New Technologies And Approaches Spur Industry Interest In Plant-Derived Drugs

In Plant-Derived Drugs Author: Steven Benowitz Date: February 5, 1996 Historically, industry interest in plant-derived pharmaceuticals has waxed and waned. But greatly improved drug-screening technologies and a concern over disappearing Third World resources (and potential sources of medicines) have fueled a resurgence of drug-industry interest in natural products and plant-derived drugs in recent years. Optimistic: James Miller of the Missouri Botanical Garden sees new technology as key to industry interest in plant-based pharmaceuticals. Photo: Steven Goldblatt Yet not everyone agrees that this renewed industry enthusiasm for going out to the field to seek plant-based drugs is widespread or long-term. Rather, they contend, labor-intensive plant-collection methods are being supplanted by newer, laboratory-based chemistry techniques. In fact, one executive at a major pharmaceutical firm discourages students from pursuing careers in natural products chemistry, believing that new technologies such as combinatorial chemistry are the wave of the future. Every year, thousands of naturally derived plant products are screened for potential use as drugs by the National Cancer Institute (NCI), pharmaceutical companies, and universities. But for all the millions spent in the effort, major successes are few and far between. For every proven anticancer drug like Taxol-known generically as paclitaxel, taken from the Pacific yew tree-there are hundreds of plant compounds that show promise initially in the test tube only to disappoint later. "Drug-discovery efforts will be very expensive and have a very small chance of paying off," says James Miller, associate curator of the research division and head of applied research at the Missouri Botanical Garden (MBG) in St. Louis. Adds Gordon Cragg, chief of the National Cancer Institute's Natural Products Branch: "One of the problems with a pharmaceutical company's investment is that the chance of finding a really good drug is one in 10,000 to 30,000." Dismayed: NCI scientist Gordon Cragg is surprised that industry investment is often short-term. Photo: Bill Branson Still, many are willing to take a risk. "A growing number of researchers in industry, academe, and government are looking to areas rich in biodiversity, such as rain forests, for sources of plants, marine organisms, and microbials," says Cragg. Over the past decade, NCI, industry, and academia have continued to spend time and money searching for plant-based pharmaceuticals, each group with different motivations. "Academic scientists seek knowledge for knowledge's sake, while also looking for publications in scientific journals," Miller points out. "Industry is bottom-line-oriented-can this produce a new drug?-and cancer institute scientists see it as a combination. "Industry is sitting up and taking note of the potential of plant-derived pharmaceuticals," Miller says, with cautious optimism. He explains that plant-derived pharmaceuticals account for only a minor percentage of a pharmaceutical company's research, though a greater percentage than a decade ago. For example, Pfizer Inc. of New York has entered into a long-term relationship with scientists at the New York Botanical Garden in the Bronx to screen North American plants for potential therapeutic activity. Merck and Co. Inc. of Whitehouse Station, N.J., has a $1 million deal with Costa Rica's National Institute of Biodiversity to screen plants, insects, and microorganisms. The renewed interest in plant-based pharmaceuticals is "technology-driven," notes Miller. "There's been a recent interest in the last decade in screening [plant-derived compounds] because the technology-including improved biotechnology processes, and better automation and robotics-has arisen for companies or research groups to be able to evaluate large numbers of samples in a short time." But new technologies won't keep scientists out of the field altogether. Researchers still need large amounts of plant compounds to be able to manufacture enough of a drug. Even if chemists in the laboratory can create a new but related molecule, the original substance that has the active ingredient is still required. Miller notes that NCI, which first began screening compounds as potential drugs back in the 1960s, "used to evaluate hundreds of compounds a year; now it can do thousands. Some firms can do tens of thousands, with robotics and biotechnology capabilities to engineer screens to look at enzymes and other chemicals for their bioactivity. As the screens have become more voracious, the search for new drugs broadens." Norman Farnsworth, a pharmacognosist-a scientist who studies the use of plants as therapeutics-at the University of Illinois at Chicago, agrees. Pharmaceutical companies continue to search the rain forest's riches in greater numbers today because "the revolution in mass screening at a molecular level has improved the technology in in vitro screening [of plant compounds]," says Farnsworth, a member of an NCI-sponsored plant collection group. Another reason, he adds, is that "synthetic chemists are not producing significantly different structures as potential drugs." A lack of such structures is one reason why "the pharmaceutical industry has bought into the idea of rational drug design," Miller comments. In rational design, scientists use their knowledge about molecular structure and biological activity to engineer on the computer screen and in the laboratory new molecules and drugs with predictable actions. "It's been a marvelously productive effort, but with one problem: It all relies on having a lead compound," he explains. Miller notes that "screening plant compounds may not necessarily produce new medicines, but it may produce new lead compounds, which may result in new discoveries. A new potential anti-AIDS compound may never become a new drug itself, for example, but it may provide medicinal chemists with new chemical mechanisms to attack the virus." Mark Blumenthal, executive director of the Austin, Texas-based American Botanical Council, cites an article that Michael J. Balick of the New York Botanical Garden coauthored with Yale University economist Robert Mendelsohn (Economic Botany, 49[2]:223-8, 1995). The authors estimated that 328 additional drugs could be developed from tropical rain forest plants alone, though only 47 drugs have been found and developed so far. They extrapolated this number from the ratio of plants already studied to those known to exist. Of some 250,000 potential plant species worldwide, he says, only 5,000 to 10,000 have been described. "It doesn't take a rocket scientist to see that there's a huge potential for plant discoveries still out there," he says. According to Farnsworth, "there are 121 prescription drugs in use today, which come from only 90 plant species. About 74 percent came from following up folklore claims. There are 250,000 species of plants in the world, so a logical person would say there are many more jackpots to be found." Okay, What Now? Plant collectors from Missouri Botanical Garden look undecided about their next move while taking a break from searching for samples of plants in Madagascar. Indeed, some of the most-prescribed medicines today originated from plants. Taxol, from the Pacific yew, is frequently held up as a success story, though it took NCI and, later Bristol-Myers Squibb Co. of Princeton, N.J., 20 years to finally get the drug to the market. The rosy periwinkle, native to Madagascar, is the source for leukemia drugs vinblastine and vincristine. The foxglove yielded the anti-heart-arrhythmia agent digitalis. Even aspirin comes from meadowsweet. Miller says he's unsure whether the increased interest will translate to more jobs, given that plant-based natural products constitute a small portion of most pharmaceutical companies' drug-research programs. He notes, however, that he's seeing more students who are interested in careers in natural products chemistry and ethnobotany. But Randall Johnson, director of the department of biomolecular discovery at SmithKline Beecham Pharmaceuticals in King of Prussia, Pa., discourages students from pursuing careers in natural products chemistry. He believes that other fields of chemistry will grow faster. New Focus: Pharmaceutical company executive Randall Johnson says that industry is shifting its drug-development methods. Johnson contends that "pharmaceutical companies have been moving away from natural products with the advent of combinatorial chemistry." The latter involves reacting a known molecule with several other chemicals, resulting in a mixture of plant-based derivatives with potential bioactivity. "It's a trend-the whole industry is shifting to this from the traditional compound-development methods. That's where a lot of companies are refocusing their resources and drug-screening efforts-away from natural products screening," he explains. Many scientists concur with Johnson. For all the recent interest and activity, not everyone is convinced that the plant-based natural products industry is gaining strength. "The interest in natural products in some companies is already beginning to decline," Cragg asserts. "It's always a bit surprising because drug discovery takes a long-term investment and not just a few years. I think that over the next three or four years, without a major drug discovery, the interest will significantly wane." The plant-derived natural products industry has "gotten a lot of press because of the biodiversity issues and people's fascination with Taxol," notes Johnson. "But it's not the highest priority at any drug company I know of. Other things are considered more likely for success." According to Johnson, SmithKline in the past has had a large natural products program in which thousands of plant, marine, and microbial extracts were stockpiled. The program has shifted focus, concentrating on fermentation-based products, including antibiotics. Combinatorial chemistry "is attractive because it's a new technology that offers many possibilities," says Johnson. He notes that plant collection and extraction are expensive and labor-intensive. Researchers always have to worry about whether a plant compound is accessible and retrievable in sufficient amounts. "It allows us to make many more products-in the past the chemist would target one compound at a time, test it and see whether it's active or not, and go to the next one. The industry moved into parallel synthesis of related compounds-vast numbers of compounds at a time. "It's provided a new source of compounds for bioassays," he says. "The chemists are smart; they look to see what kinds of structures are associated with bioactivity and build molecules around those structures." While industry attention may come and go, NCI has always remained a mainstay of the plant-based natural products arena. According to David Newman, a chemist at the National Cancer Institute's Natural Products Branch in Frederick, Md., NCI was one of the pioneers in the natural products screening game. Indiana Who? Plant collectors from the Missouri Botanical Garden navigate dangerous terrain to search for plant compounds in Cameroon. "In the 1960s, the NCI had a large collection program, contracting with academic institutions to do the chemistry. By the end of the 1970s, we decided this wasn't cost-efficient. The models used were for fast-growing tumors, which select mostly for leukemias." The screening program was halted temporarily for technical reasons in the early 1980s, and resurrected using a screen of 60 cancer cell lines. "We're looking for a specific type of response or a type we haven't seen before," he explains. "It's a triage process. If they [compounds] pass, we do preliminary pharmacology and chemistry." In fact, between 1960 and 1980, only two successful drugs were produced by the program: Taxol and a chemically modified version of camptothecin. "NCI was the first group to specify that you must make certain that compensation goes back to the country of origin," he explains. NCI has certain regulations regarding such agreements. Mindful: NCI natural products chemist David Newman notes that conservation issues "affect how the industry functions." Photo: Ernie Branson Newman says that such issues affect how the industry functions. "It used to be a grind-and-find industry. If you didn't find useful material, you discarded it and went on to the next." But now, conservation, royalty, and intellectual property matters dominate discussions between U.S. companies and other nations' governments. In 1992, an international biodiversity agreement, the United Nations Framework Convention on Biodiversity, which was signed at the Earth Summit in Rio de Janeiro, helped change public perceptions about a country's ownership of its biological resources. Says Miller: "Previously, a nation's natural resources were thought of as belonging to humanity. Now they [are] viewed as sovereign possession of a country." One special NCI-funded drug-discovery program is the National Cooperative Natural Product Drug Discovery Group (NCNPDDG), an approximately $2 million-a-year project. The program seeks potential anticancer and anti-AIDS compounds from plants and marine organisms. NCI's Cragg believes that such programs will keep industry interest in searching the rain forest, since they tend not to involve extensive company commitment and financial investment. Sidney Hecht of the University of Virginia in Charlottesville is the principal investigator on one such NCNPDDG project. Hecht, who is beginning his second five-year grant, explains that his lab's work is "mechanistically based," focusing on the biochemical and molecular activity behind the agent. The agents come from his, the university's, and industrial partner SmithKline's collections. So far, he and his collaborators have found an anti-tumor agent, which is an enzyme inhibitor, and a blocker of DNA polymerase beta, a DNA repair enzyme. One of the reasons that pharmaceutical companies shy away from investing in native plant materials is the long, expensive extraction and purification process. Another issue is the lengthy and complex licensing process. MBG's Miller notes that "ethnobotanicals may be synergistic in their effects-the result of several ingredients, which the Food and Drug Administration won't license. Western medicine functions in a paradigm that there is a single active ingredient. Finding a mixture that has therapeutic value isn't of interest to firms because you can't patent it." Shaman Pharmaceuticals, a six-year-old start-up in South San Francisco, Calif., has turned heads with its unique approach. "We don't collect plants randomly for screening," says Shaman chemist Ray Cooper. "Rather, we target a disease. Right now it's diabetes. We're collecting plants used by the traditional healers. We test those plants in biological systems in our lab-we're confirming what the native healers do." He sees the company's ability to target plant-based resources and establish relationships with Third World countries as key elements of its success. He is optimistic for the plant-derived pharmaceuticals industry, pointing to another reason for a resurgence: a growing interest in so-called alternative medicine, indicated by the establishment several years ago of the National Institutes of Health's Office of Alternative Medicine (F. Hoke, The Scientist, March 7, 1994, page 1; March 21, 1994, page 1). "That's why natural products has been exciting-the possibility of discovery," he says. "It brings complexity, challenges, and opportunities to go into new areas. Such successes such as vinblastine [rosy periwinkle] and Taxol as plant-derived products with proven therapeutic activity have fueled a resurgence. You get these cycles-one success and you can make millions. That's what drives companies to invest." Untapped Resources: Mark Blumenthal sees "a huge potential for plant discoveries." Photo: Steven Goldblatt To Blumenthal, the future of the plant-based pharmaceutical business remains uncertain. "It will depend on the preservation of rapidly depleted plant habitats throughout the world," he says, in addition to properly handling matters such as compensation to the country of origin and intellectual property rights.

New Technologies And Approaches Spur Industry Interest In Plant-Derived Drugs

Interested in reading more?

Become a Member of