[Ip-health] New York Times: For Intrigue, Malaria Drug Gets the Prize

thiru at keionline.org thiru at keionline.org
Mon Jan 16 23:32:46 PST 2012


January 16, 2012

For Intrigue, Malaria Drug Gets the Prize

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 American 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 American 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 American 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.
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

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, Dr. 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

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, Dr. Arnold said, Walter Reed scientists found wormwood
growing on the banks of the Potomac and extracted artemisinin.
Nonetheless, the drug languished. The W.H.O. 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 W.H.O.-approved. For years,
Dr. Arnold said, he tried to get permission for his Chinese collaborators
to do clinical trials in Thailand and Vietnam, but the W.H.O. 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 one million African children a year died, Dr. Arnold denounced
its indecisiveness as “genocidal.”

The American military stuck with mefloquine, despite its expense. As late
as 2002, as Doctors Without Borders clamored for artemisinin, an adviser
to the United States Agency for International Development dismissed it in
an interview with The New York Times 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 W.H.O.
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 introduction of the President’s Malaria
Initiative in 2005. Now, about 150 million doses of several combinations
are bought for poor countries each year.

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

Some Chinese and Western malariologists were outraged.

Dr. Nicholas J. 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, Dr. Li,
and a chemist, Li Ying.

Dr. Arnold, whose work with Dr. Li was mentioned in the Lasker citation,
agreed. Richard K. 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 Dr.
Tu’s citation mentioned that Project 523 was a large collaborative effort.

In an interview before the ceremony, Dr. 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, Dr. 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 prizes, either — meaning Mao would
be out of the question.

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