Malaria is often dubbed ‘the killer of children’, and even today about 2,000 young children die of malaria every single day, mostly in Africa. But in the last 15 years, the mortality rate has dropped by astounding 60 percent, due to improved prevention and treatment: about half of this reduction can be attributed modern medication like the WHO-recommended ‘artemisinin-based combination therapy’, or ACT. In 2013, almost 400 million doses were delivered. But how this therapy was discovered is a story in itself: the active ingredient artemisinin is a spin-off of the Vietnam War.
In the mid-1960s, North Vietnam asked its powerful ally China to help with the malaria problem: malaria was killing more soldiers on both sides than active combat. Mao Zedong introduced the secret military ‘project 523’ that was a contradiction in itself: During the so-called Cultural Revolution in the 1960s, intellectuals were often displaced, imprisoned and even tortured. (When the pharmacologist Youyou Tu joined this project in 1969, her own husband was a detainee in a labour camp.) On the other hand, Mao desperately needed competent researchers to fight the greatest adversary in the Vietnam War: malaria. And the prevalent strain of the parasite Plasmodium was increasingly immune to chloroquine. The project’s name refers to the day it started: May 23, 1967. More than 500 scientists were recruited in about 60 participating institutes to search for effective antimalarials.
Youyou Tu had studied pharmaceutical science in Beijing, graduating in 1955, and she had trained in traditional Chinese medicine as well. When she began studying malaria in the southern Chinese province of Hainan, she had to put her small daughter into a nursery, because her husband was still imprisoned. When she returned several months later, her daughter didn’t recognise her. On the other hand, in Hainan she had seen many young children in the last stages of malaria that died very quickly – an experience she could never forget. “The work was the top priority, so I was certainly willing to sacrifice my personal life,” she said later.
Not only the Chinese researchers were baffled by the parasite Plasmodium and its resistances, South Vietnamese and American forces faced the same problem. Western researchers had allegedly tested about 240,000 different compounds against malaria over the years, initially without success. (In the 1970s, they found mefloquine, sold today under the name Lariam.) Because of her training in traditional Chinese herbal medicine, Youyou Tu’s team scoured ancient manuscripts for information on potential antimalarials. In the ‘Handbook of Prescriptions for Emergencies’ by the Chinese writer Ge Hong from 340 CE, she found a recipe to prepare malaria medication from Artemisia annua, also called sweet wormwood.
Tu and other researchers experimented with Artemisia extracts, but the results were inconclusive: some extracts worked against Plasmodium in a mouse model, some didn’t. So Tu went back to the old manuscripts and studied the extraction method that is described in detail: She found that modern extraction methods that use boiling water destroy the active ingredient artemisinin. Next she experimented with colder extraction methods, using ether as a solvent. With this novel active agent, she was able to eradicate Plasmodium parasites in mice and monkeys. After trying the potion on herself to see whether it was safe for humans, more than twenty malaria patients were treated – and the parasite could be eradicated! This was the breakthrough everyone had been waiting for.
In the West, these findings would have made Youyou Tu instantly famous. But in Mao’s China, her team wasn’t allowed to publish their results: After all, it was a secret military project. Mao died in 1976, and with him the Cultural Revolution. In 1979, the ‘Qinghaosu Antimalaria Coordinating Research Group’ published an article in English in the Chinese Medical Journal, no authors’ names were used; qinghaosu is the Chinese name for artemisinin. The first international publication followed in The Lancet in 1982, without Tu’s name. But she had been chosen to present the findings to a visiting study group from the World Health Organization in 1981 (reference in Louis Miller’s article in Cell).
In 2007, more than 25 years later, Louis Miller and Xinzhuan Su, both researchers from the National Institute of Allergy and Infectious Diseases in Rockville, Maryland, asked their Chinese colleagues at a scientific meeting in Shanghai about the scientist who actually discovered artemisinin. At first, now one was able to tell them. Extensive research in official papers – most had been stamped ‘secret’ for many years – finally lead them to Youyou Tu, who was then known as “the professor of the three Nos“: no post-graduate degree, no membership in the Chinese Academy of Sciences, and no research experience outside China. The two American researchers published their findings in the journal Cell in 2011.
When I asked Miller, now Chief of the Malaria Cell Biology Section at the NIH Institute, why he started searching for the discoverer of artemisinin in the first place, he had a surprising explanation: “I was always curious about the discovery of quinine by the Peruvian Indians (…) that led to the Jesuits trying quinine for malaria. This discovery was one of the major life saving discoveries in medicinal medicine. I am afraid that is lost and didn’t want this second important discovery of Artemisinin to be lost.” With his inquiry, he has not only documented Tu’s achievement, he has also brought the ancient story to our attention.
Being credited with the identification and isolation of artemisinin won Youyou Tu the Lasker Award in 2011, the most important American award in medical science, and this year’s Nobel Prize. But if a discovery is credited decades later, and even more if the original finding happened in a top-secret project, there will always be people who claim that others contributed as well – undoubtedly so if more than 500 researchers had been involved. Youyou Tu is very modest about this, in a video statement commenting on her Nobel Prize she says that finding artemisinin was “the effort of an entire team”, and that this award is also “for Chinese science and for traditional Chinese medicine”.
— CCTVNEWS (@cctvnews) 7. Dezember 2015
Chinese authors and papers don’t deny Tu’s decisive role in finding artemisinin, but they emphasise the contributions of many other researchers, for instance Li Guoqiao, the leader of the clinical trials at the Guangzhou University of Chinese Traditional Medicine, or Luo Zeyuan from the Yunnan Institute of Pharmacology where the purest crystals of artemisinin were first extracted in large quantities for clinical trials, among many others. But as Xinzhuan Su, the NIH scientist searching for the discoverer of artemisin together with Louis Miller, sums up his findings: “You can see a line, very clear, of her work from the beginning to the end.” Most of all, she persevered when the obstacles seemed insurmountable. And her perseverance paid off: since the 1970s, artemisinin has saved millions of lives.
Youyou Tu was the first Chinese researcher to receive a scientific Nobel Prize for research done in China, and the first Chinese woman ever. She gave her Nobel lecture with the title, “Discovery of Artemisinin – A gift from Traditional Chinese Medicine to the World“ in Stockholm last Monday and will receive the Nobel Prize in Physiology or Medicine today.