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CIEA/NCRR/NIH Genetic and Microbiological Monitoring of Mouse and Rat Resources: Directions for the Future

Neal West

Program Director, Comparative Medicine, NCRR, NIH

Bethesda, Maryland

NIH Structure

As most of you know, there really is no centralized National Institutes of Health (NIH) planning body that decides future directions for the genetic and microbiological monitoring of rodent resources, except for a very few activities such as our sponsorship of this group through the National Center for Research Resources (NCRR). The NIH structure comprises 18 institutes and six centers. Most of our institutes and centers also have extramural and intramural components, which have very different missions and functions. This structure contributes to a very diffuse governmental authority. In our society, leadership derives not just from NIH, but also from academic, industrial, and research institutes such as The Jackson Laboratory, which, of course, we support financially, providing direction and encouragement.

Our grants do have strings attached. We produce guidelines and generate initiatives. In addition, I might mention some concrete initiatives or "case studies," particularly for the benefit of our Japanese colleagues, who may not be as familiar as others with how NIH proceeds in setting policy.

NCRR's Mission

Priority Setting for Mouse Genomics and Genetics Resources (Dove and Cox 1998) (which we call "The Mouse Report") arose from a workshop held in March 1998 and organized by NIH Director Dr. Harold Varmus to respond to the community's needs. This workshop, also referred to as the "Dove and Cox



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CIEA/NCRR/NIH Genetic and Microbiological Monitoring of Mouse and Rat Resources: Directions for the Future Neal West Program Director, Comparative Medicine, NCRR, NIH Bethesda, Maryland NIH Structure As most of you know, there really is no centralized National Institutes of Health (NIH) planning body that decides future directions for the genetic and microbiological monitoring of rodent resources, except for a very few activities such as our sponsorship of this group through the National Center for Research Resources (NCRR). The NIH structure comprises 18 institutes and six centers. Most of our institutes and centers also have extramural and intramural components, which have very different missions and functions. This structure contributes to a very diffuse governmental authority. In our society, leadership derives not just from NIH, but also from academic, industrial, and research institutes such as The Jackson Laboratory, which, of course, we support financially, providing direction and encouragement. Our grants do have strings attached. We produce guidelines and generate initiatives. In addition, I might mention some concrete initiatives or "case studies," particularly for the benefit of our Japanese colleagues, who may not be as familiar as others with how NIH proceeds in setting policy. NCRR's Mission Priority Setting for Mouse Genomics and Genetics Resources (Dove and Cox 1998) (which we call "The Mouse Report") arose from a workshop held in March 1998 and organized by NIH Director Dr. Harold Varmus to respond to the community's needs. This workshop, also referred to as the "Dove and Cox

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Workshop," was named after two of the leaders in mouse genomics and genetics. A report was generated by the members of that workshop and was put on-line on the NIH Director's home page in June 1998. The report, which describes the activities in dollars (millions of dollars), was circulated to the very broad scientific community, and expectations were very high. Everyone assumed that the money was already available; however, we still do not have the money. The process takes time, and money must be allocated in future years. Dr. Varmus, who had initiated the original mouse workshop, set up a trans-NIH working group to which I was appointed by Dr. Vaitukaitis to be the NCRR representative. Dr. Varmus came to the group at our first meeting on June 25 and said he wanted to see the infrastructure for mouse research in the United States built up, and he gave us—people from all of these twenty-some institutes and centers—the charge: Do some inventory, prepare a spreadsheet, and explain both what we are doing and what we are going to do. Obviously NCRR has a legitimate, historical, well-established record and mandate in the area of rodent resources, and especially mouse resources. We certainly do a fair amount of training, especially for veterinarians; and automatically this working group looked to NCRR, especially in the area of resources and training. As I mentioned, we are already heavily committed at The Jackson Laboratory, and we have learned much from that relationship, which has formed some of the basis for our initiatives in the planning stage. On October 5, 1988, what was called a "recalibration meeting of the mouse working group" was held, and Dr. Varmus met with a number of people who were involved in the workshop and asked us to describe where we want to go and where we would apply the resources. The only real product of that meeting was the general consensus that physical mapping must come first. Physical mapping is somewhat distant from the kind of resources and issues that are being discussed at this meeting. Nevertheless, we may have the advantage of time because many things that NCRR does (such as infrastructure and training) must come first to build an infrastructure toward future progress. Unfortunately, other emphases may siphon off or divert some of the potential resources, but Dr. Vaitukaitis has advised us to proceed. We hope to garner some additional support from other institutes and centers. In any case, we are committed to fulfill our role to serve, as Dr. Vaitukaitis has described NCRR's mission, as a catalyst for discovery. We will try to increase training, provide the resources, and plan for the phenotyping that everyone has come to realize is going to be a large part of the activities. Although I do not wish to criticize the brilliant microbiologists, biochemists, geneticists, and structural biologists who are participating, there appears to be a sudden reality check occurring in the complexities of what is called functional genomics (which I used to call phenotyping)—how many people it takes, how much effort is required, how long it is going to take, and how to

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marshall those resources to make use of the ability that now exists to generate incredibly large numbers of mutant animals. These resources will not be very useful unless an infrastructure is built and includes the pathology and phenotyping needed to make sense of changes generated in very large numbers. Database Recommendation The other part of the reality check relates to databases, which appear to be a real problem financially, conceptually, and organizationally and which sometimes appear to be an almost unsolvable issue. Everyone agrees that databases must be integrated and linked. There should be a standardized nomenclature. Needless to say, the development of databases is going to be extremely expensive. There is currently no plan to design and organize those databases. There may be others here who have a different perspective on this subject. Questions and Answers J. L. VAITUKAITIS: I would not feel negative about the direction and scope of the mouse working group activities. Some of those individuals are "gene jockeys," and it is only natural that they would suggest what they did. N. WEST: I agree, although I felt that they dominated the meeting. J. L. VAITUKAITIS: I would not worry about that at all. N. WEST: The other very timely initiative (in which Drs. Gill, Pakes, and Nomura participated) is the initiative of the August 1998 Rat Model Repository Workshop, which recommended a national rat genetic resource center to select, maintain, distribute, and preserve genetically defined rats (at least 50 new strains per year). With regard to future directions, I am not aware of any plans for implementation of the recommended rat resource center, although there might be some partnership with industry. Details of any initiative remain to be seen. Also included in the workshop report is the statement that the intramural NIH genetic resources are clearly inadequate to serve the growing needs of the extramural community and, in fact, NIH is not well structured to do that. Obviously, whatever emerges, given our mandate and our guidelines, NCRR will inevitably lead the rat resource initiatives (although we do not yet know in exactly what form). Both the mouse and the rat reports address the issues discussed here today—genetic and microbiological monitoring. However, there is a fear that something may be lost in the translation of good recommendations into actual initiatives. Many things discussed here today are very important but are also very expensive. Perhaps not fully appreciated is the great contrast—the difference in sophistication—that exists among some of the policy makers and the working groups in the meetings that I have attended at NIH and all the wonderful things I hear when I sit in a group like this.

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Learning from Each Other Obviously this group is incredibly sophisticated concerning the issues under discussion, and I have a fear that some details could be lost. You focused on many important considerations for the rodents and for other animals, including genetic monitoring, harmonization, husbandry, and cryopreservation. One additional issue relates to genetic drift. Cryopreservation is a very good way to maintain a stock against genetic drift (or loss, for that matter). My friends at The Jackson Laboratory have educated me well regarding how the economics of preservation may favor increased cryopreservation. I believe that this group—certainly individually, and collectively through many areas of expertise—has much to teach the NIH and the extramural community. There are many venues, and of course there are diverse audiences. I also believe that we at NIH have much to learn from the Japanese model for supporting these initiatives through public and private sources, including support from pharmaceutical companies. The Japanese model is structured slightly differently, and NIH may be less sophisticated with its structure. In addition, quality control standards can be raised and improved in the United States only when the public and private sectors work together closely, and I am not certain that they always have done that. I believe these US/Japan meetings will become increasingly important as the worldwide research community becomes more interactive—more scientifically integrated—and as there is more trafficking (such as in animals and embryos) and information exchange. Policy Setting To return to the local from the worldwide perspective, I think most of you know that Dr. Whitehair requested a decrease of his responsibilities sometime ago. Although he is not retiring at this time, he has requested that a new Director of the Comparative Medicine area be selected. Dr. Vaitukaitis has recently elevated the status of the Comparative Medicine area Director's position to the policy-setting level at NIH, that is, the Senior Executive Service (SES). These SES positions are very difficult to add to an institute or center at NIH. She announced this week that John D. Strandberg, D.V.M., Ph.D., currently the head of Comparative Medicine at The Johns Hopkins University, has been appointed to that position and will start at the NCRR on January 3, 1999. Unfortunately, Dr. Strandberg is unable to be present today due to a personal emergency. Nevertheless, I believe that these rodent initiatives and this key appointment are indications that the issues of concern to this group have great visibility in NCRR and at NIH. These indications bode well for the national leadership that NIH can provide in these areas.

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Reference Dove, W., and D. Cox (Summarizers). 1998. Priority Setting for Mouse Genomics and Genetics Resources. (http://www.nih.gov/welcome/directors/reports/mgenome.htm).