NHLBI, Report of the NIH Rat Model Repository Workshop

Executive Summary

Background

This is a time of great opportunity for research utilizing the rat to study biology and disease. Advances in the genome projects, including obtaining the complete sequence of the human genome within the next 3 to 5 years, and the opportunity to create and utilize animal models toward the goal of unraveling the causes of human disease have never been greater. In addition to the rapid expansion of genomic tools, there are methods for ensuring genetic and microbiological quality and new embryological tools that are, or will soon be, available for the rat. Since the rat has many unique features and advantages for use in understanding the biological and genetic bases of health and disease, protection and availability of genetically defined rat models are imperative for the research community. A set of critical needs, including strain standardization, strain preservation, and genetic and microbiological monitoring must be met for the optimal use of rat models of human disease. Fulfilling these critical needs will facilitate the development of an approach for discovery of gene function by linking physiology, genetics, and clinical phenotypes together using comparative mapping techniques, thereby enabling unparalleled opportunities for discovery in biomedical research.

As a consequence, the National Institutes of Health (NIH) Director, Dr. Harold Varmus, asked the National Heart, Lung, and Blood Institute (NHLBI) to convene a distinguished group of national and international scientists. Fifty-eight scientists met on August 19 and 20, 1998, outside Washington, DC, to discuss the needs, use, opportunities, and parameters for optimal importation, standardization, maintenance, and distribution of genetically defined rat models.

Recommendations

To meet the challenges and opportunities of the future, the workshop participants recommended the establishment of a National Rat Genetic Resource Center (NRGRC). This Center should be located in a setting that has a strong research environment and would provide a minimum of 200 well-characterized and standardized rat models. The NRGRC should accept up to 50 new rat strains per year, rederive and cryopreserve all strains, and maintain 44 rat strains as live colonies with a daily census of more than 4,000 rats. The total cost for all activities, including distribution, is $35 million for the first 5 years.

The objectives of the NRGRC would be to serve as a national, central resource that will select, maintain, distribute, and preserve genetically defined rats; to coordinate the extramural NRGRC activities with the intramural NIH Genetic Resource (NGR); to develop a cost-effective central resource that will maintain the maximum number of strains without compromising the quality of strains; to establish criteria of strain selection, preservation, and distribution of genetically defined rats to the research and supplier communities; to facilitate and implement the establishment of standards for genetic, phenotypic, and microbiological monitoring; to participate in the development of new genetic technologies, e.g., embryonic stem cell production, nuclear transfer, etc., that will improve the function of the NRGRC and be disseminated to the scientific community; to provide relevant information to the scientific community via a Web page that interfaces with other rat databases and to develop a data management system that serves the internal needs of the Center; to institute an Advisory Board to oversee the operation and activities of the NRGRC, to set broad policy guidelines, and to report to the appropriate NIH designee; to provide training to the research community in the various technologies and approaches used at the NRGRC; and to sponsor meetings to discuss various uses of the rat in biomedical research and the developments in rat genetics and genomics.

The staff of the facility should consist of a director with expertise in genetics, several scientific research staff for research and development, informatics personnel, administrative personnel, a facilities manager and facilities maintenance personnel, cryopreservation personnel, animal care technicians, and quality control technicians.

An Advisory Board should be convened to oversee the operations and activities of the NRGRC and report to the NIH its recommendations on implementation, access, and future directions of the NRGRC. This Advisory Board should consist of members with expertise in facility management, genetics, pathology, informatics, and cryopreservation. In addition, the Advisory Board should have a representative from an outside repository and representatives expert in disease models, such as transplantation, cardiovascular, toxicology, cancer, neurosciences and behavior, immunogenetics, autoimmunity, and rat reproductive biology.

Benefits

Establishment of the NRGRC will have a broad impact on a wide range of research areas by providing an effective solution to a number of problems and by providing a mechanism that will meet the current needs and anticipated increased demand due to the development of important genomic tools and resources. For example, lack of accessibility is a major limitation to studies using inbred rat models because commercial suppliers carry a very small subset of inbred rat strains. Strains of known microbiological and genetic quality will reduce the problems engendered by the lack of models of known genetic purity, which impedes research progress, compromises the value of many studies, and leads to wasteful and inefficient experiments. Strains obtained from other investigators often have infectious diseases, which can spread to the whole animal house of the recipient. It is also important to maintain existing strains, because they have extensive physiological, pharmacological, and toxicological data sets. Since exact reconstruction of a strain is not possible, their loss would be both scientifically and financially wasteful. It is also wasteful to maintain live colonies of animals for which there is often only sporadic demand, because few investigators have the technical ability to cryopreserve stocks. The NRGRC will provide the appropriate models that will be used to generate the knowledge of fundamental biological and genetic mechanisms in both health and disease that is needed to develop new diagnostic, prevention, and treatment approaches for human diseases. In an era of discovery where defining function of genes and defining pathways involved in disease are the rate-limiting steps, the rat is likely to remain a major biomedical research model system.