Reaping Pharmacological Benefits from the Oceans

Second of two articles Editor's Note: In the Sept. 27 issue of The Scientist, the author discussed some of the possibilities scientists have for generating medicinal products from organisms that live in the oceans.1 In this issue is a discussion of some of the problems and complexities involved in pursuing such possibilities. Despite the allure and promise the oceans hold for providing new medicines, virtually every aspect of pharmacological research from oceanic sources is more difficult and intrinsically slower than land-based research. And the obstacles are not likely to change anytime soon. "There are a lot of concerns about what I call Rio Convention issues; that is, if you discover something in another country's waters, will you ever be able to develop it?" explains John Faulkner, a marine chemist at Scripps Institution of Oceanography. "Some countries nowadays are controlling all research in their waters, meaning, basically, we can't go there anymore. We've just given up on the Philippines," he elaborates, noting that he plans now to restudy organisms off the California coast. "Then, the real problem with every natural product is getting enough of it to do, first, a clinical trial, and then [to produce it commercially if the trials are successful]." Expense, the difficulty of collection, and supply and demand remain major issues. As Ken Rinehart, professor of organic chemistry at the University of Illinois, Urbana, points out: "The yield for [Ecteinascidin] ET743 is one gram per ton of tunicate. Now that will treat hundreds of people,2 because it's so potent; still, we can't just go pulling out tons of tunicate and expect to get the compound that way." Photo: Todd Barsby A typical collecting site for specimens in British Columbia Adds Shirley A. Pomponi, director of biomedical research at Harbor Branch Oceanographic Institution: "We've been trying to get back to the Gulf of Mexico for three years ... to re-collect a sponge from which we have isolated a compound called lasonolide that has some unique antitumor properties. The compound is present in low amounts in the sponge, and we didn't have enough material to conduct any further in vitro or in vivo trials." Finally, in August, the opportunity came--at a cost of $14,500 a day for the ship and submersible alone--and Pomponi and colleagues found a habitat that allowed them to collect enough of the sponge to continue their work. "Now we have enough material to do those assays, as well as look at microbiology to determine if there's a microorganism responsible for production of the compound, and also look at some molecular biology and cell culture," she offers. Faulkner sums it up this way: "Marine organisms should probably be used as inspiration [for] and not as the source of the chemicals, just because of the economics of getting things out of the ocean." One proposed solution for acquiring needed supplies is aquaculture. CalBioMarine Technologies, a southern-California-based biotech firm, has shown that the aquacultural production of bryostatin (which the National Cancer Institute is investigating for treatment of melanoma, non-Hodgkin's lymphoma, and renal cancer) is feasible. "Where you have a molecular architecture that's never going to be amenable to synthesis of a whole natural product or synthesis of an analogue that's simpler, then aquaculture in certain instances is an exciting and viable alternative," maintains Raymond J. Andersen, professor of chemistry and oceanography, University of British Columbia. "And as more compounds move through the system and there's a real need for production of them in large scale, there will be more emphasis and efforts to bring these aquaculture methods along and we'll see interesting developments." Still, aquaculture cannot solve all the supply and demand problems, and the general consensus is that techniques must be developed in the lab. In July 1998, at the 9th International Symposium on Marine Natural Products in Townsville, Australia, Amy Wright of Harbor Branch reported findings that she, Robert Jacobs of the University of California at Santa Barbara, and other scientists at Harbor Branch had made. A series of topsentins from deep-water sponges of the genera Spongosorites, Hamacantha, and Dragmacidon are potent mediators of both immunologenic and neurogenic inflammation. The team has succeeded in preparing relatively simple synthetic bis-indole derivatives of the potent anti-inflammatory compounds, which may allow researchers to circumvent the difficulties and expense of collecting the deep-water sponges. (Previously, the topsentins had been shown to exhibit antiviral and antitumor response.3) Preparations are now under way at Harbor Branch to license the topsentins as candidates for drug development. The vast majority of compounds from the sea, however, are not easily synthesized--ET743, for example, takes 45 steps, and others take 100 steps or more, compared to an average of 10 to 15 steps for medicinal compounds. And many of the marine bacteria are not culturable. These realities have marine researchers now looking to biotechnology's symbiosis and gene transfer. "If you could transfer biosynthetic genes into easily culturable organisms, that will solve many of the problems we're seeing," says Faulkner. Another approach researchers have begun to consider is using a number of these marine-derived agents as warheads on monoclonal antibodies, points out David Newman, project officer for marine collections at the National Cancer Institute's natural products branch. In this case, the carrier acts as a targeting molecule--"a smart bomb, or a smart carrier with a dumb bomb"--and the warhead is a modified natural product. "Frequently when you chemically modify one of these agents, it will lose potency, but if you can deliver a less potent molecule with a very high degree of fidelity and reasonable chance of getting at the tumor, rather than here in the body, you can live with a less potent agent. ... Instead of a toxin, we're using natural products that are very, very potent," he explains. If successful, this approach could offer "a lease on life for other materials, which we have rejected," Newman adds. At the same time, researchers are still trying to figure out exactly where these unique and potent molecules are coming from. For a lot of these marine invertebrates, a growing body of evidence indicates that the host itself isn't the real chemist synthesizing the molecules; rather, it appears microbes are responsible. Various compounds from marine invertebrates have been found to be structurally related or even identical to microbial compounds. Meanwhile, Faulkner, in unpublished observations, and researchers at the University of Guam have found that the active peptides Dolastatin 3 and Dolastatin 12, which were obtained in low yield from the sea hare Dolabella auricularia, were really produced by the cyanobacterium Lyngbya majuscula or its epiphytes, which the sea hare eats.4 "The possibility that the cyanobacteria could easily be cultured might provide a renewable and higher-yielding source of all Dolastatin peptides," says Faulkner. In addition, there has been a host of claims that certain bioactive metabolites, including swinholide A, from the sponge Theonella swinhoei, and the halichondrins, are produced via symbiosis. Faulkner and colleague Carole A. Bewley last year published a review of some of those claims. A few, including swinholide A, bear out, and others do not, says Faulkner.5 Given the difficulty of obtaining enough of any given compound from marine invertebrates and the recent findings showing evidence of the role(s) of microorganisms, some researchers are rethinking their approach. "I've taken to working entirely with marine microorganisms," says William Fenical, director of the Scripps Center for Marine Biotechnology and Biomedicine. "I've had such bad experiences trying to produce drugs once you discover them. Eleutherobin, for example, is a wonderful idea, but I can't get it. What's beautiful about marine microorganisms is that you bring them into the lab, grow them, discover drugs, and when you want more, you grow more. That's the way the pharmaceutical industry has been going for nearly 50 years. So we're growing organisms like that and we're discovering molecules, and the discovery is great, fantastic." Fenical says Scripps has just licensed a microbial anticancer agent "with a very interesting effect on prostate cancer," as well as "very potent" anti-inflammatory and antiviral agents for use against herpes. "We have discovered a really interesting set of molecules that I think are going to be on a fast track for development against herpes, compounds called halovirs that are very different kinds of molecules, unlike anything seen for antiviral. And the most interesting part of it is they bind directly to the virus and deactivate its ability to penetrate the cell. That's going to be interesting, because they're not very toxic and don't have any allergenic effects." In light of the fact that there is now convincing evidence that some highly bioactive metabolites are produced by associated microorganisms, Faulkner maintains that cultured marine bacteria, cyanobacteria, fungi, and other microorganisms present "an attractive source of marine pharmaceuticals if only because they will allow pharmaceutical companies to control the production of bioactive metabolites." Not everyone, however, is sailing away from the invertebrates. "In many cases, it may be true that we should be looking at a microbial associate or a symbiotic association as the source of production of those compounds, but my guess is that there are an equal number of situations in which the host is really responsible for production of the compound as well," says Pomponi. By most accounts, the pendulum is swinging back now to marine natural products. "Despite all these molecular modeling programs available and the combinatorial chemistry going on, Mother Nature is still the supreme chemist, and we're still getting really novel lead chemical structures from marine natural products, and from terrestrial natural products," says Pomponi. "While we've done a lot of collections of marine macroorganisms, we have really only scratched the surface in terms of marine microorganisms." Moreover, discoveries of new organisms are being made with virtually every expedition. "My expectations for finding anything new on this summer's expedition were very low," Pomponi admits, "but we wound up exploring ... unique sites, sinkholes off the Florida Keys, less than a day's steam from Harbor Branch, and we found at least three new species on one dive. It just blew me away!" They will probably be of pharmacological interest, Pomponi contends, "because they're related to species that have shown interesting biological properties in the past." As for the new wave of marine-derived drugs? "It's only a matter of time," predicts Fenical. Despite the fact that the pharmaceutical companies have yet to invest in major collection efforts, they are, Pomponi notes, "making a major investment in both discovery and development." Although Harbor Branch has probably spent "at least $7-10 million in collections alone in the last 15 years," she says, "the pharmaceutical companies counter with the fact that development of one drug costs $50 million or more. It is hard to reconcile. But the new drugs will come." A.J.S. Rayl (ajsrayl@loop.com) is a freelance writer in Malibu, Calif. A.J.S. Rayl, "Oceans: medicine chests of the future?" The Scientist, 13[19]:1, Sept. 27, 1999. G. Valoti et al., "Ecteinascidin-743, a new marine natural product with potent antitumor activity on human ovarian carcinoma xenografts," Clinical Cancer Research, 4:1977-83, August 1998. S. Tsujii et al., "Topsentin, bromotopsentin, and dihydrodeoxybromotopsentin: antiviral and antitumor bis(indolyl)imidazoles from Caribbean deep-sea sponges of the family Hondriidae. Structural and synthetic studies," Journal of Chemistry, 53:5446-53, 1988. G.G. Harrigan et al., "Isolation, structure determination and biological activity of Dolastatin 12 and Lyngbyastin 1 from Lyngbya Majuscula/schizothrix calcicola cyanobacterial assemblages," Journal of Natural Products, 61:1221-25, 1998. C.A. Bewley, D.J. Faulkner, "Lithistid sponges: star performers or hosts to the stars?" Angewandte Chemie International Edition, 37:2162-78, 1998.

Reaping Pharmacological Benefits from the Oceans

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