The Chinese drug artemisinin has been hailed as one of the greatest advances in fighting malaria, the scourge of the tropics, since the discovery of quinine centuries ago.
Artemisinin’s discovery is being talked about as a candidate for a Nobel Prize in Medicine. Millions of U.S. taxpayer dollars are spent on it for Africa every year.
But few people realize that, in one of the paradoxes of history, the drug was discovered thanks to Mao Zedong, who was acting to help the North Vietnamese in their jungle war against the Americans. Or that it languished for 30 years thanks to China’s isolation and the indifference of Western donors, health agencies and drug companies.
Now that story is coming out. But as happens so often in science, versions vary, and multiple contributors are fighting over the laurels. That became particularly clear in September, when one of the Lasker Awards — sometimes called the “American Nobels” — went to a single one of the hundreds of Chinese scientists once engaged in the development of the drug.
Mao’s role was simple.
In the 1960s, he got an appeal from North Vietnam: Its fighters were dying because local malaria had become resistant to all known drugs. He ordered his top scientists to help.
But it wasn’t easy. The Cultural Revolution was reeling out of control, and intellectuals, including scientists, were being publicly humiliated, forced to labor on collective farms or even driven to suicide. However, because the order came from Mao himself and he put the army in charge, the project was sheltered. Over the next 14 years, 500 scientists from 60 military and civilian institutes flocked to it.
Meanwhile, thousands of U.S. soldiers in Vietnam were also getting malaria, and the Walter Reed Army Institute of Research began its own drug hunt. That effort ultimately produced mefloquine, later sold under the brand name Lariam.
While powerful, mefloquine has serious drawbacks, including nightmares and paranoia. In 2003, dozens of U.S. Marines in Liberia got malaria after refusing to take pills because of military scuttlebutt that several Special Forces soldiers who killed their wives after returning home from Afghanistan in 2002 had been driven insane by the drug.
China’s effort formally began at a meeting on May 23, 1967, and was code-named Project 523 for the date.
Researchers pursued two paths. One group screened 40,000 known chemicals.
Answer in tradition
The second searched the traditional medicine literature and sent envoys into rural villages to ask herbal healers for their secret fever cures.
One herb, qinghao, was mentioned on tomb carvings as far back as 168 B.C. and praised on medical scrolls through the centuries, up to the 1798 Book of Seasonal Fevers. Rural healers identified qinghao as what the West calls Artemisia annua, or sweet wormwood, a spiky-leafed weed with yellow flowers.
In the 1950s, officials in parts of rural China had fought malaria outbreaks with qinghao tea, but investigating it scientifically was new. It also had at least nine rivals from traditional medicine with some anti-malarial effects, including a pepper.
In the lab, qinghao extracts killed malaria parasites in mice. Researchers tried to find exactly which chemical worked, which plants had the most, whether it could cross the blood-brain barrier to fight cerebral malaria, and whether it worked in oral, intravenous and suppository forms.
Outmoded equipment slowed research. But by the 1970s it was known that the lethal chemical, first called qinghaosu and now artemisinin, had a structure never seen before in nature: In chemical terms, it is a sesquiterpene lactone with a peroxide bridge. Trials in 2,000 patients showed that it killed parasites remarkably rapidly.
However, the body eliminated it so fast that any parasites it missed made a comeback. So scientists began mixing it with slower but more persistent drugs, creating what is now called artemisinin combination therapy. (One new combination includes mefloquine.)
A 2006 history of the project by Zhang Jianfang, its former deputy director, contains some gripping details: petty disputes between rivals, Cultural Revolution street fighting that forced one laboratory into a basement, project doctors living on brown rice and vegetables as they did clinical trials in remote villages in China’s tropical southern mountains, and other doctors hiking the Ho Chi Minh Trail with the Vietcong.
Mao died in 1976; Project 523 was officially disbanded in 1981, though clinical work continued.
In 1979, Dr. Keith Arnold, a malaria researcher in Hong Kong who had helped the Army develop mefloquine, wangled his way into China, hoping to test his drug there. He met Dr. Li Guoqiao, who was testing artemisinin variants. They decided to try head-to-head trials, and the Chinese mystery drug beat his, Arnold said.
Soon, World Health Organization scientists asked for articles from China’s medical journals, the first of which had been published in 1977, in response to reports that a Yugoslav chemist was experimenting with wormwood.
In 1982, The Lancet had an article by Chinese researchers. It won a prize, but the check, in British pounds, could not be cashed in China.
Shortly thereafter, Arnold said, Walter Reed scientists found wormwood growing on the banks of the Potomac and extracted artemisinin. Nonetheless, the drug languished. The WHO did not endorse it until 2000, and it was not widely available until 2006.
The reasons for that delay are disputed. China was in political disarray. Different labs in and outside China were working on derivatives. Patent law had vanished under Communism, and China never took out Western patents, so there was no way a major drug company could get a monopoly and make big profits. Malaria was a disease of the poor, and today’s big donor funds did not exist.
Aid agencies could not buy drugs that were not WHO-approved. For years, Arnold said, he tried to get permission for his Chinese collaborators to do clinical trials in Thailand and Vietnam, but the WHO stalled. (As a United Nations agency, it is rarely bold, but the 1990s were a decade of particularly low morale and constant infighting.)
As nearly 1 million African children a year died, Arnold denounced its indecisiveness as “genocidal.”
The U.S. military stuck with mefloquine, despite its expense. As late as 2002, as Doctors Without Borders clamored for artemisinin, an adviser to the U.S. Agency for International Development dismissed it in a New York Times interview as “not ready for prime time” and defended chloroquine and other old, cheap drugs even though resistance to them was widespread.
A Swiss company, Novartis, finally broke the logjam. It bought a new Chinese patent on a mix of artemether, an artemisinin derivative, and lumefantrine, another Chinese drug, and took out Western patents, planning to sell it under the name Riamet at high prices to tourists and militaries; in 2001, it agreed to sell it nearly at cost to the WHO under the name Coartem.
The money to buy the drug on a large scale became available with the creation of the Global Fund to Fight AIDS, Tuberculosis and Malaria in 2002 and the Bush administration’s launching of the President’s Malaria Initiative in 2005. Now, about 150 million doses of several combinations are bought for poor countries each year.
Who gets the credit?
With that victory, surviving Project 523 scientists and some outsiders began vying for credit. In 1996, a Hong Kong science foundation recognized 10 team leaders. In 2009, Zhou Yiqing got the European Patent Office’s “Inventors of the Year” award for Coartem.
In September, the $250,000 Lasker award for clinical medical research was given to Dr. Tu Youyou, former chief of the Institute of Chinese Materia Medica in Beijing. The Lasker committee named her “the discoverer of artemisinin.”
Some Chinese and Western malariologists were outraged.
Dr. Nicholas White, a prominent Oxford malaria researcher, said it was “not fair to credit this discovery to one individual”; he named others he considered equally deserving, including the clinical trial leader, Li, and a chemist, Li Ying.
Arnold, whose work with Li was mentioned in the Lasker citation, agreed. Richard Haynes, a malaria researcher and historian at the University of Science and Technology in Hong Kong, called naming one inventor “a travesty.”
The Lasker Foundation declined to comment, other than to note that Tu’s citation mentioned that Project 523 was a large collaborative effort.
In an interview before the ceremony, Tu, 81, argued that she deserved it because her team had been the first to isolate qinghao’s active ingredient while other teams worked on the wrong plants.
Also, after rereading a manuscript by Ge Hong, a fourth-century healer, prescribing qinghao steeped in cold water for fever, she realized that boiling, the typical extraction method, was destroying the active ingredient. She switched to ether, and qinghao became the first plant extract 100 percent effective at killing malaria in mice.
And before human testing began, Tu said, she and two colleagues took it themselves to make sure it was not toxic.
Before the West even heard of the drug, she said, she was one of the four anonymous authors of the initial 1977 paper, and in 1978, she was chosen to accept the Chinese government’s overall award to Project 523.
However difficult winnowing the field would prove, the Nobel Prize committee would be forced to do it anyway. The Nobel rules specify no more than three winners. And no posthumous ones, either — meaning Mao would be out of the question.