help assuring credits for scientists, it was faster than normal to apply the seemingly successful drug on many patients than the normal convention would require. If all patients had to wait for the clarification of authorship and publication of papers, some of them would not have lived through that period.

From more than one source, it appears that Tu’s unwillingness to credit her own group members and other groups is a non-negligible factor in the controversies. There were complaints that, in her later publications, her citations sometimes skipped others to move her own name forward. It was sometimes difficult for us as a third party to communicate with Tu. It is not helpful that she keeps at her home original notebooks which belonged to her institute, making them inaccessible to others interested in the original record.

       The obscurity of Tingdong Zhang is even more striking. He remains largely unknown in academic and medical communities nationally or internationally, although there was a story about him in the New York Times in 2001. The reason is not controversies. There was a contention for patent by a member of his group (Hongde Sun), but it was quite late and the judge ruled in Zhang’s favor. It was clear, if one reads publications from 1973, that Tingdong Zhang played an undisputed key role.

The lack of recognition for Zhang may be more due to where he worked, the scarcity of English papers by him, lack of international perspective and communications. It can not be ruled out completely that he did not quite realize the significance of his own work.

It certainly did not help that most of Zhang’s papers were published in journals that were obscure even in China.

In 1998, Guoqiang Chen, Saijuan Chen, Zhen-Yi Wang and Zhu Chen published in a Chinese journal that “from the early 1970s, Harbin Medical University (HMU) discovered through clinical practices that arsenic trioxide could effectively treat APL. In the past two years, we have collaborated with HMU and used arsenic trioxide solution to treat APL patients resistant to ATRA and conventional chemotherapy”, affirming the work and priority of HMU.

In English literature, the key role of Tingdong Zhang was not mentioned and cited papers did not mention his name. Almost no English paper realized that Tingdong Zhang had published his findings from 1973 to 1979. Most English papers, including those by Chinese scholars as well as non-Chinese scholars, cited Sun et al (1992) and sometimes Peng Zhang et al (1996) as the first paper for arsenic trioxide treatment of leukemia. For example, the NEJM paper of Soignet (1998), which replicated the findings of Tingdong Zhang in the 1970s and played a major role in the international acceptance of As₂O₃ treatment for APL, mentioned recent Chinese reports of CR in APL by As₂O₃ in its introduction, and cited only the Sun et al (1992), Peng Zhang et al (1996), and Shen et al (1997). It is impossible to know from the NEJM paper that the original findings were made in the 1970s by Tingdong Zhang.

A 1996 news report in Science did mention Tingdong Zhang, but stated that he published his paper in 1992.

Tingdong Zhang has published few English papers. In 2001, Tingdong Zhang and Guoqiang Chen were co-first authors (with Zhugang Wang, Zhen-Yi Wang, Saijuan Chen in the middle and Zhu Chen as the corresponding author) published a review about As₂O₃ in an international journal Oncogene. In the introduction, they also stated recent studies of As₂O₃ treatment of APL, citing Guoqiang Chen et al (1996). On the second page, they stated that the research on As₂O₃ started in 1971, without citing any publications, and claimed to have treated more than a thousand patients of different types of cancers including “chronic granulocytic leukemia, lymphoma, esophageal cancer, and particularly APL”, but again without citing any literature. Thus, Tingdong Zhang, as a first author himself, neglected to cite his own early papers, effectively burying his own pioneering findings in 1973, 1974, and his clear understanding in 1979 that APL was the most sensitive.

In 2002, Jun Zhu, Zhu Chen, Lallemand-Breitenbach and de The published a review in Nature Reviews Cancer. In the figure illustrating milestones in APL treatments, Tingdong Zhang in the 1970s were placed, but the citation in the text was Sun et al (1992) and the explanation in the reference credited Sun et al (1992) as “first report of As₂O₃ therapy in APL”.

Furthermore, both Sun et al (1992) and Peng Zhang et al (1996) were published in Chinese, and neither cited papers of the 1970s. Thus, even if any international scholars attempted to obtain English translations of the 1992 and 1996 papers, they would still not know the original 1970 papers.

In 2008, Zhen-Yi Wang and Zhu Chen reviewed progresses in APL treatment in Blood, the initial citation for As₂O₃ was the Zhu et al (2002) review. The citations for As₂O₃ treatment of APL were Sun et al (1992), Zhang et al (1996), Chen et al (1996), Shen et al (1997) and Niu et al (1999).

Therefore, the contributions of Tingdong Zhang, and the year of his discoveries, are virtually unknown in the international literature.

Significance of Recognizing Youyou Tu and Tingdong Zhang

National and international recognitions of Tu and Zhang are not only fair to the scientists, but also important to stimulate China and the rest of the world to realize that treasures of traditional Chinese medicines remain largely untapped. One would need to be able to read Chinese literature, and distill layers of confusions, before targeting a drug against a disease, as Tu and Zhang have done in the 1970s.

       A direct suggestion is that one can test other therapeutic effects claimed by early reports. Zhang and other Chinese researchers have reported As₂O₃ treatment of multiple cancers, from liver, stomach and colon cancers to lymphomas. For example, Fang et al (1981) reported the effect on 42 cases of late liver cancer. Surgery alone led to 8% of 3 year survival and no 5 year survival whereas surgery plus Ailin No.1 led to 42% of 3 year survival, among which 5 patients lived for over 5 years. In 1988, Yuanshang Li, Tingdong Zhang, Xingrong Wang and Xu Liu published effect of Ailin No1 on cultured liver cancer cells.

An indirect inference is that rigorous studies of components of CM may lead to more discoveries. For example, drugs used vaguely by Chinese hospitals or marketed aggressively by Chinese companies (without prior stringent tests), may prove to be more powerful and specific after rigorous studies, and become more internationally acceptable and will eventually help more patients and save more lives.

Research on the history of artemisinin and Task 523 will help to understand the management of big science projects, pros and cons of large collaborative projects. Two Bombs and One Star are successful examples. Artemisinin is different from them. Projects on bronchitis and others were also costly in the 1970s and had not led to drugs in use today. Was it because they were failures or because we have not examined them in sufficient details to find the jewels?

If Youyou Tu and Tingdong Zhang are widely recognized nationally or internationally some day, we hope that the Chinese populace will not neglect the contributions of others. Task 523 was a national collaboration, involving hundreds of people including administrative organizers as well as researchers such as Luo Zeyuan of Yunnan, Zhenxin Wei of Shangdong, Guoqiao Li of Guangdong, Pengfei Li and Li Liang of Beijing, Zhaohua Wu, Weishan Zhou and Yuling Wu of Shanghai. Yurong Zhong, Yagang Yu and Muyun Ni of the Tu group also made important contributions. Soldiers and farmers were the early volunteers at a time when informed consent was not what it is now.

Most importantly, these drugs have saved lives. The work of Tu and Zhang should be respected. Their achievements should be applauded. In science, with objective criteria, debates can take us closer to truth.

Acknowledgements

While one of the authors (YR) has been interested in the topic for more than a decade and had carried on inquiries on and off, it is in recent years that we have obtained sufficient materials to provide this outline. We thank researchers and others who granted us interviews for information, Fuchu He for access to files of the Task 523 office, Xin-Yuan Fu, Siyuan Gong, Kunliang Guan, Xin Hao, Hong Ma, Bai Lu, Hua Lu, Lin Mei, Eric Oermann, Hai Rao, Xiaodong Wang, Yue Xiong, Gang Zhi, Qiuding Zhou for comments.

Relevant Literature (listed chronologically, some are files and some journals have no volume numbers and the citations are thus irregular)

Artemisinin

Jang, C.S., Fu, F.Y., Wang, C.Y., Huang, K.C., Lu, G. and Chou, T.C. (1946) Ch’ang shan, a Chinese antimalarial herb. Science 103:59.

Jang, C.S., Fu, F.Y., Huang, K.C. and Wang, C.Y. (1948) Pharmacology of ch’ang shan (Dichroa febrifuga), a Chinese antimalarial herb. Nature 161:400–401.

上海市中医文献研究馆(1965) 疟疾专辑 上海科技出版社.

军事医学科学院五所档案馆．Wg-5-4．抗常山呕吐药物的寻找，健康人试服常山半夏合剂片的副作用的观察．1967.1

中华人民共和国科学技术委员会、中国人民解放军总后勤部联合通知．《67》科十字第118号、后科字第388号．下达《疟疾防治药物研究工作协作会议》纪要及《疟疾防治药物研究工作协作规划》．附件一．1967-6-16．原全国五二三办公室．五二三与青蒿素资料汇集．内部资料．2004.

中医研究院革命委员会(1970)．常见病验方选编．北京：人民卫生出版社.

全国疟疾防治研究领导小组办公室(1975) 疟疾研究·化学合成药与临床观察专集.

全国疟疾防治研究领导小组办公室．疟疾研究·化学合成药与临床观察专集，1975-7

青蒿素协作研究组(1977)．一种新型的倍半萜内酯——青蒿素．科学通报 1977(3):142.

Qinghaosu Coordinating Research Group (1977)．A new sesquiterpene lactone-qinghaosu．Chin Sci Bull(科学通报) 1977(3):142．

中医研究院中药研究所 (1978) 青蒿抗疟研究 1971—1978

刘静明，倪慕云，樊菊芬，屠呦呦，吴照华，吴毓林，周维善（1979）.青蒿素(Arteannuin)的结构和反应．化学学报，37:129-142.

China Cooperative Research Group on Qinghaosu and Its Derivatives as Antimalarials (1982). Clinical studies on the treatment of malaria with qinghaosu and its derivatives. J Tradit Chin Med 2:45–50.

China Cooperative Research Group on Qinghaosu and Its Derivatives as Antimalarials (1982) Studies on the toxicity of qinghaosu and its derivatives. J. Tradit. Chin. Med. 2:31–38.

China Cooperative Research Group on Qinghaosu and Its Derivatives as Antimalarials (1982) Chemical studies on qinghaosu (artemisinine). J. Tradit. Chin. Med. 2:3–8.

China Cooperative Research Group on Qinghaosu and Its Derivatives as Antimalarials (1982) Antimalarial efficacy and mode of action of qinghaosu and its derivatives in experimental models. J. Tradit. Chin. Med. 2:17–24.

China Cooperative Research Group on Qinghaosu and Its Derivatives as Antimalarials (1982) The chemistry and synthesis of qinghaosu derivatives. J. Tradit. Chin. Med. 2:9–16.

Meshnick, S.R., 1998. From quinine to qinghaosu: historical perspectives. In: Sherman, I.W. (Ed.). Malaria: Parasite Biology, Pathogenesis, Protection, ASM Press, Washington, DC, pp. 341–53.

Meshnick, S.R., Dobson, M.J., 2001. The history of antimalarial drugs. Antimalarial chemotherapy. In: Rosenthal, P.J. (Ed.). Mechanisms of Action, Modes of Resistance, and New Directions in Drug Development, Humana Press, Totowa, NJ, pp. 15–25.

Eckstein-Ludwig U, Webb RJ, van Goethem IDA, East JM, Lee AG, Kimura M, O’Neill PM, Bray PG, Ward SA & S. Krishna S (2003) Artemisinins target the SERCA of Plasmodium falciparum. Nature 424:957-961.

Yang ZS, Zhou WL, Sui Y, Wang JX, Wu JM, Zhou Y, Zhang Y, He PL, Han JY, Tang W, Li Y, and Zuo JP (2005). Synthesis and immunosuppressive activity of new artemisinin derivatives. Part I. [12 (β or α)-Dihydroartemisininoxy] Phen(ox)yl Aliphatic Acids/Esters. J Med Chem 48:4608-4617.

Yang ZS, Wang JX, Zhou Y, Zuo JP and Li Y (2006). Synthesis and immunosuppressive activity of new artemisinin derivatives. Part 2: 2-[12(β or α)-Dihydroartemisininoxymethyl-(or 1’-ethyl) phenoxyl propionic acids and esters. Bioorg Med Chem 14:8043-8049.

张剑芳(2006) 迟到的报告,羊城晚报出版社, 广东

Wang ZJ, Qiu J, Guo TB, Liu AL, Wang Y, Li Y and Zhang JZ (2007). Anti-inflammatory properties and regulatory mechanism of a novel derivative of artemisinin in experimental autoimmune encephalomyelitis. J Immunol 179:5958-5965.

李豫，杨恒林 (2007) 青蒿素类药治疗疟疾的回顾与展望．云南中医中药杂志 28:46-47.

屠呦呦 (2009) 青蒿素及青蒿素类药物．北京：北京化学工业出版社

吴毓林 (2009) 青蒿素——历史和现实的启示．化学进展 21:2365-2371

Arsenic Trioxide and Leukemia

张亭栋,张鹏飞,王守仁,韩太云(1973) “癌灵注射液”治疗6例白血病初步临床观察.黑龙江医药 1973(3): 66-67.

Zhang TD, Zhang PF, Wang SR, and Han TY (1973). Preliminary clinical observations of 6 cases of leukemia treated by “Ailin solution”. Medicine and Pharmacy of Heilongjiang 1973(3):66-67.

Bernard J, Weil M, Boiron M, Jacquillat C, Flandrin G, and Gemon M-F (1973). Acute promyelocytic leukemia: results of treatment by daunorubicin. Blood 41:489-496.

哈医大一院中医科，哈医大一院检验科 (1974). 癌灵1号注射液与辨证论治对17例白血病的疗效观察. 哈医大学报 1974(2):25-30.

Departments of Traditional Chinese Medicine and Laboratory Medicine of the First Affiliated Hospital of Harbin Medical University (1974). Therapeutic observations of 17 cases leukemia treated with Ailin No.1 and dialectic theory. Journal of Harbin Medical University 1974(2)25-30.

荣福祥,张亭栋(1979). 急性粒细胞性白血病长期存活2例报告. 新医药学杂志 1979(6):31-34.

Rong FX and Zhang TD (1979). A report on long term survival of 2 cases of acute granulocytic leukemia. Journal of New Medicine and Pharmacy 1979(6):31-34.

张亭栋和荣福祥(1979).癌灵一号注射液与辩证论治治疗急性粒细胞型白血病. 黑龙江医药 1979(4):7-11.

Zhang TD and Rong FX (1979). Treatment of acute granulocytic leukemia by Ailin No.1 and dialectic theory. Medicine and Pharmacy of Heilongjiang 1979(4):7-11.

哈尔滨医科大学附属第一医院中医科 （指导:张亭栋执笔: 李元善 胡晓晨 参加人:李明祥 张鹏飞 荣福祥 孙洪德 李会荣 吴云霞 检验科血研究室）（1981）癌灵一号结合辨证施治治疗急性粒细胞型白血病73例临床小结. 黑龙江中医药 1981(4):28-30.

张亭栋 （1982） 谈谈中西医结合临床科研设计中的几个问题. 中西医结合杂志2:180-181.

张亭栋 （1983） 中医对白血病的认识和治疗. 中医杂志 1983(3):71-74.

Koeffler HP (1983). Induction of differentiation of human acute myelogenous leukemia cells: Therapeutic implications. Blood 62:709-721.

Flynn P. Miller W, Weisdorf D, Arthur D, Banning R, Branda R (1983). Retinoic acid treatment ofacute promyelocytic leukemia: In vitro and in vivo observations. Blood 62:1211-1217.

Nilsson B (1984) Probable in vivo induction of differentiation by retinoic acid acid of promyelocytes in acute promyelocytic leukemia. Br J Haematol 57:365-371.

张亭栋,李元善(1984). 癌灵1号治疗急性粒细胞白血病临床发现和实验研究。 中西医结合杂志4:19-20.

张亭栋 （1985） 急性非淋巴细胞性白血病证治. 中西医结合杂志 5: 713.

Daenen 5, Vellenga E, van Dobbenbugh OA, Halie MR (1986). Retinoic acid as antileukemic therapy in a patient with acute promyelocytic leukemia and Aspergillus pneumonia. Blood 67:559-561.

Fontana JA, Roger iS, Durham JP (1986). The role of 13-cis retinoic acid in the remission induction of a patient with acute promyelocytic leukemia. Cancer 57:209-217.

Huang ME, Ye YC, Chen SR, Zhao JC, Gu LJ, Cai JR, Zhao L, Xie JX, Shen ZX & Wang ZY (1987). All-trans retinoic acid with or without low dose cytosine arabinoside in acute promyelocytic leukemia: report of 6 cases. Chin Med J 100:949-953.

Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, Gu LJ & Wang ZY (1988). Use of alltrans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72:567-572.

李元善,张亭栋,王兴榕,刘旭(1988). 癌灵1号注射液对人肝癌细胞杀伤动力学研究. 肿瘤防治研究 15:1-3

孙鸿德,马玲,胡晓晨,张亭栋,荣福祥,王钦华,李金梅,冯秀芹 (1991) 癌灵1号结合中医辨证施治急性早幼粒白血病长期存活16例报告. 中医药信息 1991(6):39-41.

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孙鸿德,马玲,胡晓晨,张亭栋 (1992).癌灵1号结合中医辨证治疗急性早幼粒白血病32例. 中国中西医结合杂志 12:170-171.

Sun HD Ma L Hu XC Zhang TD (1992). Ai-Lin I treated 32 cases of acute promyelocytic leukemia. Chin J Integrat Chin & West Med 12:170-172.

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