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 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 untapped 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.

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.

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.

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

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 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 between 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). However, 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).

Microarray techniques also are powerful tools for examining the genomic differences between two organisms, particularly if a complete reference genome is available for comparisons. The total genomic DNA of the second organism is used as the test sample for hybridization to the genome microarray of the first organism. These data allow rapid determination of the genes found on the reference genome and genes shared between the two organisms. Such comparisons to reference genomes are very useful to identify genes that are distinctive to different individuals or strains from different environments. Medical microbiologists have taken advantage of such comparisons to find pathogenicity “islands” in disease-causing bacteria. By sequencing and building a genome array of a pathogenic bacterial strain and hybridizing the array with less pathogenic strains of the same species, genomic regions resulting in increased pathogenicity have been determined (see Fraser, p. 66 in this report). Analogously, the genes responsible for the production of bioactive molecules by marine eukaryotes or prokaryotes can be more quickly determined after the genome sequence of the model organism is determined and a complete genome array constructed.

As microarray methods become more common, duplication of effort and resources is more likely. Much of the cost of microarray technology is in the design and production of the test slide. If care is not taken, individual researchers might waste important time and effort producing duplicate microarrays for the same species. One way to reduce the risk of duplication is through centralization of a microarray production facility, either virtual or physical, for community-wide use. Such a facility may also help to standardize methods and allow comparisons of experiments conducted in different laboratories.

Proteomics

Proteomics is the characterization of the proteins specified by the genome of an organism. Proteomics is a new science that is considered to be an extension of the Human Genome Project, because it links genetics with physiology and provides clues not only to the function of genes encoding certain proteins but also to the function of the proteins. There are molecular techniques that allow determination of expressed proteins in a given system. However, these techniques are very time-consuming when used to identify the posttranslational modification of proteins. An understanding of the modification of proteins will become increasingly more important in the search for novel biomolecules.

The potent combination of classic microbiological techniques, proteomics, and genomics must be recognized. Lab culture of microorganisms, when linked with genomic analysis and the use of proteomics, represents a continuum of knowledge about the adaptations of microbes to their changing environments. Intersections of these three investigative paths may provide crucial information for identifying novel metabolites, pathogens, and for characterizing environmental remediation needs.

Unfortunately, proteomic methods are not yet high throughput and are fairly costly when considering analyses of an entire genome. As these technologies develop, especially at the national laboratories, it will be important for proteomics to be integrated into marine biomedical and environmental research programs.

Genomics and Proteomics as Exploration Science

Genomic studies are not always hypothesis driven; their fields are exploratory. The technology enables scientists to generate data from which hypotheses can be formulated and tested. This exploration activity should be considered an asset because of its potential to increase our knowledge base, and it should not be considered a liability, particularly in the review of proposals incorporating genomics and proteomics technologies. It is important to make certain, however, that genomic and proteomic data are publicly available, and in a useful form so that the data can be used for hypothesis-driven research. Therefore, it is important that genomic and proteomic databases be developed, maintained, and made available as research tools.

Recommendations to Enhance the Application of Genomics and Proteomics to Marine Biotechnology

• Incorporate genome sequencing, proteomics, and bioinformatics with nonculture-based methods to survey diverse marine environments and improve screening methods for uncultured microbes.
• Ensure that high-throughput sequencing and informatics facilities are available to the marine biotechnology research community.
• Develop a community-wide consensus on model organisms for genome sequencing, and develop both a priority list and a “wish” list.
• Develop arrays for determining differences among the genomes of different organisms.
• Develop whole-genome and EST arrays to determine gene-expression patterns of model organisms as rapid screens for bioactivity and drug discovery.
• Develop environmental genome microarray chips to identify function or coregulation of genes from the environment.
• Determine the potential usefulness of a centralized microarray facility to make reagents, develop and disseminate informatics tools, and provide training to the marine biotechnology community. Reduce redundant funding of array development and nonstandardized hybridization techniques that will prevent cross-experiment comparisons.
• Ensure that the “exploratory” data generated in both genome sequencing and functional genomic studies are available to expedite and enable hypothesis-driven science. Include the development and maintenance of useful public databases and improved training of the scientific community.

Novel Characteristics of Macro-Biomaterials from Marine Organisms

Marine biomaterials are a heterogeneous group of organic-, ceramic-, and polysaccharide-based polymers that hold promise for a variety of new approaches to the treatment of disease (see White and White, p. 79, and Laurencin, p. 83 in this report). The marine environment is home to numerous microporous materials, such as those that provide the framework for coral reefs or those that compose the spines of sea urchins. These macrobiomaterials are characterized by highly interconnected porous networks, with a wide range of porosities (Weber and White, 1973). Because of their geometric and material properties, coral structures and urchin spines are used in vascular graft construction and orthopedic surgical repairs (see White and White, p. 79 in this report). Identification of the natural convoluted geometries and fouling-resistant surface features of coral has been a key factor prompting consideration of other biotechnology approaches to successful biomimicry and biomaterials manufacture. Marine organisms can provide many more novel models for biomolecular materials design.

New biotechnologies have been introduced for biocompatible, self-limiting, implantable biomedical devices based on “storage biopolymers,” such as polyhydroxyalkanoates, which are abundant in marine microorganisms (see Laurencin, p. 83 in this report; Madison and Huisman, 1999). New opportunities also exist for high-value biomedical products, such as drug-delivery units, based on chitin from marine crabs and other crustaceans (Felt et al., 1998; Janes and Alonso, 2001; Sato et al., 2001). The enormous supply of chitin and chitosan biopolymers serves as a base for hydrogel-like hosts for various medicinal ingredients, including antibiotics, and provides good wound-dressing qualities for abrasions and ulcers. Work is under way to utilize novel combinations of storage biopolymers, particularly polyhydroxybutyrate, with coral segments to fabricate a scaffold that can be used in bone repair (Laurencin et al., 1996; Madihally and Matthew, 1999; Suh and Matthew, 2000).

Facilitating Work at Surfaces

Marine surfaces are important planes of research and exploration for biotechnological applications. Of particular interest are the characteristics of submerged natural surfaces that resist corrosion and adhesion and the opposing characteristics of selected organisms that allow them to adhere tightly to wet, slimy surfaces. The oceans' intrinsically nonstick, low-drag plant and animal surfaces and the adaptations of some species to adhere to wet surfaces hold incredible promise for future biomedical applications (Anderson, 1996). The most well-known example is perhaps the common blue mussel, Mytilus edulis, with its strong byssal threads, and adhesion discs which allow it to remain attached in very high energy environments, including pounding surf. However, to fully commercialize these characteristics, critical issues of cross link biocatalysis and water displacing posttranslational 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.

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.

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 extensively. 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 laboratory 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.

TABLE 2

Some Commercially Available Marine-Derived Biomedical Research Probes.

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 protection 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.

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, 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.

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