On Orders From Mao, Researchers Set Off On Nobel-Winning Drug Work

Oct 5, 2015
Originally published on October 5, 2015 7:34 pm

The Nobel Prize in medicine was awarded Monday to three scientists for their work on parasitic diseases.

William C. Campbell and Satoshi Omura were recognized for discovering a compound that effectively kills roundworm parasites. A Chinese scientist, Dr. Youyou Tu, won for her work in isolating a powerful drug in the 1970s to fight malaria.

For Tu, it all started in the 1960s, when Americans and North Vietnamese fighters were hurting — not just from jungle warfare with each other but also from a common enemy: drug-resistant malaria.

Scientists on both sides of the line scurried to develop a new drug that would keep troops malaria-free. American military scientists toiled in the laboratories of Walter Reed Army Institute of Research. Meanwhile, Mao Zedong ordered hundreds of Chinese scientists to develop a new drug. Tu led a team of researchers working on what was called "Project 523."

The research would eventually result in artemisinin, an extremely effective anti-malarial medication that has been credited with halving the number of malaria deaths worldwide. In addition to the Nobel Prize, Tu earlier this year won the Alpert Foundation Prize from Harvard and in 2011 the Lasker Prize for Clinical Medical Research.

In aiming to develop a new drug, her group combed the literature on traditional Chinese medicine, looking for plants that might hold promising ingredients for a malaria cure. Artemisia annua, also known as "sweet wormwood" or "qinghao," had been given as a tea to malaria patients for centuries, cited as an anti-fever medicine as early as the second century B.C., and as an anti-malarial by alchemist Ge Hong in the fourth century. When Tu's team brought it to the lab, they found that it killed the malaria parasites in mice. They eventually isolated the active ingredient — a chemical now known as artemisinin.

A fourth-century tea recipe involving the plant, the doctor wrote in the journal Nature Medicine, "gave me the idea that the heating involved in the conventional extraction step we had used might have destroyed the active components, and that extraction at a lower temperature might be necessary to preserve antimalarial activity."

The centuries-old manuscripts were right. By late 1971, they had isolated "a nontoxic, neutral extract that was 100 percent effective" against malaria in infected mice and monkeys. Tu wrote that she and her colleagues tested the new drug on themselves before starting human trials.

"This was during the Cultural Revolution, when Chinese scientists and other intellectuals were sent off to the countryside to do hard labor and be publicly humiliated," says Keith Arnold, who was researching malaria on the U.S. side at the time and would later work with the Chinese researchers. Back then, he says, they "often worked overnight and in the basement of buildings. And they were in fact harassed and treated very badly, until the word came down that these scientists were protected by Mao."

Arnold, the first Western scientist to write about artemisinin, learned about the secret national project when he met some of the scientists on a trip to China in the late 1970s. He says he looked at the data "and noticed that this was incredible. We had no compound comparable to this that would kill the parasite as quickly as this."

Despite comparative studies that showed that it far outshone the U.S. drug mefloquine, mutual distrust between East and West kept artemisinin off the international market.

"It was delayed far too long," Arnold says.

Just as Tu's work on artemisinin is being showered with recognition, malaria parasites in South East Asia have started to show resistance. Scientists are now searching for the next breakthrough drug. The world's deadliest animal remains the mosquito.

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We're going to hear some more about that anti-malarial drug now. As we've heard, it springs from traditional Chinese medicine. It was developed during the repressive years of China's Cultural Revolution, and it came about because of the war in Vietnam. Well, Keith Arnold was the first Western medical scientist to know about this drug, and he joins us from NPR West. Welcome to the program.

KEITH ARNOLD: Thank you.

SIEGEL: First, the Vietnam War, malaria and artemisinin. Tell us about the connection.

ARNOLD: Well, from the American side, we were having a problem with malaria, and we were starting then to look at mefloquine. On the other hand, the North Vietnamese were having a serious problem with malaria, and therefore, they contacted China - Mao - to ask for some help. And Mao then decided that he would support Vietnam. He sent a directive out to his scientists and so on that they should pursue the traditional medicine line, and he hoped that they would come up with something related to traditional medicine, which he was eager to promote.

SIEGEL: Now, this began in 1967, and the research continued through the years of the Cultural Revolution when Chinese scientists, like other intellectuals, were sent off to the countryside to do hard labor, to be publicly humiliated. How did this project survive during that time?

ARNOLD: Well, it survived with difficulty. All this research has - had problems. They often worked overnight and in the basement of buildings. And they were, in fact, harassed and treated very badly until the word came down that these scientists were protected by Mao.

SIEGEL: Tell me about - when you went to China in the late 1970s, how did you learn of this - what was actually a secret project?

ARNOLD: I went there to study mefloquine in comparative studies against malaria using quinine or chloroquine. When I met the appropriate scientists - there were several Chinese persons dressed in their Mao suits, and when I explained what I wanted to do, they said to me, well, we actually have a compounded drug which we think is quite good, and here's the data and information about it. And they showed that data to me. I saw the slides, and I saw the graphs of clearance and noticed that this was incredible. We had no compound comparable to this that would kill the parasites as quickly as this. So then I suggested that we use this as a comparative study, and they agreed. And then we went ahead and did the study and then published the paper The Lancet in 1982.

SIEGEL: In 1982 - I mean, I can remember as late as the late-1990s when there was litigation over the side effects of anti-malarial medication, not this. What took so long, getting this drug out there to people?

ARNOLD: Well, it gets a bit complicated. WHO did meet with the Chinese authorities in '82, '85 to try and do a collaborative research project. But both sides distrusted each other, so WHO gave up on it, had nothing to do with it for a period of time. But I continued to study research in Vietnam, mainly. The problem was that WHO would not accept any of our work and - in fact, would not let any of us use the drug because it wasn't manufactured in China according to their standards. And therefore, they ignored the use of it until it became so obvious, in the early '90s, this was a remarkable drug. And they were then obliged to actually start looking at it. But, in my view, they delayed this far too long, but it's one of those things that happened, unfortunately.

SIEGEL: You met the doctors who were doing this work in China. Dr. Tu, who was honored with the Nobel Prize, who was already honored a few years ago with the Lasker Prize, the big American prize for medicine. As I understand it, you're in the camp that says other people have been slighted by she alone being the recipient of this prize.

ARNOLD: Absolutely. And the Chinese other researchers are quite furious about this. Many of us who were basic researchers in the early years said, for example, her being named the inventor is a travesty of justice, and she should in no way receive that award. She should not have received the Lasker Award, and she certainly should not receive the Nobel Prize.

SIEGEL: That she shouldn't have received or shouldn't have received it alone, which is more accurate in your opinion?

ARNOLD: Yes, we will say that. But in fact, there are other scientists who contributed much more to the development discovery than did Tu You.

SIEGEL: Dr. Arnold, thank you very much for talking with us.

ARNOLD: Thank you.

SIEGEL: That's malaria researcher Keith Arnold. He was the first Western scientist to write about the drug artemisinin. We did seek comment from the Nobel Committee about his criticisms, and we have yet to hear back. Transcript provided by NPR, Copyright NPR.