3
Essential and Emerging Research Fields and Technologies

FUNCTIONAL GENOMICS

Gene maps of human and selected model organisms' genomes are developing to the point where serious work on gene function is a large-scale reality. The Human Genome Initiative has been very successful in achieving the goal that it set out toward less than 15 years ago; early in the 21st century virtually all genes in the human genome will be identified. This success is leading to a re-focusing of genomic research from understanding how those genes function to gene expression at the molecular level and translation into phenotypic features at the functional level. Understanding gene interaction and how genes function within whole organisms will provide the basis for translating basic research into clinical therapy and disease prevention and will benefit human health on a broader scale than ever possible before. Although progress in developing therapy for and prevention of some specific human diseases has taken place coincidentally with the genome projects, the completion of gene identification will open the way for a redirection of major efforts in gene-function studies.

The popular term for the study of how genes function to control the whole organism is "functional genomics." The attention of the biomedical research community is refocusing from detailed analysis of the genome to functional genomics. The American Physiological Society organized a workshop at the Banbury Center, Cold Spring Harbor, NY, in 1997, "Genomics to Physiology and Beyond: How Do We Get There?" at which the phrase "Genes to Health Initiative" was coined. A meeting to begin detailed planning of next steps for the Physiome Project was held in St. Petersburg, Russia, in 1997, and a followup meeting will be held in San Francisco in 1998 (Cowley 1997).

Models are critical to enable us to move from genomic to functional genomic analysis. Gene function can be assessed only by moving beyond molecular biology to the study of whole animals, whole cellular systems in culture, or computer modelling of complex biologic systems. Moreover, no gene acts alone. The interaction of genes in whole animals to produce phenotypes or diseases can be understood only by performing experiments in whole animals or with the aid of highly sophisticated computer modelling systems. Sophisticated computer systems will be required to organize, analyze, and interpret the complex data generated by such experiments.

Two approaches to understanding gene function in mice and zebrafish are gene expression analysis and mutagenesis. The first is based mainly on transcript maps with



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Biomedical Models and Resources: Current Needs and Future Opportunities 3 Essential and Emerging Research Fields and Technologies FUNCTIONAL GENOMICS Gene maps of human and selected model organisms' genomes are developing to the point where serious work on gene function is a large-scale reality. The Human Genome Initiative has been very successful in achieving the goal that it set out toward less than 15 years ago; early in the 21st century virtually all genes in the human genome will be identified. This success is leading to a re-focusing of genomic research from understanding how those genes function to gene expression at the molecular level and translation into phenotypic features at the functional level. Understanding gene interaction and how genes function within whole organisms will provide the basis for translating basic research into clinical therapy and disease prevention and will benefit human health on a broader scale than ever possible before. Although progress in developing therapy for and prevention of some specific human diseases has taken place coincidentally with the genome projects, the completion of gene identification will open the way for a redirection of major efforts in gene-function studies. The popular term for the study of how genes function to control the whole organism is "functional genomics." The attention of the biomedical research community is refocusing from detailed analysis of the genome to functional genomics. The American Physiological Society organized a workshop at the Banbury Center, Cold Spring Harbor, NY, in 1997, "Genomics to Physiology and Beyond: How Do We Get There?" at which the phrase "Genes to Health Initiative" was coined. A meeting to begin detailed planning of next steps for the Physiome Project was held in St. Petersburg, Russia, in 1997, and a followup meeting will be held in San Francisco in 1998 (Cowley 1997). Models are critical to enable us to move from genomic to functional genomic analysis. Gene function can be assessed only by moving beyond molecular biology to the study of whole animals, whole cellular systems in culture, or computer modelling of complex biologic systems. Moreover, no gene acts alone. The interaction of genes in whole animals to produce phenotypes or diseases can be understood only by performing experiments in whole animals or with the aid of highly sophisticated computer modelling systems. Sophisticated computer systems will be required to organize, analyze, and interpret the complex data generated by such experiments. Two approaches to understanding gene function in mice and zebrafish are gene expression analysis and mutagenesis. The first is based mainly on transcript maps with

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Biomedical Models and Resources: Current Needs and Future Opportunities advanced technologies, such as chip technology (Chee 1997). Biotechnology companies are already beginning to invest in this chip technology, and NCRR is less likely to have a large role in it than in more whole-animal-oriented functional analysis. In the second approach, large-scale mutagenesis programs to identify functionally important genes by phenotype will require high-quality, high-resolution genetic and physical maps for rapid, efficient cloning of the genes that underlie the phenotypes. Large mutagenesis screens in zebrafish recently have been undertaken at the Max Planck Institute in Tubingen, Germany, and the Massachusetts General Hospital in Boston, MA; over 2000 mutations in more than 500 genes essential for embryonic development have been identified, but only nine have been cloned (Zon and others 1997). The National Human Genome Research Institute has already invested substantially in the mouse map. NCRR has already invested in mapping the zebrafish genome and should continue because this initiative will support many areas of biomedical research and is unlikely to be supported by other institutions. In addition, NCRR support of the development of gene maps of other nonmouse species is likely to have a broad impact on biomedical research in many fields. AGING Medical advances have extended human life expectancy in the United States by nearly 30 years in this century, and an increasing segment of the population is now over 60 and susceptible to diseases and conditions of aging. The aging process itself is increasingly a focus of research. This research has some unique needs. One of them is the use of aged animals, which are very expensive because of the need to hold animals for long periods. There are few resources for providing the aged animals needed by investigators. We heard from the survey and the workshop participants that some individual investigators are unable to purchase these animals through standard grant mechanisms. Standard grant mechanisms also do not allow studies of sufficient length for proper investigation of disease in aged models, such as postmenopausal osteoporosis in nonhuman primates. Demand for such models is likely to rise soon, and NCRR should prepare for this demand. Some aged rats and mice are subsidized by the National Institute on Aging (NIA). NIA also supports aging colonies of nonhuman primates that are maintained at four of the regional primate research centers. Their numbers are small and their availability appears to be not widely known. Aging colonies of other species are not available through either of these mechanisms. Ironically, NCRR is faced with supporting an aging colony of chimpanzees for which there seems to be little use. NCRR could encourage the use of these chimpanzees for research on aging although these animals are not well characterized. A variable tested in aging research is calorie restriction. Studies of calorie-restricted animals would require a group of aged animals.

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Biomedical Models and Resources: Current Needs and Future Opportunities BEHAVIOR AND NEUROBIOLOGY Although a strong tradition in basic behavioral research exists, tools and techniques are only now beginning to be available for dissecting out cellular, molecular, and genetic components of behavior. Advances never before thought possible are being made in understanding and treating human "behavioral" conditions. The aging of the human population increases the need for more research on ways to improve quality of life and to lessen the burden of age-related services for everyone. That need has already increased the emphasis on studies of age-related cognitive diseases of aging and memory, such as Alzheimer's disease and other forms of senile dementia. We are becoming increasingly aware that the severity of many diseases and rates of recovery from them have psychological components. In addition, as a society we are trying to improve our children's quality of life. It is clear that early learning and conditioning affect individual lives and behavior throughout life, as well as society as whole. Proper diet and regular and exercise can improve an person's health. Witness the volume of information put out by voluntary health organizations, such as the American Heart Association or American Cancer Society and the Public Health Service encouraging people to change their behavior to decrease their risk for cancer or heart disease. AIDS is a dramatic example of impacts of social behavior on health. Individual behavior—such as lack of self control vs. violence, is directly reflected in the rising incidence of juvenile crime. Emerging fields in which behavior is viewed as an end point include biologic psychiatry, developmental biology (the modelling of specific psychiatric disorders, such as anxiety, depression, and schizophrenia) and cognitive processes (such as spatial learning, memory and age-related declines in cognition) (Palmour and others 1997). Fields in which behavior itself can affect physiologic, cellular, and even molecular processes include the use of pharmacologic and genetic models to study the effects of drug addiction and relapse and psychoimmunology (the relationship of behavior to disease resistance and recovery). Aquatic organisms have been used for many years in behavioral studies and will continue to be valuable models. For example, zebrafish are a burgeoning developmental model, in particular for their expected role in molecular genetics and will probably provide advances in embryology, neurobiology, and other fields. With sophisticated new microscopes such as two-photon detectors, the use of resonant fluorescence probes, any cellular component can be followed in transparent zebrafish embryos from inception throughout the acquisition of normal adult behaviors. Mutational analysis can be conducted to assess the role of single gene loci in defined behaviors, thus offering insight into basic mechanisms of development and neuropathology. The types of technological advances needed for that research involve all the emerging fields of understanding of brain function in living animals. Relating neurobiology to behavior requires, for example, advances in brain imaging techniques for real-time assessment of the chemistry and physiology of individual cells in awake animals. This objective includes sophisticated telemetry and video for monitoring behavior in ethologically relevant settings. Ethological assessment will require

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Biomedical Models and Resources: Current Needs and Future Opportunities improvements in electrophysiologic measuring systems, noninvasive imaging systems, and baseline behavioral measures of each model species. COMPLEX DISEASE Most premature deaths and health-care costs result from diseases caused by interaction of multiple genes and the environment—so-called complex diseases (Rogers and Hixon 1997). Examples are diabetes and cardiovascular diseases. An emerging field of biomedical research is the search for genes underlying susceptibility to common diseases (heart disease, diabetes, cancer, infectious disease, and so on). Evidence of this emphasis in human biomedical research is seen in the development of the human genome project and an increase in targeting of NIH programs to genetics, for example, nearly all the categorical institutes have program announcements for genetic research. The goal is to develop animal models that will be useful for localizing and characterizing genes that affect complex diseases or disease risk traits. There are two basic approaches to that goal. The first, and perhaps the better known, is based on the use of genetically manipulated or selected inbred rodents. The strategy is to minimize background genetic variability to permit determination of the effect of single gene mutations or susceptibility alleles on phenotype. This approach, in parallel with human studies, has identified many genes that influence susceptibility to diabetes in mice and some homologs that influence susceptibility in human beings. Inbred dog species are a resource for modelling complex disease as well (Ostrander and Giniger 1997). A second approach uses a quite different (although complementary) strategy: exploiting the natural genetic variability of non-inbred populations by using both statistical and molecular methods to determine the phenotypic effects of gene loci, explicitly taking into account the effects of environment and other genes. Nonhuman-primate systems might model some human complex diseases better than rodent systems because of the close phylogenetic relationship between human beings and other primates. Farm animals are available in very large numbers with defined families. Outbred populations of 10,000 sows and 100,000 offspring are available as a national resource that is supported by commercial agriculture. The next frontier for genome research relative to complex, multigenic human diseases is identification and analysis of the roles of genes underlying these diseases and their precursors. Frequently, the assessment will be quantitative and will require new applications of statistics and the development of new computer software, and it will involve the chromosomal localization of phenotypic traits (typically quantitative trait loci) by statistical analysis followed by fine-scale molecular mapping and cloning. Those methods were devised for the study of human and mouse genetics, but they can be effectively applied to any non-inbred species. Methods and instrumentation for reliable assessment of subtle changes in phenotype will be required.

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Biomedical Models and Resources: Current Needs and Future Opportunities Model Discovery Serendipity continues to reward curious scientists with the discovery of new models. New models are also sought for specific reasons, for example, because existing models are no longer satisfactory or new diseases are discovered. There must always be a venue to accommodate these new discoveries, and in the past decade NCRR has played a pivotal role. New mammalian models can be expected to evolve slowly, but the huge diversity of biotic systems and the commonality of problems shared by all phyla ensures that many useful new models will be discovered in the future. The workshop highlighted new models in vertebrates and invertebrates that span nearly the entire range of biomedical research, and the group consensus was that this diversity is essential to the future of NIH. Current models have shortcomings that justify the consideration of their further development as well as the discovery and development of new models. For example, as neurobiologic models, nonhuman primates and rodents both have complex nervous systems that present difficulties for cellular physiology studies. Marine mollusks, such as Aplysia, have a simpler nervous system with large cells accessible for electrophysiology. They will continue to provide important insights into relatively simple behavior and forms of learning, but will be of limited value in understanding cognitive and higher brain function. Multiple model systems are necessary because each has their own strengths, but might an intermediary model exist that could provide a better combination of positive attributes? New models, regardless of phylum, can stimulate new ways of thinking about existing models. As stated by Nobel laureate Albert Szent-Gyorgyi ''Discovery is to see what everybody has seen and think what nobody has thought." (Szent-Gyorgyi 1957) From an evolutionary perspective, it is worth remembering that sensory systems of insects have had 520 million years of refinement and miniaturization, and it might be worth while to engage modellers, engineers, and neurobiologists in using these systems as models of prosthetics for hearing, vision, and so forth. All animals, including human beings, live in symbiotic relationships with bacteria and other microorganisms, but typically only pathologic interactions are studied. Invertebrate animals, especially marine ones, constitute excellent models for studying microorganism-animal interactions, chemical signaling, and the manner in which most microbes survive as nonpathogens with animals. Recently, a model has been developed in the tiny Hawaiian sepioid squid Euprymna scolopes, which harbors the bacterium Vibrio fischeri in its light organ in a symbiosis that provides bioluminescence (McFall-Ngai and Ruby 1991); this bacterial genus contains notorious pathogens, the most notable of which is V. cholerae. Understanding of these mechanisms—based on the use of models discovered in unorthodox ways—will lead biomedical researchers to begin to understand—and interrupt—the spread of disease.

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Biomedical Models and Resources: Current Needs and Future Opportunities MATHEMATICAL MODELLING, COMPUTATIONAL SIMULATIONS, AND SCIENTIFIC DATABASES Computer management of data related to biomedical models has two components: 1) biomathematical modelling and statistical analysis of data and 2) databases that store information that can be used to support functional genomic and other research. The importance of mathematical modelling and computation in biomedical research grows as the ability to collect and distribute data increases. The rapidly growing volume of data generated in current research efforts will require data-analysis and data-management resources that are not now widely available. Many kinds of biomedical research, including work with animal models, have not taken full advantage of advances in mathematical and computational modelling technology. Many investigators might be unaware of the variety and utility of models, computational tools, and simulation environments. The database issue has more to do with the need for public databases to provide phenotypic and physiologic information to the modelling community. Two kinds of needs are apparent. First, investigators developing small databases for their own work are often willing to share the information in them with fellow scientists. But most biologists will require easy-to-use database-design tools or need user friendly templates to make their databases public. Such templates would ensure good design and foster standards for the ultimate integration of local information into larger biologic data resources. Second, larger community databases are needed to provide phenotypic or model information. Such databases require support both for startup and continued maintenance. EMERGING AND RE-EMERGING INFECTIOUS DISEASES Workshop participants underscored the pressing need to identify cost-effective animal models for many infectious diseases, such as hepatitis C and tuberculosis. Emerging and re-emerging infectious diseases pose a substantial risk to human health. In particular, persistent infectious diseases have a tremendous impact on health and on health-care costs (The National Institute of Allergy and Infectious Disease Web page: http://www.NIAID.nih.gov/newsroom/pid.htm). Investigation of host-agent symbiosis and mechanisms of pathogen persistence in immunologically responsive and nonresponsive hosts requires the full range of accessibility to animal models, including the study of invertebrate biology, to support understanding of the agent-vector-host interface. Concern was expressed that 1) immunologic research on potentially valuable nonmouse model organisms is compromised by the lack of reagents for these organisms and 2) selective study of the mouse immune system, which historically has contributed much to our understanding of immunology, provides us only with an understanding of how the mouse immune system functions. Investigators have been studying the immune system of mosquitoes and other animals that are vectors for human infectious disease. When these immune systems are understood, vector-based control measures can be

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Biomedical Models and Resources: Current Needs and Future Opportunities developed. Another reason for studying the immune system in a wide variety of taxa is to find highly conserved gene segments that control vertebrate and human immune systems. Studies of the immune system of a variety of species might shed new light on the role of the immune system in cancer. When invertebrate immune systems are understood, vector-based control measures can be developed. Another reason is to find highly conserved features of vertebrate and human immune systems (Litman 1996). Studies with sharks might shed new light on the role of the immune system in cancer. There is an urgent need to investigate infectious diseases of laboratory animals, because infectious diseases pose problems in the effective use of these animals as models. Infectious diseases, including clinically silent infections also affect the research usefulness of infected animals: Infectious diseases modify immune responses, physiology, and behavior and have been misinterpreted as phenotypic expressions of gene alterations. Infectious-disease control and diagnosis impose an unquestionable strain on maintenance costs of laboratory animals. The collective impact of infectious diseases on animal-based research is enormous.