Session 4: Public Policy, Partnerships, and Outreach
BIOMEDICAL COMPOUNDS EXTRACTED FROM CORAL REEF ORGANISMS: HARVEST PRESSURE, CONSERVATION CONCERNS, AND SUSTAINABLE MANAGEMENT
Andrew W. Bruckner, Ph.D.
Coral Reef Ecologist, Office of Protected Resources
National Oceanic and Atmospheric Administration
Coral reefs are among the most diverse and valuable ecosystems on earth. They provide an estimated $375 billion each year in economic and environmental services to millions of people as sources of food, construction materials, ornamentals, employment, areas of recreation and tourism, and as shoreline protection (U.S. Coral Reef Task Force, 2000). Natural products obtained from coral reef organisms in the expanding battle against human diseases and pathogenic infections are less well recognized but equally important. Benthic coral reef invertebrates contain a number of unusual, biologically active metabolites with important medical, agricultural, and industrial uses—including recent applications in bone grafting, skin-care products, and bioremediation projects—as insecticides and as potential treatments for cancer and microbial infections (Abu, 1992). Although many compounds of value have already been identified, it is estimated that less than 10% of reef biodiversity is known, and only a small
fraction of these species have been explored as a source of biomedical compounds (Fenical, 1996). New avenues for the commercial development of marine-derived compounds may further enhance the use of coral reef resources and contribute to the global economy. However, it is critical that a new paradigm is established that maximizes coral reef conservation efforts while promoting sustainable use.
Despite a significant human dependence on and concerns for coral reef ecosystems, compelling scientific evidence indicates that current human use and allocation of reef resources are threatening both the ecological and the social sustainability of these ecosystems. Increased harvest pressure is being placed on reef resources to supply subsistence fisheries as well as a growing international demand for reef species for food, traditional medicines, and ornaments. Unfortunately, few countries have sufficient knowledge, financial resources, or technical expertise to develop management plans for the sustainable harvest of reef species, and organisms are often extracted unsustainably for short-term economic gains. Although several coral reef species have yielded potential therapeutic agents, concern about adequate supply for preclinical and clinical studies is a critical issue in the development of new biomedical products. Many of the suitable reef species have a limited distribution or occur at a low biomass. Also, individuals often contain only trace amounts of the desired compounds; the low yield requires the harvest of substantial biomass, which may lead to depletion of natural populations (Creswell, 1995). Many species extinctions are predicted in the coming decades in response to increasing pressure from human activities and natural disturbances, and the pharmacological potential of coral reefs may be lost. The continued, largely unregulated, and unsustainable extraction of reef species may have consequences that extend far beyond the overexploitation of these organisms, as their removal may also affect associated species and communities, ecological processes, and even entire ecosystems that are critical to the overall health of the oceans.
To guarantee a continual source of coral reef organisms for biomedical research that can provide new medicines far into the future, resource managers need to ensure that harvest pressure does not contribute to the global decline of coral reefs. The first and foremost step to address sustainable harvest of reef species involves a shift from traditional, single-species fishery management approaches to an ecosystem approach that integrates the needs of the species, the environment, and society. Existing management approaches, which were developed primarily for food-fish species, typically involve managing individual species with little consideration of fishing im-
pacts on the rest of the ecosystem. Truly sustainable harvest will require changes in management approaches that emphasize precaution and imply a shift in focus from maximizing yield to minimizing ecological impacts and maintaining long-term biological and economic stability (Weeks and Berkeley, 2000). This shift in focus requires the consideration of all interactions of a target species with competitors, predators, and prey species; effects of the environment and natural disturbances; complex interactions between the target species and their habitat; and the effects of extraction on the species and its habitat.
An ecosystem approach to manage the collection of benthic reef species for biomedical research presents numerous challenges, as available information is inadequate on the biology, ecology, and population dynamics of most reef invertebrates. Through the development of partnerships among government agencies, commercial pharmaceutical companies, academia, and local communities, research in identification and screening of bioactive compounds can expand, with concurrent efforts directed toward sustainable management approaches. Benefit sharing with source countries can create economic incentives for reef conservation, provided that mechanisms are in place to direct revenues from bioprospecting toward the development of national and regional conservation programs (Verhoosel, 1998). Possible conservation strategies include the development of a system of marine protected areas and studies to catalogue the diversity and status of the resources contained within these areas. Basic research is also needed on the biology of the target species, linkages among coral reef organisms, and ecosystem processes controlling the distribution and abundance of target species. Finally, a greater emphasis must be placed on coral reef monitoring programs to evaluate harvest impacts and other threats, to provide information needed to establish a sustainable quota, and to adjust management measures in response to new information or subsequent disturbances.
Bioprospecting in coral reef environments offers developing countries an opportunity to derive income from the process of natural product research and development and can create economic incentives for biodiversity conservation. An ecosystem management approach will help prevent overexploitation of reef species, thereby offering a continual source of new products. However, additional strategies may be needed to reduce demand when a species is shown to contain valuable bioactive metabolites. In previous instances, up to 1 kilogram of a bioactive metabolite was necessary for clinical evaluation, and a more intensive, longer-term harvest may be required to support commercial production (Duckworth, 2001). Mass pro-
duction of the target organism through captive-breeding or mariculture may provide a consistent alternative supply without requiring sophisticated equipment for harvest or harvest techniques that are suitable for environmentally sensitive reef environments. Species in demand for the aquarium trade, live reef food-fish markets, and other seafood, and a variety of invertebrates as sources of bioactive compounds, are promising new species for intensive farming. Technology is also being applied to replenish and enhance wild stocks (Bell and Gervis, 1999). There is a growing awareness of the risks associated with mariculture (e.g., introduction of diseases or invasive species, dilution of gene pools and increased biological interactions with other species), but sustainable mariculture can be achieved with responsible application of technology and the use of indigenous species. Selective husbandry and other well-defined mariculture protocols may provide a new tool to improve the yield and quality of bioactive compounds, further reducing the number of individuals needed to provide large quantities of metabolites. Benefit sharing with source countries is a critical step that can provide the financial incentive for field research and monitoring, development of appropriate management strategies that promote sustainable use, and expanded mariculture efforts. Coral reef resources with important biomedical applications have the critical character of being renewable, at least when they are properly managed. Coral reef organisms that are abused can also become extinct, and potential medical benefits from these species will be lost forever.
Abu, G. O. 1992. Marine biotechnology: a viable and feasible bioindustry for Nigeria and other developing countries. MTS Journal 26:20-25.
Bell, J. D., and M. Gervis. 1999. New species for coastal aquaculture in the Tropical Pacific – constraints, prospects and considerations. Aquaculture International 7:207-223.
Creswell, R. L. 1995. Potential opportunities for aquaculture in the pharmaceutical industry. Proceedings of the International Symposium on Biotechnology Applications in Aquaculture (10) [unpag.].
Duckworth, A. 2001. Farming sponges for chemicals with pharmaceutical potential. World Aquaculture June:14-18.
Fenical, W. 1996. Marine biodiversity and the medicine cabinet: the status of new drugs from marine organisms. Oceanography 9:23-27.
U.S. Coral Reef Task Force. 2000. The National Action Plan to Conserve Coral Reefs. U. S. Coral Reef Task Force. http://coralreef.gov. 34 pages (plus appendices).
Verhoosel, G. 1998. Prospecting for marine and coastal biodiversity: international law in deep water? International Journal of Marine and Coastal Law 13:91-104.
Weeks, H., and S. Berkeley. 2000. Uncertainty and precautionary management of marine fisheries: can the old methods fit the new mandates. Fisheries 25:6-15.
PRODUCTIVE PARTNERSHIPS IN NATURAL PRODUCT DISCOVERY AND DEVELOPMENT
Joshua Rosenthal, Ph.D.
Deputy Director, Division of International Training and Research
Fogarty International Center
National Institutes of Health
Pharmaceutical research and development projects around the world are increasingly carried out through partnerships among diverse organizations. These partnerships are frequently international and may encompass highly diverse organizations to take advantage of differential expertise, technology, access to biological materials, and arrangements for sharing of benefits.
Observations on the nature and history of the International Cooperative Biodiversity Groups (ICBG) offer useful lessons on factors that predispose partnerships to stumble or succeed. The ICBGs are multidisciplinary international consortia often involving public- and private-sector institutions in efforts to discover simultaneously new pharmaceutical and agricultural agents from natural sources, and to promote scientific and economic development and biodiversity conservation in developing countries. The non profit side of these projects is supported by cooperative agreements under a joint effort of the National Institutes of Health (NIH), the National Science Foundation, and the U.S. Department of Agriculture and is administered by the Fogarty International Center of the NIH. To date, no marine ICBGs have competed successfully for funding. However, a number of the lessons these ambitious projects have yielded are likely to be useful to marine natural products and biotechnology partnerships.
The actors in today’s natural product partnerships include universities, for-profit companies, governmental agencies, conservation organizations, foundations, communities, and advocacy groups. Many partnerships among diverse organizations founder, because each entity applies its own business, cultural, or legal rules to the behavior of an entirely different type of organization. Academic scientists, for example, often mistakenly assume that the intellectual interest and good will of a collaborating industrial sci-
entist will be sufficient to maintain the commitment of that individual’s company. However, pharmaceutical companies have become very dynamic in recent years. For example, in three ICBGs involving academic and industrial scientists, the collaborative efforts of the pharmaceutical companies were initiated and directed by senior scientists who had expressed personal interest and commitment to their respective group programs. But, in each of these three cases, the companies underwent mergers and subsequent major changes in their natural product research strategies within 2 years of the initiation of the projects. In all three cases, the companies decided to withdraw from these projects, along with many of their other natural products collaborations.
Similarly, companies, universities, and U.S. NGOs may run into trouble if their representatives assume that the leader of a local governmental organization or an indigenous community can speak for and sign agreements representing his or her entire constituency. Frequently, such organizations have internal clearance and consensus-building procedures that they must elaborate before embarking on a significant project, even if they are sometimes willing to try to short-circuit the process to accommodate the needs of potential partners. These internal processes are generally opaque to the outsider and often time consuming, but it is absolutely necessary to allow for them in order to develop a sustainable collaborative project.
Arrangements for the treatment of proprietary information are frequently a challenge to diverse partnerships. Host country governmental agencies may want to document species names, collection sites, and other information to enhance management of natural resources or to track collection and research efforts to protect the interests of their countries. Furthermore, academic scientists clearly need to publish their research to advance science and their own career productivity. However, conflicts often arise, because companies generally wish to prevent their competitors from seeing their assays, other research methods, and discoveries, sometimes even after patenting them. Community and conservation groups frequently also wish to keep the names, locations, and traditional uses of biological collections confidential to protect their proprietary interests or minimize over-harvesting of threatened species by opportunists.
Poorly defined or overly restrictive confidentiality requirements can lead to wasted or duplicative research efforts and missed opportunities, thereby undermining the complementarity and synergy that most partnerships seek. For example, the absence of precise taxonomic information on a collection led one academic laboratory to waste an entire week of bioassay
guided isolation efforts on a species they had already worked on in the previous year. In another example, a company wasted a substantial amount of effort struggling with unidentified, nonspecific binding agents in a new class of assays. An open discussion of the matter with the field biologists would probably have led them much earlier to the identification of these agents and a means to deal with them.
Even when all the members of a partnership work well together, the partnership may stumble or fail because of external political or legal factors. For example, at least 50 countries have defined or are developing some type of legislation related to access to biological diversity and benefit sharing. However, few have implemented these laws in clearly defined normative procedures. Many of these countries are still negotiating the relationship of national sovereign rights to permit or participate in agreements on genetic resources with their own provincial governments or indigenous peoples’ organizations and with super national bodies, such as the Andean Pact.
Major issues that affect the success of partnerships in addition to scientific and technical capability include an organization’s stability, its administrative competence, and leadership for the project as a whole. Although exceptions exist, it is my experience that stability and predictability of research programs is highest in academia, followed by governmental programs, followed by industry. In part, this reflects the career tracks of the individuals in critical positions, but also the relative stability of the organizational types as well.
Strong and enduring partnerships are most likely to be formed by organizations that have symmetrical needs and enthusiasm for the collaboration, even if they are relatively simple arrangements limited to the exchange of specimens for technology. Hence, a partnership between a large pharmaceutical company with many sources of specimens and a small, resource-poor university in a developing country is inherently vulnerable, unless the relationship is anchored by a third organization, such as a U.S. university, that has more symmetrical relationships with the other two.
In most cases, one settles for a partnership with an organization that is less than the ideal in one or more of these respects. The organization may not have the full research capacity sought, or it may not be completely stable or administratively competent. However, the key to success is understanding its interests and capacity and planning accordingly. Conservative benchmarks, contingency plans, contract incentives, sharing of expertise and other tools can minimize the impact of these issues if one has a realistic understanding of the organization’s strengths and weaknesses at the outset.
Successful and enduring partnerships in natural products and biotechnology generally have strong leadership and carefully chosen partners, and they operate in an environment of mutual respect and fairness. They most often persist over time when the partners have both strong personal and institutional commitments, and the partnership is governed by well-defined but flexible contractual arrangements and regulations.
COMMERCIALIZATION OF MARINE BIOPRODUCTS: INTELLECTUAL PROPERTY AND TECHNOLOGY TRANSFER ISSUES
Donald Gerhart, Ph.D.
Director, Technology Transfer
University of Oregon
The commercial development of successful pharmaceutical products and medical devices is costly, time consuming, and complex. For example, commercialization of an innovative therapeutic agent from a new chemical entity (NCE) typically requires the investment of hundreds of millions of dollars. Successful commercialization further requires the sustained, coordinated efforts of thousands of people working together, worldwide, for periods of 10 years or more toward achievement of a single goal: market entry. For biomedical technologies, commercial development encompasses a dauntingly broad array of functions, including nonclinical testing (both pharmacological and toxicological), regulatory and legal affairs, clinical research, product formulation, manufacturing, packaging, labeling, marketing, sales, education, and post-market surveillance (Cato, 1988; Trenter, 1999).
Creating a commercially successful pharmaceutical product or medical device is also risky. The transition from initial laboratory-based proof-of-concept development to early-stage commercial development is so exceedingly difficult that it is known colloquially among technology developers as “The Gap” or “The Valley of Death.” In pharmaceutical development, “The Gap” is perhaps more appropriately called “The Abyss,” since the vast majority of promising research-stage therapeutic agents fail to enter clinical testing. Of those investigational new drugs that enter clinical testing, only a small proportion reach the marketplace. If a pioneering new product does manage to succeed commercially, competing generic products are guar-
anteed to enter the marketplace and erode profit margins and market share as soon as the pioneering product loses exclusivity.
For those reasons, corporations and their shareholders will invest the requisite capital and commit the necessary personnel to development of a biomedical product only when effective intellectual-property protection guarantees exclusivity for that product after market entry. It is not surprising then, that intellectual-property rights form one of the cornerstones on which the modern biomedical industry is based. Intellectual-property protection is essential to the successful commercialization of marine biomedical technologies.
Intellectual property protection can take a variety of forms, including patents, trademarks, copyrights, trade secrets, and the ownership rights derived from possession of novel tangible materials (Smith and Parr, 1998). In the United States, the Drug Price Competition and Patent Term Restoration Act of 1984 established supplemental exclusivity periods that can provide patent-like protection for new medicines for up to 7 years. Patent rights constitute the most significant form of intellectual-property protection for development-stage biomedical products and are especially important for inchoate pharmaceutical products. As biomedical products move through the industrial development pipeline, however, patent-based exclusivity is often supplemented by other intellectual property rights, particularly trademarks, trade secrets, and copyrights.
When marine bioproducts are discovered at universities and nonprofit research institutes, commercialization is dependent on successful transfer of the nascent technology from its nonprofit laboratory birthplace to the industrial development pipeline. University-industry technology transfer was first envisioned in its modern embodiment by Internet prophet Vannevar Bush in 1945. Following passage of the Bayh-Dole Act in 1980, university-industry technology transfer expanded dramatically. The most recent survey conducted by the Association of University Technology Managers credited technology transfer with generating over $40 billion in product sales, $5 billion in tax revenue, and 270,000 jobs in the United States during fiscal year 1999 alone (Pressman, 2000). These numbers underscore the economic rewards that can be reaped from successful technology transfer. Less easily quantified, but much more important, are the societal benefits that flow from technology transfer in the form of new medicines and other products that improve the quality of life.
Success in technology transfer involves understanding and respecting both academic and corporate cultures, anticipating problems arising at the
interface of these two cultures, and finding creative solutions to resolve problems before they escalate into major issues. Basic research scientists in universities and nonprofit institutions can facilitate technology transfer by deepening their understanding of the breadth of the commercial development process and the role played by patents and other forms of intellectual property. A research scientist’s awareness of and respect for the “development” in research and development often makes the critical difference between success and failure in technology transfer. Likewise, members of industry can enhance the effectiveness of industrial technology transfer programs by cultivating an appreciation of the resources, special challenges, and institutional constraints that exist in the workplaces of academic scientists.
The legal transfer of intellectual-property rights from university to industry is typically accomplished via a license agreement to an existing corporation that possesses the resources and motivation to bring the licensed technology into the marketplace (Smith and Parr, 1998). Transfer of the scientific and technical knowledge underlying the license can be facilitated by forming partnerships between academic research groups and corporate development teams. When an invention is potentially disruptive to the research-and-development pipeline of established corporations, technology transfer can be achieved by “spinning out” the discovery from the university into a start-up company. Such start-ups—small, nimble corporations specially formed to commercialize aggressively and creatively a new technology—play a peculiar role in U.S. innovation (Abramson et al., 1997).
For many taxonomic groups of marine organisms, diversity tends to increase with decreasing latitude. As a consequence of this biogeographic trend, the commercial development of marine bioproducts by industrialized nations involves the conversion of raw materials, harvested from developing countries, into value-added products. Furthermore, within the United States, many economically distressed coastal communities are situated in areas with rich marine bioresources. This situation brings into focus the monetary value of marine biodiversity, providing a hard-nosed economic rationale to supplement moral, ethical, and aesthetic arguments in support of marine conservation. As the United States moves to strengthen its support for marine bioproduct commercialization, an opportunity exists to earmark a portion of future financial windfalls for support of marine conservation and sustainable coastal development, thus preserving as-yet-undiscovered marine bioproducts for the benefit of future generations.
Abramson, H. N., J. Encarnação, P. P. Reid, and U. Schmoch, Eds. 1997. Technology Transfer Systems in the United States and Germany: Lessons and Perspectives. Part I: Overview and Comparison. National Academy Press, Washington, D.C.
Cato, A. E., Ed. 1988. Clinical Trials and Tribulations. Marcel Dekker, Inc. New York.
Pressman, L., Ed. 2000. AUTM Licensing Survey: FY 1999. Association of University Technology Managers, Inc., Northbrook, Ill.
Smith, G. V., and R. L. Parr. 1998. Intellectual Property: Licensing and Joint Venture Strategies. John Wiley & Sons, Inc., New York.
Trenter, M. L. (Ed.). 1999. From Test Tube to Patient: Improving Health Through Human Drugs. Center for Drug Evaluation and Research Special Report. U.S. Food and Drug Administration, Rockville, Md.
PLANNING, PARTNERSHIPS, AND PROGRESS IN MARINE BIOTECHNOLOGY RESEARCH AND OUTREACH IN FLORIDA
James C. Cato
William Seaman, Jr.
University of Florida Sea Grant
The Florida Sea Grant College Program is working to enhance both the immediate quality and future funding base for marine biotechnological research and education in Florida. Since 1996, a collegial effort has been underway to plan strategy, create partnerships, and increase funding. This effort began with the formation of a statewide faculty-industry group to advise on long-range planning. In 1997, two faculty participated in a national press briefing, a faculty-industry roundtable was held, a popular magazine style outreach document was published, and Florida faculty were successful in securing funds through national competitions. In 1998, a committee to advance Florida marine biotechnological research and education drafted a plan and assisted in or organized sessions at the state and national levels with the industry organization BIOFlorida and its national counterpart. During 2000, a second faculty-industry roundtable was held at BIOFlorida’s annual meeting. During 2000 and 2001, work to create a marine biotechnological research, development, and training program was initiated in the Florida legislature, and a statewide directory of research and education faculty was published.
From a single research project in 1996, Florida Sea Grant has substan-
tially expanded its marine biotechnology research, which now represents one of its two most important areas. Fourteen projects have been completed or will be completed by 2001. Another seven projects are to begin in 2002. The emphasis is on synthesis of bioactive agents, which in turn bears on sustainability of supply of potential pharmaceuticals and industrial compounds. Several other projects focus on developing anti-fouling compounds, detecting pollutants in coastal waters, improving plants for use in dune stabilization, and identifying fish for management purposes.
A statewide faculty-industry meeting in 1996 helped to define a long-range strategic plan, a research agenda, and education and development efforts. The increased research is a direct result of this planning. A call for more outreach also resulted in the development of a statewide magazine-style report on marine biotechnology. This report has assisted in bringing more visibility to the overall effort. A faculty-industry “summit” in 1997 identified bottlenecks and actions to resolve them and produced a consensus on building statewide capabilities. This event resulted in a 1998 invited session on marine biotechnology for the statewide meeting of BIOFlorida, the new industry trade organization. Research results were presented and connections made with industry partners. A second more formal “summit” in 2000, in association with BIOFlorida, attracted at least half of Florida’s faculty working in this field. Graduate students were involved, a scientific poster session was held, and a session dealt with legislation, scientific advances, and success stories from other biotechnological fields. Two marine scientists now serve on the board of directors of the industry trade organization. A statewide directory of faculty and research scientists interested in marine biotechnology research, development, and training capabilities to advance science and commerce has been completed and is available in print and on the Florida Sea Grant website.
All this activity has fostered the creation of a statewide “virtual” marine biotechnological academic department. Leadership from the strategic-planning groups and meetings organized with faculty and industry input drafted a plan to create the Florida Marine Biotechnology Research, Development, and Training Program. This plan drew the attention of the Florida legislature and the 1999-2000 and 2000-2001 sessions considered legislation to create a research, training, and development program for marine biotechnology in an academic-industry partnership. The legislation defines research priorities for the program, authorizes an appropriation, defines how proposals will be competitively selected, and creates the framework for university-industry cooperation for research projects. The bill passed all com-
mittees of the Florida house and senate during 2001 but was not passed. Attempts at passage will continue during the 2002 session of the legislature.
Statewide leadership by Florida Sea Grant since 1996 has resulted in a number of positive benefits. It has established a coherent source of funds for research and graduate students and initiated outreach to inform public audiences about marine biotechnology. It fostered the creation of a statewide network among university faculty and staff. Florida’s position among states that are national leaders in marine biotechnology has been promoted. Finally, an effort to establish long-term funding for research, education, and development has been initiated, and bridges have been built for partnerships between industry and academia.