REGULATIONS

NIH Plan for the Use of Animals in Research

in response to the 1993 NIH Revitalization Act

Note from AWIC Editor: Every effort has been made to minimize discrepencies between electronic and paper versions of this document. The paper copy, however, is the official document.

Table of Contents

Introduction

PART I - PREAMBLE

PART II - SELECTED RESEARCH HIGHLIGHTS

PART III - ACTIVITIES INITIATED SINCE 1986

PART IV - PLAN

PART V - EVALUATION

Appendices

INTRODUCTION

This Plan for the Use of Animals in Research has been prepared in accord with Section 404C of the Public Health Service Act, as amended by Section 205 of The National Institutes of Health Revitalization Act of 1993, Public Law 103-43.

As required under Section 404C (e), a standing Federal committee, the Interagency Coordinating Committee for the Use of Animals in Research, (hereinafter known as the Committee) was established at the request of the Director of the National Institutes of Health (NIH). The Committee is composed of a chairperson, designees of the directors of the 17 research institutes and 2 centers of the NIH, and one representative from each of the following agencies: the Consumer Product Safety Commission, the Environmental Protection Agency, the Food and Drug Administration, and the National Science Foundation. In addition, several liaison members with competency in relevant areas of research were appointed to the Committee. The members, alternate members, and liaison members were selected on the basis of their training, experience, and expertise in the use of model systems and in the use of animals in biomedical and behavioral research, including laboratory animal medicine. Appendix A contains a list of committee members and their affiliations.

The Committee met eight times between June and September 1993 to advise the Director of the NIH on the scope and content of the Plan, as directed under Section 404C (a). The Plan was drafted from materials compiled at Committee meetings. For reference, Appendix B contains a copy of Section 404C of the Public Health Service Act, as amended by Section 205 of Public Law 103-43.

The Report has five parts: I - Preamble; II - Selected Research highlights; III - Activities Initiated Since 1986; IV - Plan; and V - Evaluation.

PART I - PREAMBLE

As the Federal Government's principal agency for health research, the National Institutes of Health (NIH) conducts and supports biomedical and behavioral research to understand the workings of the human body, to extend healthy life, and to reduce the burdens of illness and disability. In its mission to maintain and improve the health and well-being of the American people, the NIH fosters the development and application of innovative research strategies; provides research resources; sponsors the training of research personnel; and evaluates, validates, and disseminates new information about medicine and health.

The ultimate goal of health scientists is to understand human disease in such detail so as to be able to prevent it. In general, the knowledge gained from the study of mammals, whose body systems are closest to humans, forms the basis for biomedical and behavioral research and current medical practice. The use of research animals in the laboratory remains indispensable for continued progress in human and veterinary medicine and maintenance of human and animal health. Animals are also essential for the study of complex behavior and behavioral disorders such as those associated with excessive alcohol consumption, abuse of drugs, and mental illness.

The methods and the standards of conduct in animal research have continually undergone evolution, largely because of the changing views within the scientific community itself and the development of new technologies. In some cases, model systems have reduced or eliminated the need for whole animals as research subjects without disturbing the steady progress of knowledge. Investigators continually seek the best available models of research to understand the human organism look to other scientifically valid model systems in order to identify common themes within the diversity of living things. This approach has increased opportunities for discoveries of fundamental importance. It is essential, however, to understand that the development of such model systems should be driven by the scientific process itself in order to allow investigators the freedom to select the most appropriate model to solve a medical problem. To illustrate this point, we have included in Part II a selection of research advances that were achieved using a wide variety of biological and nonbiological model systems.

In the early 1980's, the NIH recognized the rapidly changing scientific base of knowledge, and its institutes and centers sponsored a number of meetings on models for biomedical research. Notably, in the series of workshops held in 1985, panels of scientists reviewed, evaluated, and reported on the relevance of various models for biomedical research. This broad survey included invertebrates, nonmammalian vertebrates, cell and tissue culture systems, and nonbiological approaches, including mathematical and computer-assisted systems. The report of this conference contains many examples of the uses of diverse model systems to resolve important medical problems. Another conference held in 1989 assessed the status and potential of models and examined the role and future need for animals, especially for mammals, in biomedical research. A summary of the conclusions of that conference is presented in Appendix C. This document not only provides descriptions of model systems but also assesses their strengths and limitations.

The important conclusion drawn from the 1989 conference was that: "Biomedical research will be most effectively advanced by the continued application of a combination of models--mathematical, computer, physical, cell and tissue culture, and animal--in a complementary and interactive manner, rather than by concentrating on any one or a few kinds of model systems." The NIH is convinced that this paradigm will support the needs of and help fulfill the promise of modern biomedical research.

Whenever possible, scientists try to utilize the most effective means of solving technical problems with respect to reducing the time and cost of the research and improving the specificity of the result. This approach often allows researchers to examine systems in greater detail, moving from the general to the specific, e.g., from intact animals to organs, to cells, and to underlying biochemical and molecular events that occur at the subcellular level. On the other hand, after fundamental observations have been defined at the molecular and cellular levels, a full understanding of any biological system can only be achieved if whole organisms are studied within their environment in light of the information gained at more reduced levels.

For many years, NIH has conducted and supported research on the development of model systems that adequately and reliably reproduce biological processes in the intact organism. The model systems are discussed below and outlined in Appendix D.

Because advances in biomedical and behavioral research will continue to require the use of animals, the NIH takes seriously its responsibility to support the development and promulgation of methods that safeguard the welfare of the animal subjects in the research it conducts and supports. The NIH remains convinced that the vast majority of scientists are guided by their knowledge that good animal care is an integral part of good science. To do the best research, scientists use the appropriate numbers and species of animals; follow procedures that minimize pain and distress in animals, whenever possible; and use non-whole animal methods which do not compromise the goals or quality of the research.

To foster these goals, the NIH has long exercised leadership in developing and implementing policies for the humane care and use of laboratory animals. In recent years, the NIH has reexamined in great detail and refined the Public Health Service animal welfare policy. Investigators must now provide written assurances that they will use methods that minimize the number of animals and limit pain and distress. In addition, with the help of veterinary experts, the NIH has provided updated guidelines which serve as a primary reference for the high-quality care and use of laboratory animals.

Better understanding of the life functions, inherent or modified by environmental influences, of mammals, other vertebrates, and invertebrates will lead to the development of methodologies that could be used as alternatives to toxicity testing. Several NIH institutes, in particular the National Institute for Environmental Health Sciences (NIEHS), as well as the Consumer Products Safety Commission, the Environmental Protection Agency, and the Food and Drug Administration and other regulatory agencies, working through the National Toxicology Program (NTP) support programs aimed at developing and validating new methods for determining the effects of environmental agents on living organisms. Scientists continue to refine existing short-term in vitro tests and develop new tests that are reliable and predictive of adverse health effects. Some non-whole animal systems can and do complement whole animal studies, providing useful information for screening chemicals and drugs and for the study of biological processes. When employed in conjunction with tests that might otherwise require large numbers of intact animals, non-whole animal systems may lead to significant reductions in the number of animals needed. At the present time, however, such systems are not acceptable on any widespread basis as total replacements for whole laboratory animal models in toxicity testing.

The contributions of the NIH institutes in this field are summarized in the National Toxicological Program Annual Plan. As required under Section 463A of the Public Health Service Act, as amended by Section 1301, Public Law 103-43, the NIEHS will develop and validate assays and protocols, including alternative methods that can reduce or eliminate the use of animals in acute or chronic safety testing and establish criteria for the validation and regulatory acceptance of alternative testing.

  1. Models for Biomedical Research: A New Perspective, National Academy Press, Washington, D.C., 1985 Modeling in Biomedical Research: An Assessment of Current and Potential Approaches, National Institutes of Health, Bethesda, Maryland 1989. Ibid., p. 1 Public Health Service Policy on Humane Care and Use of Laboratory Animals, Washington, D.C., 1988;
    Section 495 of the Public Health Service Act, as amended by the Health Research Extension Act of 1985, P.L. 99-158
    Section 13 of the Animal Welfare Act, as amended by the Food Security Act of 1985, P.L. 99-198. Guide for the Humane Care and Use of Laboratory Animals, National Research Council, NIH Publication No. 86-23, Washington, D.C., revised 1985.

  2. National Toxicology Program: Review of Current DHHS, DOE, and EPA Research Related to Toxicology, Fiscal Year 1992.

PART II - SELECTED RESEARCH HIGHLIGHTS

This section contains a brief sampling of the many research advances in biomedical and behavioral research that use a wide variety of model systems ranging from lower animals, to cell cultures, and to physical methods. These examples serve to illustrate the breadth and depth of NIH research and how NIH institutes and centers conduct and support research that meets the directives in Section 404C of the Public Health Service Act. Most of these activities have been summarized in previous NIH biennial reports to the Congress and in the publications prepared periodically by NIH institutes and centers to inform the broader public how the NIH is expending appropriated funds to improve the Nation's health. As indicated in Section V, the Committee plans to undertake a more comprehensive evaluation of NIH awards and the resulting publications that are relevant to the objectives of the Act. These findings will be communicated to the Congress in future reports.

Screening for cancer-causing agents:
Historically, most tests for carcinogens in the environment have been performed on rats and mice. Now the NIH is supporting the development of a new model using a small freshwater fish to augment these studies. In addition to being sensitive to water-borne carcinogens at low doses, this fish offers several advantages, such as small size, short life-span, ease of propagation in a controlled environment, and homogeneous, age-matched offspring. Using this in vivo nonmammalian model, it is possible to obtain statistically significant responses when testing potential carcinogens at the low doses typical of human exposure in the environment and work place.

Developing new drugs:
A new method for evaluating anti-cancer agents for activity against major solid tumors of adults was introduced in the mid- 1980s. Panels of human tumor cell lines, chosen to reflect a range of tumor types as well as patterns of drug resistance, are used to screen drugs for anticancer properties. This system replaces one using large numbers of leukemic mice, thereby reducing the number of vertebrate animals used per compound tested. The new automated screening system, consisting of 60 cell lines representing nine different types of cancer, became fully operational in 1990 and is currently capable of testing about 10,000 synthetic compounds and extracts of plants and animals annually. Computerized systems scan the structures of thousands of new chemicals for possible testing. Although the use of this method eliminates the need for animal testing initially, active compounds must be tested in animals to determine their therapeutic efficacy and safety.

Using non-invasive technologies:
The NIH supports and conducts research to develop and refine noninvasive technologies, such as magnetic resonance spectroscopy and imaging, positron emission topography, advanced optical imaging, ultrasound, and single photon emission computed tomography. The application of imaging instrumentation can decrease the number of animals needed for a given study since it is possible to continuously monitor the biological systems in an intact animal. Moreover, these types of studies do not involve pain or discomfort to animals, permitting, in some cases, multiple studies on the same animal. Once validated in animals, many of these noninvasive techniques can be used directly on humans, possibly eliminating the need for animals altogether.

The power of the new computerized three-dimensional imaging techniques now permits researchers to pinpoint neural activity and observe the living, functional brain in normal and disease states. Visualization computing offers unprecedented opportunities for understanding the underlying mechanisms in human behavior, emotion, neurological diseases, alcohol and drug dependence, and mental disorders.

Understanding genetic pathways:
The NIH supports and conducts genetic studies using well-studied model organisms, such as: a bacterium (Escherichia coli), a yeast (Saccharomyces cerevisiae), a roundworm (Caenorhabditis elegans), and a fruit fly (Drosophila melanogaster). Large numbers of these organisms can be generated quickly, and the complexity of their genomes (the total genetic information present in their cells) is simpler than that of vertebrate animals. Nevertheless, these organisms all share a number of fundamental cellular and molecular properties with higher animals, including humans. Novel strategies which have the potential to accelerate the sequencing of the human genome are easily evaluated using these invertebrate model systems.

By studying large numbers of simpler organisms, scientists have determined the location and function of many genes (segments of DNA). These studies can sometimes reduce the numbers of higher vertebrates that traditionally have been used for these studies.

Mapping the genes of a tiny roundworm (C. elegans) will enable scientists to describe the function of each of the 959 cells that make up the adult organism. Such maps are extremely useful for a wide range of biological studies, such as the search for individual genes, including mutant genes responsible for genetic diseases.

Both humans and fruit flies (D. melanogaster) display a wide variety of genetic defects affecting the development of the eye. Fruit flies serve as models for identifying the genes involved in some inherited, degenerative diseases of the retina.

Research using fruit flies, yeast cells, and the roundworm indicates that there may be dozens of genes linked to longevity and aging. Other genes may be responsible for shortening the life span. For example, the mutation of a certain gene can more than double the nematode's normal life span. Scientists are currently attempting to isolate and clone the genes responsible for extending life span and determine what their protein products do at cellular and tissue levels.

The roundworm model also is being used to identify and clone the genes responsible for alcohol sensitivity. This study may help to identify susceptibility to the addictive effects of alcohol.

The development and improvement of gene therapy technology involves the delivery of specific genes to particular organs or cells of the body to correct inherited deficiencies or mutations. The delivery system or vector is usually a modified virus particle from which the viral genes have been removed and replaced with the gene of interest. Gene transfer vectors are initially tested in tissue culture systems. Although this method eliminates the need for animals initially, vectors must be further tested in animal models to demonstrate that they function properly in cells in a living organism.

Exploring brain function:
The NIH has for many years supported research on marine invertebrates as models of brain function in higher animals. The relative simplicity of the nervous systems of marine invertebrates and the large size of their nerve cells, make them ideal subjects for many types of neurobiological studies. Research on marine invertebrates such as the squid have revealed fundamental mechanisms of nerve impulse generation and transmission of information at contact points or synapses between nerve cells. Subsequent work in higher animals has demonstrated that these mechanisms are similar in mammals, including man. The basic molecular mechanisms, "molecular motors" that produce movement of special chemicals or neurotransmitters within the conducting fibers of nerve cells, are being investigated in the giant axon of the squid. These results, now being validated in mammals, are highly relevant to human neurodegenerative diseases, such as amyotrophic lateral sclerosis (Lou Gehrig's disease), Alzheimer's disease, and Parkinson's disease.

The study of marine snails (Hermissenda) and sea slugs (Aplysia), has contributed significantly to the uncovering of molecular mechanisms associated with memory storage and learning. Neurobiologists can actually observe physical changes occurring in the cells of these simple organisms conditioned to respond to light stimuli. If this new information can be validated in more complex animals, it may shed light on such human problems as learning disabilities in the young and on Alzheimer's disease in the elderly.

PART III - ACTIVITIES INITIATED SINCE 1986

Over the years, the NIH has convened the Nation's leading researchers to examine the role of and future need for animals, especially mammals, in biomedical and behavioral research and testing. In seeking more precise, more rapid, and less expensive ways to develop this information, these scientists also addressed the potential of using other model systems to obtain basic biological information. The participants were charged with the task of evaluating the strengths and limitations of vertebrates, invertebrates, cell cultures, mathematical models, and computer simulations as models for the study of human disease. In most cases, these symposia or workshops culminated in publications, usually monographs, containing the critical reviews and conclusions of many scientists with expertise in a wide variety of scientific disciplines. Their recommendations were not only heeded by the NIH but also shared with other Federal agencies, the Congress, the biomedical community in general, and the public. A series of three workshops that marked the beginning of a broad-based assessment of the use of animals in research and testing are cited below.

Other Activities:
In the development of model systems for specific research areas, the NIH has produced and disseminated a series of bibliographies that feature citations dealing with methods, tests, assays, or procedures; prepared directories of resource centers for scientists seeking assistance, and issued catalogs of biological materials for distribution to qualified investigators. This effort is intended to make a wide variety of biological and nonbiological systems available to health researchers

  • "Alternatives to the Use of Live Vertebrates in Biomedical Research and Testing": An Annotated Bibliography--Prepared by the Toxicology Information Program, National Library of Medicine (NLM). The purpose of these bibliographies on "animal alternatives" is to provide a survey of the literature featuring citations dealing with methods, tests, assays, or procedures that may prove useful for establishing testing models other than the use of intact vertebrates. Citations are selected and compiled quarterly by searching the bibliographic databases of the NLM.
  • Current Bibliographies in Medicine: Laboratory Animal Welfare; Pain, Anesthesia, and Analgesia in Common Laboratory Animals; and Care and Use of Laboratory Animals, National Library of Medicine (NLM).
    These three bibliographies represent a continuation of the NLM's Literature Search Series. Citations of papers and monographs are derived from searching a variety of online databases. Begun in 1984, these bibliographies are updated periodically; each contains brief reviews of citations dealing with biological and nonbiological models for biomedical and behavioral research.
  • National Toxicology Program (NTP), Review of Current Department of Health and Human Services, Department of Energy, and Environmental Protection Agency Research Related to Toxicology and National Toxicology Program, Annual Plan, Public Health Service, 1992. The NTP, administered by the Director of the National Institute for Environmental Health Sciences, maintains an integrated program in which considerable effort is devoted to the development, validation, and application of assays that may allow reductions in the use of whole vertebrate animals. These volumes have been compiled annually since the inception of the NTP which is now in its 14th year. Each year, one chapter deals with "Alternative Methods to Using Whole Animals."
  • Resources for Comparative Biomedical Research, A Research Resources Directory, National Center for Research Resources, 1991 (updated periodically). This directory contains information about the availability of high quality disease-free animals, including specialized research centers for the development of laboratory animal models ranging from lower animal forms to nonhuman primates.
  • Resources for Biological Models and Materials Research, A Research Resources Directory, National Center for Research Resources, 1991 (updated periodically). This directory lists resource centers that study nonmammalian models for research and provide critical biomaterials, such as nonmammalian organisms, viruses, bacteria, fungi, cells, human tissue, DNA probes, and chromosome libraries.
  • Resources for Biomedical Research Technology, A Research Resources Directory, National Center for Research Resources, 1992 (updated periodically). This directory lists resource centers dedicated to the application of the latest advances in the physical sciences, mathematics, computer sciences, and engineering in biomedical research.
  • Catalog of Cell Lines: National Institute of General Medical Sciences (NIGMS) Human Genetic Mutant Cell Repository, NIH Pub. No. 91- 2011 and No. 91-2944 (Supplement), 1991.
    This catalog lists the nearly 4,800 cell lines banked at the NIGMS Repository. Cells derived from tissues of people with genetic disorders and chromosomal abnormalities and normal controls are available to scientists through the repository.
  • An Annotated Guide to Texts and Journal Articles on Power and Sample Size for Scientific Studies, University of Texas Health Science Center, San Antonio, 1993. This guide, which was partially supported by the NIH Office for Protection from Research Risks, is intended to increase the awareness of research investigators and institutional animal care and use committee members of the importance of power and sample size in the conduct of biomedical research involving laboratory animals.

Research Initiatives:
In 1986, pursuant to Section 4 of "The Health Research Act of 1985," Public Law 99-158, the NIH developed "A Plan for Research Involving Animals". The Plan recognized that the NIH had conducted and supported a wide range of activities that essentially fulfilled the requirements of the law and made several recommendations designed to enhance existing efforts. Although the list is not exhaustive, many of the initiatives that were implemented are given below:

PART IV - PLAN

New and continuing solicitations for the support of biomedical and behavioral research that meet the objectives of Section 404C (a)(1) and (2) of the Public Health Service Act:

  1. Explore strategies to develop collaborative funding arrangements with other Federal agencies under Interagency Agreements, industry under Cooperative Research and Development Agreements, health research foundations, and other interested private organizations to support investigator-initiated research proposals for the development of new models for biomedical and behavioral research and testing in accord with the objectives of this legislation.
  2. Continue NIH support for resource centers that produce and supply critical biomaterials to researchers as models for biomedical and behavioral research such as: cloned genes/vectors, DNA probes, chromosomes; stably transfected cell lines; micro-organisms, including viruses, bacteria, fungi, yeasts, protozoa; nematodes; nonmammalian aquatic species; human tissues and organs; and animal and human cell lines. Promote the availability of and disseminate these resource materials to researchers seeking assistance and collaboration in health research.
  3. Continue NIH support for resource centers that promote the application of the latest advances in physical sciences, mathematics, computer sciences, computational techniques, bioengineering (e.g. noninvasive technology) to problems in biology and medicine.
  4. Encourage collaboration between experts in computer science and health researchers to solve current biomedical and behavioral research problems using advanced computerized research technologies.
  5. Continue to support projects for the use of aquatic organisms in biomedical and behavioral research.
    The National Institute of Environmental Health Sciences provides core support for five centers that use a broad spectrum of nonmammalian aquatic (marine and fresh water) organisms to study various human environmental health problems.

Dissemination of information for encouraging acceptance of such methods as stated Section 404C (a)(3) of the Public Health Service Act:

Training of scientists in the use of such methods as stated in Section 404C (a)(4) of the Public Health Service Act.

PART V - EVALUATION

The Committee will continue to meet periodically to assess progress in accomplishing the various parts of the Plan. In its evaluations, the Committee will be tracking research highlights similar to those illustrated in Part II of this document. The findings will be presented in subsequent reports to the Congress, i.e., in the Biennial Report of the Director of the NIH, and to other interested parties as necessary. In seeking ways to evaluate the impact of the Plan with respect to the objectives of the legislation, the Committee will pursue two initiatives:

APPENDICES

Office of the Director
National Institutes of Health
Dr. Louis R. Sibal, Chairman

National Institute on Aging
Dr. Richard L. Sprott, Principal
Dr. DeWitt G. Hazzard, Alternate

National Institute on Alcohol Abuse and Alcoholism
Dr. Antonio Noronha, Principal
Dr. Helen Chao, Alternate

National Institute of Allergy and Infectious Diseases
Dr. James C. Hill, Principal
Dr. Peter L. Golway, Alternate

National Institute of Arthritis and Musculoskeletal and Skin Diseases
Dr. Stanley R. Pillemer, Principal
Dr. Stephen P. Heyse, Alternate

National Cancer Institute
Dr. John Donovan, Principal
Dr. Susan M. Sieber, Alternate

National Institute of Child Health and Human Development
Dr. Allan Lock, Principal
Dr. Steven Kaminsky, Alternate

National Institute on Deafness and Other Communication Disorders
Dr. Robert J. Wenthold, Principal
Dr. Christy L. Ludlow, Alternate

National Institute of Dental Research
Dr. Ronald Dubner, Principal
Dr. Joseph L. Bryant, Alternate

National Institute of Diabetes and Digestive and Kidney Diseases
Dr. David G. Badman, Principal
Dr. Michael K. May, Alternate

National Institute on Drug Abuse
Dr. Cathrine Sasek, Principal
Dr. Lynda Erinoff, Alternate

National Institute of Environmental Health Sciences
Dr. Richard A. Griesemer, Principal
Dr. William S. Stokes, Alternate

National Eye Institute
Dr. Michael Oberdorfer, Principal
Dr. Michael Goldberg, Alternate

National Institute of General Medical Sciences
Dr. Christine Carrico, Principal
Dr. Lee Van Lenten, Alternate

National Heart, Lung, and Blood Institute
Dr. Robert S. Balaban, Principal
Dr. Mark A. Knepper, Alternate

National Institute of Mental Health
Dr. Robert Desimone, Principal
Dr. Richard Nakamura, Alternate

National Institute of Neurological Disorders and Stroke
Dr. Robert Burke, Principal
Dr. Watson Alberts, Alternate

National Institute of Nursing Research
Dr. Hilary Sigmon, Principal
Ms. Linda Cook, Alternate

National Center for Human Genome Research
Dr. David Bodine, Principal
Dr. Elke Jordan, Alternate

National Center for Research Resources
Dr. Louise Ramm, Principal
Dr. Elaine Young, Alternate

Consumer Product Safety Commission
Dr. Kailash Gupta

Environmental Protection Agency
Dr. Richard N. Hill, Principal
Dr. Mary C. Henry, Alternate

Food and Drug Administration
Dr. Neil L. Wilcox, Principal
Dr. Mack Holt, Alternate

National Science Foundation
Dr. Maryanna Henkart, Principal
Dr. Kathie Olsen, Alternate

Liaison Members

Ms. Susan Baker
Division of Research Grants

Ms. Tina Blakeslee
Office of Legislative Policy and Analysis

Dr. Richard S. Chadwick
National Center for Research Resources

Dr. Gary Ellis
Office for Protection from Research Risks

Dr. Sidney Siegel
National Library of Medicine

Ms. Susan Sherman
Office of the General Counsel

APPENDIX B

PUBLIC LAW 103-43-JUNE 10, 1993

SEC. 205. PLAN FOR USE OF ANIMAL IN RESEARCH

  1. IN GENERAL - Part A of Title IV of the Public Health Service Act, as amended by section 204 of this Act, is amended by adding at the end the following new section:

    PLAN FOR USE OF ANIMAL IN RESEARCH

SEC. 404C.

  1. The Director of NIH, after consulation with the committee established under subsection (e), shall prepare a plan:
    1. for the National Institutes of Health to conduct or support research into
      • methods of biomedical research and experimentation that do not require the use of animals; methods of such research and experimentation that reduce the number of animals used in such research; methods of such research and experimentation that produce less pain and distress in such animals; and
      • methods of such research and experimentation that involve the use of marine life (other than marine mammals);
      for establishing the validity and reliability of the method described in paragraph (1); for encouraging the acceptance by the scientific community of such methods that have been found to be valid and reliable; and
    2. for training scientists in the use of such methods that have been found to be valid and reliable.

    Not later than October 1, 1993 the Director of NIH shall submit to the Committee on Energy and Commerce of the House of Representative, and to the Committee on Labor and Human Resources of the Senate, the plan required in subsection (a)and shall begin implementation of the plan.

    The Director of NIH shall periodically review, and as appropriate, make revision in the plan required under subsection (a) and shall be included in the first biennial report under section 403 that is submitted after the revision is made.

    The Director of NIH shall take such action as may by appropriate to convey to scientists and methods found to be valid and reliable under sub-section (a)(2).

    1. The Director of NIH shall establish within the National Institutes of Health a committee to be known as the Interagency Coordination committee on the Use of Animal in Research (in this subsection referred to as the 'committee'). The committee shall provide advice to the Director of NIH on the preparation of the plan required in subsection (a).
    2. The committee shall be composed of:
      • the Directors of each of the national research institutes and the director of the Center for Research Resources (or the designs of such Directors); and
      • representative of the Environmental Protection Agency, the Food and Drug administration, the Consumer Product Safety Commission, the National Science foundation and such additional agencies as the Director of NIH determines to be appropriate, which representatives shall include not less than one veterinarian with expertise in laboratory-animal medicine.

      CONFORMING AMENDMENT - Section 4 of the Health Research Extension Act of 1985 (Public Law 99-158; 99 Stat. 880 is repealed.

APPENDIX C

An NIH Conference:
MODELING IN BIOMEDICAL RESEARCH
An Assessment of Current and Potential Approaches Applications to Studies in Cardiovascular/Pulmonary Function - and Diabetes

INTRODUCTION

The purpose of this conference was to assess the status and potential of models in biomedical research. The motivating hypothesis was that continued innovation and development in model systems is important to progress in improving the health of the nation. It was the intent of the conference to evaluate a variety of model systems, including vertebrates and invertebrates, cell cultures and physical analogs, mathematical models and computer simulations. The survey was intended to examine, among other issues, the role and future need for animals, especially for mammals, in biomedical research.

The conference was initiated and sponsored by the Division of Research Resources, the Division of Research Services, and the Office of Medical Applications of Research (OMAR) of the Notional Institutes of Health. The conference format was that of previous OMAR conferences. Most of the time was devoted to prepared presentations by invited experts. Panel members listened to these presentations and questioned the speakers. They then pre- pared this report. All the views expressed herein represent consensus of the panel.

To illustrate specifically the use of models in basic biomedical research, the conference focused on two important health problems in the United States and worldwide: cardiovascular and pulmonary dysfunction and diabetes mellitus. In accordance with congressional request, several issues were raised in advance by the conference organizers to focus the discussion:

SUMMARY OF CONCLUSIONS

General Conclusions

The panel members agreed with the conclusions of the extensive prior reports of the National Academy of Sciences (Models for Biomedical Research: A New Perspective (1985)) and of the National Research Council and Institute of Medicine (Use of Laboratory Animals in Biomedical and Behavioral Research (1988)).

An important new conclusion drawn from this conference is that biomedical research will be most effectively advanced by the continued application of a combination of models-mathematical, computer, physical, cell and tissue culture, and animal-in a complementary and interactive manner, rather than by concentrating on any one or a few kinds of model systems.1

Each system in current use has unique strengths and limitations. Mathematical and computer models are useful in formalizing concepts and evaluating data; they may also prove generally useful in predicting metabolic responses and, in some cases, whole animal responses to new drugs. Cells grown in tissue culture have provided important information related to biochemical mechanisms, molecular biology, and intracellular metabolism. However, animal models remain absolutely essential because they are the most extensive and reliable paradigms for man. These general conclusions are developed in more detail for various models in the following paragraphs.

(1 Although it was not directly pertinent to cardiovascular health or diabetes, one presentation of the conference provided an excellent example of the necessity of using a variety of animal models in developing a single drug. This example pertains to the preclinical and clinical development of ivermectin for treatment of onchocerciasis, a class of parasitic diseases affectinq livestock and causing river blindness in man. This drug was tested in infected mice and found to have a narrow toxic-therapeutic ratio. However, when potential toxicity was tested in a variety of animal species, great differences in toxic threshold were found. Without pretesting in several mammalian species, there would have been no way to establish the safe dose levels in man. Such levels were established on the basis of animal testing; and to date, the drug has been used safely to treat some 120,000 humans and millions of cattle, swine, sheep, and horses.)

Conclusions on Specific Models

  1. Mathematical, Computer, and Physical Models
    Mathematical models and computer simulations are finding increased utility and application as the unity of biochemical processes becomes better established and as the available computing power increases. Strengths of such models are:
    • They codify facts and help to confirm or reject hypotheses about complex systems. They reveal contradictions or incompleteness of data and hypotheses. They can often allow prediction of system performance under untested or presently untestable conditions. They may predict and supply the values of experimentally inaccessible variables.
    • They may suggest the existence of new phenomena. Some limitations of such models are:
      • The selection of model elements may be suboptimal.
        Incorrect models can fit limited data, leading to erroneous conclusions.
        Simple models are easy to manage, but complex models may be needed.
      • Realistic simulations often require a large number of parameters. the values of which may be difficult to obtain.
      The general potential of mathematical models is good when there is sufficient knowledge of the system to follow the formulation of strong hypotheses. As our ability to acquire data expands and the sophistication of computing increases, more effective and broader applications may be expected. The limitations of prediction due to system complexity will remain, but further advances are to be anticipated with confidence. Physical models, often anologs, are similar in their advantages and disadvantages to computer models. However, they are at present even more limited in their ability to represent accurately the complex interactions that occur within living systems.
    2. Nonmammalian Models
    Nonmammalian species can serve as excellent models for certain biological processes and structures, and are indispensable in the study of others. Much of what we know about microvascular physiology has come from studies of the frog mesentery. The giant axon of the squid was the key experimental system at the birth of modern neuroscience. Intertaxonomic transfer of information must be approached, nevertheless, with great caution, because species differences can be great or even, as in embryonic development, fundamental. The strengths of nonmammalian models are:
    • They are often more readily available and less expensive than mammals. The process they are meant is represent is often displayed more simply and directly than in higher animals.
    • Their tissues and organs are more accessible and may lend themselves more easyily to microscopic observation, dissection, and laboratory handling. Some of the limitations of nonmammalian models are:
      • Unless some fundamental similarity to the human system under study is established, the results from nonmammalian species cannot be interpreted reliably for application to the human system.
      • There are many important diseases of mammals for which analogs in lower forms do not exist.
    3. Culture Models
    The culture of cells, tissues, and organs including those of human origin, has reached a very high level of sophistication and has been responsible for many new discoveries. Some advantages of this technique are that cells and tissues in culture:
    • Can be maintained in a defined, controlled environment. May retain the differentiated functions that existed in the whole body system. Provide a rapid and less expensive means of evaluating physical and chemical agents.
    • Have allowed the discovery of information that would not have been obtainable from research on more complex systems. Some of the limitations of this technique are that:
      • Cultured cells may lose their differentiated function.
        Cultures may not mimic the in vivo response because of the absence of the complex tissue and organ interactions that ordinarily give rise to it.
        The genetic status of the cells can be variable and uncertain.
      • A particular behavior may be due to infection of the culture by an unknown and undetected pathogen.
  2. Mammalian Models
    It is clear from the historical record that mammalian models have been central to the development of modern medicine, both for understanding normal physiology and for developing diagnoses and therapies. This centrality continues, and for many subtle and long-term effects of drugs or therapies there is no alternative, Some of the strengths of mammalian models are:
    • Humans are mammals. Mammalian models in which disease development and response to therapy are similar to those in humans can very often be found. Mammalian models provide standardized and federally mandated methods for testing the safety and efficacy of new drugs before they are released for human clinical trials.
    • Mammalian models offer the only reliable testing for complex prostheses or interventions in which the collective response of the whole system is important. Some limitations of mammalian models are:
      • There are species differences in details of anatomy and physiology so that similarity of test mammalian species to human systems must be established before results can be applied.
      • Some otherwise desirable mammalian models may be expensive and difficult to acquire and maintain

sPECIFIC CASES

  1. Cardiovascular and Pulmonary Dysfunction Progress depends critically upon continued use of mammalian models. Mammalian models hove a long and successful history in the discovery of cardiovascular drugs. Mathematical models, computer simulations, and the development of sophisticated in vitro test systems such as cell cultures have contributed greatly to the understanding of the cardiovascular system and the discovery of new therapeutic agents. Nonetheless, these model systems cannot supplant animal models because cardiovascular diseases such as atherosclerosis, congestive heart failure, acute myocardial infarction, and stroke are too complex in be simulated comprehensively or evaluated in vitro by a mathematical model.

    There are many examples in which an incomplete knowledge of human disease necessitates the use of complex animal models to understand pathophysiology and to evaluate new drugs. The recent introduction of thrombolytic agents in the treatment of acute myocardial infarction, thrombosis. and pulmonary embolism illustrates this point. Animal models are required to study the synergistic action of thromboxane synthase inhibitors or receptor antagonists with thrombolytic agents. This synergistic action results in more rapid dissolution of the clot and reperusion, as well as a markedly lower incidence of reclusion.

    Cardiac mechanics and hemodynamics lend themselves readily to mathematical and computer modeling. Thus, the achievements to date and the prospects of future research in this area provide an example of the potential of mathematical and computer modeling. In the computer studies of blood flow in the heart, the normal function of the heart can be elucidated, and diseases that influence the mechanical function of the heart and its valves can be examined and visualized. In addition, one can use computer models as test chambers for the design and evolution of prosthetic heart valves. In such modeling, the details of flow patterns and sequences of mechanical events can be reproduced with remarkable accuracy. It is possible to select, for example, the best combination of curvature and pivot point for heart valves of the single-disc type to optimize blood flow and minimize pressure losses.

    Despite the success of computer modeling of blood flow through the pumping heart, however, computer studies are not able to predict reliably the long-term performance of prostheses in vivo, with regard especially to biological response to a new material or to the longterm deposition of plaque. Such biological responses require long-term animal models for evaluation before the use of a designed device or procedure in humans. Structural modeling of myocardium offers another example of the respective roles and interdependence of computer models and date derived from biological studies. In developing mathematical models of myocardial tissue, use was made of microscopic observations of a hierarchy of microstructural elements comprising a matrix. Some of these elements connect neighboring fibers and prevent slippage. Energy of muscular contraction may be stored in the matrix to augment diastolic filling by elastic recoil. Differences between invertebrate and mammalian hearts are traceable in part to matrix differences. The theoretical models incorporate a weave, coiled structures, and strut elements of the observed matrix. The mathematical analyses shows that the struts limit myocyte lengthening in diastole and tend to equalize myocyte shortening in systole throughout the ventricle. The analysis suggests that the intact matrix aids in the maintenance of normal myocardial blood flow.

    Such detailed modeling of the myocardium is possible only by an interplay of careful anatomical study, detailed computer modeling, and comparison of the performance of the model with data on the heart in situ to verify the results. After such computer models are developed, disease states such as infarction may be simulated. However, details of blood flow restriction cannot now be modeled reliably by computers.

    In pulmonary physiology a similar synergy of mathematical models and animal experiments has developed. Computer models of the lung need detailed anatomical data, data on the mechanical properties of the tissue, and transport characteristics of liquid and proteins across the membranes of capillary blood vessels and lymphatics. When the complexity is modeled properly. liquid and protein exchange can be simulated and regions of localized damage can be assessed. This lung model is a good example of a complex representation that requires animal experiments for validation. The model can be trusted only after verification with biological experimental data.

    Another example is found in studies of the effect of high-dose recombinant interleukin-2 (IL-2) on the microcirculation the lung during prolonged use. Computer model- ing did not provide an explanation of observed results and a new type of animal experiment was therefore indicated. It was found that microvascular injury in the lung was not the likely explanation of rising lymph flow.

    Endothelial cell behavior is an example of in vitro modeling using cell cultures. These studies were initiated in response to questions about atherosclerosis. Experiments were designed to explore the effects of fluid shear stress on cultured endothelial cell layers. The development of the cell cultures and experimental apparatus for applying controlled sheer stresses illustrates the interaction between physical techniques and biological methods. Some of the observed results were surprising, and they may be relevant to disease processes. Shear stress effects include reorganization of the endothelial cell cytoskeleton, enhanced endocytosis, prostaglandin production, and differential cell adhesiveness. Furthermore, laminar and turbulent flows have different effects in triggering cell division. Some of these processes have also been observed and studied in vivo.

    It is hoped that the biophysical insights gained by such studies of in vitro systems will broaden understanding of the role of hemodynamic shear stresses as modulators of endothelial structure and function and as contributing factors in vascular disease. Such models will probably an increasing role in the explanation of observed disease patterns and mechanisms.
  2. Diabetes Mellitus

    Although hyperglycemia is the hallmark of diabetes mellitus, the latter is not a single disease. The majority of diabetic individuals in the United States have type II diabetes mellitus (noninsulin-dependent diabetes mellitus), which is usually characterized by onset after the age of 40, obesity, variable degrees of insulin resistance, and decreased insulin secretion. Type I diabetes mellitus (insulin-dependent diabetes mellitus) has many characteristics of an autoimmune disease with a more profound defect in insulin secretion than seen in type II. Although there is a genetic component to both diseases, it is different for the two types.

    Because of the heterogeneity and the degenerative complications of these diseases involving the eyes, kidneys, peripheral and autonomic nervous systems, and large blood vessels, no single animal model exists that encompasses all aspects of either types of diabetes. As a consequence, research related to diabetes has used several mammalian models. In addition, a broad spectrum of other models -nonmammalian organisms, perfused organs, cells grown in culture and mathematical and computer models- have provided relevant and sometimes critical information.

    The entire literature on control and regulation of carbohydrate metabolism and a large portion of the literature of endocrinology provide a brood data base for modeling all aspects of diabetes.

    The best available models for type I diabetes mellitus are the BB rat and the NOD mouse. These demonstrate many of the autoimmune phenomena characteristic of the human disease. They have provided the opportunity to evaluate the effects of manipulating the immune system as well as several environmental factors on the development of diabetes. Thus, neonatal thymectomy, administration of immunosupressive drugs, and antibodies against various lymphocytes have been effective in preventing diabetes in these models. The BB rat and NOD mouse provide the opportunity to investigate more precisely targeted forms of immune modulation that might then be applicable to patients with type I diabetes mellitus. Although these models are quite useful in studying the etiology of this form of diabetes, the rodents do not develop the long-term complications that are the major clinical problem in patients.

    Several genetic models for diabetes exist in different strains of mice. These are relevant to type II diabetes because they are also associated with obesity and do not hove an absolute insulin deficiency. The OB/OB and the db/db mice have been studied because hey exhibit tissue resistance to the action of insulin and do not hove severe insulin deficiency at the onset of diabetes.

    In addition to the genetic forms of diabetes in rodents, the disease can be produced in a wide range of mammals by surgical removal of the pancreas, administration of drugs such as streptozotocin or alloxan, or overfeeding. Although such animals hove provided fundamental knowledge concerning the metabolic effects of hyperglycemia and insulin deficiency, they do not have the underlying genetic background that is found in either type I or type II human diabetes. Such animals may develop morphological and functional changes in the eyes, kidneys, and nerves after several years of diabetes, but it is not established unequivocally that these changes are identical to the long-term complications found in diabetic patients. Nonetheless, these models as well as the genetic ones have been used to evaluate various strategies for treatment of the complications.

    Studies in various organ preparations have elucidated mechanisms involved in regulation of carbohydrate metabolism and the secretion, degradation, and action of insulin and other relevant hormones. Perfusion of the isolated dog and rat pancreas demonstrates that insulin is secreted in a biphasic fashion following an acute glucose stimulus. Furthermore, continuing insulin secretory activity is pulsatile, which might have an important influence on its physiologic function. Deficiencies in first- and second-phase insulin secretion in type II diabetics are important factors in their inability to metabolize a glucose load. Perfusion experiments on rats and dogs have demonstrated the role of the liver in regulating peripheral insulin levels because the hormone secreted by the pancreas must traverse the live before reaching the general circulation. In addition. the liver plays a central role in regulating carbohydrate metabolism. This process is exquisitely sensitive to insulin and is influenced by several other hormones, including glucagon and catecholamines. Perfusion of adipose tissue and hindlimb preparations of rats and dogs provides fundamental information related to insulin action on carbohydrate, fat, and protein metabolism.

    Isolated nerve preparations from normal and diabetic rats have demonstrated significant biochemical aberrations that could be relevant to the development of diabetic neuropathy in patients. They, along with animal models of diabetes, provide data that can be used to evaluate therapeutic approaches to diabetic neuropathy.

    Mammalian cells grown in tissue culture have generated information concerning carbohydrate, fat, and protein metabolism as well as insulin secretion and metabolism. Factors involved in the regulation of insulin secretion have been studied extensively in isolated islet cell preparations. In addition, such cells have been maintained in culture for use in transplantation into diabetic animals. Whole animal experiments are essential for solving the immunologic problems associated with transplant rejection as well as for the evaluation of the effects of metabolic control on diabetic complications. Research with isolated hepotocytes has complemented that in the perfused liver and permitted elucidation of the biochemical basis for the physiologic effects of insulin and other hormones important in the regulation of hepatic carbohydrate metabolism. Isolated hepatocytes have also been useful in delineating the metabolism of insulin. Study of adipocytes and myocytes which are insulin-sensitive cells, has provided insight into the intracellular actions of the hormone. These actions are relevant to the insulin resistance observed in patients with type II diabetes mellitus.

    Because retinopathy and accelerated atherosclerosis are common complications of both types of diabetes, investigation of endothelial cells from capillaries and arterioles can provide information related to the etiology of these complications. Such studies also provide the opportunity to evaluate therapeutic agents for the complications.

    Use of nonmammalian preparations including unicellular organisms, insects, and fish has aided our understanding of the distribution of insulin-like polypeptides. Furthermore, these models have been helpful in identifying the molecular structure of the human insulin receptor, its positioning in the plasma membrane, and its biochemical function. Studies using cells obtained from patients with unusual types of diabetes have demonstrated structural and functional abnormalities of the insulin receptor that have a genetic basis and which, if present to a lesser extent, might explain the insulin resistance observed in patients with type II diabetes. Although cultured cells may permit the examination of systems without complex regulatory influence, their biological relevance to mammalian diabetes is as yet incompletely understood.

    Because insulin occupies a central role in the regulation of carbohydrate metabolism, development of computer algorithms for its delivery and the regulation of plasma glucose levels, as well as for the elucidation of dynamics of insulin secretion and insulin action, is of paramount importance. The biphasic release of insulin and its pulsatile nature have been modeled mathematically. Defects in first- and second-phase insulin secretion are present in diabetes and it is possible that abnormalities in pulsatile insulin release may also have relevance to diabetes. The "minimal model of insulin action" permits quantification of insulin sensitivity in normal subjects and in those with a variety of disease states. This relativly simple test has many advantages over more complex methods for measuring insulin action, and it may have predictive value in epidemiological studies aimed at identifying subjects at risk for diabetes mellitus.

    Animal studies are essential in the development of new pharmacological agents, but the final determination of their safety and efficacy requires human clinical trials. Human subjects are integral to any assessment of the ability to prevent the development of diabetic complications by strict glucose control. The Diabetes Control and Complications Trial is an example of such a study. Although evaluation of new therapeutic alternatives is important, it is also necessary to attempt to identify factors that predict which high-risk individuals subsequently develop type I or type II diabetes mellitus.

SUMMARY & RECOMMENDATIONS

Models are indispensable for biomedical research. There is no branch of life science or medicine in which the current knowledge base is not determined in some way by the results of research with models. The status reports presented to us at this conference, representing two of the most active subdisciplines -cardiovascular/pulmonary physiology and pathology and the attack upon diobetes are eloquent testimony to that assertion. These examples of outstanding research highlight another important point: Progress in the war against these and other diseases depends not only on a steady flow of insights from research employing models but also upon research based on a variety and more often on a combinationof models.

The two groups of diseases singled out for special consideration in this conference illustrate the case. We have made progress in reducing the toll taken by cardiovascular disease, in port because of insights gained through mathematical analysis and computer simulation of the cardiac cycle. We have profited from new studies in the comparative anatomy of myocardium. Advances in the biophysics and molecular biology of channels and receptors have contributed to progress. Our successes have been based in part upon study of simple physical analogs of the heart. But always and without fail, progress has resulted from submission of such modeling results to the test of validity in the intact mammal - the last stopping point before application of new knowledge and therapies to the situation in man.

The same precisely is true for diabetes mellitus. This group of diseases, in which the fundamental mechanisms remain to this day elusive despite decades of intense study, is nevertheless better understood than ever before, with the possibility of prevention now apparently realistic. Such understanding has resulted from the close collaboration of clinicians, basic scientists, and theorists, whose computational work has been either the good of new and incisive observations on the disease in animal models and human victims, or the explanation of hitherto enigmatic phenomena associated with the disease state.

It follows, therefore, because cardiovascular disease and diabetes mellitus are not likely to be fundamentally different from other categories of human pathology, that models and the ideas derived from them are inextricably woven into the fabric of knowledge and practice in the biomedical sciences. The future of biomedical rescorch depends on even denser intertwining.

It is no longer practical to design drugs for human and veterinary use without the aid of sophisticated computer modeling, including the most advanced computer graphics. The physiological compartment models upon which much of our understanding of complex control mechanisms is based cannot be imagined or tested without mathematics and computing. The molecular analysis of signals and gates controlling flows into and out of compartments depends on experiments with lower animals or molecules derived from them. The setting of treatment protocols with drugs depends on prior knowledge gained from animal screening and testing. In the end, the validity of every proposal about the nature and mitigation of human disease must be verified by appropriate testing in an appropriate mammalian model system.

This last is the critical point. Some advances in modeling of the post decade, driven by explosive growth of computing power and molecular biology, have allowed reduction in the number of vertebrate animals required in certain systems for the development of drugs. The more there is of design, and the less of trial and error, the more directly the results of research can be applied to man. The manifold costs of higher animal testing can be reduced, and those costs are the best -perhaps the only- incentive for the development of still better models. But: those same triumphs of modeling simultaneously create opportunities for new kinds of research and therapeutic intervention. These opportunities then call for validation in the approptiate mammalian models and eventually by means of clinical trials in man. The evidence of this resides in nearly every case of a medical "breakthrough" since the 1960's.

Therefore, it is not possible to predict the consequences of current advances in theory building and analysis for the number of mammals to be used in future research. The writing of computer programs, the identification and cloning of genes implicated in disease, the proliferation of cultured cell types that carry out differentiated functions in vitro, the prediction by equation of complex control outcomes in whole animals- all of these will become, in the decades ahead, the tools of most biomedical research qroups. But it is extremely unlikely that these remarkable tools will substitute, to any significant extent, for experimental vertebrate animals.

The tools will unquestionably help to reduce the toll of human suffering. Continued improvement of the techniques by which experimental animals are cared for and employed in research will unquestionably improve their lot. But we cannot now predict that the numbers of animals needed for research will decline, however much we would wish it to. It is much more likely, in fact, that the numbers required will remain unchanged so long as the manpower engaged in biomedical research and the intensity of effort devoted to it remain unchanged.

Speaking quantitatively (only), simple model systems, from the physical analog or the differential equation to the particularly suited invertebrate animal, will not provide meaningful "alternatives" to experimental mammals. They will not reduce the quantity of research on higher animals. What modeling does provide, and will provide in even greater abundance during the decades to come, is new insights, new opportunities undreamed of earlier, for the alleviation of human suffering caused by disease.

It is therefore our first recommendation that the NIH (within its intramural and extramural programs) and other agencies charged with the support of biomedical research seek new means and create new programs to encourage theoretical biology, to support new collaborations and new models, and to catalyze the application of the attack upon disease which is the hallmark of contemporary developed societies, and of their obligation to the developing world. We urge interagency collaboration across the federal government to accomplish this objective.

Our second recommendation is as much to our colleagues -- scientists, physicians, administrators -- as to the agencies of government. It is that we join in responding with the truth about animals in research to the misinformation and disinformation that has been so widely distributed and has been given currency in the media. We hold the truth to be that:

C0NFERENCE PANEL

Gordon H. Soto, Ph.D.
Panel and Conference Chairperson
Director, W. Alton Jones Cell Science Center, Inc.
Lake Placid, New York

Henry T. Bohnson. M.D.
Chief, Division of Cordiothoracic Surgery
Professor of Surgery
Department of Surgery
University of Pittsburgh
Pittsburgh, Pennsylvania

James B. Field M.D.
Rutherford Professor of Medicine
Division of Endocrinology and Metabolism
Director, Diabetes and Endocrinology Research Center
Baylor College of Medicine
Houston, Texas

Y.C. Fung, Ph.D.
Professor of Bioengineering
Department of Applied Mechanics and Engineering Sciences
University of California at San Diego
La Jolla, California

Paul R Gross, Ph.D.
Vice President and Provost
University of Virginia
Charlottesville, Virginia

Larry Horton
Associate Vice President for Public Affairs
Stanford University
Stanford, California

Steven E. Kahn, M.B., Ch.B.
Associate lnvestigator
Veterans Administration Medical Center
Acting Investigator
Division of Metabolism, Endocrinology, and Nutrition
Department of Medicine
University of Washington
Seattle, Washington

Séndor J. Kovécs Ph.D., M.D.
Assistant Professor of Medicine
Washington University School of Medicine
Washington University Medical Service
St. Louis Veterans Administration Medical Center
Director, Catheterization Laboratory Research
Jewish Hospital of Washington University Medical Center
Adjunct Assistant Professor of Physi