Life-Saving Products from Coral Reefs

During the past decade, marine biotechnology has been applied to the areas of public health and human disease, seafood safety, development of new materials and processes, and marine ecosystem restoration and remediation. Dozens of promising products from marine organisms are being advanced, including a cancer therapy made from algae and a painkiller taken from the venom in cone snails. The antiviral drugs Ara-A and AZT and the anticancer agent Ara-C, developed from extracts of sponges found on a Caribbean reef, were among the earliest modern medicines obtained from coral reefs. Other products, such as Dolostatin 10, isolated from a sea hare found in the Indian Ocean, are under clinical trials for use in the treatment of breast and liver cancers, tumors, and leukemia. Indeed, coral reefs represent an important and as yet largely untapped source of natural products with enormous potential as pharmaceuticals, nutritional supplements, enzymes, pesticides, cosmetics, and other novel commercial products. The potential importance of coral reefs as a source of life-saving and life-enhancing products, however, is still not well understood by the public or policymakers. But it is a powerful reason for bolstering efforts to protect reefs from degradation and overexploitation and for managing them in sustainable ways.

Between 40 and 50 percent of all drugs currently in use, including many of the anti-tumor and anti-infective agents introduced during the 1980s and 1990s, have their origins in natural products. Most of these were derived from terrestrial plants, animals, and microorganisms, but marine biotechnology is rapidly expanding. After all, 80 percent of all life forms on Earth are present only in the oceans. Unique medicinal properties of coral reef organisms were recognized by Eastern cultures as early as the 14th century, and some species continue to be in high demand for traditional medicines. In China, Japan, and Taiwan, tonics and medicines derived from seahorse extracts are used to treat a wide range of ailments, including sexual disorders, respiratory and circulatory problems, kidney and liver diseases, throat infections, skin ailments, and pain. In recent decades, scientists using new methods and techniques have intensified the search for valuable chemical compounds and genetic material found in wild marine organisms for the development of new commercial products. Until recently, however, the technology needed to reach remote and deepwater reefs and to commercially develop marine biotechnology products from organisms occurring in these environments was largely inadequate.

The prospect of finding a new drug in the sea, especially among coral reef species, may be 300 to 400 times more likely than isolating one from a terrestrial ecosystem. Although terrestrial organisms exhibit great species diversity, marine organisms have greater phylogenetic diversity, including several phyla and thousands of species found nowhere else. Coral reefs are home to sessile plants and fungi similar to those found on land, but coral reefs also contain a diverse assemblage of invertebrates such as corals, tunicates, molluscs, bryozoans, sponges, and echinoderms that are absent from terrestrial ecosystems. These animals spend most of their time firmly attached to the reef and cannot escape environmental perturbations, predators, or other stressors. Many engage in a form of chemical warfare, using bioactive compounds to deter predation, fight disease, and prevent overgrowth by fouling and competing organisms. In some animals, toxins are also used to catch their prey. These compounds may be synthesized by the organism or by the endosymbiotic microorganisms that inhabit its tissues, or they are sequestered from food that they eat. Because of their unique structures or properties, these compounds may yield life-saving medicines or other important industrial and agricultural products.

Despite these potential benefits, the United States and other countries are only beginning to invest in marine biotechnology. For the past decade, Japan has been the leader, spending $900 million to $1 billion each year, about 80 percent of which comes from industry. In 1992, the U.S. government invested $44 million in marine biotechnology research, which is less than 1 percent of its total biotechnology R&D budget; an additional $25 million was invested by industry. In 1996, the latest date for which figures are available, U.S. government marine biotechnology research investment was estimated at only $55 million. Even with limited funding, U.S. marine biotechnology efforts since 1983 have resulted in more than 170 U.S. patents, with close to 100 new compounds patented between 1996 and 1999. U.S. support for marine biotechnology research is likely to increase in the coming years. According to the National Oceanic and Atmospheric Administration, marine biotechnology has become a multibillion industry worldwide, with a projected annual growth of 15 to 20 percent during the next five years.

Expanded efforts by the United States and other developed countries to evaluate the medical potential of coral reef species are urgently needed in particular because of the need for a new generation of specialized tools and processes for collection, identification, evaluation, and development of new bioproducts. The high cost and technical difficulties of identifying and obtaining marine samples, the need for novel screening technologies and techniques to maximize recovery of bioactive compounds, and difficulties in identifying a sustainable source or an organism for clinical development and commercial production are among the primary factors limiting marine bioprospecting activities.

The identification and extraction of natural products require major search and collection efforts. In the past, invertebrates were taken largely at random from reefs, often in huge quantities, but bioprospectors rarely provided an indication of the amount of organisms they were seeking, making it difficult to assess the impact associated with collection. Chemists homogenized hundreds of kilograms of an individual species in hopes of identifying a useful compound. This technique often yielded a suite of compounds, but each occurred in trace amounts that were insufficient for performing a wide range of targeted assays necessary to identify a compound of interest. For example, in one report a U.S. bioprospecting group collected 1,600 kg of a sea hare to isolate 10 mg of a compound used to fight melanoma. Another group collected 2,400 kg of an Indo-Pacific sponge to produce 1 mg of an anticancer compound. Yet, as much as 1 kg of a bioactive metabolite may ultimately be required for drug development.

Targeting a promising compound is only the first step; a renewable source for the compound must also be established before a new drug can be developed. Many suitable species occur at a low biomass or have a limited distribution, and in some cases a compound may occur only in species exposed to unusual environmental conditions or stressors. Because these compounds often come from rare or slow-growing organisms or are produced in minute quantities, collecting a target species in sufficient amounts for continued production of a new medicine may be unrealistic.

Sustainable management

It is estimated that less than 10 percent of coral reef biodiversity is known, and only a small fraction of the described species have been explored as a source of biomedical compounds. Even for known organisms, there is insufficient knowledge to promote their sustainable management. Unfortunately, a heavy reliance on coral reef resources worldwide has resulted in the overexploitation and degradation of many reefs, particularly those near major human populations. Managing these critical resources has become more difficult because of economic and environmental pressures, and human populations continue to grow.

Seahorses are a prime example of a resource that is rapidly collapsing. Demand for seahorses for use in traditional medicine increased 10-fold during the 1980s, and the trade continues to grow by 8 to 10 percent per year. With an estimated annual seahorse consumption of 50 tons in Asia alone, representing about 20 million animals supplied by 30 different countries, collection pressures on seahorses are causing rapid depletion of target populations. According to a study by Project Seahorse, seahorse populations declined worldwide by almost 50 percent between 1990 and 1995. In the absence of effective management of coral reefs and the resources they contain, many species that are promising as new sources of biochemical materials for pharmaceuticals and other products may be lost before scientists have the opportunity to evaluate them.

Thus, as a first step in promoting continued biomedical research for marine natural products, countries must develop management plans for sustainable harvest of potentially valuable invertebrates. This must occur before large-scale extraction takes place. Because most of the desired species for biotechnology have little value as a food fishery, management strategies for sustainable harvest have been lacking, and much of the information needed on the population dynamics or the life history of the organisms is unknown. However, through joint efforts involving scientists, resource managers in the source country, and industry, it is possible to develop management plans that promote sustainable harvest, conservation, and equitable sharing of benefits for communities dependent on these resources.

For instance, researchers in the Bahamas identified a class of natural products, pseudopterosins, from a gorgonian coral (Pseudoterigorgia elisabethae) that have anti-inflammatory and analgesic properties. With help from the U.S.-funded National Sea Grant College Programs, the population biology of the species was examined in detail, with relevant information applied toward development of a management plan for sustainable harvest. This has allowed researchers to obtain sufficient supplies over a 15-year period without devastating local populations. By ensuring an adequate supply, this effort ultimately led to the purification of a product now used as a topical agent in an Estee Lauder skin care product, Resilience. In 1995, pseudopterosin was among the University of California’s top 10 royalty-producing inventions; today it has a market value of $3 million to $4 million a year.

Commercialization

New avenues for the commercial development of compounds derived from coral reef species may enhance the use of these resources and contribute to the global economy. If properly regulated, bioprospecting activities within coral reef environments may fuel viable market-driven incentives to promote increased stewardship for coral reefs and tools to conserve and sustainably use coral reef resources. These activities may also promote beneficial socioeconomic changes in poor developing countries.

Unfortunately, the difficulty in finding new drugs among the millions of potential species, the large financial investment involved, and long lead times that often take place before drugs can be brought to market has meant that the resources themselves have relatively low values. The anticancer metabolite developed from a common bryozoan, Bugula spp., is currently worth up to $1 billion per year. But the value of one sample in its raw form is only a few dollars. This makes it difficult to add significant value to coral reefs for conservation strictly on economic terms.

When bioprospecting has resulted in significant funds for conservation, special circumstances have been involved. The most success has been achieved when bioprospecting is carried out through international partnerships that include universities, for-profit companies, government agencies, conservation organizations, and other groups. Partnerships allow organizations to take advantage of differential expertise and technology, thereby providing cost-effective mechanisms for collection, investigation, screening, and development of new products. Partnerships also facilitate access to coral reef species, promote arrangements for benefit sharing, and assist in improving understanding of the taxonomy and biogeography of species of interest.

Many of the marine natural products partnerships negotiated in recent years between private firms and research institutes in developing countries have involved outsourcing by large R&D firms. In this approach, large companies engaged in natural products R&D work with suppliers, brokers, and middlemen in developing countries to obtain specimens of interest and with specialized companies that conduct bioassays or chemical purification of natural products. Through the development of contracts with several large pharmaceutical companies, Costa Rica was able to ensure that substantial funds were directed toward conservation. This was successful primarily because Costa Rica developed tremendous capacity to provide up-front work in taxonomy and initial screening of samples, which may not be the case in other developing countries.

An alternative approach often undertaken in the United States and Europe involves in-licensing, in which large R&D companies acquire the rights to bioactive compounds that have been previously identified by other firms or by nonprofit research institutes. For example, the National Cancer Institute (NCI) provides government research grants that support marine collecting expeditions and preliminary extraction, isolation, and identification of a compound and its molecular structure and novel attributes. Once a potentially valuable compound is identified, NCI may patent it and license it to a pharmaceutical company to develop, test, and market. In this approach, the company is required to establish an agreement with the source country for royalties and other economic compensation. In addition, scientists in the host country are invited to assist in the development of a new product, and the U.S. government guarantees protection of biodiversity rights and provides provisions for in-country mariculture of organisms that contain the compound, in the event that it cannot be synthesized.

The Convention on Biological Diversity (CBD) is leading an international effort to develop guidelines for access to coastal marine resources under jurisdictions of individual countries for marine biotechnology applications. The CBD is calling for conservation of biological diversity, the sustainable use of marine resources, and the fair and equitable sharing of benefits that arise from these resources, including new technologies, with the source country. Ratification of this agreement, from the standpoint of expanded development in marine biotechnology, requires that coastal nations agree on a unified regime governing access to marine organisms. Countries with coral reefs must also establish an acceptable economic value for particular marine organisms relative to the R&D investment of the biotech firm involved in the collection of the organism and the development of a new bioproduct. Although this type of international agreement would significantly affect the operations of the U.S. marine biotechnology industry, the United States cannot play an effective role in the process because it is not a party to the convention.

Options for sustainable use

The development and marketing of novel marine bioproducts can be achieved without depleting the resource or disrupting the ecosystem, but it requires an approach that combines controlled, sustainable collection with novel screening technologies, along with alternative sources for compounds of value. Instead of the large-scale collections that were formerly commonplace, more systematic investigations are now being undertaken, in which certain groups are targeted and the isolated materials are tested in a wide variety of screening assays. These collection missions involve the selective harvest of a very limited number of species over a broad area, with a focus on soft-bodied invertebrates that rely on chemical defenses for survival and marine microorganisms that coexist with these organisms. Assays used in major pharmaceutical drug discovery programs are also beginning to consider the function of the bioactive compounds in nature and their mechanisms of action, which can provide models for the development of new commercial products.

The ability to partition collections into categories of greater and lesser potential has raised the value of these species. For instance, sponges are ideal candidates for bioprospecting, because a single sponge can be populated by dozens of different symbiotic bacteria that produce an extraordinary range of chemicals. In Japan, researchers have examined more than 100 species of coral reef sponges for biomedical use, and more than 20 percent of them have been found to contain unique bioactive compounds. With greater knowledge of appropriate types of organisms for screening, companies may be willing to pay a premium for exclusive access to promising research prospects, thus creating an incentive to conserve ecological resources in order to charge access fees.

With the advent of genomic and genetic engineering technologies, bioprospectors now have environmentally friendly and economically viable alternative screening tools. For any given species, a suitable sample consists of as little as 1 to 1.5 kilograms wet weight. In one screening approach, scientists collect small samples of an organism, extract the DNA from that species and its symbiotic microbes, and clone it into a domesticated laboratory bacterium. Thus, the genetically engineered bacterium contains the blueprint necessary to synthesize the chemical of interest, and it can ultimately create large quantities of the chemical without additional reliance on the harvest of wild populations.

Although synthetic derivatives provide an alternative to wild harvest, sometimes synthesis proves impossible or uneconomical; for example, in the case of an anticancer compound extracted from a sea squirt (tunicate). Mass production of a target species through captive breeding or mariculture may provide a consistent alternative supply. Many coral reef organisms that are in demand for the aquarium trade and the live reef food fish trade, and several invertebrates that contain valuable bioactive compounds, such as the sponges, are promising new species for intensive farming, and there are already a number of success stories. For example, sponge mariculture capitalizes on the ability of sponges to regenerate from small clippings removed from adult colonies. To minimize harvest impacts, only a small portion of the sponge needs to be removed for aquaculture; the cut sponge heals quickly and over time will regrow over the injury.

Mariculture offers another benefit as well. Through the use of selective husbandry or other mariculture protocols, it may be possible to select for a particular genetic strain of a species that produces a higher concentration of a metabolite of interest, thereby reducing the number of individuals needed for biotechnology applications. Mariculture can also provide a source of organisms to restock wild populations, which provides additional incentive for participation by a developing country with coral reef resources.

Four key steps

Coastal populations worldwide will continue to rely on coral reefs for traditional uses, subsistence, and commerce far into the future. In many cases, increased, unsustainable rates of collection coupled with pollution, habitat destruction, and climate change are threatening the vitality of these precious ecosystems. Coral reefs are vast storehouses of genetic resources with tremendous biomedical potential that can provide life-saving sources of new medicines and other important compounds, if these precious resources are properly cared for. To meet this challenge, research communities, government agencies, and the private sector must interact more effectively.

Through four key steps, the benefits of these activities can extend far beyond their medicinal potential to provide sustainable sources of income for developing countries and promote increased stewardship for the resources. First, there is a need for investment incentives to encourage partnerships among governments, local communities, academia, and industry to increase marine natural product research in coral reef environments. Second, those who stand to gain from the discovery of a new product must direct technical and financial assistance toward research and monitoring of the target species and the development and implementation of sustainable management approaches in exporting (developing) countries. Third, it is critical that biotech firms promote equitable sharing of benefits to include entire communities or source countries from which the raw materials come. Finally, expanded efforts are needed to reduce the demand for wild harvest and to improve the yield of bioactive compounds, including mariculture and selective husbandry and genomic and genetic engineering.

Without environmentally sound collection practices, only a few will benefit financially from new discoveries, and only over the short term. In the long term, communities may ultimately lose the resources on which they depend. Many species will perish, including those new to science, along with their unrealized biomedical potential. The ultimate objective of marine biotechnology should not be to harvest large volumes and numbers of species for short-term economic gains, but rather to obtain the biochemical information these species possess without causing negative consequences to the survival of the species and the ecosystems that support them. We must strive for a balance among the needs of human health, economics, and the health of our coral reefs, all of which are inextricably intertwined. This approach will ensure that marine resources that may prove valuable in the fight against disease will be available for generations to come.