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Suggested Citation:"Closing Comments / Summary of Presentations." National Research Council. 1999. Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1998 US/Japan Conference. Washington, DC: The National Academies Press. doi: 10.17226/9617.
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Suggested Citation:"Closing Comments / Summary of Presentations." National Research Council. 1999. Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1998 US/Japan Conference. Washington, DC: The National Academies Press. doi: 10.17226/9617.
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Page 82
Suggested Citation:"Closing Comments / Summary of Presentations." National Research Council. 1999. Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1998 US/Japan Conference. Washington, DC: The National Academies Press. doi: 10.17226/9617.
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Page 83
Suggested Citation:"Closing Comments / Summary of Presentations." National Research Council. 1999. Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1998 US/Japan Conference. Washington, DC: The National Academies Press. doi: 10.17226/9617.
×
Page 84
Suggested Citation:"Closing Comments / Summary of Presentations." National Research Council. 1999. Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1998 US/Japan Conference. Washington, DC: The National Academies Press. doi: 10.17226/9617.
×
Page 85
Suggested Citation:"Closing Comments / Summary of Presentations." National Research Council. 1999. Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1998 US/Japan Conference. Washington, DC: The National Academies Press. doi: 10.17226/9617.
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Page 86
Suggested Citation:"Closing Comments / Summary of Presentations." National Research Council. 1999. Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1998 US/Japan Conference. Washington, DC: The National Academies Press. doi: 10.17226/9617.
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Page 87

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Closing Comments / Summary of Presentations Thomas J. Gill III Menten Professor of Experimental Pathology and Professor of Human Genetics University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania INTRODUCTION In the Introduction to his talk, Dr. DeGeorge presented his disclaimer as a federal official in the regulatory business. That reminds me of the situation in the Middle Ages: By volunteering to go on a crusade, you were forgiven all of your past sins and debts. I would like to take the same position now and point out that undoubtedly my summation reflects views through which I cannot help but filter what I hear. Many of these views are probably not new. Dr. Nomura pointed out that the US/Japan meetings began in 1980 and that the Rat Genetic Nomenclature Committee was established in 1994. That com- mittee meets in conjunction with the Rat Workshop and has dealt with nomencla- ture problems quite consistently. Even before 1980, however, there was a very strong relationship between science in Japan and in the United States. There was a formal US/Japan scientific exchange that dates back to the late 1960s and early 1970s, and I participated in some of the immunological exchanges under that program. So this is a longstanding relationship, and I think we have built good bridges scientifically and technically. NEED FOR GENETICALLY DEFINED ANIMALS Of the needs I have heard expressed at this meeting, I have noted the impor- tant need for genetically defined animals. The problem involved in fulfilling this need is not just with the generation of the animals but also with defining the animals. One aspect of this problem has been illustrated by some of the discus- 83

84 MICROBIAL AND PHENOTYPIC DEFINITION OF RATS AND MICE sions that came up today, that is, the use of the words “outbred,” “closed colony,” and “random.” I think everyone who used those words today used them differ- ently. The standard genetic definition of an outbred colony is one that is structured genetically, specifically to maximize diversity; random bred refers to any animals that are running around; and closed colony, to animals running around in a relatively confined space. Each group is genetically very different. Unfortu- nately, not only is the terminology different, but also the animals are used differently. Especially in large-scale technological settings, this difference has been a major drawback. The background of a specific genetic defect is very important. The expres- sion of a gene is a function not only of the gene itself, but also of its background. What we see in human genetics as variable penetrance is really (at least in my opinion) the expression of a major gene modified by several modifier genes, rather than one gene simply not showing up in one setting quite as strongly as it does in other settings. This expression is another example of the importance of genetic background and the definition of genetic background in trying to perform disease-related studies. It has been pointed out that there has been a very strong thrust in the past decade or so, when molecular biology has come to the fore, to ignore live animal studies. A number of my colleagues in the medical and scientific world have said that we basically no longer need experimental animals because with genetic tools, we can study humans and solve all of the problems—not only of disease but also of basic biology. Unfortunately, this was the funding position of the NIH for a long time, and I think one unfortunate aspect of this attitude in the NIH is that many animal resources have been let go and many developments in basic animal models have been put on the back burner. I certainly hope that the Mouse Genome Initiative and the Rat Genome Initiative will do something to change this. DEVELOPMENT OF GENETICALLY ENGINEERED ANIMALS Another big problem that we face today is the result of the development of genetically engineered animals. As an example, if you insert a transgene (such as HLA-B27, to study arthritis) and you find significant phenotypic variation, you must note that this phenotypic variation may be a function of where the transgene is inserted. There is generally no way to insert a transgene in a specific place consistently. Therefore, the transgenic animal having HLA -B27 in one laboratory is used the same way as the HLA-B27 transgenic animal in another laboratory, but they may be significantly different. I think also, as one continues to look at gene expression, it is necessary to look not only at the gene that has been trans- ferred but also at the control regions that affect the expression of that gene. If you look at studies on the beta globin genes in the human globin system, you will see that the long-range locus control region for the beta globin system is

THOMAS J. GILL III 85 located far away from the beta globin genes themselves. So if you want to look at a genetic expression problem, you have to look not only at the genes them- selves, but also at the locus control regions, which may be quite far away. This is the kind of genetics problem that must be addressed by any group trying to standardize animals for genetic research. The terms now coming into general use reflect this need: “physiological genetics” and “physiological genomics.” Physi- ological genetics is an old term, which I believe you will find in some of the early writings of William Castle. The term has been revivified now that genomics has become a promising field. One of the major impetuses for the development of experimental animals and for putting the effort into experimental animals that is represented by our meeting today is the tremendous impact of genomics and the possibility that it will solve many physiological problems. At the risk of alienating a number of my colleagues, I would like to point out that molecular biology is a tool. Molecular biology is no different from serology, coat color, or eye color; it is a tool to look at variation and the transmission of traits from parent to offspring—that is what genetics is. Ultimately, you cannot do these kinds of studies unless you have live animals, and I think that this point has been missed by a large part of the scientific community and, unfortunately, by a large part of the funding agencies that supports the scientific community. It is fashionable to support molecules but not animals. Now that we are swinging back toward animals, we find that we have lost great resources, many of which I think are critical to future progress. We must develop models that are important for biomedical research and for the study of disease. This is not to say that the study of molecular biology to understand gene function is not important; however, as was pointed out a long time ago, disease is an experiment of nature, and it is a probe by which you can perturb a normal biological system. Thus, from the basic scientific point of view, you can look at a disease model as a perturbation of a normal physiological function. From the medical point of view, you can look at a disease model as a way to give you some insight into the pathogenesis of human disease that will be useful in diagnosis and treatment. As animal models are developed, I think one has to have the focus on the development of useful disease models, which, in the long run, will be useful both biologically and medically. Because transgenic and recombinant animals and various disease models are generated “in everyone’s closet,” there has to be a mechanism for deciding which ones are going to be preserved and which ones are going to be lost. As a pathologist, in a world other than the scientific world in which I am now speak- ing, you make a diagnosis; you know that sometimes you are going to be wrong; you are never going to forget your mistakes; but you have to live with them and move on. I think the same kind of mentality has to be brought into the selection of disease models. You have to make the best judgment you can make at the time, make your selection and move on knowing you are going to make some mistakes but accepting the fact that you are going to have to live with them.

86 MICROBIAL AND PHENOTYPIC DEFINITION OF RATS AND MICE I will not belabor my well-known reservations about animal welfare and alternative medicine, but I think that looking at medical problems from the point of view of the worm or the computer is not the best approach. I unabashedly think humans are more important than worms or computers, but one cannot experiment on humans except in very restricted contexts. There are some who argue against the use of animal models who have seriously suggested that experi- mentation should be carried out on humans—either volunteers or prisoners. It is difficult to believe that people can make that kind of a suggestion; it is positively atrocious. IMPORTANCE OF DISEASE MODELS To illustrate the importance of disease models in a variety of settings, it is necessary to look not only at the importance of understanding the disease pro- cesses and their treatments, but also at the translation of research into clinical practice. Two examples follow. You all know the famous story of Pasteur and his rabies vaccine, for which he grew the virus in rabbit spinal cord. Little Joseph Meissner was inoculated and saved from rabies. The vaccination then became standard medical practice. In later years, we find out that the autoimmune responses to the rabbit spinal cord caused demyelinating diseases in some cases, but by then it was standard medical practice. If you did not vaccinate, you could get sued; however, if you did vaccinate, you ran the risk of disease. It was not until many years later and much experimentation that the virus was grown in eggs and did not cause the auto- immune problems. The problem, however, was that the vaccine was not thoroughly evaluated prior to its use, and it took from the middle of the 19th century to the middle of the 20th century to rectify this problem. My second example is a more current problem that has been generated by the treatment of recurrent spontaneous abortion in a population in which childbirth is being delayed until a later and later time. There are more problems with concep- tion, more problems with fertility, and enormous social pressure to do something about fertility in the setting where it is impaired. Some studies based on one animal experiment and four patients in London proposed that immunizing women with their husbands’ leukocytes to develop blocking antibodies prevented the rejection of the fetus. It became a major industry in obstetrics practice. I can assure you that the basic science is wrong; and the clinical studies (few of which were done thoroughly), when put together in a meta analysis, support the fact that this procedure is at very best marginally effective and probably not generally effective. So here is a very recent example of how something was taken on the basis of an unconfirmed animal study and put into clinical practice. It is now a tremendous problem, which we are trying to analyze and rectify. Thus, the role of good animal models and the thorough study of disease and its treatment before translation into the clinic are important.

THOMAS J. GILL III 87 STANDARDIZATION AND MONITORING It is important to standardize animals for research with oversight by the scientific community. This means that the broad scientific community, with combined knowledge in the various aspects of disease, genetics, and microbiol- ogy, should oversee the development and dispensing of these standardized ani- mals. In my opinion, the concept of standardizing animals and monitoring them has not been appreciated thoroughly. Dr. Nomura has pointed out this concept at a number of our meetings. From the genetics point of view, it is necessary to determine whether you monitor one gene or several genes for a polygenic system; or do you monitor the genome of the whole animal. From the microbiological point of view, do you monitor a standard panel or do you monitor everything you can put your hands on; or is there a difference? How do you characterize initially and how do you monitor? The point has been raised and emphasized several times about how you enforce this monitoring. We can sit around and talk to each other, and we all believe that these ideas are good. Agreement is not the problem. The problem is in convincing someone else to believe that these ideas are good. From a very practical point of view, you can talk to your colleagues but in 99 out of 100 times, the ideas will go in one ear and out the other. Theodore Roosevelt pointed out that the best approach to diplomacy is to walk quietly and carry a big stick. The big stick in this area is the journal editors. If a journal will not publish a paper unless a certain minimal genetic and microbiological characterization of the animals is used, it will have a greater impact on changing behavior than all of the committee reports that have ever been written. From the supplier’s point of view, there is obviously a strong motivation. Although I do not impugn anyone’s idealistic motivations, in practi- cality, doing adequate genetic monitoring and adequate microbiological monitor- ing is expensive, which in turn increases the price of the product and decreases the sales of the product. Thus, there is a built-in thrust against monitoring from the commercial point of view. From the scientific point of view, the experimenter may want to know every- thing, which is unrealistic. It is necessary to hit a balance somewhere in between. I believe the way to achieve balance is to find what is minimally necessary and then enforce this minimum by having consumers basically say that they will not buy animals from suppliers unless there is this minimal microbiological profile and this minimum genetic profile. RAT REPOSITORY WORKSHOP The Rat Repository Workshop resulted from the recognition (albeit very belatedly) of the major role that the rat played as a model for human disease as

88 MICROBIAL AND PHENOTYPIC DEFINITION OF RATS AND MICE well as basic biology. With due apologies to my colleagues from The Jackson Laboratory, most of genetics started with the rat from the work of William Castle. However, Clarence Little was better connected socially and politically, and he managed to obtain funding to build The Jackson Laboratory, which advanced the use of the mouse. The rat geneticists’ level of political sophistication was not as great; consequently, the rat slipped into oblivion. Nevertheless, the rat is now being recognized again as a major experimental animal in basic research and in clinical research. In my opinion, the idea that there is competition among the animal models is wrong. Unique contributions can be made from the mouse genetics point of view, the rat genetics point of view, and the human genetics point of view. If you can find much of the same basic cellular machinery in a yeast and in a Droso- phila, then among these three mammalian species, something found in one spe- cies will have implications in the other species. I believe that the work in these three species should be integrated into a combined approach for looking at basic genetic processes and for studying disease processes. NATIONAL RAT GENETICS RESOURCES CENTER The objectives of the National Rat Genetics Resources Center may be sum- marized briefly as follows. The Center will 1. serve as the national central resource that will select, maintain, distribute, and preserve genetically defined rats; 2. coordinate extramural activities of the National Rat Genetics Resources Center and the intramural NIH genetic resource; 3. develop a cost-effective central resource that will maintain the maximum number of strains without compromising the quality of the strains; 4. establish criteria for strain selection, preservation, and distribution of genetically defined rats for research; 5. establish standards of genetic, phenotypic, and microbiological monitoring; 6. develop new genetics technologies such as embryonic stem cell produc- tion (which is still somewhat of a problem in the rat), nuclear transfer, and so forth, which will improve the function of the resource and be disseminated to the scientific community; 7. develop and maintain a database that will serve the internal needs of the Center, provide relevant information to the scientific community, and interface with other rat databases; and 8. institute an advisory board to oversee the operation and activities of the National Rat Genetics Resources Center to set policy guidelines and to report to the appropriate NIH designee.

THOMAS J. GILL III 89 It is absolutely critical for an advisory board to have extensive input into what is being done because those advisors are not only the users, but also the experts in the area. They should advise on all decisions, provide training to the research community in the various technologies and approaches to be used at the Center, and sponsor meetings to discuss various uses of the rat in biomedical research and developments in rat genetics and genomics. RECOMMENDATIONS In conclusion, I would like to make the following suggestions to this group and, more broadly, to the NIH. 1. Develop a short (8- to 12-item) list of specific, critical microbiological tests that rats and mice should have. Although many tests may be desirable, we should list the most important and expand the list later. No one will pay attention to a long list. 2. Develop a short (8- to 12-item) list of specific, critical genetics tests that rats and mice should have. This list also can be expanded later. 3. Send the two lists described above to journal editors and request that this information be required for publication. Publicize these lists widely and urge users to require this information from suppliers. Send the list to suppliers and urge that they conform. These letters should go out under the joint heading of ILAR and ICLAS. 4. Establish close working relationships with those involved in the Mouse Genome Project and the Rat Genome Project. These are the people with whom we must communicate. The US/Japan Meeting could be held in conjunction with one of the major mouse or rat meetings in the same way that the International Rat Genetic Nomenclature Committee meets just before the International Workshops on Alloantigenic (henceforth, Genetic) Systems in the Rat. 5. Develop close and constant interactions among the groups interested in monitoring, nomenclature, and experimental work. The people involved will overlap considerably.

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US-Japan meetings on laboratory animal science have been held virtually every year since 1980 under the US-Japan Cooperative Program on Science and Technology. Over the years these meetings have resulted in a number of important documents including the Manual of Microbiologic of Monitoring of Laboratory Animals published in 1994 and the article Establishment and Preservation of Reference Inbred Strains of Rats for General Purposes published in 1991. In addition to these publications, these meetings have been instrumental in increasing awareness of the need for microbiologic monitoring of laboratory rodents and the need for genetic definition and monitoring of mice and rats.

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