5
Recommendations

All information-gathering aspects of this study revealed the importance of models in past advances in biomedicine and the critical role that models will play in the next 5–10 years of biomedical research. Equally clear were the common themes that facilitate and impede model development and use across all disciplines and types of models. NCRR, especially through its Comparative Medicine Program and its biotechnology development and resource-sharing programs, is uniquely positioned to understand and support model development, infrastructure needs, and preservation. The committee sets forth below six recommendations for actions that NCRR could take to address issues described earlier. Each section begins by stating the recommendation and it then explains the needs addressed.

ENCOURAGE AND SUPPORT RESEARCH DIRECTED AT IMPROVING RESEARCH ANIMAL UTILITY, AVAILABILITY, HEALTH, WELFARE, AND MAINTENANCE.

In the September 1997 NCRR Scientific Planning Forum, Louis W. Sullivan, forum co-moderator, made the following statements:

  • "Science cannot be highly programmed."

  • "Opportunities must be created for young people to enter scientific fields."

  • "The peer-review process also plays an essential role in maintaining the vitality of science."

The committee endorses those points, and our comments on research, training and academic infrastructure below underscore these principles. The NCRR Comparative Medicine Program can play a pivotal role in enhancing the utility and availability of animal models and the quality of animal-related research and laboratory animal welfare through expanded and stabilized competitive research funding. Comparative Medicine Program research support must be directed toward 1) issues of laboratory animal health and welfare (investigation of laboratory animal diseases, advanced diagnostics, behavioral research, and so on); 2) improved methods of animal acquisition, maintenance, propagation, and preservation; 3) development of genetic maps of additional model species; and 4) development of advanced technology relevant to NIH global needs for animal modelling and animal-related research (such as improved methods for phenotype assessment). Research support, indirectly, is the most important element for supporting a comparative medicine academic infrastructure that provides the appropriate environment for residency and research training, an academic "home" for comparative medicine



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities 5 Recommendations All information-gathering aspects of this study revealed the importance of models in past advances in biomedicine and the critical role that models will play in the next 5–10 years of biomedical research. Equally clear were the common themes that facilitate and impede model development and use across all disciplines and types of models. NCRR, especially through its Comparative Medicine Program and its biotechnology development and resource-sharing programs, is uniquely positioned to understand and support model development, infrastructure needs, and preservation. The committee sets forth below six recommendations for actions that NCRR could take to address issues described earlier. Each section begins by stating the recommendation and it then explains the needs addressed. ENCOURAGE AND SUPPORT RESEARCH DIRECTED AT IMPROVING RESEARCH ANIMAL UTILITY, AVAILABILITY, HEALTH, WELFARE, AND MAINTENANCE. In the September 1997 NCRR Scientific Planning Forum, Louis W. Sullivan, forum co-moderator, made the following statements: "Science cannot be highly programmed." "Opportunities must be created for young people to enter scientific fields." "The peer-review process also plays an essential role in maintaining the vitality of science." The committee endorses those points, and our comments on research, training and academic infrastructure below underscore these principles. The NCRR Comparative Medicine Program can play a pivotal role in enhancing the utility and availability of animal models and the quality of animal-related research and laboratory animal welfare through expanded and stabilized competitive research funding. Comparative Medicine Program research support must be directed toward 1) issues of laboratory animal health and welfare (investigation of laboratory animal diseases, advanced diagnostics, behavioral research, and so on); 2) improved methods of animal acquisition, maintenance, propagation, and preservation; 3) development of genetic maps of additional model species; and 4) development of advanced technology relevant to NIH global needs for animal modelling and animal-related research (such as improved methods for phenotype assessment). Research support, indirectly, is the most important element for supporting a comparative medicine academic infrastructure that provides the appropriate environment for residency and research training, an academic "home" for comparative medicine

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities investigators in medical schools, and an environment for research extending into multidisciplinary NIH programs. Issues of relevance to the discipline of comparative medicine, such as diseases of laboratory animals, are highly important to NCRR, but might not be of obvious relevance to categorical institutes and initial review groups (IRGs), which are faced with priority decisions for grant applications directed toward issues of human health. Therefore, research-grant applications directed toward comparative medicine programmatic goals are not likely to fare well in the mainstream of NIH IRGs, in part because of irrelevance, but also because many Comparative Medicine Program-directed proposals tend to be for applied research. It is imperative that NCRR Comparative Medicine Program staff assist in guidance of NCRR-relevant applications through the NIH review process. Research grant applications directed toward Comparative Medicine Program goals must be subjected to the highest standards of peer review; this will ensure high-quality comparative medicine research, training environments, and stature of the discipline. The Comparative Medicine Program Review Committee has, in the last several years, maintained this standard. The Comparative Medicine Program needs to attract more and higher-quality applications, but that cannot happen without creation of a scientific constituency that contributes to the goals of the Comparative Medicine Program. The sparseness of such a constituency of competitive scientists underscores the urgency of training veterinarians for research careers and extending comparative medical, whole-animal training to nonveterinarians. We emphasize, however, that laboratory animal health and welfare issues have also been well served by nonveterinarian comparative medical scientists, particularly virologists, microbiologists, geneticists, and behaviorists. Broad communication regarding the opportunities for Comparative Medicine Program research support will encourage scientists outside the discipline of comparative medicine to contribute to problems facing comparative medicine and result in an infusion of new insight and new energy. That, in turn, will increase the quality and competition for Comparative Medicine Program grants and invigorate the comparative medicine academic infrastructure through increased awareness and collaboration. NCRR can achieve participation by the scientific community through clearly elucidated and universally publicized program announcements that emphasize general themes of interest. How NCRR becomes aware of developing trends in biomedical model research is addressed later. Considering the trends in research based on animal models, there clearly are research areas that the NCRR Comparative Medicine Program can emphasize through program announcements. The growing importance of genetically altered laboratory mice during a period of federal austerity in spending for animal-related health care and infrastructure poses a pressing need. These mice pose unique problems in their need for specialized housing and health care. Demands for specialized housing, increasingly stringent animal welfare regulations, and increasing demands for cost-effective animal care seem to be opposing forces. Scientifically stringent behavioral research is needed to develop a scientific base for research animal welfare and to confirm (or negate) the value of regulations that pose an impediment to research based on animal models. Because animal models are involved in well over half of NIH-sponsored biomedical research, it

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities would be impossible for NCRR to support development of all new models that might be needed for research. NCRR can most effectively use its funds by investing in improved technology or new model development that will affect multiple research fields as well as development of means to preserve the NIH investment in already-created models by further characterization: of genetic background, physiology, phenotype, behavior, pathology, and genetics. Some specific subjects with the most pressing needs for research are described below. LABORATORY ANIMAL HEALTH AND WELFARE That the health and welfare status of experimental animals can have a serious impact on experimental results is often overlooked or not well understood by investigators who are not used to working with whole animals. Healthy-appearing animals can harbor microorganisms that are not overt pathogens but whose presence can alter the animals' response to experimental manipulation. Environmental inadequacies can affect experiments as well and frequently the behavioral patterns of the animals themselves can signal an animal's discomfort. The next two subsections deal with recommendations in these areas. Diagnosis and infectious disease Our laboratory animal infectious-disease guard appears to be down and there is an emergence of new, as well as previously known, infectious diseases (Jacoby and Lindsey 1997). Something should be done to improve infectious-disease surveillance. Genetically engineered mice are frequently immunodeficient and require extra vigilance. Many these strains are shipped from research laboratory to research laboratory with various degrees of animal health surveillance in different institutions. Pigs or other species of animal whose tissues and organs are used in xenotransplantation studies must be free of any pathogens, but few are well defined, and the impact of potential xenozoonosis has not been fully explored in immunosuppressed recipients. Improving animal health monitoring and health status could be remedied with a combination of approaches. For new and emerging diseases in any species, a funding mechanism that replaces a major contribution of the former DIL is one part of the solution. The recommendation is not to reinstate the former DIL; rather the need is for resources to investigate new disease outbreaks and make it possible to conduct immediate studies to prevent potential spread of an infection throughout a facility and spread of unknown agents to other institutions that receive the animals. In such circumstances, there is neither sufficient time nor preliminary information for submitting a grant proposal to pursue spontaneous disease outbreaks with current funding mechanisms. Regional or specialized foci of expertise (not necessarily physical centers) to take on such problems might constitute a practical approach. These foci of expertise would also be in an excellent position for disease characterization and development of diagnostic tools to help control infections. Further education of investigators is essential.

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities Aquatic organisms, insects, and some other nonmammalian organisms require specialized care and directed study by specially trained veterinarians. Behavior Behavioral studies are important in two ways for animal model research. First, an understanding of behavior is critical for the development and evaluation of models and the interpretation of data from experiments that use model animals. The paradox of behavior is in its apparent simplicity vs. its actual complexity. Sophisticated equipment is not required to assess behavior itself; it can be visually observed. Yet observed behavior is the product of many factors and of interconnections and feedback systems between genes and internal and external environments. It is essential to determine the baseline conditions against which experimental manipulations are to be measured if experimental results are to be interpreted correctly. For example, rearing monkeys alone can affect brain growth. Researchers raising monkeys in individual cages to avoid cross-contamination in infectious-disease experiments must recognize that part of the brain pathology observed may come from conditions of rearing, as opposed to infectious agents (Struble and Risen 1978). Second, behavior offers important indicators of health and ''wellness" in animal colonies. The behavior of a given model organism must be understood in detail if such techniques and short-and long-term maintenance protocols are to be developed. Failure to attend to the behavioral needs of the species results in stress and disease and in the end compromises the quality of the model. Housing environments can affect disease progression, immunity, and psychopathologic findings. For example, some individually housed monkeys develop a self-injuring syndrome that interferes with experiments. Many rodents, reptiles, birds, fish, cephalopods, and other species maintained or reared under crowded conditions become more aggressive, and this can lead to injury or even cannibalism. Ethologists and comparative psychologists should be actively solicited to conduct or collaborate in behavioral studies because these disciplines have developed rigorous and quantitative experimental methods of analyzing animal behavior. Ethologists, in particular, receive broad integrative biology training that enables them to address questions of causation, function, development, and evolution of behavior. Study sections should be organized to accommodate competent review of behavioral studies. Such cross-fertilization with animal care specialists, neurobiologists, pathologists, and others will repay itself many times over. Behavioral scientists will be valuable in assaying behavioral phenotypes in various organisms, from Drosophila to zebrafish to nonhuman primates. When it is relevant, NCRR should encourage and support field studies and laboratory studies of wild-derived species kept in captivity to develop solid biologic and behavioral bases for selecting the laboratory conditions under which the species should be quarantined, maintained, cultured, or studied. The regulations for animal care, the determination of per diem rates, and the daily protocols for animal care all depend on such studies, but they have generally not been done except in the case of a few model

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities organisms. In some, if not many, cases a result of the studies will be a reduction in the overall cost of acquiring and maintaining model organisms. Furthermore, the model will have increased quality for experimental use. Standards developed for laboratory care of mammals seldom, if ever, apply to other animals, particularly with respect to behavioral repertoires. It might be advisable and appropriate to co-fund some such studies with the National Institute of Mental Health. IMPROVED ANIMAL ACQUISITION, MAINTENANCE, PROPAGATION AND PRESERVATION Current models all have shortcomings that justify the consideration of new model discovery, and new model development, regardless of phylum, can stimulate new ways of thinking about existing models. NCRR can facilitate new model discovery by monitoring needs or opportunities (see the final recommendation in this chapter) and providing startup funds for initial development. Genetic engineering of mice has opened a new era in animal model research. Conditional targeted mutations will enable another quantum leap forward. One of the primary factors impeding use of genetically engineered mice is the lack of resources to maintain and distribute the large numbers being created. Many investigators who are skilled in the genetic engineering of mice or who use them in research are not trained in the genetics of breeding or in the animal husbandry skills needed for maintenance. Foci of expertise could be created for maintaining and distributing genetically engineered animals and providing expertise to assist investigators who use the animals. Centralized maintenance programs can provide breeding expertise, genetic quality, and health surveillance more efficiently than individual investigators' laboratories. NCRR has been the primary source of support for one such maintenance and distribution center at The Jackson Laboratory in Bar Harbor, Maine. It has taken a strong lead in using the cooperative mechanism for sharing of funding among NIH institutes whose grantees use its mice. Yet this national resource can handle only a small proportion of the mice, and now rats, being created. The Jackson resource should be expanded or other such centralized resources created. NCRR cannot be the sole support for this growing need and is encouraged to continue to use its base support to leverage additional NIH institute sharing of support for such resources. In the past and today, animal-based research has relied heavily on resources and services provided by commercial producers of laboratory animals. Commercial breeders have responded to the needs of the research community by providing healthy, disease-free, genetically monitored animals in a cost-effective manner. Barrier and isolator colonies, rederivation procedures (hysterectomy and embryo transfer), cryopreservation, and animal transportation systems have been developed to meet the general research requirements of the federal government, academe, the pharmaceutical industry, and other commercial and nonprofit sectors. Characterized animals of many species have been made equally available to all investigators, for example, production of disease-free rats, mice, and other rodents; development and maintenance of colonies of aged rats and mice; isolator production of nude and SCID mice; production of conventional and barrier-raised

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities dogs and cats; development of nonhuman primate colonies; and production of miniswine. Because the cost of new construction and renovation is high, NCRR could look to commercial producers to supplement institutional colonies. Commercial breeders could be brought in as partners to investigators and institutions to help meet needs for maintenance and solving problems. Outsourcing mechanisms—such as contracts between research institutions and commercial breeders to provide and distribute animals of the required genotypes, phenotypes, and health quality—could be developed and used to relieve the intense pressure on research resources and institutions. For supply of some wild-derived organisms, centers for acquisition and supply of animals are needed, rather than breeding colonies of genetically defined animals. Techniques for careful and injury-free acquisition and transport of wild animals to the laboratory have yet to be developed for many species, particularly aquatic ones. A great need has been identified for the preservation of many different laboratory animal species. Research is needed to make cryopreservation and recovery more reliable, cheaper, and applicable to a broader range of species. For example, it costs thousands of dollars to cryopreserve a single mouse line and thousands more to recover it from the frozen state because of the uncertain outcome and the often-necessary repeated attempts. Support to make common the practical use of cryopreservation of ovaries, ova, sperm, and intracytoplasmic sperm injection would probably facilitate the use of this technology for a wide variety of animal species. DEVELOPMENT OF GENETIC MAPS FOR ADDITIONAL MODEL SPECIES There is a critical role for NCRR in furthering functional genomics studies in outbred models, particularly primates and some aquatic organisms. Such species are outside the mission of the Human Genome Project. For example, nonhuman primates, dogs, and cats develop many of the same complex diseases that afflict human beings, but genetic maps for these species are woefully inadequate. Mutagenesis programs using zebrafish are likely to play a major role in increasing the understanding of gene function. The genetic map of the zebrafish is in progress, with NCRR funding, but needs to be improved. Results of 40 years of neurobiologic and behavioral research exist for Aplysia, and it continues to be used in research on neurobiology and behavior; but virtually nothing is known about its genetics. Identification of biomedically relevant phenotypes is driven by the disease or metabolic process in question and thus is unlikely to be a primary responsibility of NCRR. Not so obvious, however, are identifying appropriate models for disease-related phenotypes and finding the genes that underlie the phenotypes. There is an important role for NCRR in both. Identifying appropriate models for disease-related phenotypes is a fundamentally a database problem, in which information on the physiology, pathology, metabolism, and so on, of a wide variety of species should be made available to those engaged in research on common diseases. Likewise, experimental information that refines the characterization of model organisms should be continually incorporated into a database (curation). Because of its personnel's broad experience with laboratory animals, NCRR is the obvious sponsor for the building and maintenance of such a database.

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities With respect to finding genes that underlie disease-related phenotypes, although targeted mutation and transgenic rodent models will continue to be important, application of human-derived genetic-analysis methods to non-inbred animal models offers a powerful tool for the study of the genetics of disease susceptibility. To advance such study, NCRR could Fund development of relatively high-density (5–10 centimorgans) gene maps for selected species—such as selected nonhuman primates, dogs, and zebrafish not funded by other institutes. Fund the development of statistical methods required to use the gene maps to localize genes of physiologic or phenotypic interest. Fund the development and maintenance of colonies so that they are structured with the informative pedigrees required for mapping and chromosomal localization. Fund the training of scientists in the use and appreciation of the statistical methods required and the training of colony managers who can develop and maintain pedigreed colonies. INSTRUMENTATION DEVELOPMENT AND MINIATURIZATION There was interest in and need expressed for support of developing technologies for phenotypic analysis of animals. Two major types of technology advances would enhance phenotype assessment in experimental animals: 1) instrumentation that increases the ability to do micromanipulation or microsurgery and 2) noninvasive methods—such as ultrasonography, magnetic resonance imaging, and nuclear magnetic resonance—to make assessments or monitor physiologic changes in living animals. Many animals have specific problems of size and need for sedation if they are to remain still for an analysis; these, however, can be major obstacles in an experiment. There is considerable interest in improved technology, especially for neurobiologic and reproductive studies. Investigators are interested in development of smaller instruments with telemetry applications for evaluating "in-life data" in small animals (for example 20 g, or mouse size) for assessing physiologic characteristics, such as EEG, ECG, blood pressure, and activity. Valuable information can be gained from experimental animals that are much smaller than human beings, but the equipment needed to carry out the experiments or evaluate phenotypes either does not exist or is scaled for human beings. One approach that has worked well for developing small instruments is to piggyback on existing technology by miniaturizing or adapting instrumentation. The physiology of any system is a dynamic process that continues over the life of an animal, but many methods for physiologic assessment require obtaining vital tissue or organ specimens. In studies that use those methods, representatives of the organism being studied must be sacrificed at different points during life. Not only does that prevent following the same system in a single animal, but no matter how careful the investigator is, there is always the risk that different animals will be exposed to slightly different environments, and this affects experimental results and their interpretation. Instruments and methods for noninvasive phenotype assessment would enable repeated

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities assessments in the same animal and reduce the number of animals required for statistical validity. CREATE A NATIONAL NETWORK OF COMPARATIVE MEDICAL EXPERTISE TO SUPPORT NIH RESEARCH EFFORTS ON ANIMAL MODELS, SUCH AS PHENOTYPIC AND GENOTYPIC ASSESSMENT AND DISEASE DIAGNOSTICS It seems unlikely that a productive approach to phenotype assessment is to train all molecular geneticists in pathologic, behavioral, or other types of sophisticated phenotypic assessment. Furthermore, many models require more than one kind of expertise for assessment, such as knowledge of brain architecture and expertise in behavioral testing. Genetically engineered mice should be screened for histopathology; whether the expected phenotype occurs or not; such animals might have other interesting phenotypes that make them useful as models for multiple systems or diseases. Such diagnostics not only define the extent and its similarity to human disease of any expected pathology but also might detect unexpected results that broaden the value of the model created. Research with aquatic organisms will also benefit from foci of expertise. NCRR is encouraged to explore ways to create regional centers or foci of expertise "without walls" that scientists who want to assess the phenotypes of their genetically engineered organisms can turn to for help in pathologic and phenotypic assessment. Research with aquatic organisms will also benefit from foci of expertise. Laboratory rodents are susceptible to a large number of infectious agents, and infectious agents are emerging as important confounding issues with other laboratory animal species, including large animals for xenotransplantation research. Diagnostic methodology for laboratory animal infectious diseases has not advanced appropriately, in part because of the hiatus created by discontinuation of Diagnostic Investigative Laboratory support and in part because of the paucity of scientists involved in applied comparative medical research. Development of molecular diagnostic methods for laboratory animal infectious diseases is needed to reduce cost, increase efficiency, increase sensitivity and specificity, and expand diagnostic capabilities to agents of emerging significance or agents in which accurate diagnostic methods are lacking. This requires support for applied research, and this effort can best be served within centers of comparative medical expertise. TO PROMOTE MULTIDISCIPLINARY INTERACTION The trend toward study of complex diseases often requires that a scientist have access to expertise in a variety of disciplines. The foci of expertise recommended above also can provide opportunities for scientists with different kinds of expertise to interact.

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities Such centers can be the catalyst for productive interdisciplinary collaborations. They could contribute to establishing a national network of integrative biology expertise that is described in more detail with the next recommendation. Collaboration with United States Department of Agriculture/Agriculture Research Service on the pig genome project should be considered. CREATE A NATIONAL NETWORK OF INTEGRATIVE-BIOLOGY EXPERTISE THAT CAN SERVE THE ENTIRE BIOMEDICAL RESEARCH COMMUNITY ACADEMIC INFRASTRUCTURE FOR INTEGRATIVE BIOLOGY RELATED TO ANIMALS Physical infrastructure is an important element of the NCRR mission. A less obvious but equally important element is academic infrastructure. NCRR has a responsibility and need to develop a strong network of comparative medicine academic infrastructure to maximize opportunities for training and research relevant to integrative biology. Veterinarians, PhDs, and related comparative medicine scientists, trained for scientific careers in comparative medicine, require placement in academic departments that understand the special needs of comparative medicine and that can nurture and sustain faculty careers in comparative medicine. Options for veterinarians to find stable research faculty opportunities in medical schools or other medical research institutions are few. Outstanding science-driven comparative medicine departments in such institutions provide an academic home for research and clinical veterinarians and the environment for academically superior residency training (which should not be supported directly by NIH but is crucial to the NIH mission). Furthermore, residents specializing in laboratory animal medicine or pathology are an important source of people who matriculate into research training programs. Effective recruitment of outstanding candidates into residency programs and capture of the best of them for scientific training require superior academic environments and role models. Academic infrastructure also provides the opportunity for recognition and investigation of emerging and existing diseases of contemporary laboratory animal populations, such as the discovery and investigation of infectious diseases peculiar to genetically altered mice, investigation of behavioral and environmental needs of laboratory animals, and development of advanced technologies in mammalian genomics and husbandry of genetically altered animals. Without a science-driven academic infrastructure, comparative medicine is destined to function in a service, regulatory role. A group of concerned comparative medicine scientists have formulated a suggestion for NCRR to rebuild a cost-effective and modern comparative medicine academic infrastructure. The concept is called the Comparative Medicine Biotechnology Network, (CMBN). Its objectives are to develop nationally coordinated resources to provide expertise and infrastructure in support of animal-based research and to protect

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities animal health, to enhance the development and preservation of vital animal models through access to core facilities and technologies, to provide training for aspiring and established investigators who seek working knowledge of comparative medicine and organismal biology, and to establish a telemedicine network to provide interactive expertise in investigative, diagnostic, and clinical comparative medicine. The text of the proposed characteristics of a CMBN is provided in Appendix D. At the very least, the proposal sets the stage for NCRR to develop a vision for a comparative medicine academic infrastructure. The CMBN plan offers the cost-saving advantages of shared resources to meet the national needs of the NIH research community. The committee considers it an attractive option for serious NCRR consideration. MATHEMATICAL MODELLING, COMPUTATIONAL SIMULATIONS, AND SCIENTIFIC DATABASES The importance of mathematics, modelling, and computation in biomedical research grows as the ability to collect and distribute data increases. The growing volume of data generated in current research efforts requires personnel and resources to create the models and tools to manage and analyze the data. However, many fields of biomedical research, including work with animal models, have not taken advantage of advances in mathematical and computational modelling and database technology. Many investigators are unaware of or cannot access the sizable collection of models, computational tools, simulation environments, and databases that are available to the modelling community. We recommend that NCRR take a number of steps to address those problems. Those steps involve efforts to encourage and facilitate interdisciplinary research programs; training of doctoral-level students, postdoctoral trainees, and scientists in quantitative methods of analysis, including experimental design and statistical analysis; development and dissemination of information technologies appropriate for biomedical applications; and development and maintenance of databases. Encouragement and Facilitation of Interdisciplinary Research Bringing together biologists and scientists trained in the mathematical sciences can have results that work in two directions: biologists can learn and apply modelling and simulation methods to their work, and mathematicians can be introduced to biologic research. We stress the importance of a thorough understanding of the biologic processes underlying mathematical and simulation models, which implies the necessity for both commitment and opportunity in these interdisciplinary efforts. We believe that a mechanism for funding biomedical research that specifically calls for an interdisciplinary modelling approach should be established. It would attract scientists with mathematical and modelling skills to apply their expertise in a laboratory or field setting and simultaneously encourage biologic scientists to frame their research in a manner conducive to a modelling approach.

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities We believe that existing modelling and simulation tools should be made more accessible to biomedical scientists. This should be done by designing interfaces and tool assembly systems that are appropriately framed for biomedical research, making modelling and simulation tools available on the World Wide Web, and developing and promoting documentation, reviews, and evaluations of available software so that biomedical scientists could better select and apply existing modelling tools in their research. Development and Dissemination of Appropriate Information Technologies Not only do we see the necessity to develop and facilitate the use of modelling software itself, but we also note the need for integration of these tools with the databases that contain the relevant data to support modelling and simulation analyses. There is a need for workshops that call together experts and practitioners in the relevant fields with the aims of integrating methods and research problems for working scientists in the various disciplines. A Web site should be created to distribute information about interdisciplinary modelling and informatics issues. The site would contain such information as a calendar of events and locations of resources, expertise, and databases. Development and Maintenance of Databases, Interdisciplinary Modelling and Informatics Issues. The Site Would Contain Such Information as a Calendar of Events and Locations of Resources, Expertise, Software, and Databases. Database problems have become a ubiquitous concern in modern biomedical research. The scale of the problems is such that solutions will require the coordinated efforts of a wide range of NIH institutes, including NCRR. Although the totality of the task is beyond the charge of this workshop (other than to acknowledge NCRR's role in the efforts), some recommendations relevant to NCRR were discussed: NCRR should have a role in creating, maintaining, and distributing databases (typically of a small scale initially) that complement and support those funded by other institutes. These databases should not be left to ad hoc design, but should be developed in cooperation with database developers. The development of common templates could assist the rapid development of small databases by individual scientific groups while ensuring good design and consideration of future database needs, such as sharing information between databases. These would include information on modelling (as described above) and animal model resource and gene map data. Explicit statements of the need for this capability came from scientists funded by other NIH institutes, as well. Critical to all NCRR database efforts must be consideration of quality control. Recommendations include establishment of guidelines and templates for the creation and maintenance of databases so that both access and future expansion can be facilitated; establishment of a formal publication process whereby the validity, limitations,

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities applicability, and liability of and responsibility for individual databases are reviewed and documented; establishment of cost-benefit criteria for creating, and especially for continuing the maintenance of, databases (based on use statistics, and so on); recognition that curation of databases is critical, and that databases inevitably incur financial costs which must be met, especially for personnel (programming, data entry, and management and training). INCREASE THE COMMITMENT AND RESOURCES FOR CONSTRUCTING AND RENOVATING ANIMAL RESEARCH FACILITIES 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 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 has traditionally provided important support for updating (renovating) animal facilities, promulgating better health and welfare of research animals. Funding for renovation needs to be increased to maintain the integrity of existing animal facilities and modify them to meet modern housing needs. In addition, there has been a steady and substantial increase in animal populations in the nation's research facilities, owing largely to burgeoning mouse populations but also to the increasing emphasis on integrative biology using all types of models. Research institutions failed to predict the trend, and often reduced their animal holding space in the 1980s. Mouse populations are rising by 20% per year in some institutions, and many animal facilities are full to capacity. A combination of forces—including crowding, increased interinstitutional traffic, and diminished health surveillance and diagnostic support—has created dry tinder for devastating epizootics of infectious disease among irreplaceable mouse colonies. At one time, NCRR's predecessor, the Division of Research Facilities and Resources (DRFR), was a major source of funding for animal facilities. During the 1960s, DRFR had about $100 million annually for funding construction of research facilities, including animal facilities. In 1969, however, DRFR lost its construction authority; when construction authority was returned to its successor, the Division of Research Resources, for a limited period in the 1980s and to NCRR in 1995 and 1996, the annual amount was never greater than $10–12 million. NCRR's current annual budget for construction is about $20 million. It is critical that NCRR and its advisory board find a way to persuade NIH to increase the NCRR budget for construction and renovation without adversely affecting research funding.

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities REINVIGORATE AND EXPAND TRAINING OPPORTUNITIES IN INTEGRATIVE BIOLOGY NCRR has a responsibility to train comparative medicine scientists (herein defined as persons who specialize in disciplines that contribute to laboratory animal integrative biology) to serve the growing needs of NIH research based on animal models and the diversity of models encompassed by that research. 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 who can serve at the whole-organism level. Furthermore, emphasis on animal-model research and concerns of society about humane use of animals mandate NIH to support a scientifically based rationale 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 in the concepts and practicalities of animal handling to serve the NIH research mission. Veterinarians and PhDs are well suited for comparative medicine careers because of their broad multispecies (comparative) base of knowledge, but this must be the base on which further clinical and research training is built. No other NIH institute provides training for veterinarians in comparative medicine, but the need for such people clearly spans the entire NIH mission. Society demands, and prudence requires, that the NIH biomedical research investment be protected by well-trained laboratory animal veterinary specialists. Veterinarians do not receive laboratory training in veterinary school, so they must seek specialty residency training. Despite its importance, residency training is not within the realm of NIH support, and laboratory animal residency training has been recently de-emphasized by NCRR. Nevertheless, NCRR can indirectly but substantially foster critically needed laboratory animal residency training through the development of academic infrastructure. Research training is already being emphasized, and renewed efforts to recruit veterinary students (T35s), including members of underrepresented minorities, to careers in comparative medicine are under way and are encouraged by this committee. Veterinarians are an important, but not exclusive, component of the comparative medicine community. NCRR research training should be expanded to encompass other disciplines that contribute to mammalian and nonmammalian integrative biology, including pathology, physiology, biostatistics, mathematical modelling, and behavior. Contributions to comparative medicine have been made by medical pathologists, geneticists, microbiologists, virologists, and behaviorists. Thus, NCRR research training opportunities should be extended to nonveterinary scientists, but such training must be focused on career development and training environments within the discipline of comparative medicine. NCRR training-program opportunities should be offered to graduate veterinarians who are seeking research training, which is in keeping with current activity. These training grants can be made more flexible and can provide PhD or equivalent research training for veterinarians, postdoctoral training to recruit qualified research veterinarians into comparative medicine careers, and postdoctoral training for PhD or MD scientists with interest or skills needed for integrative biology and

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities comparative medicine. Consideration should be given to allowing training programs to develop consortiums with other institutions that provide needed academic expertise in fields of importance to comparative medicine. For example, opportunities for high-quality training in animal behavior or aquatic animal pathology could be expanded by providing the research experience for individual trainees under qualified mentors in a cooperating sister institution, but within the context of a training program based in the home institution. That would allow a much greater breadth and depth of training opportunities and would serve the diverse programmatic needs of NCRR better. Research training must prepare trainees for independent, competitive research careers so that NIH research can benefit from the input of comparative medicine scientists. Veterinary-research career training (like physician-scientist training) has special considerations. Research must be its focus, but trainees might desire continued access to clinical material during the research training process. That would ensure affiliation of veterinary scientists with clinical issues in comparative medicine, ensure their allegiance to the discipline of comparative medicine as their careers develop, and ensure that NCRR will attract such scientists as participants in its future scientific programs. Scientific training must not be mixed with residency training, however, because the dual forces would dilute the product of each. Research training typically requires more than four years of intensive laboratory experience, so training grants should reflect this full commitment of time. Furthermore, research veterinarians (like physicians) will have already invested much time and money in their career development and cannot be expected to seek further postdoctoral training on completion of a residency program plus a PhD or equivalent research training experience. NCRR must be cognizant of that and foster mechanisms for jump-starting young veterinary comparative medicine scientists with competitive funding opportunities. Careers in comparative medicine, regardless of discipline, must also be supported by sustained opportunities for research funding in comparative medicine. Because of the recent emphasis on and need for behavioral scientists in biomedical research and in animal care centers, a specific effort should be made to attract ethologists and comparative psychologists to study biomedical model organisms. For example, the subdiscipline applied ethology has emerged recently and made contributions to some domestic farm animal programs; redirecting ethologists toward biomedical models would be a way forward. One possible mechanism would be to solicit their input and studies through requests for proposals that focus on behavior. To improve the efficiency of animal use and facilitate humane treatment of research animals, NCRR should foster training of NIH investigators in the research use of animal models, phenotypic analysis, animal-related technology, and other issues that facilitate NIH research. That training should be supported through development of a comparative medicine academic infrastructure, workshop grants, scientific ''outreach" information via computer networks, and development of literature for the scientific community. NCRR also needs to increase public awareness of the value of animal-related research and its importance to human (and animal) health. NCRR is the appropriate venue for this activity of importance to all NIH institutes.

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities Training in biomathematical modelling and computational biology is important, including training of doctoral students, postdoctoral trainees, and scientists. There is an immediate need for workshops and short courses to introduce mathematicians and computer scientists to biological problems and biologists to mathematical and computer problems. Opportunities should be provided for postdoctoral training and experience in modelling and simulation at the laboratory research level. Doctoral training is the ideal stage for learning interdisciplinary methods of the sort that we envision. This training should take place in programs that offer the appropriate range of faculty specialization. It might be necessary for NCRR to fund the establishment or enhancement of such programs. OBTAIN PROGRAM GUIDANCE FROM THE SCIENTIFIC COMMUNITY Science is moving so rapidly that scientists cannot predict what will be the disciplines or types of research that need models more than 5 years from now. NCRR must devise methods to monitor developing changes and be responsive to biomedical research needs. Two methods that are at hand can be effective: improved use of existing methods and the appointment of periodic independent advisory groups. USE EXISTING MECHANISMS BETTER Comparative medicine program staff should use the Comparative Medicine Review Committee as scientific advisers better, inasmuch as its statutory function is that of an advisory committee. The mechanism is in place, but it has been underused in the last several years. With a properly selected committee of scientists involved in competitive scientific careers, it offers an effective means of assessing the trends and needs of the NIH research mission. NCRR has an active and interested program staff. Although the reduction in travel budgets for NIH program staff has made it more difficult for them to get out into the scientific community, we encourage the NCRR administration to provide as many opportunities as financially possible for staff to participate in relevant workshops, scientific meetings, and so forth. The National Advisory Research Resource Council is also a valuable group, and NCRR should make more use of it to keep in touch with developments in the scientific community. FUND INDEPENDENT EXTERNAL ADVISORY GROUPS EVERY FOUR YEARS It is to NCRR's advantage to obtain a fresh "outside" look at the opportunities and needs of models for biomedical research regularly. Two mechanisms are available:

OCR for page 24
Biomedical Models and Resources: Current Needs and Future Opportunities organizing small workshops to assess specific fields and asking independent agencies outside NIH to convene working groups to provide reports like this one.