Chinese herbal garden leads the way

 N. Gopal Raj

The work carried out by Chinese scientists has transformed malaria treatment — from traditional knowledge to modern medical therapy.

More than 40 years ago, amidst the upheaval and turmoil of the Cultural Revolution in China, and against the backdrop of the Vietnam war, hundreds of Chinese scientists embarked on an ambitious effort to find a drug that would conquer drug-resistant malaria. The result was the discovery of artemisinin, a compound found in plants, which, with its derivatives, is now widely used around the world to treat the disease.

This year, a highly prestigious Lasker Award went to Youyou Tu, an 81-year-old Chinese scientist who played a key part in that discovery.

Prof. Tu had led a team that “transformed an ancient Chinese healing method into the most powerful antimalarial medicine currently available,” observed the U.S.-based Lasker Foundation when they recognised her work with the Lasker-DeBakey Clinical Medical Research Award. Millions of lives across the globe, especially in the developing world, had been saved as a result, they pointed out.

In the midst of the Vietnam war, another desperate battle was being fought against Plasmodium falciparum, the most deadly of the malaria-causing parasites which had become resistant to the drug chloroquine. The U.S. came up with another drug to clear the parasite from the body — mefloquine. North Vietnam, for its part, appealed to China for help in fighting this disease.

In response, on instructions from Chairman Mao Zedong and Premier Zhou Enlai, the Chinese government organised a meeting in Beijing on May 23, 1967 to discuss the problem. A secret nationwide programme, known as project 523, was then launched, involving over 500 scientists from about 60 different laboratories, write Louis H. Miller and Xinzhuan Su of the U.S. National Institute of Allergy and Infectious Diseases in a recent article in the journal Cell.

As the work was considered a military secret, no communication about the research to the outside world was allowed. Besides, during the tumult of the Cultural Revolution, publication in scientific journals was forbidden. Although information flowed freely within the group, no one outside the project knew anything about it at the time, they noted.

Prof. Tu was then a principal investigator at the Institute of Chinese Materia Medica of the China Academy of Chinese Medical Sciences (CACMS) at Beijing.

“My institute quickly became involved in the project and appointed me to be the head of a malaria research group,” she reminisced in a commentary published recently by the journal Nature Medicine. “Our group of young investigators started working on the extraction and isolation of constituents with possible antimalarial activities from Chinese herbal materials.”

Prof. Tu and her colleagues began by scouring the literature on traditional Chinese medicine, scrutinising ancient texts and folk remedies. They investigated more than 2,000 Chinese herbal preparations, of which 640 appeared promising. Of these, some 380 extracts involving about 200 herbs were chosen for testing in mice. Unfortunately, “progress was not smooth, and no significant results emerged easily,” she writes in her article.

The turning point came when an extract from a plant known to the Chinese as Qinghao (Artemisia annua or sweet wormwood) “showed a promising degree of inhibition against parasite growth.”

But subsequent experiments came up with much lower levels of inhibition. Prof. Tu came to the conclusion that this could be due to problems in extracting the active ingredient. She found a clue in an ancient Chinese text, The Handbook of Prescriptions for Emergency Treatments by Ge Hong, that goes back some 1,700 years.

The text recommended soaking Qinghao in water, then wringing out the juice and drinking it. “This sentence 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,” according to Prof. Tu. Consequently, they switched to a lower-temperature extraction method.

Even so, as Dr. Miller and Dr. Su narrate in their paper, the extract was still toxic. That problem was taken care of by purifying the extract to remove an acidic portion that had no anti-malarial activity. The remaining neutral extract, given the label ‘extract number 191,' could completely clear the parasites when tested in mice and monkeys.

Prof. Tu presented the work at a project 523 meeting at Nanjing in March 1972. That same year, her group identified “a colorless, crystalline substance” as the active chemical compound. They called it Qinghaosu, which means the ‘basic element' in Qinghao. The world would come to know it as artemisinin.

Using the information she provided, two teams, one at the Yunnan Institute of Drug Research and the Shandong Institute of Chinese Traditional Medicine, were able isolate pure crystals of the compound. Chinese scientists determined its three-dimensional crystal structure in 1975 and published the data two years later. The first step in clinical trials is to establish the safety of the new drug. Since it was not possible to carry out such a trial in the milieu of the Cultural Revolution, Prof. Tu and her colleagues themselves took the plant extract to prove that it could be safely administered.

When the plant extract was tested on patients with malaria in Hainan province, the results were dramatic. Those treated with the plant extracts quickly got better while those given chloroquine did not.

Guoqiao Li of the Guangzhou University of Chinese Traditional Medicine carried out clinical trials using a purified form of artemisinin. These studies were the first to suggest that a combination therapy involving artemisinin and another anti-malarial drug was needed to prevent recurrence and development of resistance, according to Dr. Miller and Dr. Su.

“Artemisinin works quickly within hours compared to mefloquine's slow parasite clearance,” they noted. But as artemisinin levels in the body drop quickly, another drug must be given along with it to obtain and sustain a cure.

It was only in December 1979 that the first English language report on Qinghaosu was published, drawing international attention to what the Chinese scientists had achieved. By then, the drug had been successfully tested in over 2,000 people.

In 1979, when visiting Chinese colleagues working on malaria, Keith Arnold of the Roche Far East Research Foundation in Hong Kong was shown data that indicated that this ‘herbal remedy' was clearing malaria faster than quinine and chloroquine. Three years later, Dr. Arnold was a co-author along with Prof. Li in a paper that appeared in the prestigious medical journal, The Lancet, reporting a clinical trial that compared the anti-malarial activity of mefloquine and Qinghaosu. In 1984, they reported in The Lancet another clinical trial that looked at the effect of administering Qinghaosu alone and in combination with other drugs. “Qinghaosu alone had a rapid rate of parasite clearance, no side effects, but a high recrudescence rate,” they pointed out and added that combination therapy was indicated.

In October 1981, a U.N.-sponsored meeting of the Scientific Working Group on the Chemotherapy of Malaria was held in Beijing. Invited to speak, Prof. Tu presented a report on ‘Studies on the Chemistry of Qinghaosu.'

Her talk covered not just artemisinin but also some of its even more powerful derivatives. As the Lasker Foundation noted, in the course of her structural studies, Prof. Tu had modified the chemical structure of artemisinin to create a compound that had 10 times its punch and reduced the risk of recurrence. This compound provided the basis for other artemisinin-derived drugs. These derivatives also tended to remain in the body longer and are at the heart of today's therapies.

In her article in Nature Medicine, Prof. Tu remarked that “the efficacy of artemisinin and its derivatives in treating several thousand patients infected with malaria in China attracted worldwide attention in the 1980s.”

The work carried out by the Chinese scientists has transformed malaria treatment. According to the World Health Organisation-World Malaria Report, the number of artemisinin-based combination therapy courses procured has shot up from 11.2 million in 2005 to 76 million a year later and reached 158 million by 2009.

“[Prof.] Tu pioneered a new approach to malaria treatment that has benefited hundreds of millions of people and promises to benefit many times more,” observed the Lasker Foundation. “By applying modern techniques and rigour to a heritage provided by 5,000 years of Chinese traditional practitioners, she has delivered its riches into the 21st century.”