Researchers Plumb Depths To Fight A Wide Array Of Human Diseases

As his boat rocks gently on the Caribbean Sea a few miles off the coast of Jamaica, William Fenical dons his scuba gear, slips overboard, and disappears into the warm waters. Although deep-sea diving is a pleasure for Fenical, taking the plunge, in this case, is by no means a recreational pursuit. Meeting Grounds For Marine Biotechnologists For more information on marine natural products and pharmaceuticals, contact: American Society for Microbiology 1325 Massachusetts Ave., N.W. Washington, D.C. 20005-4171 Phone: (202) 737-3600 Fax: (202) 942-9340 (For the appropriate E-mail address, call the above number.) Michael Goldberg, Executive Director David Schlessinger, president American Society for Molecular Marine Biology and Biotechnology P.O. Box 51456 Pacific Grove, Calif. 93950 Phone: (408) 655-6214 Fax: (408) 373-1254 E-mail: fh.dap@forsythe.stanford.edu Dennis A. Powers, president A three-year-old journal, Molecular Marine Biology and Biotechnology (Blackwell Scientific Publications Inc., Boston), associated with ASMMBB, is the only United States journal that covers basic and applied marine biotech. Contact Powers for more information on the journal. American Society of Pharmacognosy Department of Pharmacognosy School of Pharmacy University of Mississippi University, Miss. 38677 Phone and fax: (601) 232-7026 E-mail: pgclark@vm.cc.olemiss.edu Alice Clark, president Fenical is a marine chemist at the Scripps Institution of Oceanography in San Diego, and the object of this dive is to gather samples from the feathery seaplume, a type of coral. Back in his lab at Scripps, Fenical and colleagues will extract a substance called pseudopterosin from the soft- bodied creature. Working with clinicians, physicians, and other biomedical researchers, Fenical's industry collaborators will soon be conducting clinical trials using the compound to find new and better ways to combat inflammatory diseases. Throughout the world, marine scientists and their partners in industry, academia, and government are now searching for more effective drugs to treat a variety of diseases, including AIDS, cancer, and asthma. These international research collaborations draw on expertise from numerous disciplines: Ecologists, biochemists, oncologists, cell biologists, microbiologists, molecular biologists, pharmacologists, and clinicians are just some of the researchers involved in these efforts. "Our program represents marine science--the discovery side," says Fenical of his part in a multidisciplinary research team at Scripps, which is run by the University of California, San Diego. "We're the ones that get into the water and get the materials and have a big freezer back at the lab to store the stuff. We extract, isolate, and identify the material. And once we do that, we collaborate." Compounds have been extracted from marine plants and animals for centuries--Pliny the Elder described the toxic properties of sea hares in the genus Dolabella more than 2,000 years ago. Modern interest in drugs from the sea resurfaced about four decades ago. But the current wave of activity has welled up in the last five to 10 years, researchers agree. "The majority of drugs are discovered in nature, certainly historically. Drugs from natural sources have been the foundation of the treatment of human disease," says Fenical. But "why do we need to discover new drugs from the sea?" he asks. Because, say Fenical and others, some organisms that cause disease have evolved resistance to currently used drugs, and medical science has conquered only a small portion of human disorders. So what does the sea have to offer biomedicine that researchers can't get on the land or in a test tube? Fenical explains: "Marine animals have evolved two basic mechanisms to survive: physical defenses, such as spines and shells; and chemical defenses, which you find in soft-bodied animals that swim around in the ocean and are completely left alone." "These animals are noxious as hell. So we go to these highly chemically defended invertebrates, and for one reason--we know they're rich in unusual organic compounds." Fenical notes, however, that when his group began its investigations they foresaw no direct connection between defense and anti- disease activity. That they have found this relationship in some sea creatures was "just serendipity," adds Fenical. According to David Newman, a chemist at the Natural Products Branch of the Division of Cancer Treatment at the National Cancer Institute (NCI), such connections are just what NCI scientists are counting on to find treatments for several types of cancer as well as AIDS. One of NCI's first contracts associated with marine organisms was initiated in 1985 with the Australian Institute of Marine Sciences to collect plants and animals on the Great Barrier Reef. Two compounds derived from marine animals are currently in Phase I and II trials as anti-tumor agents, and others are "in the pipeline," says Newman. The potential for finding new, efficacious drugs from the sea is only one part of the overall surge in the larger field of marine biotechnology in the last decade. According to Oskar Zaborsky, president of the Institute for BioEnviron- mental Information and Studies (IBIS), a nonprofit organization located in McLean, Va., there are three very active areas in this growing discipline (see story on page 15). "One is the drug area--that sort of can't be denied--the second is specialty enzymes from marine microbes [M.E. Watanabe, The Scientist, May 30, 1994, page 14]. And the third one is aquaculture." The Many Faces of Marine Biotech Marine biotechnology covers a broad range of topics. According to a new book on the subject, entitled Marine Biotechnology, Volume I: Pharmaceutical and Bioactive Natural Products (D.H. Attaway, O.R. Zaborsky, eds., New York, Plenum Press, 1993), the discipline is defined simply as "the use of marine organisms or their constituents for useful purposes in a controlled fashion." Don Renn, director of exploratory technology at FMC Corp. in Rockland, Maine--a company that has been producing products from seaweeds for the biomedical research and development market for almost three decades--makes two main distinctions beyond the book's definition. He explains that marine biotech can mean either manipulating plants and animals genetically to obtain useful products from them such as in some aquaculture ventures; or using products derived from marine organisms for high-tech purposes such as gels for molecular biological techniques or in pharmaceuticals. Some institutions even divide their departments along the disciplines that encompass marine biotech. According to Madilyn Fletcher, director of the Center of Marine Biotechnology at the University of Maryland Biotechnology Institute in Baltimore, three areas of research cover the center's activities: aquaculture and fisheries molecular biology and biotechnology; natural products and processes; and marine pollution and bioremediation. The natural products component includes marine pharmaceuticals, she says. --K.Y.K. Interest in marine biotech is "exploding,' says Rita Colwell, a marine microbiologist and president of the Baltimore-based University of Maryland Biotechnology Institute. "I wrote an article published in Science in 1983 [R.R. Colwell, "Biotechnology in the marine sciences," 222:19-24], and since then more than 1,000 papers have been published on marine natural products and various aspects of marine biotechnology. Also since then, funding in the United States has grown to about $80 million, if you take into account both federal and private industry." Total federal funding for marine biotechnology for fiscal year 1993 was nearly $50 million. The Marine Biotechnology Investment Act, which was passed in the House of Representatives, is also expected to pass the Senate at the close of the current session, according to David Attaway, director of the marine biotechnology program for the National Sea Grant College Program in the National Oceanographic and Atmospheric Administration. The act authorizes $20 million for each of its first two fiscal years and $25 million for each of two subsequent fiscal years to fund research in marine biotechnology. "Of course," says Attaway, "it's not often that authorized amounts reach appropriated amounts. This authorization sets the limit; the appropriation sets the amount." Congress has already increased the budget for the Sea Grant Program for fiscal year 1994 by $3.2 million, according to Attaway. This amount was earmarked for marine biotechnology research. NOAAUs Sea Grant conducted a special call for proposals to utilize these funds, receiving 256 grant applications requesting a total of $25 million for the first year of research. Attaway says that although the proposals were top-notch, Sea Grant could fund only 20 of them. One way to find new drugs from any natural source is to gather samples and test them broadly on cultures of cells. Investigators from all over the world collect samples from marine systems--as well as rainforests, deserts, and just about every other ecosystem on Earth--and send them to NCI's Natural Products Repository in Frederick, Md., which houses more than 500,000 samples of plants, marine life, and microorganisms. Here they are stored, extracted, and screened for activity against a variety of tumor-forming cancers--such as breast, colon, and prostate cancer--for which there are no effective drugs. Preliminary testing against HIV using extracts from seaweeds is also under way. Kenneth Rinehart, a chemist at the University of Illinois in Urbana, is working with NCI on two compounds that may prove useful for a number of cancers. Didemnin B, a substance extracted from a marine animal called a tunicate and found in the western Caribbean Sea, is currently in Phase II clinical trials for non-Hodgkin's lymphoma and a type of central nervous system tumor. However, this extract--which is the marine compound at the most advanced stage of development for use as an anti-cancer agent--has remained in Phase II for five years because of debilitating side effects. "I'm on the edge," says Rinehart about the results so far in the didemnin B trials, "because patients' responses to it varied from complete to partial, with only about 20 percent of them showing this response. But people at the NCI were very pleased with that. "But, I'm not convinced that didemnin B is the best didemnin to be using. There is a new one called dehydro-didemnin with six times the potency as didemnin B," he says. This new tunicate compound is owned by a Spanish pharmaceutical company called Pharmarmor. ET 743--another compound derived from Caribbean tunicates-- is currently in preclinical trials and is "scheduled for Phase I trials after the first of the year," says Rinehart. Thus far, ET 743 has not "encountered any serious toxicology problems and its activity in vivo looks very good against leukemia, melanoma, ovarian sarcoma, and breast and lung cancers." Given these and other drugs that are in various stages of testing, Rinehart says he "is very hopeful" that several new compounds will be on the market in the coming years. Also taking a "shotgun approach" to testing marine compounds for new drugs is David Manyak, president and chief executive officer of Oceanix Biosciences Corp. in Hanover, Md., a biotechnology firm with about 30 employees. Manyak says his company obtained Novascreen--a receptor- binding assay--from Baltimore-based Nova Pharmaceutical Corp. more than a year ago to simultaneously screen dozens of substances derived from marine organisms. "We're most interested in screening for compounds to treat central nervous system disorders such as epilepsy, Parkinson's disease, and Huntington's disease," says Manyak. He says Oceanix is also interested in screening for anti- infective agents. To do this, the company has a research agreement with the University of Maryland Center of Marine Biotechnology (COMB). "We have an exclusive license to screen a collection of marine microbes from COMB. So we are building up copies of those microbes internally and that library numbers 5,000," says Manyak. "We are screening 40 to 60 receptors at once, so we think we'll have a very high probability of finding new drugs in a number of categories just because of the breadth of our library of microbes and screening activities." Rather than screen several types of marine organisms for potential antidisease activity, Fenical is concentrating his efforts on one type of organism, which he hopes can be used for a variety of applications. His group's main interest is identifying anti-inflammatory agents to treat such diseases as arthritis, asthma, and psoriasis. "When we became committed to investigating inflammatory diseases, we realized that we had focused our efforts very narrowly," Fenical says. "But that turned out to be a wise decision because we were able to bring together sufficient expertise to construct a well-informed research program. "Our goal is to create new drugs which are far superior than existing drugs. We obviously don't wish to reinvent the wheel." The substance at the most advanced stage of development in the labs of Fenical and colleagues is pseudopterosin, a chemical extracted from the seaplume, which he calls a "very potent anti-inflammatory." Pseudopterosin "will be in clinical trials within the next few months," he says. Fenical and his academic colleagues are working with Thomas Sharp, executive vice president and director of research and development at OsteoArthritis Sciences Inc., a two-year-old biotechnology firm with about 35 employees located in Cambridge, Mass. Sharp reports that pseudopterosin will soon be tested as a topical anti-inflammatory for dermatitis. "We expect to submit an investigational new drug application [to the Food and Drug Administration] at year end," he says. "The exciting thing about this project is that this drug has a novel structure and is unrelated to currently available drugs to treat dermatitis," Sharp says. "We believe it will have fewer side effects than currently available drugs." The collaboration between biomedicine and marine sciences does not end at the lab or hospital doorstep. IBIS's Zaborsky says that scientists searching for new remedies to fight human disease are taking a growing interest in the burgeoning field of marine biodiversity and its preservation. The reason for this meeting of seemingly divergent disciplines, he says, is "partly the need for new drugs and, for myself and others, the shared conviction that there is a logical connection between biodiversity and biotechnology, which can be positively reinforced. "If people have drug-development programs, they can couple these with biodiversity programs, so what is found in nature can be preserved. What we [IBIS] try to do is look at that in combination with the National Cancer Institute and the National Institute of Allergy and Infectious Diseases." For example, Zaborsky recently submitted a proposal--with NCI--entitled RInternational Cooperation in Marine Biotechnology for Pharmaceutical Development and Preservation of Marine Biodiversity" to the State Department. The proposal requests funds to set up an international framework to link academic, industry, and government research in these areas.

Researchers Plumb Depths To Fight A Wide Array Of Human Diseases

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