The Role of Traditional Medicine in Drug Discovery
Eric Chivian, MD, is the founder and Director of the Center for Health and the Global Environment at Harvard Medical School. In 1980, he co-founded, with three other Harvard faculty members, International Physicians for the Prevention of Nuclear War, which won the 1985 Nobel Peace Prize. Aaron Bernstein, MD has been affiliated with the Center for Health and the Global Environment since 2001 and is currently a resident in the Boston Combined Residency in Pediatrics. Together they wrote Sustaining Life: How Human Health Depends on Biodiversity which presents a comprehensive review of how human medicines, biomedical research, the emergence and spread of infectious diseases, and the production of food all depend on biodiversity. In the excerpt below the authors look at how traditional medicine has led to some of our most important modern drugs.
Ethnobotany, that is, the scientific study of the use of plants by native cultures, including their use as medicines, can be said to have begun with Carl Linnaeus, who in the 1730s published Flora Lapponica, his detailed account of plant use by the Lappish, or Sami, people, living north of the Arctic Circle. These observations, like many made since then that draw on knowledge of the natural world gathered over many generations by indigenous peoples, have contributed significantly to the practice of medicine today.
The history of two modern pharmaceuticals—quinine and artemisinin serve to illustrate our enormous debt to traditional medical healers.
The isolation of the antimalarial drug quinine from the bark of cinchona trees (e.g., Cinchona officialinis) was accomplished by the French chemists Pierre- Joseph Pelletier and Joseph-Bienaimé Caventou in 1820. The bark had long been used by indigenous peoples in the Amazon region for the treatment of fevers. Spanish Jesuit missionaries, after the conquest of the Inca Empire in Peru in the late sixteenth and early seventeenth century, learned of this use from the natives and found that the bark was effective in preventing and treating malaria. They brought this knowledge, along with the bark, back to Europe, where it became widely used and was often referred to as “Peruvian bark.” With quinine as the model, chemists subsequently synthesized the antimalarial drugs chloroquine and mefloquine, and they have continued to modify the basic structure of quinine to produce even more effective agents, such as the new antimalarial bulaquine.
The Sweet Wormwood plant (Artemesia annua) was also used as a treatment for fevers in China for more than 2,000 years (it is called qing hao in Chinese), but it was not until 1972 that the active compound artemisinin (qing hao su, which means the active principle of qing hao) was extracted and later identified as a potent antimalarial drug by Chinese scientists. This effort was part of a systematic examination at that time of indigenous plants in China as sources of new medicines. More soluble derivatives, artemether, artether, and artemotil, have been developed in recent years. These medicines, in combination with other antimalarials such as mefloquine, have proved highly effective in treating malaria, particularly the most deadly form caused by Plasmodium falciparum (see chapter 7 for a further discussion of malaria), which has become increasingly resistant to the first-line treatments chloroquine and sulfadoxine-pyrimethamine—in Asia, South and Central America, and Africa. Given that malaria, despite intensive efforts by the world community, continues to kill between one and three million people each year, approximately three-fourths of whom are African children, and to cripple economies around the world, the importance of artemisinin and other effective antimalarials cannot be overstated.
Another possible use of artemisinin is in the treatment of cancer. Its antimalarial activity is thought to be due to its interaction with iron, present in very high concentrations in the malarial parasite. Since some cancer cells, particularly leukemia cells, also have high iron concentrations, they may also be killed by artemisinin, as has been demonstrated in some initial studies with cancer cells in tissue culture. The potential of artemisinin and its derivatives as cancer chemotherapeutic agents is being actively investigated in a variety of anticancer screens.
The combination of a high demand for artemisinin-based antimalarials and limited commercial-scale production of Artemesia annua (in only a few locales in China and Vietnam) has left artemisinin-based therapies in short supply. The World Health Organization has stepped in to develop a plan to bolster production.
One possible solution to the supply problem may come from biotechnology. Scientists in California have recently produced the base structure of the chemical artemisinin in the bacterium Escherichia coli, and in yeast (Saccharomyces cerevisiae), by transferring the necessary genes from Artemisia annua into these microbes. For E. coli or yeast to become a viable source for artemisinin, the base structure would need to be modified, and the entire process would have to be scaled up to achieve commercial production levels.
Traditional medicine, as practiced by indigenous people today, relies on its own version of “clinical trials,” where natural products continue to be used only if they have been shown to be effective. These trials may take place over very long periods of time, sometimes over hundreds of years by generations of healers, and they lead to a vast and detailed knowledge of the medicinal properties of many natural substances. That is why many believe there is such enormous potential for finding new medicines among those used by traditional healers.
But there are also problems in using these leads for drug discovery. For one, there is the problem of diagnosis. In the absence of diagnostic tools such as blood tests, X-rays, MRIs, and invasive techniques such as surgery, traditional healers must rely largely on a patient’s history, on the physical exam, and on the external manifestations of disease, all of which can be unreliable. Superstition may also prevent accurate diagnosis and, along with the placebo effect, cloud objective evaluation of the success of treatment. Furthermore, some diseases, for example, those involving the elderly, such as Alzheimer’s and most cancers, may be rare in some indigenous populations where life expectancy is short. Finally, knowledge may or may not have been faithfully transcribed from one generation to the next. Traditional medical practices in several parts of Asia, including China, Japan, Korea, and India, have been recorded in great detail over the centuries in written texts, in contrast to those in some other parts of the world, such as among South American Indians, where the passage of knowledge has been primarily by oral means. While these oral traditions may reflect very careful trials and observations, they are prone to errors as a result of unreliable transmission and anecdotal reports.
Nevertheless, indigenous healers have been critically important in the discovery of many new drugs. One study demonstrated that of 119 drugs (derived from some ninety plant species) currently in use in one or more countries, almost three-quarters were discovered by extracting the active chemicals from plants used in traditional medicines.
Tragically, traditional healers now face a double threat—both from the loss of biodiversity that depletes the natural sources that make up their pharmacopoeia, and from encroachment by the outside world that may wipe out their cultures. In the first three-quarters of the twentieth century, more than ninety tribes have become “extinct” in Brazil alone. Scientists are racing to record the secrets these native healers hold before they and the plants and other species they use are gone.