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Natural Products from the Sea: Ethnopharmacology, Nutrition and Conservation

Townsend Letter for Doctors and Patients, Feb, 2001 by Tim Batchelder

Introduction: Chemical Diversity and Evolution

The sea represents the most promising source of medicinal and nutritional natural products of the future. Traditional peoples have used natural products from the sea for medicinal and nutritional purposes for thousands of years. Natural products from the oceans are promising in part because of the incredible diversity of chemical compounds created by marine organisms. Since conditions in the marine environment are so different from those on land most classes of marine organism show molecules with unique structural features. Also, since many marine organisms are sessile they have evolved a wide variety of chemicals for defense, as well as communication and reproduction.

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These unique molecular structures are precisely what are needed to help make new drugs and nutritional supplements. Terrestrial sources of drugs and nutritional products have been well explored, but less than one percent of marine species have been screened for organisms that contain or excrete novel compounds. Of the 27 diverse phyla of life, only 17 occur on land, yet 27 of the 27 occur in the ocean and so the largest proportion of biodiversity is in the ocean, As disease resistance to antibiotics and other drugs continues to increase, chemistry may not be able to meet the ever-increasing need for more efficient and more effective compounds. The oceans represent an untapped source of new medicines. (Pomponi 1999.)

Pharmaceuticals from the Sea

Despite the promise of marine natural products the pharmaceutical industry has been slow to explore this resource. However, smaller natural products firms, biotech companies and the National Cancer Institute (NCI) have begun exploring the oceans as a source of medical natural products in more depth and some products from this research are now in the clinical pipeline, with more in pre-clinical development. For more information see NCI's Natural Products Branch at http://dtp.nci.nih.gov. Some examples of compounds currently under study include:

* Bryostatin 1, isolated from the bryozoan Bugula neritina, an organism that attaches itself to the bottoms of boats off the coast of California, primarily for use as a treatment of melanoma, non-Hodgkin's lymphoma, and renal cancer.

* Dolostatin 10, a linear peptide derivative isolated from the sea hare Dolabella auricularia from the Indian Ocean, for use in the treatment of breast and liver cancers, solid tumors, and leukemia.

* AE941, a shark cartilage preparation, for use in treatment of various tumors.

* Ecteinascidin-743 (ET743) (Rinehart et al. 1981), a compound isolated from a Caribbean tunicate, has shown activity against ovarian (Valoti et al. 1998) and other tumors.

* Dehydrodidemnin B, isolated from Mediterranean tunicate Aplidium albicans, is being tested for its anticancer properties.

* An anti-inflammatory, manoalide, isolated from the Palauan sponge Luffariella variabilis and patented by the University of California for psoriasis. (Rinehart et al. 1981)

* Discodermolide, a metabolite of the deep-sea sponge Discodermia, which is immunosuppressive and cytotoxic, (Longley 1991) has potent antiproliferative activity due to its ability, to stabilize microtubules, (Haar et al. 1996; and Kowalski et al. 1997). Novartis licensed it as a cancer treatment.

* Halichondrin B, isolated from the Japanese sponge Halichondria okadai, for melanoma and leukemia.

* Isogranulatimide, derived from a Brazilian tunicate, is a G2 checkpoint inhibitor that is shown to kill p53-tumor cells. It is also easy to synthesize which allows researchers to make analogues. (Roberge et al. 1998; Berlinck et al. 1998.)

* Debromohymenialdisine (DBH), one of several constituents of the common Palauan shallow-water sponge Stylotella aurantium, (Williams, Faulkner 1996) is easily synthesized and is being developed for treatment of osteoarthritis.

* An anti-inflammatory compound, Pseudopterogorgia elisabethae, extracted from the sea fan, is being used in an Estee Lauder skin care product, Resilience.

Production Methods

One major limitation to acquiring natural products from the sea versus land is the reduced accessibility of ocean environments. Bristol-Myers Squibb, one of the few major pharmaceutical companies to look into marine-derived compounds, recently returned licenses for eleutherobin, a compound isolated from a small Australian soft coral of the genus Eleutherobia, because they couldn't get enough of it. It is often difficult to obtain enough of a marine natural product to do a clinical trial, let alone produce it commercially. Pharmacological research in oceanic sources is slower and more difficult than land-based research. Property rights also continue to be a problem, following the Rio Convention. Discoveries made in another country's waters cannot be used. Some countries nowadays are controlling all research in their waters which prevents other researchers from gaining access. For example, the yield for [Ecteinascidin] ET743 is one gram per ton of tunicate. One ton will treat hundreds of people but this amount is hard to harvest due to conservation restrictions. (Valoti et al. 1998) The cost of research is also limited by the remote location of many marine resources. It sometimes takes researchers years to gain the funds and equipment to return to a remote ocean location which might harbor important natural products. For example, a ship and submersible costs $14,500 per day typically (Pomponi 1999).

Health Care Industry

Natural Products from the Sea: Ethnopharmacology, Nutrition and Conservation

Townsend Letter for Doctors and Patients, Feb, 2001 by Tim Batchelder

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