Biomedical Applications of Marine Natural Products: Overview of the 2001 Workshop

INTRODUCTION

Marine biotechnology has demonstrated its potential across a broad spectrum of applications that range from biomedicine to the environment. Nevertheless, despite noteworthy successes (Tables 13) and the inherent promise of the ocean’s vast biological and chemical diversity, marine biotechnology has not yet matured into an economically significant field. Fundamental knowledge is lacking in areas that are pivotal to the commercialization of biomedical products and to the commercial application of biotechnology to solve marine environmental problems, such as pollution, ecosystem disease, and harmful algal blooms.

To identify hurdles that are slowing the implementation of marine biotechnology within the biomedical and environmental sciences, the Ocean Studies Board (OSB) and the Board on Life Sciences (BLS) of the National Research Council (NRC) convened two workshops on marine biotechnology. One examined issues limiting the application of biotechnology to marine environmental science (October 1999; National Research Council, 2000), and the other examined issues surrounding biomedical benefits from marine natural products (November 2001).

In this report, the OSB and BLS ad hoc Committee on Marine Biotechnology summarize and integrate information obtained from the two workshops and highlight areas where new investments are likely to pay the



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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products Biomedical Applications of Marine Natural Products: Overview of the 2001 Workshop INTRODUCTION Marine biotechnology has demonstrated its potential across a broad spectrum of applications that range from biomedicine to the environment. Nevertheless, despite noteworthy successes (Tables 1–3) and the inherent promise of the ocean’s vast biological and chemical diversity, marine biotechnology has not yet matured into an economically significant field. Fundamental knowledge is lacking in areas that are pivotal to the commercialization of biomedical products and to the commercial application of biotechnology to solve marine environmental problems, such as pollution, ecosystem disease, and harmful algal blooms. To identify hurdles that are slowing the implementation of marine biotechnology within the biomedical and environmental sciences, the Ocean Studies Board (OSB) and the Board on Life Sciences (BLS) of the National Research Council (NRC) convened two workshops on marine biotechnology. One examined issues limiting the application of biotechnology to marine environmental science (October 1999; National Research Council, 2000), and the other examined issues surrounding biomedical benefits from marine natural products (November 2001). In this report, the OSB and BLS ad hoc Committee on Marine Biotechnology summarize and integrate information obtained from the two workshops and highlight areas where new investments are likely to pay the

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products highest dividends in fostering the implementation of marine biotechnology in the environmental and biomedical arenas. DRUG DISCOVERY AND DEVELOPMENT The U.S. public is aware of the societal benefit of effective drug therapy to treat human diseases and expects that treatment will improve and become ever more accessible to the nation’s population. This expectation is predicated on a continued and determined effort by academic scientists, government researchers, and private industry to discover new and improved drug therapies. Natural products have had a crucial role in identifying novel chemical entities with useful drug properties (Newman et al., 2000). The marine environment, with its enormous wealth of biological and chemical diversity (Fuhrman et al., 1995; Field et al., 1997; Rossbach and Kniewald, 1997), represents a treasure trove of useful materials awaiting discovery. Indeed, a number of clinically useful drugs, investigational drug candidates, and pharmacological tools have already resulted from marine-product discovery programs (Table 1). However, a number of key areas for future investigation are anticipated to increase the application and yield of useful marine bioproducts (see Fenical, p. 45 in this report). The broad areas where advances could have substantial impact on drug discovery and development are (1) accessing new sources of marine bioproducts, (2) meeting the supply needs of the drug discovery and development process, (3) improving paradigms for the screening and discovery of useful marine bioproducts, (4) expanding knowledge of the biological mechanisms of action of marine bioproducts and toxins, and (5) streamlining the regulatory process associated with marine bioproduct development. New Bioproduct Discovery and Supply The ocean is a rich source of biological and chemical diversity. It covers more than 70% of the earth’s surface and contains more than 300,000 described species of plants and animals. A relatively small number of marine plants, animals, and microbes have already yielded more than 12,000 novel chemicals (Faulkner, 2001). Unexamined habitats must be explored to discover new species. Most of the environments explored for organisms with novel chemicals have been accessible by SCUBA (i.e., to 40 meters). Although some novel chemicals have been identified at high latitudes, such as the fjords of British Colum-

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products TABLE 1 Some Examples of Commercially Available Marine Bioproducts Product Application Original Source Pharmaceuticals Ara-A (acyclovir) Antiviral drug (herpes infections) Marine sponge, Cryptotethya cryta Ara-C (cytosar-U, cytarabine) Anticancer drug (leukemia and non-Hodgkin’s lymphoma) Marine sponge, Cryptotethya cryta Molecular Probes Okadaic acid Phosphatase inhibitor Dinoflagellate Manoalide Phospholipase A2 inhibitor Marine sponge, Luffariella variabilis Aequorin Bioluminescent calcium indicator Bioluminescent jellyfish, Aequora victoria Green fluorescent protein (GFP) Reporter gene Bioluminescent jellyfish, Aequora victoria Enzymes Vent and Deep Vent DNA polymerase (New England BioLabs) Polymerase chain reaction enzyme Deep-sea hydrothermal vent bacterium Nutritional Supplements Formulaid (Martek Biosciences) Fatty acids used as additive in infant formula nutritional supplement Marine microalga Pigment Phycoerythrin Conjugated antibodies used in ELISAs and flow cytometry Red algae Cosmetic additives Resilience (Estée Lauder) “Marine extract” additive Caribbean gorgonian, Pseudopterogorgia elisabethae   SOURCE: Adapted from Pomponi (1999).

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products bia and under the Antarctic ice, the primary focus of marine biodiversity prospecting has been the tropics. Tropical seas are well-known to be areas of high biological diversity and, therefore, logical sites of high chemical diversity. Much of the deep sea is yet to be explored, and very little exploration has occurred at higher latitudes. With rare exceptions (e.g., the analysis of deep-sea cores to identify unusual microbes), marine organisms from the deep-sea floor, mid-water habitats, and high-latitude marine environments and most of the sea surface itself have not been studied. The reason for this deficiency is primarily financial: oceanographic expeditions are expensive, and neither federal nor pharmaceutical-industry funding has been available to support oceanographic exploration and discovery of novel marine resources. The potential for discovery of novel bioproducts from yet-to-be discovered species of marine macroorganisms and microorganisms (including symbionts) is high (see Carter, p. 47 in this report; de Vries and Beart, 1995; Cragg and Newman, 2000; Mayer and Lehmann, 2001). To optimize identification of marine resources with medicinal potential, the best tools for discovery must be used at all stages of exploration: in new locations, for collection of organisms never before sampled, and for the identification of chemicals with pharmaceutical potential. Increased sophistication in the tools available to explore the deep sea has expanded the habitats that can be sampled and has greatly improved the opportunities for discovery of new species and the chemical compounds that they produce. New and improved vehicles are being developed to take us farther and deeper in the ocean. These platforms need to be equipped with even more sophisticated and sensitive instruments to identify an organism as new, to assess its potential for novel chemical constituents, and if possible, to nondestructively remove a sample of the organism. Tools and sensors that have been developed for space exploration and diagnostic medicine need to be applied to the discovery of new marine resources. Perhaps the greatest untapped source of novel bioproducts is marine microorganisms (see Fenical, p. 45 in this report; Bentley, 1997; Gerwick and Sitachitta, 2000; Gerwick et al., 2001). Although new technologies are rapidly expanding our knowledge of the microbial world, research to date suggests that less than 1% of the total marine microbial species diversity can be cultured with commonly used methods (see Giovannoni, p. 65 in this report). That means chemicals produced by as many as 99 percent of the microorganisms in the ocean have not yet been studied for potential commercial applications. These organisms constitute an enormous un-

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products tapped resource and opportunity for discovery of new bioproducts with applications in medicine, industry, and agriculture. Developing creative solutions for the identification, culture, and analysis of uncultured marine microorganisms is a critical need. With the enormous potential for discovery, development, and marketing of novel marine bioproducts comes the obligation to develop methods for supplying these products without disrupting the ecosystem or depleting the resource. Supply is a major limitation in the development of marine bioproducts (Cragg et al., 1993; Clark, 1996; Turner, 1996; Cragg, 1998). In general, the natural abundance of the source organisms will not support development based on wild harvest. Unless there is a feasible alternative to harvesting, promising bioproducts will remain undeveloped. Some options for sustainable use of marine resources are chemical synthesis, aquaculture of the source organism, cell culture of the macroorganism or microorganism source, and molecular cloning and biosynthesis in a surrogate organism. Each of these options has advantages and limitations; not all methods will be applicable to supply every marine bioproduct, and most of the methods are still in development. Understanding the fundamental biochemical pathways by which bioproducts are synthesized is key to most of these techniques. Molecular approaches offer particularly promising alternatives not only to the supply of known natural products (e.g., through the identification, isolation, cloning, and heterologous expression of genes involved in the production of the chemicals) but also to the discovery of novel sources of molecular diversity (e.g., through the identification of genes and biosynthetic pathways from uncultured microorganisms) (Bull et al., 2000). Manipulation of heterologously expressed secondary metabolite biosynthetic genes to produce novel compounds having potential pharmaceutical utility is at the forefront of current scientific achievements and has tremendous potential for creation of novel chemical entities (see Moore, p. 61 in this report; Khosla et al., 1999; Du and Shen, 2001; Floss, 2001; Rohlin et al., 2001; Staunton and Wilkinson, 2001; Xue and Sherman, 2001). In approaches parallel to those used for terrestrial soils, efforts need to be made to clone useful secondary metabolite biosynthetic pathways from natural assemblages of marine microorganisms (e.g., “cloning of the ocean’s metagenome”). Use of these approaches to provide solutions to natural-product supply and resupply problems should be increased.

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products Screening for Bioactivity Screening of natural materials for biologically active compounds has undergone radical changes over the past decade. With the advent of high-throughput-screening (HTS) technologies, an enormous number of materials, over 600,000, can be screened for a particular biological or biochemical property in a relatively short time, 2 to 4 months (Landro et al., 2000; Engels and Venkatarangan, 2001; Manly et al., 2001). Hence, a screen for a given disease target may be in operation for 3 months, during which time, marine natural products will be competing with large libraries of synthetic chemicals. New strategies for handling natural-product “mixtures” must be developed to synchronize with the accelerated HTS timetables. Marine natural-product mixtures, or extracts, must be purified and their active components rapidly identified. Development of technology to allow the prefractionation of crude extract materials prior to biological assay may allow for the rapid examination of active compound structures. Another arena for improvement is the efficient elucidation of known and new natural-product structures. Hybrid analytical techniques that combine high-performance liquid chromatography (HPLC) with mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy are becoming more common and accessible to natural-products chemists, and use of such techniques will expand in a variety of scholarly settings (Peng, 2000; Wilson, 2000). Continuous technological advances are needed in analytical chemistry associated with marine drug discovery to keep pace with comparable advances in biological screening of natural materials. Currently, investigators do not have access to a broad range of biological assays for marine bioproduct discovery. Innovative strategies are needed that link groups of investigators to efficient drug-discovery programs. Such partnerships are envisioned for broad evaluations of new marine biomaterials in assays targeting a more complete range of human diseases (e.g., infectious, cardiovascular, cancer, neurodegenerative diseases, allergy and inflammation, and other metabolic disorders) as well as agricultural and veterinary needs. The increased number of discoveries of biomaterials possible through these partnerships and a corresponding improvement in the sophistication of their handling and distribution will encourage greater industrial evaluation of novel marine bioproducts.

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products Understanding Mechanisms of Action The clinical and commercial development of many marine natural products languishes because of insufficient knowledge of how the compounds function in biological systems (Faulkner, 2000). It is precisely this understanding of pharmacological mechanism of action that has driven the development of such well-known pharmaceuticals as the potent anticancer metabolite paclitaxol (Taxol) from the Pacific yew tree (see Jordan and Wilson, p. 52 in this report; Correia and Lobert, 2001). Strategies that might be used in accelerating the development of marine biomaterials include focused mechanism-of-action studies, screening of libraries of purified marine metabolites by mechanism-based high-throughput assays, and characterization of a compound’s biological effect using functional genomic and proteomic approaches. At the same time, it is crucial to make advances in integrated pharmacology to understand the effects of new and experimental drug therapies at the molecular, cellular, organ, and whole-animal levels. Molecularly based chemical ecological studies are a complementary approach to learn how marine biomaterials exert their properties in nature. In general, a greater emphasis on studying the mechanisms by which marine metabolites exert their potentially valuable properties will translate into an increased number of clinical candidates entering the development pipeline. Marine organisms have demonstrated their utility as models to understand disease processes in humans (Table 1) (see Walsh, p. 57 in this report). Priority should be given to the identification and development of new model marine organisms to (1) identify novel targets for disease therapy, (2) discover novel chemicals for drug development, and (3) provide alternatives to current animal (and human) testing of drugs. With more complete genome sequences available from novel organisms, it will be more likely that an analog to human mutations can be found in a convenient test organism. Of critical importance in the development of new models is the availability of genome sequences from marine organisms. Genomic approaches, including whole-genome studies of appropriate model organisms, will accelerate discovery of new targets and new marine-derived drugs.

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products Recommendations for Enhancing Drug Discovery with Marine Biotechnology Explore new habitats. Develop tools to discover new resources. Discover and culture new marine microorganisms (including symbionts). Provide sufficient supply of bioproducts. Develop new screening strategies. Pursue strategies to hasten the discovery of new materials. Combine resources of academic, governmental, and industrial laboratories to expand access to biological screens in a variety of therapeutic areas. Expand research on pharmacological mechanisms. Establish new marine model organisms. Expand research on marine bioproduct biosynthesis and molecular biology. GENOMICS AND PROTEOMICS APPLICATIONS FOR MARINE BIOTECHNOLOGY Genomics Genomics is the sequencing, annotating, and interpreting of information contained within the genome of an organism. Genome sequences of microorganisms represent the majority of the earliest work in genomics (Fraser et al., 2000a,b; Nelson et al., 2000) and have led to a better understanding of the biology of the organisms sequenced (Nierman et al., 2000). Microorganisms have been the focus of genomic research, probably because they have smaller genomes and therefore represent a more manageable sequencing goal. Recent technological breakthroughs in automated DNA sequencing and computational power have made it possible to rapidly sequence and annotate even large or complex genomes (Nelson et al., 1999; Heidelberg et al., 2000). Representations of the entire metabolic potential of microorganisms derived from the application of bioinformatics have indicated the presence of hitherto unsuspected metabolic pathways in even some very-well-characterized bacteria. Such genomic information provides a new basis for understanding physiological processes, such as responses of indicator species to environmental changes, stimuli that cause

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products an organism to synthesize a product of potential human benefit, or discovery of new gene targets for drug therapy, to name just a few (Read et al., 2001). The pharmaceutical industry has taken advantage of microbial genomics to search for novel vaccine targets in pathogenic microorganisms, greatly reducing the time and cost of drug target discovery (Pizza et al., 2000). We have learned a tremendous amount during the infancy of the “genomic revolution.” During this early period of genomic research, both basic and applied scientific questions have been addressed, and many have been answered. The ability to determine fully the genomic structure of an organism has allowed for finer resolution and greater speed in addressing specific biomedical questions, such as determining potential vaccine candidates from bacterial pathogens (Saunders et al., 2000). The genomic revolution has also led to the discovery of novel processes with major ecological implications, such as a rhodopsin-driven proton pump in an abundant but uncultured proteobacterium from the ocean’s surface. This discovery— based on the application of genomics to analyses of easily collected but uncultured marine microorganisms—has opened a new path to understanding of light-harvesting and near-surface open-ocean primary productivity (Béjà et al., 2000, 2001). Current genomic methods enable researchers greater speed, sensitivity, and resolution over other commonly used molecular methods. As the science of genomics continues to mature, new technologies will emerge. Their implementation and integration with other technologies will be essential for advancement in the marine biomedical and environmental sciences (Cary and Chisholm, 2000). With recent decreases in sequencing costs and increases in the number of high throughput sequencing facilities at private, governmental, and nonprofit laboratories in the United States, complete genome sequencing of many established and novel model organisms, including eukaryotic marine organisms, is realistically attainable (Fraser, p. 66 in this report). In addition, the development of genomic technologies, such as bacterial artificial chromosomes (BACs) enabling the cloning of large DNA fragments, and the expansion of computational tools for genomic analysis now allow the complete sequencing and genomic analysis of entire biological systems to be an achievable goal. Many marine eukaryotic organisms (e.g., corals, sponges, and tube worms) maintain large and diverse populations of microbial symbionts. The complete genome sequences of these consortia will not only lead to unprecedented understanding of the interactions be-

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products tween host and symbiont, but will also expedite the discovery of novel metabolites, such as drugs and fine chemicals, that are the products of such consortia. As much as 40% of a genome encodes for genes whose functions remain unknown, highlighting genome sequencing and annotation as a parts list, but not the organism’s instruction manual. These unknown gene functions represent a starting point for scientists studying either a specific organism or a biological relationship (e.g., host and symbiont). However, for complete genome sequences to be utilized by the greatest number of scientists possible, particular species or strains must be identified and carefully selected as models (see Walsh, p. 57 in this report). Genomic information should enable as large a scientific community as possible to expand its current research; the selection of an inappropriate organism will not allow for a broad application. Although the cost of sequencing has decreased, it is still important not to waste effort on redundant genomic projects. To reduce duplication of effort, the sequence data and the databases and tools that allow scientists to analyze and utilize the data must be maintained and made accessible. Additionally, projects that require sequencing of large genomes must be subjected to a careful cost and value analysis of finished genome versus draft sequencing (a less expensive approach, with missing genes and misassembled regions of the genome). The scientific community at large must take responsibility for many of these pragmatic considerations, selection of appropriate model species for sequencing, maintenance of publicly accessible databases, and determination of the relative value of finished genome versus draft sequencing. Marine Microbes and Genomics A large and interesting pool of potentially bioactive molecules is likely to be affiliated with the microbial population of the oceans (see Fenical, p. 45, and Giovannoni, p. 65 in this report). These populations are typically composed of a few cosmopolitan organisms, but the overall group diversity is very high. It has been a problem to bring many of these organisms into culture where they can be studied more easily. Currently, methods are being developed that have allowed several of these cosmopolitan marine bacteria to be cultured. There are numerous other marine microorganisms that have not been cultured. Some of these bacteria might be culturable when more innovative approaches are developed (see Giovannoni, p. 65 in this report). How-

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products ever, it is unlikely the species diversity of the oceans will be brought completely into pure culture. As a more tractable alternative, genomic and bioinformatic methods are powerful new tools to access the gene products of these uncultured microorganisms. The total DNA from an environmental sample can be purified without first culturing the organisms (Ward et al., 1990, 1992; Rondon et al., 2000). This environmental DNA can be sequenced analogously to a genome and allows access not only to the protein products of uncultured bacterial species, but also to the genomic potential of the environment (or “ecological genomics”). The current technology is already in place for such survey sequencing of environmental DNA. Following bioinformatic analysis, cloning and expression of selected genes from the uncultured bacteria will likely lead to the discovery of novel bioactive molecules. These methods have been used successfully in looking for antimicrobial proteins from uncultured soil bacteria. DNA Microarrays Microarray technologies offer an additional tool for high-throughput analyses of the genome of an organism and the responses of an organism to specific changes. In an organismal DNA microarray, thousands of protein-encoding DNA sections are arrayed on a solid support structure (e.g., glass slide or nylon membrane). The array is then hybridized with a nucleic acid from a test sample, and the genes common to both the microarray and the test sample can be detected. As one example of an application of DNA microarray technology, the nucleic acid test sample can be the total messenger RNA (representing those genes that are likely being expressed as proteins) isolated before and after introduction of an environmental stress (e.g., addition of a pollutant, challenge with a bioactive molecule, and change in temperature). In this case, the genes that the organism differentially expresses as a result of the stress can be determined. Therefore, microarrays can be useful tools to examine gene expression patterns of a model organism in response to a variety of stimuli. That capability makes them powerful new diagnostic tools with applications in environmental monitoring, bioremediation, and drug discovery and reiterates the importance of careful selection by the scientific community of model organisms for complete genome sequencing. Obviously, this tool is most powerful for organisms for which the complete genome is sequenced, but even if expressed sequence tags (ESTs) are spotted on the microarray, experiments can yield very useful information (see Walsh, p. 57 in this report).

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products istics, critical issues of cross link biocatalysis and water displacing post-translational modifications of secreted adhesive biopolymers must be resolved (see Benedict, p. 69 in this report). In addition to the submerged biological and physical surfaces, the air-sea interface is important as a biomaterial source and model for bioengineering of new artificial lungs and biolubricants. The sea surface is ubiquitously coated with surface-active natural molecules that are the modulators of gas and particle exchange across the liquid-gas interface. Similar analogies exist between sea-surface films and natural biolubricants of human tear films in the blinking human eye. Applications for Novel Marine Biomaterials There are many areas in which a better understanding of physiological processes in marine organisms may improve the development of biomedical tools. For example, coral growth and healing may improve the understanding of bone development and healing. A better understanding of the principles of biomimicry of marine surfaces may allow the development of micro- and nano-structured implants for tissue regeneration. Sea-surface explorations should be a routine part of deep sea and coral examinations for materials with bioengineering and tissue-engineering applications. New photocatalytic materials will likely be found in the uppermost sea-surface zones otherwise neglected in explorations of deep sea and coral surfaces, as evidenced by the recent discoveries of light-driven photopigment reactions near the sea-air boundary (Béjà, et al., 2000, 2001). Biotechnological tools may reveal how marine biocatalysis promotes secure underwater adhesion, with strength and security yet unmatched by terrestrial sources and synthetic approaches. Underwater self-cleaning, self-lubricating plant and animal surfaces may be better understood with new biotechnology, the results of which could be used for the benefit of dry eye and dry mouth sufferers and lubricant-depleted human tissues. The sustained productivity and economic successes of collection and bioengineering of kelp and other macroalgal products into agars, alginates, and food products provide models for the future of marine biotechnology as it applies to marine biomaterials. Another goal is to identify and exploit the micro- and nano-scale novel characteristics of marine organisms that can make excellent templates for biomaterials and drug delivery of therapeutic devices with potential application in human medicine and bioengineering.

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products Recommendation for Enhancing Development of Marine Biomaterials Explore for new sources and characterize the novel physical and chemical characteristics of marine biomaterials for potential innovative biomedical and environmental engineering applications including biomolecular materials design. PUBLIC POLICY, PARTNERSHIPS, AND OUTREACH IN MARINE BIOTECHNOLOGY Although marine biotechnology has an expanding impact on biomedical, agrichemical, and environmental applications, important knowledge gaps still exist. More discussion among scientists, private businesses, legislators, and the public must be organized to ensure broader implementation and commercialization of products. These gaps include issues of intellectual property rights, mechanisms of technology transfer, knowledge of regulatory requirements (Gerhart, p. 94 in this report), resource sustainability (Bruckner, p. 87 in this report), and the importance of forging partnerships between and among the various constituent stakeholders (see Rosenthal, p. 91, and Cato and Seaman, p. 97 in this report). Businesses, legislators, and the public need to understand the importance and promise of ocean biodiversity as a source for marine biotechnological innovation and recognize the promise and problems of marine biotechnology as they specifically relate to environmental and biomedical applications. Intellectual Property Rights and Technology Transfer The commercial development of marine bioproducts is complex, time-consuming, expensive, and risky (see Gerhart, p. 94 in this report). Thus, protection of an individual’s intellectual property rights through patents, copyrights, trade secrets, or trademarks for a potential product is essential for encouraging commercial development of that product (Smith and Parr, 1998). However, academic environments create special challenges for individual patent protection, primarily because academic culture is based on intellectual freedom, open discourse, and individual achievement. The role of the university is viewed as one of creating and disseminating knowledge, not withholding and protecting information. Indeed, most university research is externally funded, and investigators are expected to publish exten-

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products sively. Thus, a fundamental disconnect exists between the general view of the university’s mandate for openness and access and the need for patent protection to ensure that products and ideas developed within an academic setting can be realistically available for the lengthy and expensive process of commercialization. To facilitate the interaction of industry and academia, most universities now maintain offices that facilitate technology transfer. The concept of university-industry technology transfer is attributed to Vannevar Bush, science advisor to President Franklin Delano Roosevelt. Initially, the idea was driven by concerns about U.S. national security during World War II. In 1980, the Bayh-Dole Act modernized the concept and stimulated the creation of the university technology transfer programs as we know them today. This act mandates that university researchers must disclose inventions made with federal support and requires universities to report inventions to the U.S. government. According to the act, universities may elect to take title to an invention resulting from federally funded research but notes that if they do so, they must diligently pursue patenting and commercialization. Universities typically accomplish technology transfer through licensing (Abramson et al., 1997). The Regulatory Process Federal regulations control the development and marketing of bioproducts with human health and safety implications. Preclinical- and clinical-product development related to the regulatory process can take an average of 5 to 7 years and can cost from $15 million to more than $200 million (Cato, 1988; Trenter, 1999), with some reports of costs as high as $800 million (DiMasi, 2001). This cost can be one of the most important hurdles to surmount in the development of a marine-derived bioproduct. Mechanisms to streamline the process and lower the expense must be explored if marine bioproduct development for medical applications is to succeed. A look at the marine bioproducts available today through the advances of marine biotechnology suggests that numerous products of marine origin have already been successful. Products have been brought to market (Tables 1 and 2), and ideas have been licensed for commercial development (Table 3). Despite these successes, there are concerns that the potential of many marine bioproducts is being compromised because the transition from labo-

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products TABLE 2 Some Commercially Available Marine-Derived Biomedical Research Probes Source Probe Function Price Sponge Manoalide Phospholipase A2 inhibitor $120/mg Calyculin A Protein phosphatase inhibitor $105/25 µg Luffariellolide Phospholipase A2 inhibitor $100/mg 12-epi-scalaridial Phospholipase A2 inhibitor $136/mg Latrunculin B Actin polymerization inhibitor $90/mg Mycalolide B Actin polymerization inhibitor $212/20 µg Swinholide A Actin microfilament disruptor $100/20 µg Dinoflagellate Okadic acid Protein phosphatase inhibitor $75/25 µg Bryozoan Bryostatin 1 Protein kinase C activator $88/10 µg Sea hare Dolastatin 15 Microtubule assembly inhibitor $125/mg   SOURCE: BioMol [www.biomol.com]. ratory discovery to early commercial development has not been efficient or successful, and regulatory hurdles have not been surmounted. To overcome these bottlenecks it is necessary to educate marine scientists more aggressively about intellectual property rights and regulatory processes. That education should result in increased invention disclosure rates that will preserve nascent patent rights and ensure that more products are available for commercialization. Efforts should also be made to encourage transitional research, thus enhancing the movement of an idea to marketable product. Sustaining Resources Through Diverse Partnerships Because the continued successful development of marine biotechnology is intimately connected with ocean biodiversity, it is essential that efforts be made to ensure that biodiversity is protected. Tropical regions with especially rich biological marine ecosystems are often regions of intense poverty (see Bruckner, p. 87 in this report). Short-term, regional financial incentives, which seem to have an immediate impact on the poverty, must be balanced with the long-term sustainability of the resource. Partnerships must be developed to protect marine resources in tropical areas in particular, thus ensuring a positive economic outcome and the long-term protec-

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products TABLE 3 Marine-Derived Antitumor Compounds Licensed for Development Marine Source Drug Organism Current Status Sponge Discodermolide Discodermia dissoluta To enter Phase I trials in 2002; licensed to Novartis Isohomo-halichondrin B Lissodendoryx sp. Licensed to PharmaMar S.A.; in advanced preclinical trials Bengamide Jaspis sp. Synthetic derivative licensed to Novartis; in clinical trials Hemiasterlins A & B Cymbastella sp. Derivatives to enter clinical trials in 2002; licensed to Wyeth-Ayerst Girolline Pseudaxinyssa cantharella Licensed to Rhone Poulenc Bryozoan Bryostatin 1 Bugula neritina In Phase I/II clinical trials in U.S./Europe; U.S. National Cancer Institute (NCI) sponsored trials tion of the resource (see Rosenthal, p. 91 in this report). In all cases, commercial development from natural populations of marine organisms must be sustainable if it is to make economic sense. Sustainability is one of the central challenges in further development of marine biotechnology, and it must be addressed before large-scale marine harvests can begin. Innovative approaches to partnerships between stakeholders can help to support access to marine resources and to ensure their development as sustainable assets. Agreements that include training and education of local populations can be particularly valuable for long-term resource sustainability.

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products Marine Source Drug Organism Current Status Sea hare Dolastatin 10 Dolabella auricularia Phase I clinical trials in U.S.; NCI sponsored trials Tunicate Ecteinascidin 743 Ecteinascidia turbinata Licensed to PharmaMar S.A.; in Phase III clinical trials in Europe and in U.S. Aplidine Aplidium albicans In Phase II clinical trials; licensed to PharmaMar S.A. Isogranulatimide Didemnum granulatum Licensed to Kinetik, Canada Gastropod Kahalalide F Elysia rubefescens In Phase I clinical trials; licensed to PharmaMar S.A. Actinomycete Thiocoraline Micromonospora marina Licensed to PharmaMar S.A.; in advanced preclinical trials   SOURCE: Data from David J. Newman, National Cancer Institute, Natural Products Branch, Frederick, Md. Enhancing Public Awareness and Understanding of Marine Biotechnology As marine biotechnology rapidly evolves, there is an increasing gap between use of technology and the public’s understanding of that science and its implications. To avoid the public’s misunderstandings that plague agricultural biotechnology (e.g., genetically modified foods), it is essential that scientists partner with the public to provide information that addresses both the promise and possible problems of marine biotechnology. A multitier approach should be developed that connects individuals from science,

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Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products education, business, and media to address the public’s formal and informal educational needs (Cato and Seaman, p. 97 in this report). For marine biotechnology, implementation of improved technology transfer, sustainable environmental stewardship, innovative partnerships, and enhanced public education should result in increased production of marine bioproducts and approved marine therapeutics, enhanced revenues from marine bioproducts, and positive impacts on coastal economic development. Recommendations to Enhance Research and Development, Partnerships, and Outreach for Marine Biotechnology Aggressively educate marine scientists about intellectual property rights and regulatory processes to increase invention disclosure rates and preserve patent rights so that more products will be available for commercialization. Encourage academic rewards for transitional research between academic and industry scientists to facilitate the commercialization of marine bioproducts. Develop innovative approaches to partnerships between stakeholders to support access to ocean resources and to ensure their use as sustainable assets. Educate the public to the promise and problems of marine biotechnology to avoid fears rooted in misunderstanding and misconception. Enhance technology transfer services in universities. REFERENCES 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. Anderson, J. M. 1996. Biomaterials and medical implant science: present and future perspectives: a summary report. Journal of Biomedical Materials Research 32:143-147. Béjà, O., L. Aravind, E. V. Koonin, M. T. Suzuki, A. Hadd, L. P. Nguyen, S. B. Jovanovich, C. Gates, R. A. Feldman, and E. F. DeLong. 2000. Bacterial bacteriorhodopsin: evidence for light-driven proton pumping in the sea. Science 289:1902-1906. Béjà, O., E. N. Spudich, J. L. Spudich, M. Leclerc, and E. F. DeLong. 2001. Proteorhodopsin phototrophy in the ocean. Nature 411:786-789. Bentley, R. 1997. Microbial secondary metabolites play important roles in medicine; prospects for discovery of new drugs. Perspectives in Biology and Medicine 40:364-394.

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