Lasker~DeBakey
Clinical Medical Research Award

Award Presentation by Lucy Shapiro

Not often in the history of clinical medicine can we celebrate a discovery that has eased the pain and distress of hundreds of millions of people and saved the lives of countless numbers of people, particularly children, in over 100 countries. The discovery, chemical identification, and validation of artemisinin, a highly effective anti-malarial drug, is largely due to the scientific insight, vision and dogged determination of Professor Tu Youyou and her team at the Institute of Chinese Materia Medica in Beijing. The statistics on malarial infections are horrendous. Professor Tu's work has provided the world with arguably the most important pharmaceutical intervention in the last half century.

The story behind Professor Tu's work that led to the discovery of artemisinin, could easily be the stuff of a novel set during Chairman Mao's cultural revolution. In the late 1960s, a secret military project in China, Project 523 (for May 23), was established by Chairman Mao and Premier Zhou to develop new anti- malarial therapies for the mosquito-borne infection that was devastating civilian and military populations. At that time, most malarial infections had become resistant to chloroquine, the most commonly used drug. In the Vietnam War, the number of soldiers who died of drug-resistant malaria was much higher than that from casualties in both combating sides. The mandate of Project 523 was to screen traditional Chinese herbal medicines with a goal of compound identification, chemical validation, and demonstration of effectiveness in malaria patients. Project 523 was a competitive effort launched with approximately 50 institutes across China involved in the endeavor.

In early 1969, Professor Tu was appointed head of the Project 523 research group in her institute, where traditional medicine was practiced side by side with modern chemists, pharmacologists and other scientists. Tu's team collected and tested over 2000 folk remedies, ultimately focusing their efforts on 380 extracts from 200 herbs and testing their effectiveness in clearing the malarial parasite from the bloodstream of infected mice. Although promising, one of the herbs, culled from the sweet wormwood tree, yielded variable results. However, as early as 340 AD, a Chinese physician, Ge Hong, recommended, in a medical archive entitled "Emergency Prescriptions Kept Up One's Sleeve," that an extract of a similar herb was useful for the treatment of "intermittent fevers." Most Chinese herbal medicines are prepared as a heated tea, but hiding up Ge Hong's sleeve was the observation that to be effective, his herb for "intermittent fevers" should not be heated. Acting on this ancient observation, Tu carried out cold ether extraction of the herb, removed an acidic portion of the extracted material, and obtained a compound with high anti-malarial potency and low toxicity. Human trials in a small number of cases showed that the extract, artemisinin, was non-toxic and more effective than chloroquine.

In 1977, Tu and her team obtained crystalline artemisinin that was 100% effective against the malarial pathogen. In collaboration with scientists in Shanghai, she identified the structure of the compound, which turned out to be completely different from any known anti-malarial drug. Tu then went on to develop an artemisinin derivative, dihydroartemisinin, that proved to be ten times more potent. Many scientists from other institutes across China joined efforts to improve the extraction procedure and conduct extensive clinical trials. Up to 1979, nothing from Project 523 was published because it was a secret Chinese military project. Then, in December 1979, the first English language report was published, but as was the custom in China at that time, the authors were anonymous. In October 1981, Professor Tu, invited to present her work at a meeting sponsored by the World Health Organization, faced an enthusiastic international audience. The first high profile trial of artemisinin was published in 1982 as a collaborative effort of Keith Arnold from the Roche Far East Research Foundation and Guoqiao Li from the Guangzhou College of Traditional Medicine.

As is commonly found with any new drug, the target pathogen eventually develops resistance mechanisms. To help protect artemisinin, it is now delivered as a combination therapy with a second drug. Artemisinin-based combination therapies became available in the late 1990s and are in widespread use. In 2001, the WHO signed an agreement with Novartis, the manufacturer of one of these drug combinations and Novartis is supplying the drug at no cost to public health systems where the disease is endemic.

To this day, the commercial source of artemisinin is still extracts from the sweet wormwood tree, first referred to in 340 AD and first made into a powerful, rapidly-acting, non-toxic anti-malarial drug by Professor Tu Youyou — a remarkable drug that is now saving lives throughout the world. Artemisinin was found to clear malarial parasites from our bodies faster than any other drug in the history of this disease. To quote Barry Bloom, the Chair of the Technical Expert group on Affordable Medicines of the Global Fund for AIDS, TB and Malaria, artemisinin is "the only drug ever to take moribund individuals with cerebral malaria and bring them back to life."

Professor Tu is to be celebrated for her extraordinary recognition of the potential of the Chinese herbal medicine, artemisinin for the treatment of malaria, her elegant isolation and characterization of this complex molecule, and for shepherding this drug into a highly effective treatment that is in use throughout the world.