Botanists Ply Trade In Tropics, Seeking Plant-Based Medicinals

A renewed interest in ancient pharmaceuticals spurs debate over the extent to which natives should be compensated Lisa Conte, president of two-year-old Shaman Pharmaceuticals in San Carlos, Calif., needed a way for her company to find new therapeutic agents to compete with massive drug-screening efforts and biotechnology-based drug-discovery initiatives waged by the major pharmaceutical companies. The strategy she came up with was to look for leads from plant-based, non-Western medicines used by indigenous peoples in regions of diverse flora, like the tropics. Although all the clinical data aren't in yet, Conte's scientists succeeded in finding an antiviral agent derived from a medicinal plant used in South America that acts against respiratory viruses in vivo and in vitro. With a patent pending on the pure compound isolated from the plant, Conte hopes to start clinical trials later this summer. And Conte says she's already discussing licensing arrangements with some larger drug companies. A notable recent development on the ethnobotanical front is creation of a jointly owned company established by Syntex Pharmaceuticals International Ltd. (SPIL) and the Hong Kong Institute of Biotechnology (HKIB) last April 15. The new company, HKIB/Syntex Ltd., will build a research facility in Hong Kong to screen synthetics and natural compounds based on traditional medicines for their potential as new drugs. Two research institutes of the Chinese Academy of Sciences in the will also participate in this venture. A collaboration between the Chinese medical establishment and a Western pharmaceutical company comes as no surprise to ethnobotanists. "The Chinese have a sophisticated medical system which merges the old and the new, and the East and the West," says Douglas Daly, associate director at the Institute for Economic Botany at the New York Botanical Society in New York. "On some level, physicians there have already done some of the selective screening of compounds which can save a little time for advanced drug development." HKIB/Syntex is the first three-way research collaboration between the United States, Hong Kong, and China, according to Domini Man-Kit Lam, director of HKIB. "It is also the first time Hong Kong has participated in such a large-scale systematic pharmaceutical discovery program," he says. An announcement from Syntex Corp., the parent company of SPIL, quotes a Chinese Academy of Sciences member: "This joint research program...will use exquisitely sensitive contemporary screening techniques to systematically identify an develop active ingredients from medicinal plants and herbs that the Chinese have employed for thousands of years for the treatment of different ailments. "....Any success we encounter in this program will have a global impact and benefit people throughout the world." --R.E. "There are both opportunities and an urgency to look at plant-based pharmaceuticals now, since whole species of plants in the rain forest are being destroyed and we may not have a chance to look at them again," Conte says. She hopes that efforts, such as her company's, to find plant-based drugs will spur conservation of natural resources and create economic alternatives to the destruction of some 50 million acres--an area the size of the state of Washington--of tropical rain forest that occurs each year. The significance of Shaman's antiviral, besides its potential $1 billion worldwide market, is that the plant it comes from can be sustainably harvest-ed--there is enough of the plant growing in the tropics that it can be picked without endangering the species' viability. Shaman Pharmaceuticals is actively working with a few of the native South American populations to ensure little harm is done to the environment during collection. And the young company has other, similarly derived drugs under development. Shaman scientists are part of a growing number of researchers in industry, botanical societies, government, and academia looking to areas rich in biodiversity, such as the rain forests, as sources for potential new drugs. Owing to advances in drug-screening technologies, plants and ethnobotanicals--vegetation used in "traditional," or non-Western, native medicinal systems--can be cost-effectively screened for the potential medicine chest that they can fill. But, more important, these scientists feel an urgency to do this research today because they fear that if they don't begin to conserve the environment soon, natural resources and indigenous populations who have knowledge about the medicinal use of their local plants will be destroyed. According to a New Haven, Conn.-based, market research firm, Technology Management Group, about 75 companies and 112 research institutions worldwide are developing drugs based on traditional medicines for a variety of disorders, including allergies, AIDS, diabetes, and stomach ulcers. Chinese, Japanese, Indian, Philippine, African, Latin American, and Indonesian native medicinal systems are among those under serious investigation. More than 200 companies and almost as many research institutions worldwide are looking for plants as sources of pharmaceuticals. The surge of interest in this research, though, raises ethical, legal, and scientific questions for the botanists and drug companies that perhaps were not addressed before synthetics replaced botanicals as the source for drugs in the 1930s. These include, in addition to figuring out how to harvest the plants from which the drugs are derived in an environmentally sound way, the question of how to develop mutual economically and scientifically beneficial relationships with the governments and the natives of Third World countries where the plants are grown. Private and public symposia, sponsored by the Rainforest Alliance, a New York environmental group, are being held throughout this year to generate discussion on these issues to avert problems that could arise during this plant prospecting process. Experts in the field, including the scientists Conte collected for her board of directors and for her scientific advisers, think plans to excavate new drugs from traditional medical systems and from plants will be successful despite the challenges. Norman Farnsworth, director of the program for collaborative research in the pharmaceutical sciences division at the University of Illinois in Chicago, who isn't associated with Shaman, says: "There are 121 prescription drugs in use today in many different countries in the world that come from only 90 species of plants. Of those 121, 74 percent came from following up native folklore claims. There are 250,000 species of plants on the planet. A logical person would have to say there are lot more jackpots out there." But, to date, fewer than 1 percent of all the endangered plants and trees in the rain forest have been tested. "If the same amount of money was put into the R&D of new drugs from plants, marine organisms, or traditional medicines, you would get the same payoff as if you invested in synthetics or molecular modeling," says Farnsworth. While Shaman Pharmaceuticals concentrates on ethnopharmaceuticals--drugs based on traditional medicine systems--some of major pharmaceutical houses, like Merck, Sharp & Dohme Research Laboratories of Rahway, N.J.; SmithKline Beecham of Philadelphia; Glaxo Inc. of Research Triangle Park, N.C.; and Syntex Corp. of Palo Alto, Calif. (see story, page 25) are increasing their screening of plants in general, as well as ethnobotanicals, to discover the elixirs for the next century. Evidence that such an approach to drug discovery is undergoing a renaissance can be seen by new collaborations among industry, gov- ernment, botanical societies, environmentalists, and academia. Farnsworth and his group, for example, have recently been awarded a National Cancer Institute (NCI) grant that creates a consortium among industry, academia, and government to find new drugs for cancer. This group will use the traditional medicine approach as their guide. Improved Drug Screens In addition to the concern of pharmaceutical companies and scientists about the diminishing environment, technological advances have been a significant driving force in this rebirth of interest in plants and ethnobotanicals for medicine. Today there are more and better drug screening assays for different disease states, such as cancer, diabetes, and arthritis, which cover many different human systems, including the cardiovascular, muscular, and nervous systems. "In the past you only had costly, in vivo screens. Using biotechnology, people now have isolated receptors and enzymes involved in pathology," says Matthew Suffness, program coordinator for natural products at NCI. "Robotics allows you to screen in vitro tens of thousands of samples in the time it took you to do 20 or 50 10 years ago. "In the pharmaceutical industry, until recently, what was rate-limiting was the assay capacity. Now what's rate-limiting is having things to screen. "Ten years ago we would finish with our samples for cancer drugs and I couldn't give them away to anyone in the industry. It was too expensive to screen the goos and gunks. Now the companies are calling me and are working with the people who collect the plants [and other natural products, like marine specimens, and] are hot to trot because their screens can absorb them all." One of the born-again pioneers in screening extracts of natural products for drugs against AIDS and cancer is NCI. Though the institute had been active in screening natural products since the 1950s, the program was cut in 1981. But in September 1988 it was funded again. "We've been getting plants from tropical areas through contracts with the Missouri Botanical Garden that collects for us in Africa, with the New York Botanical Garden for Central and South America areas, and with the University of Illinois in Chicago for South East Asia," says Gordon Cragg, chief of NCI's natural products branch. NCI asks these groups to collect many different species of plants for their screening system but doesn't necessarily emphasize plants only used in traditional medicines. "We don't give priority to traditional medicine because in these systems, cancer may not be all that well defined," Cragg says. But he does see the validity of the approach. "The bark from which taxol [a drug being investigated against cancer, purified from the rare yew tree located in the Pacific Northwest] was [isolated] was only later found to have been used by the native Indians." NCI screening stopped in the early 1980s, says Cragg, because its methodology was faulty. At the time it had only a mouse leukemia cell line in which to test an extract's growth-inhibition capabilities, since cancer is a proliferative disease. Now it has 60 cancer cell lines and some T cell lines infected with HIV, the human immunodeficiency virus. While lung, colon, central nervous system, ovarian, skin, and many other cancers are represented in the NCI screen, the institute is still trying to develop breast and prostate cancer cell lines. "We look for selective killing of different cell lines in our cancer screen," says Cragg. "If an agent kills many of the cultures, most likely we just have a very toxic substance." Since the HIV infected cell lines normally die, NCI scientists test for growth promotion in the presence of a plant extract in the AIDS drug screen. Because of the biotechnology boom of the 1980s and waning interest in ethnobotany in government, academia, and industry, there is currently a shortage of professors at universities with expertise in this area. "Academia hired the molecular biologists that could bring in the multimillion-dollar grants, who essentially pushed out those who collected and described plants," says Mike Balick, director of the Institute for Economic Botany at the New York Botanical Gardens (NYBG) in New York. "So today, universities have little capability to teach and do research in the field. We have to rebuild our field from the ground up because students want this profession to be taught on campus." Recently, though, some schools, such as Tulane University in New Orleans and Connecticut College in New London, have begun to rehire ethnobotanists to do research and to teach. But, says Balick, "ethnobotany is a different field than it once was. It is now an intensive, interdisciplinary study of the relationship between plants and people. We work with nutritionists, anthropologists, food scientists, economists, lawyers, and we look at questions from many perspectives. You get a rather interesting answer when you look at issues from five or six different points of view." Thorny Issues This complex field of medicinal plants and ethnobotany, however, poses legal and ethical issues, such as compensation to native populations for their work in plant identification and collection. "We in the botanical community are at the forefront of trying to build relationships and strike compensation arrangements with governments and individuals from any potential benefit that can be found from these plants," says NYBG's Balick, who has lived in 20 countries in the last 10 years as part of his ethnobotanical field work. One issue facing ethnobotanists is what kind of drugs should be developed. "Tropical countries suffer from a different complement of diseases than the developed world," says Douglas Daly, assistant curator at the Institute of Economic Botany. "Should we focus on disease of relevance to them? And what if we share a disease; should we develop a drug and then send it back to the country in a nice package that they can't afford?" To address these issues of compensation and disease relevance, Balick and NCI are giving any data compiled from the plant screening back to the indigenous populations or their representatives. They also established a royalty mechanism so that if any drug is developed from a plant 10 years from now, either a research institution or a governmental agent will get a percentage of the profit from it. "We hope that by giving them the data, we encourage them to conserve and maybe develop industries themselves around the harvest or cultivation of these plants," Balick says. NCI will also pay to train foreign scientists in U.S. laboratories and for equipment to help set up foreign research facilities. Shaman Pharmaceuticals set up a nonprofit research organization, called the Healing Forest Conservancy (HFC), to work with local peoples, and their support organizations. The conservancy hopes to stimulate local academic, industry, and government support to maintain medicinal plant biodiversity in various regions in the world. A portion of the profits generated by the commercialization of plant-derived compounds will be distributed to the appropriate people or organizations that participate in plant collection, to enable them to engage in sustainable harvesting or management of natural resources. "This is extremely important. None of the other drug companies have this kind of model," says Balick. While drug companies are interested in the benefits from plant-based pharmaceuticals, they are still not doing their share in promoting conservation in these areas, say many ethnobotanists. "They think that they will be able to synthesize the active component of a plant-derived drug once it has been isolated, and they are not interested in developing sustainable industries," says Shaman's Conte. "But they won't be able to get away with that anymore. They are under increasing pressure from environmental groups forcing them to do something for these tropical countries." Sustainable harvesting of a plant with medicinal properties is a critical issue for the success of ethnobotanical ventures. The problem of not having enough natural resources for drug development has recently become apparent with taxol, a drug being investigated by four pharmaceutical companies for the treatment of cancer. It takes six 100-year-old Pacific yews to extract sufficient taxol to treat one patient. Environmental activists are concerned about the impact of this kind of destruction of the trees. To prevent such a shortage from happening with other plant-based drugs, research on sustainable harvesting has to be done. A new three-year, $15,000 fellowship offered by the Periwinkle Project, which is part of the Rainforest Alliance, supports research leading to sustainable cultivation, harvesting, or processing of medicinal plants as an economic alternative to rain forest destruction. "Part of the impetus behind this fellowship was to bring attention to the fact that this kind of research is not being done," says Sarah Laird, director of the Periwinkle Project. The periwinkle is a plant known in Cuba, the Philippines, and South Africa for its ability to treat inflammation, rheumatism, and diabetes. In the late 1950s, the drugs vinblastine and vincristine were isolated from the periwinkle by scientists at Eli Lilly & Co. in Indianapolis. The two drugs are now widely used as cancer chemotherapy agents. As a way to gain the attention of scientists, doctors, and health care professionals about this dynamic field, the Rainforest Alliance and the Institute of Economic Botany will be holding a two-day symposium at Rockefeller University in New York September 27-28. As it stands now, the first day's sessions will deal with the "success stories" of plant-derived drug development, its role in future human health, and the importance of biodiversity in maintaining that effort. The second day will address conservation and economics of medicinal plant research in the tropics as well some of the legal agreements that could benefit local peoples. The organizers hope that the conference will inspire biologists to get more involved in the field in some capacity. "To be a biologist these days requires a certain amount of social responsibility," says Daly. "In the work that I do with ethnobotany, I am trying to strike a balance between science and activism."

Botanists Ply Trade In Tropics, Seeking Plant-Based Medicinals

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