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Biomedical Models and Resources: Current Needs and Future Opportunities 4 Overriding Issues ISSUES WITHIN THE PURVIEW OF NCRR MAINTENANCE AND PRESERVATION Maintenance of living stocks is a bedrock of biomedical research and is one of the major and unique contributions of NCRR. As self-evident as that sounds, there are frequent complaints throughout the biomedical community that the biology and logistics related to healthy maintenance of model organisms cause continual problems that hinder research. Information gathered by the committee shows that those issues transcend all phyla. Recently, the issues have been outlined with regard to aquatic organisms (Lohr and others 1995; Morse and Nealson 1996). One issue that affects maintenance is how cost recovery is calculated for different species. There are inequities in the cost recovery required for different research resources; to the extent that it can affect this, NCRR could provide a leadership role by setting standards that could be applied equitably for all species. All animal models require a source of support at the whole-organism level to for continued maintenance to make them available to other scientists and to protect the investment made in initial development. Such continued support is much less glamorous than the research that developed the models originally, but their continued maintenance is critical. Some support can come from user fees but frequently total recovery of costs of animal colony maintenance results in user fees that are prohibitively high for investigators' research grants. The P40 mechanism has been successfully used by NCRR to help support model organism colonies and should be continued and expanded. Many other factors, such as quality of health surveillance and animal facilities are addressed elsewhere in this report. In 1990 an ILAR/NRC study detailed the need for preservation of important animal resources and gave examples of animal models (ranging from dogs to rodents to birds) that had been lost due to lack of funding or cryopreservation methods (NRC 1991). The present committee determined that the need still exists for several reasons. There has been underuse of current technologies of cryopreservation and underdevelopment of cryopreservation technologies needed to help alleviate this problem. The current status of cryopreservation of different species is highly variable. In the mouse, for example,
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Biomedical Models and Resources: Current Needs and Future Opportunities embryos from many strains tend to freeze and recover well. Gametes from hybrid mice also can be cryopreserved, but those from most inbred strains and genetically modified strains cannot. Bovine sperm has been routinely cryopreserved for a long time. In other species, the success is much more variable. Aquatic organisms cannot be successfully preserved by either embryo or gamete cryopreservation. Some models have been lost because no practical preservation methods were available at the time when an individual laboratory could no longer support a particular model. Some wild-derived models are lost because of inadequate funding to bring them into the laboratory or develop them for use as models. The cost of cryopreservation is an impediment for most researchers because research grants typically do not provide funding for cryopreservation and because current methods, such as freezing embryos in mice, are relatively expensive. Providing funds for development of more cost-effective methods, such as freezing gametes, would alleviate this preservation cost. For example, the cost of cryopreserving a mouse strain might vary from a few thousand to 10,000 dollars, depending on the method and ease of freezing. Once the initial investment in cryopreserving a stock is made, the maintenance cost drops to a few dollars per year, compared with $3,000–4,000 per year to maintain a minimal breeding colony. The cost of recovery may be a few hundred to $3,000, but one recovery is less than the annual cost of keeping a stock in the breeding colony. Improvement, perfection, and reduction of the cost of embryo, ovum, ovary and sperm freezing are needed. Demand for some models might lessen from time to time, but often increases later. If these models' gametes could be frozen easily and stored during down periods, there could be reductions not only in per diem charges but also in the space required. Animal research space for genetically engineered mice now being produced is becoming scarce. Maximal use of that space could be accomplished if strains and stocks being held in animal rooms were cryopreserved. FACILITY INFRASTRUCTURE Today, more than ever, animals of the highest quality are needed to support the sophisticated animal models required to meet today's research challenges. Additional high-quality animal holding and maintenance space is required throughout the research community. A major problem that became apparent from all of our sources is that animal space has been depleted at many institutions. Major forces causing the depletion are the explosion in the number of genetically altered mice; the increasing animal care regulations; the increased demand for space to respond to them; the increased technology, such as barrier caging, required for housing laboratory animals; and the decrease in funding available from NCRR for construction and renovation of animal care facilities. AVAILABILITY OF EXPERTISE AND TRAINING Biomedical science is moving into the next phase of understanding the function at the whole-organism level of genes identified at the molecular level. During the
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Biomedical Models and Resources: Current Needs and Future Opportunities ascendancy of molecular biology, there was a concurrent diminution in emphasis on training scientists in all phases of integrative biology. A result is that there is now a gap in available expertise in disciplines that can serve the integrative interface of whole-organism biology. A repeated theme in the workshop and other forums that provided input to this committee (NRC 1994a) has been inaccurate or incomplete physiologic, pathologic, and behavioral phenotyping of models. Furthermore, many basic scientists are unaware of or reluctant to use opportunities for integrative models. The growing demand for integrative scientists (scientists who specialize in whole-animal studies) mandates expanded training of scientists in these disciplines, and increased accessibility of the scientific community to integrative expertise. INFECTIOUS DISEASE, ANIMAL HEALTH Several important issues related to infectious diseases and their diagnosis in laboratory animals have arisen because of changes in animal-related research funding, including the phase out of the former Diagnostic and Investigational Laboratory (DIL) program supported by NCRR, the added cost to individual investigators due to the Circular A-21 requirements, the widespread use and transfer from institution to institution of transgenic and gene "knockout" mouse models, and emerging adventitious infectious agents not previously recognized. In addition to the obvious risk of losing irreplaceable colonies to infectious disease, this is a very important issue because of the confounding effects, including known mistakes of interpreting results from animal studies due to previously unknown underlying infections; these pathogens are undetected because in many institutions systems to monitor and eliminate them are poorly supported. A common example is the burgeoning and highly mobile populations of genetically altered mice that have various health problems, require specialized care, and must be protected from adventitious infectious diseases through increased diagnostic surveillance, rederivation, containment housing, prophylactic drug use and other activities. Despite those increased needs, support was precipitously compromised in several ways almost at once when NCRR support for DILs was withdrawn. Over the course of 30 years, DILs provided most of the support for discovery and investigation of laboratory animal diseases and supported the development of nearly all the diagnostic assays now used by the international scientific community to protect research animal health. DILs were not ideal, and many failed to live up to their potential; but some were stellar and contributed greatly to scientific and technologic advances in comparative medicine. The increasing direct cost to individual investigators due to the changes in indirect-cost support of animal research facilities has forced cost reductions in animal care, including cutbacks in diagnostic and health surveillance of animals, which are often shipped around the world. A recent survey (Jacoby and Lindsey 1997) revealed that infectious agents are once again either common or not tested for at many institutions. Many genetically altered mice have immunologic perturbations that render them susceptible to otherwise-innocuous and widespread emerging pathogens, such as parvoviruses, Helicobacter species, and Pneumocystis carinii. Other common infectious agents, such as mouse
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Biomedical Models and Resources: Current Needs and Future Opportunities hepatitis virus and rat coronavirus, continue to pose a risk to the health of all research animals or, equally important, to the validity of scientific data derived from infected animals. Many such infectious diseases need thorough study to develop prevention, control, therapeutic, and diagnostic strategies. Helicobacter, a group of newly discovered and widespread murine pathogens, is an obvious example. Because of inadequate knowledge and diagnostic technology, diagnostic laboratories have difficulty diagnosing or speciating this important group of murine pathogens. The increased interinstitutional traffic in genetically altered mice is compounding the problem. Those problems are relevant for many other species, but at present are especially pertinent to mice. ISSUES BEYOND THE SCOPE OF NCRR Workshop participants, survey responders, and the committee discussed three issues that have a serious impact on biomedical-model development and use but are so broad that they cannot be resolved by NCRR alone. The committee recognizes that these three reviews are beyond the charge of the present committee, but will describe the issues because they were pervasive and recurrent topics at the workshop and in the surveys. CIRCULAR A-21 Many survey respondents and workshop participants considered the designation of animal care facilities as a specialized service facility under OMB Circular A-21 (Federal Register 1997) to be an impediment to biomedical research. Federal auditors of academic institutions have inconsistently applied this particular aspect of A-21, so some institutions have been forced to recover the total costs of their animal facilities through increased per diem charges. Most institutions have not yet been forced to adopt such a cost allocation scheme because the new interpretation is being implemented sequentially in different types of institutions, for example, large universities were affected first. At institutions forced to recover costs through direct charges, per diem charges for animal care have more than doubled. It has been difficult for investigators to suddenly find such money. Furthermore, there is a concern among investigators that such high charges for using animals in their research puts them at a competitive disadvantage for fund-raising. In response to increased charges, investigators have tried to reduce charges by decreasing animal use or by decreasing veterinary services; this could result in a decrease in the quality of animal care. This controversial issue is clearly beyond NCRR alone and is the subject of a study by ILAR and, separately, by the National Research Council's Government-University-Industry Research Roundtable. There is not unanimity of opinion on this matter among either university administrators, scientists, animal facility managers, or auditors and accountants. The principal issues are 1) criteria that should be used by auditors for cost allocation between direct cost centers and the facility and administrative (F&A) cost center, 2) financial and scientific ramifications of uniform application of the designation of animal care facilities as specialized cost centers and 3) the arguments for and against the cost allocation
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Biomedical Models and Resources: Current Needs and Future Opportunities proposed in OMB Circular A-21 to determine a defensible set of allocation principles for animal care. INTELLECTUAL PROPERTY RIGHTS Advances in science have progressed through the sharing of intellectual, technical, and material resources. Scientific tools have generally been available to all investigators in a nonexclusive manner. During the last several years, there has been a substantial increase in the patenting of animals, animal products and reagents, and research tools and techniques. Some believe the aggressive enforcement of some patents and the broad interpretations of these patents have resulted in severe limitations on the use and distribution of some animals and research tools. Although intellectual property and research success should be protected, a balance is needed between patenting and research access to avoid severe restrictions on the free flow of information and biomedical resources. For example, the use of the oncomouse and the Cre-lox mouse model technologies is severely restricted by broad-based aggressive "reach-through" actions by patent holders. National involvement at all levels, with possible issue of a new national policy, is needed to resolve this issue in a satisfactory and appropriate manner. Two recent workshops sponsored by the National Research Council described the concerns of the scientific community in considerable detail (NRC 1994b; NRC 1996b). DATABASES AND CONFIDENTIALITY An emerging issue of critical concern to workshop members was the issue of data-sharing vs. confidentiality (NRC 1997). There is an increasing call from NIH for collaborative sharing of research databases, many of which contain data that explicitly identify individuals who might not have given consent to their wider distribution. This problem is exacerbated by the increasing capability of data-analysis methods to extract individual and confidential information from extensive collections of ostensibly innocuous research data. This issue is beyond the scope of this study on biomedical models, but it is mentioned because failure to resolve it is a potential impediment to future sharing of data related to comparison of biomedical models and human conditions.
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