Biomedical Models and Resources

Current Needs and Future Opportunities

Committee on New and Emerging Models in Biomedical and Behavioral Research

Institute for Laboratory Animal Research

Commission on Life Sciences

National Research Council

NATIONAL ACADEMY PRESS
Washington, D.C.
1998



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Biomedical Models and Resources: Current Needs and Future Opportunities Biomedical Models and Resources Current Needs and Future Opportunities Committee on New and Emerging Models in Biomedical and Behavioral Research Institute for Laboratory Animal Research Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1998

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Biomedical Models and Resources: Current Needs and Future Opportunities NATIONAL ACADEMY PRESS 2101 Constitution Avenue, NW Washington, D.C. 20418 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract/Grant No. 1 R13 RR11835 between the National Academy of Sciences and the National Center for Research Resources, National Institutes of Health, Department of Health and Human Services. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the organizations or agencies that provided support for the project. The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce M. Alberts is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. William A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council. Library of Congress Cataloging-in-Publication Data Biomedical Models and Resources: Current Needs and Future Opportunities International Standard Book Number 0-309-06035-4 Library of Congress Catalog Card Number 97-81454 Additional copies of this report are available from National Academy Press, 2101 Constitution Avenue, NW, Lockbox 285, Washington, D.C. 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu Copyright 1998 by the National Academy Press. All rights reserved Printed in the United States of America

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Biomedical Models and Resources: Current Needs and Future Opportunities COMMITTEE ON NEW AND EMERGING MODELS IN BIOMEDICAL AND BEHAVIORAL RESEARCH Muriel T. Davisson (Chair), The Jackson Laboratory, Bar Harbor, Maine Stephen W. Barthold, University of California, Davis, California Bennett Dyke, Southwest Foundation for Biomedical Research, San Antonio, Texas Roger T. Hanlon, Marine Biological Laboratory, Woods Hole, Massachusetts Robert Russell, Harlan Sprague Dawley, Inc., Indianapolis, Indiana Philip A. Wood, University of Alabama, Birmingham, Alabama Staff Ralph Dell, Director Thomas Wolfle, Study Director Kathleen Beil, Project Assistant The Institute for Laboratory Animal Research (ILAR), formerly known as the Institute of Laboratory Animal Resources, was founded in 1952 under the auspices of the National Research Council. A component of the Commission on Life Sciences, ILAR develops guidelines and disseminates information on the scientific, technological, and ethical use of animals and related biological resources in research, testing, and education. ILAR promotes high-quality, humane care of animals and the appropriate use of animals and alternatives. ILAR functions within the mission of the National Academy of Sciences as an adviser to the federal government, the biomedical research community, and the public.

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Biomedical Models and Resources: Current Needs and Future Opportunities INSTITUTE FOR LABORATORY ANIMAL RESEARCH COUNCIL John VandeBerg (Chair), Southwest Foundation for Biomedical Research, San Antonio, Texas Christian R. Abee, Department of Comparative Medicine, University of South Alabama, Mobile, Alabama Muriel T. Davisson, The Jackson Laboratory, Bar Harbor, Maine Bennett Dyke, Southwest Foundation for Biomedical Research, San Antonio, Texas Gerald F. Gebhart, Department of Pharmacology, College of Medicine, University of Iowa, Iowa City, Iowa James W. Glosser, Massillon, Ohio Margaret Landi, Department of Laboratory Animal Science, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania Charles R. McCarthy, Kennedy Institute of Ethics, Georgetown University, Washington, DC Robert J. Russell, Harlan Sprague Dawley, Inc., Indianapolis, Indiana Richard C. Van Sluyters, School of Optometry, University of California, Berkeley, California John G. Vandenbergh, Professor, Department of Zoology, North Carolina State University, Raleigh, North Carolina Peter A. Ward, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan Tom Pollard, Ex Officio, Chairman, Commission on Life Sciences, President, Salk Research Institute, La Jolla, California ILAR Staff: Ralph Dell, Director Thomas Wolfle, Study Director Kathleen Beil, Project Assistant Carol Rozmiarek, Research Assistant Susan Vaupel, Managing Editor, ILAR Journal

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Biomedical Models and Resources: Current Needs and Future Opportunities COMMISSION ON LIFE SCIENCES Thomas D. Pollard (Chair), The Salk Institute for Biological Studies, La Jolla, California Frederick R. Anderson, Cadwalader, Wickersham & Taft, Washington, DC John C. Bailar, III, University of Chicago, Illinois Paul Berg, Stanford University, Stanford, California Joanna Burger, Rutgers University, Piscataway, New Jersey Sharon L. Dunwoody, University of Wisconsin, Madison John L. Emmerson, Eli Lilly and Co. (Ret.), Indianapolis, Indiana Neal L. First, University of Wisconsin, Madison, Wisconsin Ursula W. Goodenough, Washington University, St. Louis, Missouri Henry W. Heikkinen, University of Northern Colorado, Greeley, Colorado Hans J. Kende, Michigan State University, East Lansing, Michigan Cynthia J. Kenyon, University of California, San Francisco, California David M. Livingston, Dana-Farber Cancer Institute, Boston, Massachusetts Thomas E. Lovejoy, Smithsonian Institution, Washington, DC Donald R. Mattison, University of Pittsburgh, Pennsylvania Joseph E. Murray, Harvard University, Wellesley Hills, Massachusetts Edward E. Penhoet, Chiron Corporation, Emeryville, California Malcolm C. Pike, Norris/USC Comprehensive Cancer Center, Los Angeles, California Jonathan M. Samet, The Johns Hopkins University, Baltimore, Maryland Charles F. Stevens, The Salk Institute for Biological Studies, La Jolla, California John L. VandeBerg, Southwest Foundation for Biomedical Research, San Antonio, Texas Staff Paul Gilman, Executive Director

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Biomedical Models and Resources: Current Needs and Future Opportunities Preface Models and model systems are a critical component of biomedical research aimed at improving human health. They include living animals of many taxa, cells and cultures, and computer and mathematical simulations, and they provide valuable surrogates for experimental research that cannot be carried out on human beings. The detailed understanding of the human genome and some model organisms' genomes achieved with advances in genome technology have opened wide the door for research to understand the function of genes and to use that understanding for disease prevention and therapy. Models will be more important than ever for functional genomics (the study of the behavior and physiology of genes) for research on the complex disease systems that remain to be conquered, and for preclinical testing of preventive or therapeutic approaches. The plethora of possibilities for developing model systems and doing research with them will always exceed the projected levels of funding available from the National Institutes of Health (NIH); that fact led the NIH National Center for Research Resources (NCRR) to ask the National Research Council for this report. The Comparative Medicine Program of NCRR has played a strong role in the development and support of biologic models. To help assist in continuing this role, NCRR sought guidance for setting funding priorities. Specifically, NCRR asked that the NRC identify the models and technologies necessary to support biomedical research in the most rapidly advancing fields over the next 5–10 years, NCRR's role in facilitating model and technology development, and strategies that NCRR might use in allocating scarce resources to competing needs in model and technology development and maintenance. This report attempts to provide that guidance through an assessment of the opportunities and needs for model development and use. Although the committee bears full responsibility for the content of the report, we would be remiss if we did not acknowledge the assistance of the many others who contributed their time, expertise, and advice. A workshop on biological models, held in Washington, DC, on 11–12 December 1997, was organized to address the subject through three approaches—scientific disciplines, overriding issues that affect many scientific disciplines, and types of biologic models (the agenda and list of participants are provided in Appendix B). The workshop was attended by 20 participants and an equal number of discussants, including representatives of NCRR, speakers who summarized critical components of the report and led discussions, breakout group leaders, and participants who developed, for the committee, their recommendations. The committee found the process extremely informative and hopes that all those people will find this report a suitable expression of its appreciation. A survey was developed and distributed through the directors of the categorical NIH institutes to intramural and extramural scientists who receive NIH funding and who use biologic models. The survey was also sent to the directors of major academic biomedical research institutions for dissemination to key investigators in their institutions and disseminated electronically through the Mouse Genome Informatics and

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Biomedical Models and Resources: Current Needs and Future Opportunities Comparative Medicine bulletin boards. The survey (attached as Appendix A) sought to characterize important research fields of the future, models and technologies that would be needed to support that research, and the proper role of NCRR. We are indebted to those who took time to complete the survey and provide us with their thoughtful comments. The report also drew information of the scientific literature, related NRC reports on biologic models and the sharing them among scientists, NCRR's Scientific Forum (September 1997), and NCRR's own survey conducted through the Federal Register (62:4781-2). This report has been reviewed by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the NRC's Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the authors and the NRC in making the published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The content of the review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their participation in the review of this report: Franklin D. Costantini, Columbia University, New York, NY John C. Donovan, Rhone-Poulenc Rorer, Collegeville, PA James Fox, Massachusetts Institute of Technology, Cambridge, MA Alan M. Goldberg, Johns Hopkins University, Baltimore, MD John E. Halver, University of Washington, Seattle Leland H. Hartwell, Fred Hutchinson Cancer Research Center, Seattle, WA Alan Hillyard, Base4 Bioinformatics, Mississauga, Ontario Cynthia Kenyon, University of California, San Francisco Theodore W. Kurtz, University of California, San Francisco John J. McGlone, Texas Tech University, Lubbock Daniel Pomp, University of Nebraska, Lincoln Joseph E. Wagner, University of Missouri, Columbia Peter A. Ward, University of Michigan Medical School, Ann Arbor John L. VandeBerg, Southwest Foundation for Biomedical Research, San Antonio, TX While the individuals listed above have provided many constructive comments and suggestions, responsibility for the final content of this report rests solely with the authoring committee and the NRC. To the committee, reviewers, and staff, I extend my deepest appreciation. Members of the committee devoted weekends and tireless energy to meet short deadlines. To the reviewers, who also worked under short deadline and whose efforts greatly improved the science and comprehension of our report, I am most appreciative. The value of this report to NIH and biomedical science in general is a measure of their effort. I appreciate the guidance and support provided by the Institute for Laboratory Animal Research (ILAR) staff throughout. Kathleen Beil provided timely and important communications to the committee and workshop participants in arranging travel and

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Biomedical Models and Resources: Current Needs and Future Opportunities lodging and in disseminating and receiving the survey. Regis Krah developed the survey instrument and assisted in the analysis. Ralph Dell's persistent nudging to meet deadlines and to stay focused when the topic seemed to lack focus and his management of the review and publication were of inestimable value. Norman Grossblatt's editing made the report eminently more readable, for which all readers will be appreciative. And, finally, I appreciate working with Tom Wolfle, who assisted in numerous ways throughout the study, as well as in the development of the report. Errors of omission or commission should be communicated to ILAR, NAS 347, National Research Council, 2101 Constitution Avenue, Washington, DC 20418. Muriel Davisson, Chair Committee on New and Emerging Models in Biomedical and Behavioral Research

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Biomedical Models and Resources: Current Needs and Future Opportunities Contents     CONTENTS   xi     EXECUTIVE SUMMARY   1 1.   INTRODUCTION   6     THE COMMITTEE'S CHARGE AND APPROACH   7     STRUCTURE OF THE REPORT   8 2.   BIOMEDICAL MODEL DEFINITION   10 3.   ESSENTIAL AND EMERGING RESEARCH FIELDS AND TECHNOLOGIES   12     FUNCTIONAL GENOMICS   12     AGING   13     BEHAVIOR AND NEUROBIOLOGY   14     COMPLEX DISEASE   15     MODEL DISCOVERY   16     MATHEMATICAL MODELLING, COMPUTATIONAL SIMULATIONS, AND SCIENTIFIC DATABASES   17     EMERGING AND RE-EMERGING INFECTIOUS DISEASES   17 4.   OVERRIDING ISSUES   19     ISSUES WITHIN THE PURVIEW OF NCRR   19     Maintenance and Preservation   19     Facility Infrastructure   20

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Biomedical Models and Resources: Current Needs and Future Opportunities     Availability of Expertise and Training   20     Infectious Disease, Animal Health   21     ISSUES BEYOND THE SCOPE OF NCRR   22     Circular A-21   22     Intellectual Property Rights   23     Databases and Confidentiality   23 5.   RECOMMENDATIONS   24     ENCOURAGE AND SUPPORT RESEARCH DIRECTED AT IMPROVING RESEARCH ANIMAL UTILITY, AVAILABILITY, HEALTH, WELFARE, AND MAINTENANCE   24     Laboratory Animal Health and Welfare   26     Diagnosis and infectious disease   26     Behavior   27     Improved Animal Acquisition, Maintenance, Propagation and Preservation   28     Development of Genetic Maps for Additional Model Species   29     Instrumentation Development and Miniaturization   30     CREATE A NATIONAL NETWORK OF COMPARATIVE MEDICAL EXPERTISE   31     To Support NIH Research Efforts on Animal Models, Such as Phenotypic and Genotypic Assessment and Disease Diagnostics   31     To Promote Multidisciplinary Interaction   31     CREATE A NATIONAL NETWORK OF INTEGRATIVE-BIOLOGY EXPERTISE THAT CAN SERVE THE ENTIRE BIOMEDICAL RESEARCH COMMUNITY   32     Academic Infrastructure for Integrative Biology Related to Animals   32     Mathematical Modelling, Computational Simulations, and Scientific Databases   33     Encouragement and Facilitation of Interdisciplinary Research   33     Development and Dissemination of Appropriate Information Technologies   34     Development and Maintenance of Databases, Interdisciplinary Modelling and Informatics Issues. The Site Would Contain Such Information as a Calendar of Events and Locations of Resources, Expertise, Software, and Databases   34

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Biomedical Models and Resources: Current Needs and Future Opportunities     INCREASE THE COMMITMENT AND RESOURCES FOR CONSTRUCTING AND RENOVATING ANIMAL RESEARCH FACILITIES   35     REINVIGORATE AND EXPAND TRAINING OPPORTUNITIES IN INTEGRATIVE BIOLOGY   36     OBTAIN PROGRAM GUIDANCE FROM THE SCIENTIFIC COMMUNITY   38     Use Existing Mechanisms Better   38     Fund Independent External Advisory Groups Every Four Years   38 6.   CRITERIA   40     REFERENCES   42     APPENDIXES   45

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