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Introduction

Studying human health involves two general experimental approaches: examining human or primate cells, tissues, and organs that constitute relatively direct models of human disease; and using a variety of model systems that offer special features and advantages that are not available for study in human beings or primates but can be applied to human health issues. There is enormous complementary of models used in biomedicine because of the fundamental nature of life on earth, that is, the biochemical and genetic unity of life and the principles and mechanisms of evolution, all of which provide an irrefutable rationale for wide-ranging comparative studies to understand the human condition.

There is excitement and optimism over the prospects for future biomedical research provided by advances and applications in molecular biology during the 1990s. The Committee on New and Emerging Models in Biomedical and Behavioral Research shares the optimism and applauds the National Center for Research Resources (NCRR) support of such work as the mapping of the genome of Caenorhabditis elegans and zebrafish, but we also stress the importance of renewed interest in organismic biology. Understanding living organisms is important not only to ensure their health and welfare but also to understand how genes function to control whole organisms. The latter point is, after all, the ultimate goal of molecular biology. Seeking to understand the function of genes is functional genomics, also termed "physiologic genomics" (Cowley 1997), the "Physiome Project" (Bassingthwaight 1995), or the ''Genes to Health Initiative" (Cowley 1997).

There are signs of a broadening of perspective to consider a more integrative and evolutionary approach to human disease. In practice, that means that not only will specific mechanisms of diseases be studied in detail, but questions concerning why a disease has evolved and the multiple factors that have led to it can be addressed in increasingly great detail. Clearly, the infrastructure to support this type of research is strained, and the strain underlies all the scientific issues related to biomedical models that are addressed in this report.

A decade ago, models for biomedical research were analyzed in depth (NRC 1985 Appendix C). The present committee's deliberations in 1997 found that many of the findings and recommendations of the 1985 committee's report still ring true. This report is meant not to replace the earlier one, but to focus more specifically on the part that NCRR has played, and will play, in biomedical progress.



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Biomedical Models and Resources: Current Needs and Future Opportunities 1 Introduction Studying human health involves two general experimental approaches: examining human or primate cells, tissues, and organs that constitute relatively direct models of human disease; and using a variety of model systems that offer special features and advantages that are not available for study in human beings or primates but can be applied to human health issues. There is enormous complementary of models used in biomedicine because of the fundamental nature of life on earth, that is, the biochemical and genetic unity of life and the principles and mechanisms of evolution, all of which provide an irrefutable rationale for wide-ranging comparative studies to understand the human condition. There is excitement and optimism over the prospects for future biomedical research provided by advances and applications in molecular biology during the 1990s. The Committee on New and Emerging Models in Biomedical and Behavioral Research shares the optimism and applauds the National Center for Research Resources (NCRR) support of such work as the mapping of the genome of Caenorhabditis elegans and zebrafish, but we also stress the importance of renewed interest in organismic biology. Understanding living organisms is important not only to ensure their health and welfare but also to understand how genes function to control whole organisms. The latter point is, after all, the ultimate goal of molecular biology. Seeking to understand the function of genes is functional genomics, also termed "physiologic genomics" (Cowley 1997), the "Physiome Project" (Bassingthwaight 1995), or the ''Genes to Health Initiative" (Cowley 1997). There are signs of a broadening of perspective to consider a more integrative and evolutionary approach to human disease. In practice, that means that not only will specific mechanisms of diseases be studied in detail, but questions concerning why a disease has evolved and the multiple factors that have led to it can be addressed in increasingly great detail. Clearly, the infrastructure to support this type of research is strained, and the strain underlies all the scientific issues related to biomedical models that are addressed in this report. A decade ago, models for biomedical research were analyzed in depth (NRC 1985 Appendix C). The present committee's deliberations in 1997 found that many of the findings and recommendations of the 1985 committee's report still ring true. This report is meant not to replace the earlier one, but to focus more specifically on the part that NCRR has played, and will play, in biomedical progress.

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Biomedical Models and Resources: Current Needs and Future Opportunities THE COMMITTEE'S CHARGE AND APPROACH This report addresses the role of NCRR in supporting models for biomedical research and their infrastructure. Accordingly, it is limited in scope and is intended to answer the following specific questions: What is NCRR's role in model development, support, and infrastructure? What can NCRR do that is unique and not likely to be undertaken by other elements of the National Institutes of Health (NIH)? How should NCRR establish funding priorities? What criteria can NCRR use to set funding priorities? The report suggests criteria and actions needed to identify useful new animal and computer models for biomedical and behavioral research; tools, technologies, and other resources needed to develop and support the models; and barriers to their development and support. It discusses the role of NCRR in the development of the models and recommends how NCRR should set priorities for support of animal-based research and technologies that will broadly influence the future of biomedical science. The study reported here covered mammals, nonmammalian terrestrial and aquatic vertebrates and invertebrates, and computer modelling systems. The authors of the report also studied model preservation and looked for evidence that useful animal models or strains were lost because of a lack of support. The data and perspectives provided in this report represent the consensus of the committee and were derived from a survey of a cross section of the scientific community, discussions with scientists in both academe and industry (those who receive NCRR support and those who do not), a workshop, and the committee members' own expertise. A survey was targeted at several segments of the scientific community involved in developing and using animal and nonanimal models for biomedical research. It was sent to all the NIH institute directors with a request that it be forwarded to relevant extramural program officers in their institutes, and that names of extramural scientists who use biologic models be provided to the Institute for Laboratory Animal Research (formerly the Institute of Laboratory Animal Resources), ILAR. It was also sent to the directors of animal facilities and to chairs of animal care and use committees chairs at major research institutions nationwide with a request that they ask investigators in their institutions who use biologic models to complete it and return it to ILAR. The survey was placed on the National Academy of Sciences Web site for nearly two months and was put on the Comparative Medicine and the Mouse Genome Informatics Listserves. It was not intended that the survey yield a statistically valid sample of the scientific community. Rather, it was targeted to major public and private institutions that receive NIH support, and the ones that responded were generally self-selected or appointed within their institutions. The data derived from the 69 surveys returned to ILAR were informative and helpful and served as part of the committee's data-gathering efforts for this report. The survey instrument is in Appendix A. The committee also reviewed the model-related results of a survey conducted by NCRR in the Federal Register, a summary of which was provided at NCRR's September 1997 scientific planning forum.

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Biomedical Models and Resources: Current Needs and Future Opportunities The committee hosted a workshop on December 11–12, 1997, at the Cecil and Ida Green Building of the National Academy of Sciences in Washington, DC. The 20 participants included scientists with research expertise in complex genetic traits, aging, neurobiology and behavioral sciences, infectious and adventitious diseases, veterinary medicine, computer modelling, and database development. They included scientists who work with nonhuman primates, large and small laboratory mammals, nonmammalian vertebrates, invertebrates, aquatic species and mathematical models. Nearly 20 discussants attended the workshop. These discussants were coming from pharmaceutical and toxicology testing companies, from government, and from academe. The workshop approached the issues of models for biomedical research by emerging research, by overriding issues that affect all research, and by species (in the breakout sessions). Nationally prominent scientists discussed the emerging development of biologic models and what NCRR's role should be in this development. The biographic sketches of the committee, the workshop agenda and a list of participants are included in Appendix B. The committee also drew on information and perspectives presented at related workshops and conferences held in the last two years. Representatives of the committee attended the Armed Forces Institute of Pathology workshop "Animal Models of Human Disease for the 21st Century" on December 8–10, 1997, and the workshop "Genetic Architecture of Complex Traits" sponsored by the National Institute of General Medical Sciences on December 10–11, 1997. The committee reviewed a report of a Zebrafish workshop (Zon and others 1997), a report of the NCRR strategic forum held in September 1997, a report prepared for the director of NIH by representatives of the mouse-genetic community (Nadeau and Meisler 1997) and several other published papers and reports. Finally, the committee members communicated with colleagues in each of their fields of expertise to obtain direct in-depth perspectives on those scientists' visions of the future of models for biomedical research. This report is a distillation of information from all those sources and is a consensus of the committee members' views. STRUCTURE OF THE REPORT The results of the committee's deliberations are presented in four chapters as follows. • ESSENTIAL AND EMERGING RESEARCH FIELDS AND TECHNOLOGIES The committee did not intend to predict or direct research into any field, but several research fields and technologies were repeatedly brought to its attention. Those "emerging" fields in which NCRR is thought to play an important role are discussed in this chapter. They include issues as varied as functional genomics, behavior and neurobiology, aging, complex diseases, model discovery and impediments to discovery, mathematical modelling and databases, and infectious diseases. It is largely in support of these essential and emerging fields that NCRR involvement is thought to be critical. OVERRIDING ISSUES Several issues are independent of species or field of research and appear to affect investigators to various degrees. The overriding issues discussed in this chapter include

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Biomedical Models and Resources: Current Needs and Future Opportunities issues that are NCRR-specific—unlikely to be supported by other agencies or organizations—and issues that are beyond the scope of NCRR but nonetheless important for the biomedical enterprise. Examples of the former are maintenance and cryopreservation, academic and facilities infrastructure, training, and informatics and miniaturization of instrumentation and databases. Examples of the latter are the contentious issue of indirect costs as detailed in Circular A-21 and intellectual property rights. RECOMMENDATIONS The purpose of this report is to recommend a role for NCRR in developing and supporting biologic models. The committee's recommendations are grouped into the following categories: animal health and welfare, national centers of expertise, animal facilities, training, interdisciplinary research, and scientific advice to NCRR. The committee believes that these categories are the ones most suited to NCRR and are critical to the success of biomedical research. CRITERIA The committee's recommendations would be incomplete without criteria by which funding priorities can be set. That is the subject of this chapter. This chapter deals specifically with which models to support and which infrastructure will lead to the most productive research and the best models. The suggested criteria result from a composite of all the data used by the committee, with emphasis on the survey.