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The Biological Integrity of Laboratory Rodents Robert O. Jacoby Professor of Comparative Medicine, Yale University New Haven, Connecticut The value of small rodents to biomedical research is beyond question. About half of the extramural grants awarded annually by the US National Institutes of Health require some use of laboratory animals. Because more than 95% of such use involves mice and rats, public investment in rodent-based research is enor- mous. Statistics for research in Japan are probably comparable. It follows that the quality of much biomedical research relies substantively on the quality of laboratory rodents. During 1993, the NCRR conducted a national survey of laboratory animal use, facilities, and resources. It reported that more than 7,000,000 mice were used annually among approximately 500 institutions (NCRR 1997). Anecdotal estimates indicate that the annual rate of increase in the use of rats and mice is about 20% (annual workshop of animal resources directors of major American universities, 1998), which suggest that annual use in the United States this year will exceed 15,000,000. Additionally, a recent poll by the Howard Hughes Medical Institute of approximately 60 constituent sites suggested that rodent use will increase by 1 to 3 times current levels during the next decade (J. Alford, Administrative Manager, Howard Hughes Medical Institute, personal communication during presentation at 1998 annual meeting of the Animal Resources Directors of Major American Universities). Scientists treasure reproducibility. The word that describes what scientists doâresearchâimplies the necessity of reproducibility for scientific investigation. The study of living things, a fundamental activity of biomedical scientists, pre- sents a perennial challenge for attaining and sustaining reproducibility, especially when research involves complex organisms such as rodents. For the first two trimesters of the current century, genetic variability and rampant infection made 12
ROBERT O. JACOBY 13 animal research a risky business. However, steady progress in improving the health and genetic quality of laboratory mice and rats since the 1960s has reduced this risk and enhanced the value of animal experimentation in virtually every field of biology and medicine. Great progress occurred not only in the detection, elimination, and prevention of common pathogens, but also in the genetic ma- nipulation of the mouse and rat through sophisticated breeding schemes. These advances provided access to novel mutants such as widely used models of im- mune dysfunction. Thus, as the century draws to a close, laboratory mice and rats have become vanguards of animal-based research. They are small enough (and big enough), tame enough, fertile enough, cheap enough, healthy enough, and genetically uniform enough to meet critical standards for mammalian modeling. These attributes were less obvious for a while, not very long ago. Advances in molecular biology and biotechnology, especially during the 1970s and 1980s, were viewed by some as a harbinger of reduced reliance on vertebrate animal experimentation. In vitro or invertebrate alternatives offered opportunities for cheaper and faster answers to some scientific questions. In fact, many insti- tutions experienced a decline in animal research during those decades. This trend occurred despite the fact that genetics, neoplasia, immunology, metabolism, and a host of other areas remained well suited to exploration in vertebrate models. But doubts about the relevance of vertebrate animal research are now moot, because, ironically, many of the tools and concepts that suggested imminent tempering of animal-based research became stimulants for an explosive growth in animal use. Molecular and developmental biologists put the mouse genome âin motionâ and changed the face and potential of animal-based research dramati- cally and permanently. The impact of the genetically altered mouse, which is still a scientific infant, and its cousin, the genetically altered rat, which is by compari- son a scientific fetus, is reflected in their anointment, with âdigestibleâ hyberbole, as the âE. colisâ of the 21st century. The advent of genetically altered rodents, however promising scientifically, also is associated with biological, technological, logistical, and financial chal- lenges that are emerging at an astounding rate. The challenges for assuring biologic integrity in genetically altered animals are dealing with intervening infections in diverse environments using diverse assessment standards and diverse terminology. Most of these challenges stem from the development, characteriza- tion, production, distribution, housing, husbandry, and health care associated with novel animals. And they raise a fundamental question: With so many genetically new animals being developed and used in so many places, by so many people, so quickly, how can their biological integrity be defined and ensured? The following remarks attempt to highlight briefly some of the issues flowing from this question with the expectation that others at this meeting will address them in greater depth. My definition of âbiological integrityâ is incomplete, but, for the moment, consider the term to mean âthe stability of intrinsic and extrinsic factors that
14 MICROBIAL AND PHENOTYPIC DEFINITION OF RATS AND MICE define the structural and functional characteristics of an animal.â Therefore, the benchmarks for defining a laboratory rodent in the era of genetic engineering must include at least the establishment, standardization, and monitoring of fac- tors such as genotype, phenotype, microbial status, and environmental quality. Criteria such as reproductive capacity and other health-related factors such as susceptibility to infection should also be considered. These concepts also imply that biological integrity can be perturbed by in- trinsic or extrinsic interference, which may be overt or subtle. This threat is especially relevant considering the diversity of settings in which genetically engi- neered rodents are being made. Variability can be caused by genetic drift; the influence of genetic background on the penetrance of a phenotypic trait; opportu- nistic infection that may be pathogenic, disruptive to normal responses, or condu- cive to erroneous phenotyping; environmental stresses such as noise, vibration, and threatening odors; and many other factors. Variability also can be abetted by diverse or ill-defined terminology. For example, and as noted elsewhere in these proceedings (Lindsey, 1999), the term âspecific pathogen freeâ has lost value because of the lack of precision with which it often is employed and perceived. Additionally, the increased use of animals inherently increases risks to biological integrity from dense housing and increasing exchanges of animals and animal products among laboratories, nationally and internationally. Because worldwide reliance on laboratory rodents will increase for the fore- seeable future, internationally standardized criteria and definitions should be developed as benchmarks for the biological integrity of laboratory rodents. A number of questions should be answered in formulating a transnational strategy to achieve this goal, a few of which are cited here. What are the criteria and definitions that should be used to measure biological integrity? Which assess- ments should be performed and how often? Who should perform the assess- ments? How should assessment results be reported and accessed? What sources are available to support research and development of new or improved assess- ment methods? Who should be responsible for funding assessment programs and how can the funds be leveraged for maximum benefit to biomedical research and the health of laboratory animals? The time is ripe for international cooperation and action on these important issues. Meetings such as the US/Japan conference in session today can and should play a central role in getting planning under way. REFERENCES Animal resources directors of major American universities. 1998 annual workshop. Cincinnati, Ohio. Lindsey, J. R. 1999. Current status of pathogen status in mice and rats. Pp. 39-43 in Proceedings of the US/Japan Meetings, October 23, 1998. National Academy Press, Washington, DC. NCRR [National Center for Research Resources], National Institutes of Health. 1997. The national survey of laboratory animal use, facilities and resource. USPHS, Washington, DC.
