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National Research Council (US) Committee on Marine Biotechnology: Biomedical Applications of Marine Natural Products. Marine Biotechnology in the Twenty-First Century: Problems, Promise, and Products. Washington (DC): National Academies Press (US); 2002.
National Research Council (US) Committee on Marine Biotechnology: Biomedical Applications of Marine Natural Products.
Washington (DC): National Academies Press (US); 2002.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. Fun-damental 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.
Some Examples of Commercially Available Marine Bioproducts.
Marine-Derived Antitumor Compounds Licensed for Development.
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 highest dividends in fostering the implementation of marine biotechnology in the environmental and biomedical arenas.
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.
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 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.
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.
