Biomedical Models and Resources: Current Needs and Future Opportunities
National Research Council
National Academy Press
Washington, D.C. 1998
This report was produced at the request of the National Center for Research Resources (NCRR) and is based on the expertise and perspectives of the members of the NRC Committee on New and Emerging Models in Biomedical and Behavioral Research (biographical data are provided in Appendix B), on published data, and on information gathered by the committee through a survey and a workshop, discussions with other scientists, and the comments of those who reviewed the committee’s draft report. This report addresses the role of the NCRR in supporting models for biomedical research and their related 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 NIH institutes?
How should NCRR establish funding priorities?
What criteria can NCRR use to set funding priorities?
The authors of this report considered mammals, nonmammalian terrestrial and aquatic vertebrates and invertebrates, and computer modeling
Reprinted from National Research Council. 1998. Biomedical Models and Resources: Current Needs and Future Opportunities. National Academy Press, Washington, D.C.
systems of multisystemic—organisms. The committee recognized the importance of in vitro models, but did not cover them in this report for a variety of reasons detailed in the report. The authors of this report also studied model preservation and looked for evidence that useful animal models or strains had been lost because of a lack of financial 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 academe and industry (both those who receive NCRR support and those who do not), a workshop, and the committee members’ own expertise.
Recurrent themes in all the sources of information on which this study drew were training of whole-animal scientists, improved methods and instrumentation for physiologic assessment, infrastructure for animal-based research, databases for phenotypic information, sophisticated computer programming to handle statistical analysis of complicated data and to model complex biologic systems, multidisciplinary approaches, and shared resources.
The committee found that expanded and stabilized competitive research funding would provide a better and more cost-effective infrastructure to enhance the utility and availability of animal models and the quality of animal-related research and laboratory animal welfare. Issues that need to be addressed include laboratory animal health and welfare (investigation of laboratory animal diseases, advanced diagnostics, and behavioral research); methods of animal acquisition, maintenance, propagation, and preservation; genetic maps of additional model species; advanced technology relevant to global National Institutes of Health (NIH) needs for animal modeling and animal-related research (such as methods for targeted mutagenesis, phenotype assessment, and so on); and alternatives to mammalian models or methods to reduce the need for them in research.
The failure of precision phenotyping to proceed at the same rate as genetic engineering and molecular technology has hampered the exploitation of genetically engineered model organisms. Reliable phenotype assessment was a need that arose repeatedly in the information that we gathered from all fields of research. The most common needs described were for accurate and reliable behavioral assessment, biotechnology development for physiologic assessment, pathologic assessment, and analysis of complex data.
For example, behavioral assessment in genetically engineered mice is a rapidly growing field of research. Yet many investigators entering the field are molecular biologists who know how to “knock out” genes but have little or no experience in behavioral assessment. There is frequently disagreement among laboratories about the meaning of results of particular tests. Some investigators use learning in the Morris water maze as a measure of spatial hippocampal learning; others disagree that the test clearly measures
this aspect of learning. When investigators do use the same methods (such as the Morris water maze) to assess behavior and learning, they often fail to recognize the effect on experimental results of even small changes in test conditions. The test setup or details of the experimental protocol can vary greatly from one laboratory to another and produce different results that might reflect the experimental conditions rather than a biologic difference.
The trend toward study of complex diseases frequently requires that a scientist have access to expertise in various disciplines. The committee felt that some scientists might want to learn various disciplines but that many would benefit from access to shared resources that would provide the technology and expertise to assist in the analysis of complex phenotypes and disease issues. Such “foci of expertise” (whether physical or coordinated among different institutions) also would provide opportunities for scientists with different kinds of expertise to interact. They could be the catalyst for productive interdisciplinary collaborations. Foci of expertise could contribute to establishing a national network of integrative biology expertise.
Construction and renovation of animal facilities for the most widely used organisms (such as genetically engineered rodents) and emerging organisms (such as aquatic vertebrates and invertebrates) were found to constitute an infrastructure need that was important enough to set out by itself in the recommendations.
Because of trends toward model diversity, functional genomics, gene therapy, cancer biology, aging, infectious disease, neurobiology, and so on, there is a critical need to train scientists in whole-organism research. Furthermore, emphasis on animal-model research and concerns of society about humane use of animals mandate that NIH support scientifically based rationales for the humane and efficient management of laboratory animals and for dealing with their intercurrent diseases or special medical and husbandry needs. NCRR must train people to be able to handle the concepts of integrative biology to serve the NIH research mission. Broadening the training program would expand the comparative medicine scientific community, strengthen the comparative medicine academic infrastructure, and enlarge the body of scientists who can address the kinds of issues defined by this study.
The committee recognized that NCRR’ s comparative medicine and biotechnology programs already have mechanisms in place to address many of the issues raised in this study. NCRR has programs for training future scientists how to work with animals; it already evaluates and funds animal facilities and disease research; it funds and provides to researchers the Guide for the Care and Use of Animals (NRC 1996a); it was a pioneer at NIH in recognizing the potential of nonmammalian systems; it funds technology development and large shared resources; and it is beginning to seek
out and nourish projects with other government agencies and the private sector.
The recommendations listed below derive from the problems and opportunities uncovered by this study and can be addressed by expansion or modification of existing NCRR programs.
NCRR should encourage and support research directed at improving research animal utility, availability, health, welfare, and maintenance.
The committee, recognizing that science cannot be highly programmed supports the essential role of the peer-review process. Nevertheless, there is a need to improve technology that facilitates research and supports the discovery or creation of new models and the preservation of existing models. Some specific needs for increased support were identified: diagnosis and control of infectious disease; studies of animal behavior; improved animal acquisition, maintenance, and propagation; preservation of existing models and species; production of nonmouse gene maps; and development and miniaturization of instrumentation for physiologic measurements. Maintenance is important for model preservation and deserves careful consideration by NCRR.
NCRR should create a national network of comparative medicine expertise
To support NIH research efforts on animal models, such as phenotypic and genotypic assessment and disease diagnostics.
To promote multidisciplinary interaction.
Reliable phenotype assessment requires increased research on accurate and reliable behavioral assessment, new technology for physiologic and pathologic assessment, and new methods for analysis of complex data. The study of complex diseases will require that a scientist have access to expertise in various disciplines. To enhance phenotype assessment, development of multidisciplinary groups coupled with training programs in the various disciplines should be considered.
NCRR should create a national network of integrative biology expertise that can serve the entire biomedical research community.
The committee found that there is a need for experts in comparative medicine who are well trained in laboratory animal medicine and in research methodology as embodied in the concept of a comparative medicine biotechnology network. There is also a need for improved quantitative and mathematical modeling techniques that can be applied to biology. That will require efforts to encourage and facilitate interdisciplinary research programs; training of doctoral students, postdoctoral students, and scientists; development and dissemination of information technologies appropriate for biomedical applications; and development and maintenance of databases.
NCRR should construct and renovate animal research facilities.
Animal populations in the nation’s research facilities are increasing substantially because of burgeoning mouse populations and the increasing emphasis on integrative biology with all types of models. The resulting crowding, coupled with increased interinstitutional traffic and diminished health surveillance and diagnostic support, has created dry tinder for devastating epizootics of infectious disease among irreplaceable animal colonies. Funding is urgently needed for new construction to expand animal holding capacity in many research institutions. Funding is also needed to build specialized animal holding facilities that can be shared by investigators who are using animal models, such as level 3 biocontainment facilities for infectious-disease research and facilities for unique species of animals not typically available to the biomedical research community, such as marine and aquatic animals. Such facilities fall within the realm of creating a network of facilities and expertise that support the national research effort.
NCRR should reinvigorate and expand training opportunities in integrative biology.
Because of trends toward model diversity, functional genomics, gene therapy, cancer biology, aging, infectious disease, neurobiology, and so on, there is a critical need to train comparative medicine scientists with whole-animal experience. Furthermore, emphasis on animal-model research and concerns of society about humane use of animals mandate that NIH support scientifically based rationales for the humane and efficient management of laboratory animals and for dealing with their intercurrent diseases or special medical and husbandry needs. NCRR must train people to be able to handle the concepts of comparative medicine to serve the NIH research mission. NCRR can foster critically needed laboratory animal residency training through the development of academic infrastructure. Veterinarians are an important, but not exclusive, component of the comparative medicine community, and NCRR research training should be expanded to encompass other disciplines that contribute substantially to mammalian and nonmammalian integrative biology, including comparative medicine, pathology, and physiology; biostatistics; mathematical modeling; and behavior.
NCRR should obtain program guidance from the scientific community.
Science is moving so rapidly that scientists cannot predict what disciplines or types of research will need models more than five years from now. NCRR must devise effective methods to monitor developing changes and be responsive to biomedical research needs. Two approaches can be effective: 1) improved use of existing methods, such as the Comparative Medicine Review Committee and staff participation in relevant workshops, scientific meetings, and retreats with scientific groups (like Gordon Conferences); and 2) the convening of periodic (every four years) independent advisory
panels and small workshops to assess specific fields or asking independent agencies outside NIH to convene working groups to provide reports like this one.
To aid NCRR in setting priorities, the committee suggests the following criteria for assigning high priority to models and model support systems:
The model is appropriate for its intended use(s).
A specific disease model faithfully mimics the human disease.
A model system is appropriate for the human system being modeled.
The model can be developed, maintained, and provided at reasonable cost.
The model is of value to several scientists or for multiple purposes.
The model is reproducible and reliable, so results can be confirmed.
The model is reasonably available and accessible.