Tatsuji Nomura

Director, Central Institute for Experimental Animals

Kawasaki, Japan

During the US/Japan Meeting about 15 years ago, we decided to select specific microbiological items based on criteria that determine minimum requirements. As Dr. Itoh explained, these requirements correspond to those of the International Council for Laboratory Animal Science (ICLAS).

The ICLAS concept of microbiological monitoring is the same as that for genetic monitoring, that is, monitoring of animals that have been genetically controlled (such as inbred, hybrid, or congenic animals). Microbiological quality monitoring is applied only to microbiologically controlled animals that are barrier sustained, such as gnotobiotes and SPF animals.

In the United States and Europe, there is no microbiological monitoring; however, there is health monitoring. I can understand this concept because, from a practical standpoint, disease is the most important in those countries. However, health monitoring does not cover the microbiological quality of the animals. In addition, we have had recent experiences with new users—molecular geneticists—who have asked for more sophisticated high-quality mice for analysis of the expression of the introduced gene. For these users, we believe that it is important to monitor the microbiological quality of the animals.

It is our desire to reach a consensus regarding worldwide minimum requirements for genetic and microbiological monitoring. Each country has its own requirements for microbiological monitoring, which can be added as options; but we should at least establish minimum requirements.

T. GILL: I believe the critical point in monitoring is not with people who understand (such as with all of us, who agree), but with the political process. Unless a lot of people make a lot of noise, nothing is going to happen. If you publish a set of standards, the microbiological and genetic standards must be checked. If you promulgate the standards among the scientific community, then when scientists ask for animals they will ask the suppliers, "Do you fulfill these criteria? If you don't, we won't buy animals from you." Therefore, I think that a relatively simple list of microbiological requirements and a simple list of genetic requirements that correspond with each animal should be developed, and the scientific community should be encouraged not to buy from suppliers who do not provide this information.

T. NOMURA: What you describe is happening in Japan. The pharmaceutical industry will never buy from a breeder who has no test results from the ICLAS Monitoring Center. This has made the quality of breeders very high. As I mentioned, the United States should have a reliable, neutral, authorized monitoring center for microbiology and genetics on which everyone can depend.

T. GILL: The key point is that an institution independent of the animal suppliers has the authority to apply pressure from the pharmaceutical users to maintain these standards. That is why assigning the implementation of standards to the suppliers will never work because increasing profit is the basic drive of the suppliers. Sometimes high quality and increasing profits do not exactly mesh. Consequently, an outside group has to apply this pressure, and I think the users are the outside group that has to do this.

T. NOMURA: ICLAS is the only neutral organization that can do that.

T. ALLEN: You bring up a problem that is a real issue at NIH. Even though there were rules everywhere that you could not do what I am going to describe, it still happened. Within 6 months after we were finished with the ectromelia outbreak in 1979 to 1980, one of my colleagues on an airplane sat next to a man who had in his pocket a mouse that he was bringing in from the same institution where the outbreak originated to get around the rules and regulations. Asking staff to spend $1000 for a map test when they are on a budget is really a major problem.

T. NOMURA: I would like to mention again that the microbiological monitoring requirements that we selected are based on the contamination map of Japan. We have checked and know what agents are currently spreading. In addition, the standards for selection have to be decided by the users, not by the breeders. In Japan, we try to focus on the most critical users—industry. This focus is especially important when they are conducting long-term 2-year toxicology studies and they ask us to check certain items, especially pathogens causing inapparent infections. We base our selection in this way.

Neal West

Program Director, Comparative Medicine, NCRR, NIH

Bethesda, Maryland

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.

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

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

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.

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.

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.