Industry Investors Show Increased Interest In Denizens Of The Deep

Denizens Of The Deep Author: Karen Young Kreeger Stymied by drug-resistant tumors and antibiotic-outwitting microbes, researchers are taking the plunge and sifting through the largely unexplored biodiversity offered by marine organisms. Drugs and other products from the sea have been a steadily growing research interest for the last 20 years. Recently, however, backers from business and government have stepped up their involvement, opened up their wallets, and broadened their scope in the field of marine biotechnology. FATHOMING THE POSSIBILITIES: Scientists, including Harbor Branch's Shirley Pomponi, and investors are looking to the ocean as a new source of drugs, such as the antitumor compound derived from these sea squirts. In 1992-the latest date for which figures are available-the United States government spent about $44 million in marine biotechnology research across seven areas of study: molecular genetics, biomaterials, metabolism, fouling organisms, bioprocessing, environmental science, and aquaculture (D.H. Attaway, D.J. Grimes, Journal of Marine Biotechnology, 2:105-7, 1995). Using data collected between 1991 and 1992, Raymond A. Zilinskas, an associate professor at the University of Maryland's Center for Public Issues in Biotechnology, and colleagues determined that U.S. industrial investment in marine biotechnology was about $25 million, estimating it would reach $60 million in 1994 (R.A. Zilinskas, R.A. Colwell, D.W. Lipton, R.T. Hill, The Global Challenge of Marine Biotechnology: A Status Report on the United States, Japan, Australia, and Norway, Maryland Sea Grant College Program, University of Maryland, College Park, 1995). Of the 59 companies surveyed, 50 percent of the firms concentrated in four areas: aquaculture; chemistry and natural products; microbiology; and bioremediation. "Industry is becoming more interested in the marine area than they have been," states Georgia Persinos, editor and publisher of Washington Insight, a North Bethesda, Md., newsletter for natural-products scientists. "And they're not all [small] biotech companies." For example, last August Pfizer Central Research, in Groton, Conn.-the research arm of the pharmaceutical giant Pfizer Inc.-expanded its natural products program to include collaborative research agreements with the Maryland Biotechnology Institute's Center of Marine Biotechnology (COMB) and the Marine Biological Laboratory (MBL) in Woods Hole, Mass. The company is screening marine microbes for disease-fighting and industrial enzyme potential. MIX AND MATCH: ChromaXome cofounders Michael Dickman and Kathleen Thompson seek novel compounds from thousands of marine microbe species. By collecting, growing, or synthesizing natural compounds made by an array of marine creatures-microbes, sponges, corals, and sea slugs, among others-investigators are screening compounds in hopes of adding to the medical arsenals against cancer, AIDS, inflammation, and dozens of other conditions (K.Y. Kreeger, The Scientist, Sept. 19, 1994, page 14). "Natural products make great drugs," says Michael Dickman, president of ChromaXome Corp., a private biotech firm in San Diego. "In 1994, half of the top 25 drugs on the market in terms of sales were either natural products or based on natural products, now made synthetically or semisynthetically [SCRIP World Pharmaceutical News, No. 2035, page 19, July 1995]." "Marine biotech is still a pioneering area," says Janice Thompson, a marine biologist who is now an independent adviser to several companies with interests in marine biotechnology and natural products drug discovery. "But, we've reached a point at which we can now identify some marine biotech areas that have a disproportionate advantage for business. For example, some marine enzymes can perform under extreme conditions" of temperature and pressure, such as those needed in industrial applications. Extracting enzymes useful in industrial processes is an up-and-coming area in marine biotechnology, she notes. "However," Thompson remarks, "marine biotechnologies alone are not sufficient to attract investment capital. The business plan must be sound." Jeff Margolis, president and CEO of Aurora Capital Corp., an investment banking firm in New York, notes that "the marine biotech world has been an historically underexploited area of opportunity" for a variety of reasons, especially the difficulties and cost involved in obtaining and maintaining specimens. The "buzzword" these days in drug discovery is combinatorial chemistry-the synthesis of thousands of compounds from known sources vs. screening from natural products, according to Persinos. Nonetheless, she says, "natural products will yield the most novel compounds-ones that [chemists] could never find with a combinatorial library." However, maintaining a constant supply of raw material for the lab and clinic-mostly from natural resources in developing countries-is an issue that still plagues the field. To meet this challenge, companies developing new recombinant, cell culture, fermentation, and seafarming technologies are banking on the need to bypass harvesting from nature. Because of this direction, Margolis says, "marine biotechnology will be a more appealing investment opportunity, albeit it's still relatively early. I think that many of the techniques that have been developed for other uses in the biotechnology field will be adapted quite nicely to the marine world." Only about 1 percent to 2 percent of the total federal investment in biotechnology has been devoted to the broad field of marine biotech. Still, says Shirley Pomponi, director of the division of biomedical marine research at the Harbor Branch Oceanographic Institution in Fort Pierce, Fla., "there seems to be job opportunities for natural products chemists, particularly with small biotech companies. In terms of job security, though, there is the risk that start-up companies may fail, and larger pharmaceutical companies may drop marine natural products drug-discovery efforts in favor of screening combinatorial libraries." Almost a year and a half ago, the National Cancer Institute (NCI) sponsored clinical or pre-clinical cancer trials of six substances from marine invertebrates (F. Flam, Science, 266:1324-5, 1994). This year, the tally stands at five, according to David Newman, a chemist at NCI's natural products branch. Because it was too toxic, didemnin, a substance derived from a tunicate, has "returned to Davy Jones' locker," quips Newman. Of the remainder, two have made it through later clinical-trial hoops. Bryostatin, from the bryozoan Bugula neritina, is now in Phase II trials. Phase I trials using dolasstatin, from the sea hare Dolabella auricularia, are about to begin. The other three either are on hold or their clinical-trial applications are still pending in the U.S. Cancer isn't the only target. OsteoArthritis Sciences Inc., a private biotech firm in Cambridge, Mass., has an investigational new drug (IND) application for a substance derived from the seawhip for use against dermatitis-OAS 1000, a semisynthetic pseudopterosin derivative. Thomas Sharp, the firm's executive vice president for research and development, looks forward to the commencement of clinical trials at Massachusetts General Hospital sometime this year. One small-scale product involving a seawhip extract, which is already on the market, is Est}e Lauder's Resilience. The skin cream is purported to stay the ravages of aging. And Martek Biosciences Corp. of Columbia, Md., a publicly held biotech firm with a small marine-based program, is producing docosahexaenoic acid (DHA)-an important structural fatty acid found in the human brain-as an infant formula additive. Martek ferments the marine microalgae Crypthecodinium cohnii to manufacture DHA. The World Health Organization, among other groups, has recommended that DHA be added to all infant formulas. DHA, now being used in Belgium and Holland, is expected to get approval stateside later this year. Where does the next wonder drug come from? One way is to screen collections of compounds using biological assays to come up with a "hit"-activity against a specific disease target. "We do 20 to 40 assays per year in a variety of major therapeutic areas: antibiotics, antiviral [drugs]; cardiovascular, gastrointestinal, and central nervous system targets; and inflammation and tissue repair, which includes anti-inflammatories and anti-cancer drugs," says Brad Carte, senior investigator in the department of biomolecular discovery at Philadelphia-based SmithKline Beecham Pharmaceuticals. Researchers at Harbor Branch assay and share their libraries of chemical extracts from thousands of marine organisms. In one of its long-standing collaborations, the institute provides extracts to Kenilworth, N.J.-based Schering-Plough Research Institute, the research arm of Schering-Plough Corp. Schering screens the extracts for activity and collaborates with Harbor Branch on the chemical workup. Harbor Branch's Pomponi notes that the alliance has resulted in the patenting of three potentially useful compounds from sponges. The oceanographic institution is also working in varying capacities with three small biotech firms: Mitotix Inc. in Cambridge, Mass., on a selected subset of extracts of marine invertebrates and microorganisms that have been pre-screened for specific activity by Harbor Branch; Tularik Inc. of South San Francisco, Calif., a biotech firm interested in infectious diseases and immune system disorders; and ChromaXome. Carte says that although industry is moving more toward combinatorial chemistry, "companies are still putting money into natural products. I think in the future the effort might be two-pronged. My feeling is that natural products is where they're going to get the novel leads for pharmacological substances, and those will be optimized using combinatorial chemistry." "Marine microbes is a recurring theme that you're going to hear all over the place," predicts Thompson. In fact, according to Zilinskas's report, 18.2 percent of the companies surveyed reported that bacteria was the major class of organism they studied. Fungi and microalgae constituted the main research interest for another 11.7 percent. "We've had a shift in focus towards anti-infectives," says David Manyak, president and CEO of Oceanix Biosciences Corp., a private biotech in Hanover, Md. "We have a high number of hits from extracts in this area. I think theoretically there's a very strong case for finding new antibiotics from marine microbes. In nature they presumably produce chemicals that inhibit other microbes from overgrowing them, and these might be great antibiotics." The most promising group out of Oceanix's in-house library of more than 7,500 marine microbes: actinomycetes, a family of bacteria from which 70 percent of current antibiotics originate. Pfizer's collaborative foray into the marine realm is based solely on marine microbes. At Maryland, molecular ecologist Russell Hill will look for new and unusual strains of actinomycetes. Hill's colleague Frank Robb, whose specialty is marine hyperthermophiles, will collect these organisms that live at high temperatures. And at MBL, microbiologist Norman Wainwright will collect microbes from around Cape Cod. Back at the Pfizer lab, company scientists will test extracts from these microbes against disease targets. Bioengineering firms are also joining in. Aphios Corp., a private company in Woburn, Mass., uses a low-cost, efficient extraction technique called supercritical fluid technology-utilized in other industries for decaffeinating coffee, for example-to extract active ingredients from natural substances. The company's method has been successful for refining taxol from yew tree needles. Last November Aphios won a $2 million Advanced Technology Grant from the National Institute of Standards and Technology for its fledgling marine microbe program. "Aphios will develop fermentation methods that mimic the natural saline marine environment for the large-scale manufacture of new antibiotics, antifungals, and anti-cancer drugs," remarks Aphios founder Trevor Castor. The company has signed a cooperative research agreement with Bristol-Myers Squibb Co. of New York to identify substances that will ultimately become drugs. The alliance has four other partners: Harbor Branch, which will isolate and supply the microbes; CalBioMarine Technologies Inc., in Carlsbad, Calif., which will develop culture media; One Cell Systems Inc., another Cambridge, Mass., biotech, which will perform further microbe analysis; and researchers at the Massachusetts Institute of Technology, who will scale up the fermentation process. Phytera Inc., a private biotech firm in Worcester, Mass., is applying its expertise in plant natural products to expand into the marine area. Using roboticized, high-throughput screening, the company is "focusing exclusively on marine microbes-actinomycetes, other bacteria, and fungi," according to CEO and president Malcolm Morville. Currently, to obtain a marine compound for use in research or clinical trials, investigators have to trek to the field-mostly from waters outside the U.S. However, notes Pomponi, "it's becoming more and more difficult to get permission to access another country's genetic resources. This is due primarily to the increased concern for conservation of natural resources, as well as the source country's requests for what they consider to be 'fair and equitable' sharing of financial benefits." GOING TO GREAT DEPTHS: A deep-water sea fan collected by Harbor Branch scientists. Now, relates Pomponi, institutions and investors must be "prepared to provide economic benefits, such as technology transfer and a share of the royalties," to the countries of origin. "Sharing of royalties is often difficult to negotiate at the collection stage. Representatives of the host countries often have an unrealistic expectation of the royalties that a pharmaceutical company is willing to share." Nevertheless, Pomponi notes, Harbor Branch has entered into agreements with a number of government agencies. For example, in its agreement with the Galapagos National Park Service in Ecuador, the institute provides for both technology transfer and sharing of royalties it may eventually receive from deep-water invertebrates collected there. Although she doesn't think collection issues have slowed the momentum of the field, Pomponi says some pharmaceutical companies "are not interested in screening samples collected outside the U.S. because previously negotiated agreements [with other countries] may be challenged if a compound proves to be successful and the country feels that it isn't receiving its fair share of the royalties. It is essential to have a very clear understanding of each party's expectations and needs." UNCHARTED WATERS: Maryland's Madilyn Fletcher notes that "there's so much more to be discovered" in the biodiversity of marine environments. Madilyn Fletcher, director of Maryland's Center of Marine Biotechnology, lists three budding strategies to avoid collecting material from nature: culturing organisms; using recombinant methods to clone the targeted substance into microbes; and developing marine invertebrate cultures to produce cellular factories to churn out compounds of interest. In this last category, Fletcher points to the work of Rosemary Jagus, an associate professor at the center who is refining culture techniques for sea urchin cells. CalBioMarine is aiming to circumvent the need to collect marine organisms by growing them in the ocean. The company's president, Dominick Mendola, describes this strategy as "marine pharmaceutical aquaculture-the culturing of marine organisms for pharmaceutical purposes. We're the only one in the U.S. to do this." CalBioMarine is refining the method for raising bryozoans to come up with a steady, reliable supply of bryostatin. On the other hand, ChromaXome uses recombinant surrogates to produce natural-and somewhat unnatural-compounds. "It's the same as combinatorial chemistry in that we produce a wide variety of chemical diversity," says president Dickman, "but rather than using a series of parallel reactions, we use a biological system." He refers to ChromaXome as a "combinatorial biology" company. Using marine microbial collections from Harbor Branch, ChromaXome scientists remove all of the DNA from a given species and pool it with all of the DNA from up to 1,000 other species. One pool consists of all of the proteins that the microbes would naturally make. "We transfer all of this DNA into an industrial expression system, like E. coli or yeast," explains Dickman. "If we get a hit in a screen, you almost have a production system waiting for you." The other gene pool is one purely of human design. "We take those same 1,000 species, chop up their DNA, and mix and match it to get different proteins that wouldn't normally interact together in nature, hopefully to produce something novel," reports Dickman. He says some deals with large pharmaceutical firms are in the offing, but declines to talk about them yet. "They want to access our technology and screens to build a program around our technology." Although research in marine biotech was considered "exotic" five to 10 years ago, it is "no longer a fringe area," Thompson observes. Still, researchers and biotech executives agree that the industry is still in its adolescence. "There's so much more to be discovered," maintains Fletcher.

Industry Investors Show Increased Interest In Denizens Of The Deep

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FATHOMING THE POSSIBILITIES: Scientists, including Harbor Branch's Shirley Pomponi, and investors are looking to the ocean as a new source of drugs, such as the antitumor compound derived from these sea squirts.