Discovering an Antimalarial Drug in Mao’s China

When her father gave Tu the name “Youyou,” he started with characters from the Chinese classic Book of Odes: “The deer bleat: ‘yōu yōu’ while eating wild ‘hāo’” (呦呦鹿鸣，食野之蒿). The next line, he composed himself: “Green as the hāo grass, repaying the spring sun” (蒿草青青，报之春晖).

Eerily predictive in hindsight, the “hao” in these lines stood for the plant qinghao, or Artemisia annua L. (sweet wormwood), from which artemisinin, the antimalarial drug, was first isolated. Little did her father realize that Tu Youyou would eventually be internationally known for discovering the antimalarial properties of artemisinin, a molecule that inhibits the parasite and is directly responsible for saving the lives of millions of people.

However, the blandly clinical package of artemisinin and artesunate tablets reveals little about how the key compound was first discovered. Chinese researchers scoured ancient medical texts containing written records of malaria outbreaks and the plant-derived recipes that were used to treat them nearly two thousand years ago. It was from these texts that artemisinin was rediscovered.

“Cumulatively the deadliest of the human infectious diseases,” malaria has been documented throughout recorded history. It is caused by Plasmodium parasites, which are transmitted to humans through the bite of infected mosquitoes. Multiple species of Plasmodium infect humans, but P. falciparum is the most prevalent and has killed more people than any other. The complex life cycle and genetic diversity of Plasmodium make malaria especially difficult to eradicate. Current vaccines and medicines work by intervening against these life phases. Artemisinin-based drugs work by causing Plasmodium proteins to unfold and by inhibiting new proteins from folding properly, which eventually destroys the parasite.

Artemisinin was unearthed as part of a secret Chinese military project between 1967 and 1981, with the most significant milestones overlapping with the Cultural Revolution (1966-1976). But how did a time period historically associated with political frenzy and the persecution of intellectuals, researchers, and academics give birth to one of the world’s most successful drugs?

The existing literature written in English on this story tends to attribute Tu Youyou’s achievements to a solo discovery, an understandable consequence of Tu receiving the Nobel Prize in Physiology or Medicine in 2015. But with the help of newly published Chinese volumes on artemisinin’s discovery in China, we can uncover a more complex picture that situates Tu within the context of a formative moment for the resurgence of Chinese medical traditions during the final decade of Mao’s rule.

Discovery

During the Vietnam War, malaria was a major health concern for soldiers. While it's challenging to confirm exact numbers, it has been cited that nearly 82,000 cases of malaria occurred within the U.S. Army and Marines between 1965 and 1971. In response to the precipitous rise in incidence, governments on both sides of the Pacific began a systematized search for antimalarial treatments. The U.S. focused on developing artificial substances, such as mefloquine, a synthetic analog of quinine, an antimalarial compound derived from the bark of cinchona trees. Over the course of 12 years, the Walter Reed Army Institute of Research (WRAIR) screened more than 250,000 compounds in search of an efficacious treatment.

Northern Vietnam, in turn, sought help from China, which was also experiencing a significant malaria burden, with around 10 million people infected each year. Upon being asked for aid in 1964, the communist leader Mao Zedong responded: “Solving your problem is also solving ours.”

Thus began Project 523, named after the date of a secret national meeting held in Beijing between May 23 and 30, 1967. Organized by the National Commission of Science and Technology and the General Logistics Department of the People’s Liberation Army (PLA), the purpose of the meeting was to form a combined military and civilian program dedicated to malaria prevention and control. It established the Leading Group of the National Malaria Research Team, with members from the Ministry of Health, the Ministry of Chemical Industry, and the Chinese Academy of Sciences. Regional 523 offices were set up to coordinate activities with the national team under military supervision, to which affiliated institutions around the country would report.

The 1967 meeting outlined three main objectives: To develop anti-malarial therapeutic drugs, anti-malarial preventive medicine, and mosquito repellent. Research activities began around the country under four coordination groups: chemical synthesis, Chinese medicine, repellent, and on-site prevention. Due to the Cultural Revolution, a turbulent period of violence and ideological upheaval, most of the scientific research taking place in China had been put on pause in 1967. As it fell under the aegis of the military, Project 523 became a fortunate anomaly. In January 1969, Tu Youyou joined Project 523 as a group leader at the Institute of Chinese Materia Medica (ICMM). Tu had been working at the ICMM ever since graduating from Peking University in 1955 with a degree in pharmacognostical study.

At Project 523, Tu spent her first few months consulting traditional Chinese medical texts. By reading old books, collecting historical remedies, and talking to Chinese medicine experts, she gathered more than 2,000 possible treatments, summarized 640 prescriptions, and submitted her compiled report, titled “Antimalarial Collections of Recipes and Prescriptions”(Kangnue danmi yanfangji) to the Project 523 Office in April of 1969.

Qinghao, the plant from which artemisinin is derived, had already been identified by the Project as one of the important subjects of the study. Even so, it received little research attention. In oral interviews conducted by historians at Peking University, many researchers responded that they might have screened qinghao but failed to notice its special efficacy amongst the large number of candidates.

Tu’s focus first fell on pepper (hujiao), as it had been a common Chinese herbal ingredient and a folk antimalarial remedy. In August and September of 1969, she and Lang Linfu, a core member of her group, carried out clinical experiments in Hainan, with pepper-based tablets (“jiugao wanji”) that the duo had made based on folk traditions and historical records. Their results suggested that pepper helped to mask some of the symptoms of malaria, but did not effectively inhibit Plasmodium, the root cause.

In 1970, at the height of the Cultural Revolution, Project 523 was paused at ICMM as the whole institute became enveloped in the nationwide campaign of catching “May Sixteenth elements”—people suspected of acting as counterrevolutionaries. After a brief hiatus, ICMM formed a new research group in July 1971 and resumed work under Tu’s leadership.

As part of this work, they consulted herbal recipe books once again, scouring instructions for details that they had previously missed. One of these seemingly small yet critical details about preparation involved temperature. In Emergency Prescriptions Kept up One’s Sleeve (Zhouhou Beijifang), China’s first emergency manual, Jin Dynasty physician and alchemist Ge Hong (284-363) wrote: “Qinghao, one bunch, take two sheng [2 x 0.2 l] of water for soaking it, wring it out, take the juice, ingest it in its entirety.” Most Chinese herbal recipes would have mentioned heating, which was the conventional way to extract compounds. But in Ge Hong’s instructions, there was no mention of heating.

Because it was convention, scientists at the ICMM typically extracted their compounds by heating up plants and herbs. However, Tu’s research group was willing to reconsider whether this was the proper way to treat A. annua (Qinghao) leaves. Their use of a cooler temperature was directly reflected in the efficacy of the samples.

Records from ICMM confirm that the effectiveness of artemisinin-based samples from Tu’s group was consistently less than 50 percent until October 4, 1971. But shortly after, sample number 191 was prepared using ethyl ether extracts—with no heating—and reached 100 percent inhibition of Plasmodium.

Beginning December 6, experimental results consistently showed 100 percent efficacy in rodents. The main change Tu’s group made was largely inspired by the Jin dynasty instructions, and it was simply to use ether for a cold soak of the Qinghao leaves. In addition to the low temperature, their use of ethyl ether—instead of ethanol—also significantly contributed to the extract’s efficacy, as the active compound in qinghao is lipophilic. From there, more qinghao extracts were made that took away possible acidic and alkaline ingredients. The neutral sample was deemed the most stable and effective extract.

On March 8, 1972, Tu Youyou attended a meeting held by the National Project 523 Office, as the representative of ICMM. Titled “Discovery of Antimalarial Chinese Herbal Medicine Under the Guidance of Mao Zedong’s Thoughts,” her presentation reported the 100 percent efficacy rate of the sample crude ether neutral extract from qinghao in both rodent and simian (primate) malaria experiments.

Her team’s success is even more impressive in light of the fact that their discovery was, in some capacity, a low-probability event. As it turned out, A. annua L. was a particularly tricky plant to work with. Most of the plant does not contain artemisinin, but only a small part of its leaves. Additionally, the concentration of artemisinin contained in the plant is heavily influenced by the location in which it is grown and the season in which the plant is harvested. In their original experiments, Tu’s team selected their leaves from mature Beijing A. annua L., which generally contained a very low concentration of artemisinin.

Through the collaborative efforts of more Chinese institutions, it would take another half a year to isolate the active component of artemisinin, and an additional three years to determine its chemical structure.

tu Science

Even with refinements owed to modern chemistry, Tu's identification of A. annua L. was simply a rediscovery of ancient knowledge. Qinghao has been recorded in Chinese books for two thousand years, with the earliest being Recipes for Fifty-Two Ailments (Wushi’er Bingfang, dated to around 215 BCE), a text written upon silk discovered in a Han dynasty tomb in Mawangdui. The emergency manual that gave Tu the key insight as to the successful extraction method was the earliest record in China for using qinghao to treat malaria. Later medical books, including the famous encyclopedia Bencao Gangmu (Compendium of Materia Medica), also recorded use cases for qinghao.

Before Tu’s group joined the Project in 1969, the Shanghai Research Institute of TCM Literature had already compiled a Compendium of Malaria in 1965. A foundational text during Project 523, it compiled anti-malarial therapeutics from traditional methods, based on classical texts and expert experiences. Tu’s group consulted this compilation when they re-screened experimental candidates in 1971, just before their critical discovery.

This research method was an expression of how medicine in China was practiced at the time. For almost two decades prior, the new nation had experimented with integrations of Western biomedical and traditional Chinese medical traditions, thus creating a lineage of medical workers trained—to varying degrees—in both.

After four years of a national effort to “scientize Chinese medicine” (zhongyi kexuehua), which designated Chinese doctors to study Western biomedicine, Mao Zedong reversed course in 1954, setting a new priority of “Western doctors study Chinese medicine (xiyi xuexi zhongyi).” The goal, as expressed by the president of the Chinese Medical Association in response to Mao, was to create “China’s New Medicine” that “will possess a basis in the natural sciences, will have absorbed the ancient and the new, the Chinese and the foreign, all medical achievements.”

After working at the ICMM for four years, Tu Youyou joined the third class of the special training program created under Mao’s new priority. From 1959 to 1961, she studied classical Chinese medical texts, learned theories, and shadowed experts in their clinical practice. In her Nobel biography, Tu would refer to this program as a formative experience for her lifelong work with artemisinin.

Project 523 bore a particular political and cultural significance for Chinese medicine at a time when debates of what constituted science and scientific practice went hand in hand with ideological struggles. Historian Jia-Chen Fu wrote that Project 523 served as a great opportunity for “ideological celebration of, as well as practical necessity for, self-reliance,” a value celebrated in Mao’s China.

In this light, scouring old Chinese remedies for new treatments for a disease specifically troublesome during war was entirely intuitive for Chinese biomedical scientists like Tu Youyou in the mid-20th century. Fu also suggested clinical experimentation was close to the experiential nature of traditional Chinese herbal medicine, while an extract produced through chemical analysis would have been more epistemologically foreign to the doctors predominantly trained in Chinese medicine.

Artemisinin was not the first case of biomedical extraction based on Chinese medical recipes. In 1926, Kehui Chen and Carl Schmidt from Peking Union Medical College had isolated ephedrine from the common Chinese herb Mahuang. This discovery “ignited a research fire” on ephedrine for the relief of asthma, with more than 500 scientific papers published around the world by 1929.

What differed in the period of Project 523 was a socialist struggle of connecting and integrating “tu” and “yang" sciences, with tu embodying the tradition and experimental values of Chinese medicine and yang representing the professional research and theoretical focus of Western medicine. Under Maoist socialism, tu science came to symbolize the mass participation in, and the restoration of, native Chinese knowledge.

Thus, Project 523 mainly encapsulated the values represented by tu science. Economic challenges during the project also meant that Tu’s group had to be creative with their material practices. Instead of working with proper extracting containers, she and her colleagues used seven large water vats to make the extracts in large quantities in a short time, embracing the Maoist notion of “material challenges through self–reliance.”

Tu’s husband recalled how she often came home smelling of alcohol and diethyl ether. Due to a lack of ventilation and protection equipment, Tu even got infected with toxic hepatitis. After successful testing on animals, Tu and her colleagues volunteered to test the drug sample on themselves, spending a week in a Beijing hospital to do so. After confirming they experienced no side effects, Tu and her colleagues carried out the first clinical trial on human patients in Hainan between August and October 1972, which continued to demonstrate qinghao extract’s high efficacy.

For a country with poor research conditions, this level of voluntary individual sacrifice was made possible by the strong motivational role ideology played, emphasizing collective goals.

Delays

In the early 1980s, eager to push artemisinin onto the international market, China turned to the World Health Organization (WHO). At the fourth meeting of the Scientific Working Group on the Chemotherapy of Malaria, held in Beijing in 1981 and sponsored by the WHO, the World Bank, and the UN Development Programme (UNDP), Chinese scientists presented their research on artemisinin. The next year, hoping to receive support from WHO’s experts, Chinese scientists showed TDR (the Special Programme for Research and Training in Tropical Diseases, co-sponsored by WHO, World Bank, UNICEF and UNDP) representatives around factories in multiple cities, only to be disappointed to learn that none met the F.D.A.’s Good Manufacturing Practice standards for drug production.

TDR-Chemal (the Scientific Working Group on the Chemotherapy of Malaria in TDR) recommended that Walter Reed Army Institute of Research (WRAIR) work with China in 1983, but the collaboration gradually fell apart due to a host of factors, including a lack of trust between the U.S. and China, as well as misunderstandings between TDR and China on the intentions of the collaboration.¹ At the same time, the U.S. WRAIR had discovered A. annua in Washington, D.C. while China had missed the opportunity to apply for patents, ultimately prompting the U.S. to conduct its own artemisinin research.²

The WHO’s hesitation to quickly adopt artemisinin, in part, came from the neurotoxicity of other artemisia species used for making absinthe. As a result, only Vietnam, Cambodia, and Burma chose to use artemisinin and its derivatives manufactured in Vietnam and China without WHO approval, dramatically reducing malaria cases with few, if any, reports of harmful effects.

It was only in 2005, after the emergence of widespread resistance of P. falciparum to monotherapy with conventional drugs like chloroquine and sulfadoxine-pyrimethamine, that the WHO recommended treating malaria with drugs in combination with artemisinin. With help from the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM), artemisinin-based combination therapy became much more economically accessible worldwide. Anthropologist Elizabeth Hsu, who did her fieldwork on artemisinin in East Africa, noted that the WHO’s recommendation made a significant difference in the local perception of artemisinin, transforming it from a Chinese “wonder drug” to a Western medicine.

Keith Arnold, who had worked on malaria research at the WRAIR during the same time as Project 523, concluded that the world would have benefited if artemisinin adoption happened much earlier, and that “millions of dollars [...] have been poured into replicating work already done” by Chinese scientists decades ago.

Meanwhile, on the other side of the Pacific, the U.S. Department of Defense administered mefloquine, the synthetic drug developed at Walter Reed in the U.S., to its soldiers for nearly a quarter century. Despite the Pentagon and health professionals’ awareness of its significant neuropsychiatric side effects, which include vertigo, tinnitus, insomnia, vivid nightmares, visual and auditory hallucinations, paranoia, seizures, mood swings, and suicidal ideation, the F.D.A. only issued “the strongest ‘black box’ warning” against the drug in 2013.

From its initial discovery in the early 1970s to the WHO’s official recommendation in the early 2000s, artemisinin took more than a quarter century to become a globally adopted drug.

Rediscovery

As long as it took for artemisinin to become widely adopted, though, recognition of Tu’s name and contribution to its widespread use took over a decade longer. Few journal articles were written about the project using her (or anyone’s) name before 2010. When Louis Miller, now Chief of Malaria Cell Biology at the NIH, attended a malaria conference in Shanghai in 2008, he asked: Who discovered artemisinin? Nobody had an answer.

Extensive research into previously confidential documents led Miller and his colleague Xinzhuan Su to Tu Youyou. Miller and Su published an article on Tu’s story in Cell in 2011. This gesture of attaching Tu’s name with the discovery of artemisinin would be responsible for Tu winning the Lasker in 2011 and the Nobel in 2015.

When asked why he insisted on finding Tu’s name, Miller invoked the discovery of Quinine from Peruvian Indian knowledge: “This discovery was one of the major life saving discoveries in medicine. I am afraid that [it] is lost and didn’t want this second important discovery of Artemisinin to be lost.”

Even so, the attribution of artemisinin’s discovery to Tu Youyou alone has been contested and criticized by historians, as well as mainstream media in China. Historians at Peking University—Zhang Daqing, Li Run, and Rao Yi—explained that Tu’s group and Project 523 happened under a different system from common Western research protocols. Instead of the Principal Investigator, Tu served as a Principal Director, carrying out a project assigned to her by the State. This categorical misattribution under-credits the massive collective effort and coordination that made artemisinin the globally recognized drug today.

As part of their effort to thoroughly document this project, Zhang, Li, and Rao published a 500-page oral history in 2015 and a monograph on the Project in 2017 that addressed sources in both Chinese and English. Extensive research led to their emphasis that Project 523 was an early example of what was dubbed the “Big Science” of medicine in China. From its inception, dozens of institutions across the country coordinated to work toward the single goal of making antimalarial drugs as hastily as possible. Given China’s limited economic power and scientific research experience in the '60s and '70s, the Project mobilized the most human and material resources possible at the time.

The reason Project 523 was able to mobilize massive resources was because it was a covert state project born out of an urgent mission to aid a political ally during wartime. By 1971, more than 70 research institutions across a range of sectors joined the effort. Medical research groups were joined by pharmaceutical companies, chemical and spice factories, botany institutes, and insect science institutes. Alongside Tu’s group at ICMM were many other research groups in hospitals and universities that worked on making mosquito repellents from a wide range of plants, developing antimalarial acupuncture, developing quinine and quinidine, isolating compounds from yingzhao (Artabotrys uncinatus (L.) Merr.), isolating zinc pyridinethione from lingshuianluo (Polyalthia nemoralis), and more. It was within this nexus of ideas and materials that Tu worked.

Even while schisms about how much credit to bestow individually on Tu Youyou remain, the story surrounding the discovery of Artemisinin deserves to be more widely known. Precipitated by the dire consequences malaria caused to soldiers in a complex war and Mao’s agenda to merge Chinese and Western medicine, or tu and yang sciences, artemisinin traversed through a vast range of actors, geographies, and methodologies. The principal discovery happened during the thick of the Cultural Revolution in an episode of history commonly connoted as anti-science. A single sentence regarding the temperature at which to process a plant from a 1700-year-old Chinese text made possible the isolation and production of a now globally consumed drug.

Although unlikely to serve as a model for any future drug discovery due to its unique configuration of historical circumstances, artemisinin’s (re)discovery in Cold War China is a story of how an uncommon arrangement of human and material resources and methodologies gave rise to one of the most important medical breakthroughs of the 20th century.

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Wendi Yan is a researcher and artist. She studied History of Science at Princeton University and is a Steve Jobs Archive Fellow. Her projects can be found at wendiyan.com.

Cite this essay: Wendi Yan. "Discovering an Antimalarial Drug in Mao’s China." Asimov Press (2024). DOI: https://doi.org/10.62211/81bp-06ft

Footnotes

1. Between January 1983 and September 1985, China’s artemisinin committee held correspondence and in-person meetings with WRAIR and TDR scientists over the drafting of an agreement on the research collaboration. China wanted to limit the collaboration to the technical realm and lead the key tasks in research, and proposed to amend certain clauses in the agreement drafted by the U.S Department of Defense, including letting Chinese scientists bring artemisinin to the U.S (instead of having them handed over by WHO).
2. In 1985, Daniel Klayman published an article in Science about Chinese scientists’ discovery of artemisinin and WRAIR’s investigation on A. annua that began in 1983. Klayman reported the results that the artemisinin yield from the A. annua grown in the D.C. vicinity was much smaller than the varieties grown in the Sichuan Province in China, but still concluded with an optimistic note that “there is now a wide interest in QHS [qinghaosu, artemisinin], and plans are being made to cultivate A. annua in the United States so that adequate supplies of the material will be available for study.”