Biotechnology Turns To Ancient Remedies In Quest For Sources Of New Therapies

Sidebar: For Further Information - Alternative Medicine With consumer interest in "natural" remedies on the rise, some academic and corporate researchers have begun to look for new drugs among ancient remedies. Several such efforts focus on the rich, detailed pharmacopoeia of Chinese herbal medicine, which has been painstakingly recorded and passed on for generations. In contemporary China-as in much of the world-herbal concoctions remain the predominant form of medication. In the hands of Western scientists, however, traditional herbs represent potential sources of single active compounds. BUDDING PROMISE: Sylvia Lee-Huang and colleagues have identified molecular mechanisms by which a protein derived from bitter melon, shown here, may act to suppress HIV infection. These projects, though still in their infancy, grew out of the pharmaceutical industry's longtime practice of seeking drug leads in plants. Some of the many plant-based medicines include digitalis, from foxglove, used to treat congestive heart failure and cardiac arrhythmias; pseudoephedrine, from the Chinese herb ma huang (Ephedra spp.), a decongestant; and anticancer drugs vinblastine and vincristine, from the myrtle, Vinca rosea. Botanical compounds also provide leads for the development of synthetic pharmaceuticals. Only a handful of biotech and pharmaceutical companies and academic researchers are pursing the development of therapeutics from Chinese herbal medicine. But some researchers in the field see great potential for its growth. "Scientists have only been able to exhaustively examine approximately one-half of 1 percent of the higher plants on this planet for their chemical compositions and pharmaceutical potential," notes Michael Balick, director of the New York Botanical Garden's Institute of Economic Botany. "Yet these species have yielded about one-quarter of all the drugs on the pharmacist's shelf." In light of that ratio, Balick says, there are great advantages to tapping the folk wisdom of peoples who have "pre-screened plants over thousands of years of experimentation and found hundreds-if not thousands-of plants with therapeutic potential." Thus, he and others argue, ancient traditions represent a shortcut to developing effective medicines. Traditional Chinese medicine represents a particularly useful source of such information, according to Balick. "The Chinese ethnopharmacopoeia has several advantages [over other native herbal traditions]. It's written down, taught in medical schools, and has been refined and developed over thousands of years. It's a living, vibrant system compared with other traditional systems around the world that are in danger of dying out." FIELD WORK: Michael Balick of the New York Botanical Garden dries plant specimens in Belize to be tested by the National Cancer Institute Other researchers, however, question the wisdom of seeking promising molecules among the plethora of chemicals that constitute a single plant, let alone a typical Chinese medicine, which may contain a dozen different herbs. Some critics argue this process is bound to be less efficient than either synthetic or combinatorial chemistry, two more widely used methods for generating pharmaceutical leads. Moreover, they say, ancient medical traditions are based on anecdotal evidence, not scientific study. Meanwhile, some researchers who believe in the therapeutic potential of traditional medicines assert that pure chemicals won't be as effective as whole herbs. They also worry that individual active compounds may produce undesirable side effects in the absence of balancing chemicals present in a traditional remedy. PATENTING PROBLEMS: Tianhan Xue cites a reason for low profitability of natural products as compared with traditional drugs. But in the United States market, nutritional supplements derived from whole herbs do not yield profits on a par with those of true drugs, according to Tianhan Xue, a consultant in pharmaceutical chemistry based in Santa Barbara, Calif. "Generally speaking, it's difficult to patent a natural product" that has been traditionally used as a therapeutic, he says, because that use is considered prior art. And if a natural product does receive a patent, it's likely to be so limited as to severely restrict potential profits, he adds. Nevertheless, a few academic researchers are exploring the use of traditional Chinese medicines-most of which consist of a complex mixture of herbs and herbal extracts-in treating disease. Similarly, some companies are developing drugs from active fractions of medicinal herbs for the more open Asian market. And as the Food and Drug Administration (FDA) gains familiarity with complex botanical medicines, the agency is likely to develop standards for the evaluation and approval of well-characterized chemical mixture as drugs, according to Freddie Ann Hoffman, deputy director of the medical staff in the agency's Office of Health Affairs. CALLING ALL POLYGLOTS: Edwin Lennox of Pharmagenesis says researchers who speak Asian languages are needed. "The climate is changing in the U.S., and there is already a greater acceptance of herbal medicines in Europe," observes Edwin Lennox, chief scientific officer at Pharmagenesis Inc. Based in Palo Alto, Calif., Pharmagenesis develops novel pharmaceuticals based on leads from Chinese traditional medicines. Among the signs of growing institutional interest in herbal medicines, Lennox cites the creation of the Office of Alternative Medicine (OAM) within the National Institutes of Health (J. McIntyre, The Scientist, Jan. 22, 1996, page 3). OAM funds research on the use of traditional Chinese herbs in treating such conditions as menopausal hot flashes and warts. In addition, the passage of the 1994 Dietary Supplement and Health Education Act, which exempts herbal "nutraceuticals" ("functional foods" with an added health benefit beyond traditional nutritional value) and vitamins from FDA's rigorous drug-approval process (K.S. Brown, The Scientist, March 4, 1996, page 1), made possible the manufacture and sale of relatively crude herbal preparations. Despite the apparent promise of natural products, including Chinese herbs, it's important to recognize that they represent only one potential source of new pharmaceutical leads. Searching for candidate compounds among natural products is an "arduous process," according to Eric Larson, group director for new lead discovery and development at Pfizer Inc. of Groton, Conn. Under an agreement with the China Academy of Traditional Medicine in Beijing, Pfizer is studying traditional Chinese herbs as potential sources of new medicines. "There are reasons to think we'll find active products [in Chinese herbs]; they should be a richer source than random botanical samples," Larson continues. But he adds that for Chinese herbs, as for any potential pharmaceuticals, "one still has to deal with issues of stability, pharmacokinetics and metabolism, toleration, and supply." Thus, "we're constantly comparing [the search for leads in Chinese herbs] with combinatorial chemistry and synthetic compound screening." SKEPTICAL FORECAST: Paul Gross of the University of Virginia believes researchers will give up on "ancient nostrums, for whose effectiveness there is at best anecdotal evidence." Some critics believe that such comparisons will ultimately lead pharmaceutical companies to abandon the search for leads among traditional remedies. Given limited human and financial resources for research, "reasonable people will ask how much time and money should be spent studying ancient nostrums, for whose effectiveness there is at best anecdotal evidence, as compared with candidates for which there is a calculable probability of success," says Paul Gross, University Professor of Life Science, emeritus, at the University of Virginia. "ARDUOUS PROCESS": Eric Larson of Pfizer notes issues of stability, pharmacokinetics, toleration, and supply. "If you ask me whether, as a society, we should devote major and precious resources to the detailed investigation of these ancient beliefs, my answer is 'no,'" Gross adds. Nevertheless, he advises would-be researchers in the area that if an employer searching for active compounds among folk remedies "will pay for honest, serious science . . . do it, by all means-as a job." Some researchers, however, believe that once the potential of traditional medicines begins to be realized, more scientists will be needed. "We've found that more than half of the plants used by native peoples that we've investigated are active in our animal models of disease," states Steven King, senior vice president for ethnobotany and conservation at South San Francisco, Calif.-based Shaman Pharmaceuticals Inc. Research at Shaman focuses on the discovery and development of pharmaceuticals based on medicinal plants used by indigenous peoples in Africa, South America, and Asia. "What we call 'ethnomedical investigation' forms the core of our strategy to jump-start the development of novel drugs," King explains. Shaman's staff includes the standard roster of drug-company scientists-medicinal chemists, biologists, physicians, and quality-control and manufacturing specialists-along with natural-products chemists and pharmacognosists (scientists who specialize in descriptive pharmacology dealing with crude drugs). In addition, the company hires ethnobotanists, plant taxonomists, and physicians who work with the indigenous peoples of South America, Africa, and Asia. In general, King adds, Shaman seeks scientists with extensive international experience and a multilingual background. "Language skills are important," agrees Lennox of Pharmagenesis. "We badly need people with both scientific knowledge and the ability to deal with people in Asia." He adds that for the moment, his company relies mainly on Chinese botanists to identify plants of interest and note their sources for the purpose of quality control. But, he predicts, "the time will come when we will want to cultivate certain plants, especially with the idea of producing high yields of certain molecules. We'll also eventually want to understand and possibly manipulate the biochemical pathways that produce active compounds." In the meantime, Pharmagenesis is focusing its efforts on developing therapeutics that augment or suppress the immune response, or that stimulate red-blood-cell production. Compounds in development include three different active fractions derived from Chinese herbs currently undergoing preclinical and clinical trials in China. The company's strategy is first to isolate such active fractions for testing and possible commercialization in China, and later to purify single molecules for clinical testing in the U.S. 'BRIDGING THE GAP': Sylvia Lee-Huang combines Western scientific training with knowledge of traditional medicine to identify antiviral properties of plants such as the Himalayan fruit tree, which yields GAP31, an antiviral and antitumor compound. Academic researchers such as Sylvia Lee-Huang, a biochemistry professor at the New York University (NYU) School of Medicine, are also attempting to isolate and characterize active molecules in Chinese herbs. Lee-Huang combines Western scientific training with a thorough knowledge of traditional medicine, imparted by her mother, a Chinese physician. By studying the mechanism of action of active ingredients derived from herbs, she says, she hopes "to bridge the gap between Western science and traditional Chinese medicine." Research in Lee-Huang's laboratory has led to the identification of several proteins with antiviral and antitumor activities in vitro (S. Lee-Huang et al., Proceedings of the National Academy of Sciences, 92:8818-22, 1995; S. Lee-Huang et al., Gene, 161:151-6, 1995). In collaboration with scientists including Hsiang-Fu Kung, chief of the Division of Basic Sciences of the National Cancer Institute and Hao-Chia Chen, chief of molecular structure and protein chemistry in the Endocrinology and Endoreproductive Branch of the National Institute of Child Health and Human Development, she subsequently cloned the genes for these proteins in order to produce large amounts of pure compound for animal studies, which are currently under way. The researchers have also identified multiple molecular mechanisms by which one of those proteins, derived from bitter melon (Monmordia charantia), may act to suppress HIV infection. Lee-Huang notes that there's been "tremendous interest from companies of all sizes in developing clinical studies of these compounds." NYU and NIH, which supported the research, jointly own these inventions. Pure, bioactive compounds isolated from Chinese herbs can feed directly into the standard drug-development pipeline and, thus, promise profits on a par with those of other medicines. So it's not surprising that most biotech companies studying these herbs are attempting to identify specific active molecules as pharmaceutical leads. But several researchers insist that by reducing Chinese medicines to single active ingredients, their overall effectiveness will be lost. "It's very easy to take a Chinese herb with multiple functions, go after a single active chemical, and forget about the total picture," observes pharmacognosist Albert Leung, president of AYSL Corp. of Glen Rock, N.J., a publishing and consulting company. He is also the original author of the Encyclopedia of Common Natural Ingredients Used in Food, Drugs and Cosmetics, now in its second edition (A.Y. Leung, S. Foster, New York, Wiley-Interscience, 1995). "The real challenge," Leung says, "is to take traditional herbs used for specific purposes and discover how they work." Internet Resources: Alternative Medicine Home Page: http://www.pitt.edu/~cbw/altm.html AYSL Corp.: http://www.ayslcorp.com Paracelsian Inc.: http://www.paracelsian.com Pfizer Inc.: http://www.pfizer.com NIH Office: Office of Alternative Medicine OAM Information Center 9000 Rockville Pike, Room 5B-38 Bethesda, Md. 20892 (301) 402-2466 Fax: (301) 402-4741 That's a difficult proposition, because "modern science can't handle multiple effects," he explains. "Well-known, useful herbs never get a complete study, because [Western scientists] behave like the blind men examining the elephant. They can only describe the trunk, the ear, the tail-they never understand the whole animal." Rather than attempt to describe every active chemical present in a Chinese herbal prescription, as well as their interactions, Leung and others advocate evaluating such complex formulas as a whole. But to make such evaluations feasible, manufacturers would need to produce complex botanical products in carefully controlled, chemically consistent batches. "We need to have standard preparations of herbal supplements," agrees Geoffrey P. Cheung, deputy director of OAM. At the moment, he adds, "we don't have that guarantee." Leung describes the situation more vividly: "It's a mess, a real Wild West. There are no regulations [governing the composition of herbal supplements]." Some unscrupulous manufacturers, he says, "are making millions selling water and hydrolyzed starch." But efforts are being made to correct this situation. A panel currently reviewing the 1994 Dietary Supplement and Health Education Act may recommend changes that would tighten regulations for the manufacture, regulation, and labeling of dietary supplements. They expect to release their report in April. The need for quality-control standards in the preparation of herbal supplements may also represent a source of future jobs. If companies hope to identify herbal preparations by some sort of chemical fingerprint, they will need scientists to establish chromatographic and spectroscopic profiles of active ingredients, according to John Babish, chief scientific officer and vice president of Paracelsian Inc. of Ithaca, N.Y. Paracelsian tests Chinese herbal extracts for signal transduction activity through the use of targeted, proprietary screening technologies. "Our objective is to produce pharmaceutically active compounds, including mixtures, and to do so reproducibly," Babish explains. "That means being able to specify their composition, potency, and the effects they produce." It's not inconceivable that well-defined mixtures could successfully navigate FDA's drug approval process, says the agency's Hoffman. In order to evaluate a compound's safety and effectiveness, she explains, "we'll need a consistent test article, but not necessarily a single chemical entity." FDA faces similar challenges in establishing evaluation criteria for complex botanical medicines as it did for genetically engineered medicines two decades ago, she observes. "Hopefully, there will be a new addressing of compounds from natural products, just as there was for recombinant products at that time," Hoffman adds. "There's a lot of potential in this area, though its development ultimately depends on whether companies are interested. From the number of phone calls I'm getting, I believe there's interest." Alison Mack is a freelance science and medical writer based in Wilmington, Del.

Biotechnology Turns To Ancient Remedies In Quest For Sources Of New Therapies

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