AWIC

PLAN FOR THE USE OF ANIMALS IN RESEARCH

Provided by the Animal Welfare Information Center
United States Department of Agriculture
National Agricultural Library



Department of Health and Human Services
United States Public Health Service
National Institutes of Health

October 1993


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........................................4

PART II - SELECTED RESEARCH HIGHLIGHTS..................10

PART III - ACTIVITIES INITIATED SINCE 1986..............14
NIH - Supported Meetings..........................15
Other Activities..................................20
Research Initiatives..............................22

PART IV - PLAN..........................................26
Research Initiatives..............................26
Information Dissemination.........................29
Training..........................................31

PART V - EVALUATION.....................................32

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

1 Models for Biomedical Research: A New Perspective, National Academy
Press, Washington, D.C., 1985

2 Modeling in Biomedical Research: An Assessment of Current and
Potential Approaches, National Institutes of Health, Bethesda, Maryland
1989.

3 Ibid., p. 1 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.

Microorganisms (e.g., yeasts, bacteria), invertebrates, and lower
vertebrates are used to provide simple, manageable systems to gain
insight into fundamental processes that are relevant to
understanding the nature of human diseases and disorders. In
particular, the wide array of marine and freshwater invertebrates
represent a great potential for biomedical research. These lower
organisms are excellent models for the study of certain basic life
processes because they permit manipulation and reduce complexity
that can obscure understanding of a basic biological process.
Although the fundamental knowledge obtained using these diverse
species is generally applicable to humans, interspecies transfer
of information must be approached with caution and requires
validation in higher animals.

The culture of cells, tissues, and organs of animal and human
origin in an environment outside the body, collectively known as
in vitro systems, has reached a high level of sophistication and
allows scientists to study the effects of substances on cellular
events in isolation from other biological phenomena. Such methods
often provide reliable data that may be difficult or impossible to
obtain in whole animals.

The fact that the above tests are conducted in isolated systems,
independent of other complex biological systems, creates
limitations in their interpretation. In the end, the validity of
such tests must be verified by testing in appropriate mammalian
model systems and possibly in later human clinical trials.

Mathematical, computer, and physical models, which have a long
tradition of use in the physical sciences and engineering, can
complement animal experimentation. The use of computers as
research tools in biomedicine has dramatically increased as more
biological processes are understood quantitatively and described
in mathematical relationships. Although the use of computers
alone cannot produce new biological information, they enable
scientists to analyze vast amounts of data and test ideas. For
example, computer simulations have extended scientists' ability to
use three-dimensional visual images to relate structure and
biochemical function of molecules.

More recently, high performance computing has made it possible to
observe phenomena that previously could only be inferred. The
development of new imaging technologies, such as ultrasound or
nuclear magnetic resonance spectroscopy, has provided a spectrum
of noninvasive tools that permits visualization of soft tissues
and organs in the intact organism without causing pain or
distress.

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.

4 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.

5 Guide for the Humane Care and Use of Laboratory Animals, National
Research Council, NIH Publication No. 86-23, Washington, D.C., revised
1985.

6 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:

0ver 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.

7 Trends in Bioassay Methodology: In Vivo, In Vitro, and Mathematical
Approaches, National Institutes of Health, Bethesda, Maryland, Pub. No.
82-2382, 1982.

National Symposium on Imperatives in Research Animal Use: Scientific
Needs and Animal Welfare, National Institutes of Health, Bethesda,
Maryland, Pub. No. 85-2746, 1985.

Models for Biomedical Research: A New Perspective, National Academy
Press, Washington, D.C., 1985.


NIH-Supported Meetings:

The 1986 Plan recommended sponsoring or cosponsoring conferences,
workshops, and symposia designed to increase the biomedical community's
awareness of newly-developed methods in a wide variety of research
areas related to the mission of NIH institutes and centers. These
workshops served as tutorials encouraging investigators to use the best
mammalian models, to develop new systems using nonmammalian models, to
use new technologies that complement animal research, to use procedures
that minimize pain and discomfort of research animals. Two workshops
specifically addressed the use of aquatic organisms as models for
biomedical and behavioral research.


Modeling in Biomedical Research: An Assessment of Current and
Potential Approaches. Application to Studies in
Cardiovascular/Pulmonary Function and Diabetes, National
Institutes of Health, Bethesda, Maryland, 1989.

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. In addition to evaluating a variety of
model systems, the a panel of experts examined the role of
and future need for animals in biomedical research, focusing
on two important health problems, cardiovascular disease and
diabetes. A summary of this conference may be found in
Appendix C of this report.

Workshops on Cardiovascular Dynamics and Modeling (U.S./France
Agreement), Bethesda, Maryland, 1985, and in Paris, France, 1987.
The proceedings are published in Colloque INSERM, Vol. 138, Paris,
1988.

These workshops were conducted under an international
agreement between the U.S. and France on instrumentation and
biomedical engineering to assess the status and potential of
models for cardiovascular research.

Use of Laboratory Animals in Biomedical and Behavioral Research,
National Research Council, National Academy Press, Washington,
D.C., 1988.

The NIH cosponsored this project which was conducted under
the aegis of the National Academy of Sciences. A special
Committee was appointed by the National Research Council to
examine such issues as patterns of animal use, benefits
derived from the use of animals, and alternative methods in
biomedical and behavioral research. One segment of the book
is devoted to "alternative research methods."

Workshop on Marine Life Resources as reported in Biological
Bulletin, 176:337-348, 1989.

This workshop, supported in part by the National Center for
Research Resources, was organized to consider the
contributions of marine and freshwater (aquatic) organisms as
models for biomedical and behavioral research; and to assess
the need for resource sites that would provide these animals
to the research community. The report gives numerous
examples of the broad range of research topics that can be
investigated using aquatic species.

Animal Care and Use: Policy Issues in the 1990s, National
Institutes of Health, 1989.

This conference was sponsored jointly by two offices within
the NIH, the Office of Laboratory Animal Welfare and
the Office of Animal Care and Use, to increase awareness of
the impact of the U.S. Department of Agriculture regulations
and Public Health Service policy governing the care and use
of research animals.

Workshops on New Models in the Life Sciences (U.S./Japan
Agreement), Yokohama, Japan, 1990, and Bethesda, Maryland, 1991.

These workshops were conducted under an international
agreement between the U.S. and Japan on science and
technology to exchange views on new experimental models,
including in vitro technology.

Workshop on "New Animal Models for Research on Aging," National
Institute on Aging, Bethesda, Maryland, 1989. The meeting report
of this workshop was published in Experimental Gerontology,
26;411-439, 1991.

The purpose of the workshop was to discuss the advantages or
specific features of animal models not typically used in
research on aging. The spectrum of models included mammals,
reptiles, fishes, birds, and invertebrates.

Workshop on Carcinogenesis Testing with Fish, National Institute
of Environmental Health Sciences, Research Triangle Park, North
Carolina, 1991.

This workshop evaluated the current use and availability of
fish as models for determining the carcinogenic potential of
chemicals in the environment.

Current Developments in In Vitro Teratogenesis, National Institute
of Environmental Health Sciences, Research Triangle Park, North
Carolina, 1989, published in Environmental Health Perspectives
94:265-268, 1991.

This conference reevaluated the use of in vitro teratology
assays, examined the validation process for in vitro tests,
and discussed progress in the validation of in vitro
teratology screens. Participants supported further
development of short-term in vivo and in vitro systems for
prescreening developmental toxicants.

Preparation and Maintenance of Higher Mammals During Neuroscience
Experiments, A Report of a National Institutes of Health Workshop,
Publication No. 91-3207, 1991.

This workshop provided assistance to health researchers,
veterinarians, and members of institutional animal care and
use committees regarding the care and use of animals in
neuroscience research.

Recognition and Alleviation of Pain and Distress in Laboratory
Animals, National Academy Press, Washington, D.C. 1992

Supported in part by a grant from the National Center for
Research Resources, this publication was prepared by the
Committee on Pain and Distress in Laboratory Animals,
National Research Council, Institute of Laboratory Animal
Resources. The volume provides a ready source of information
on pain and distress, and describes methods for the
prevention, reduction, or elimination of pain, stress, and
distress in laboratory animals.


Workshops on the "Use of Noninvasive Imaging Techniques in Alcohol
Research," National Institute on Alcohol Abuse and Alcoholism
Research Monograph No. 21, DHHS Pub. No. 92-1890, 1992.

The final workshop in this series emphasized the use of
noninvasive techniques, such as Computerized Tomography,
Magnetic Resonance Imaging, to study alcohol-related brain
damage and the effect of treatment.

Workshop on "Alcoholism in Flies and Worms: Genetic Insights from
Invertebrate Systems," Research Society on Alcoholism, 1993.

The National Institute on Alcohol Abuse and Alcoholism
organized this workshop to stimulate the use of invertebrate
models to study the development and function of the nervous
system and to determine the genetic basis for behavioral and
developmental responses to ethanol.

International Workshop on "Predicting Chemical Carcinogenesis in
Rodents", National Institute of Environmental Health Sciences,
Research Triangle Park, North Carolina, 1993.

This workshop evaluated numerous methods for predicting the
ability of a chemical to cause cancer in rodents, including
computer generated rules, physico-chemical properties,
structure-activity relationships, short-term in vitro
biological assays, and subchronic studies in rodents. The
participants concluded that further improvements in the
predictive process can lead to reductions in the number of
animals used, improve public health, and encourage new
approaches to understanding of the mechanisms of
carcinogenesis.

Symposium on "Models in the Life Sciences: New Mathematical and
Physical Models of Biosystems and Organs," Warsaw, Poland, 1993.

The purpose of this NIH workshop was to exchange information
on the use of nonanimal models being developed for research
in immunology cardiac performance, lipid transport,
hemodialysis and peritoneal dialysis.


Workshop on Behavioral Methods and Animal Care, National Institute
of Mental Health, 1993.

This workshop is intended to provide assistance to health
researchers, veterinarians, and members of institutional
animal care and use committees regarding the care and use of
animals in behavioral research; a report is in preparation.

Workshop on "Eye Irritation Testing, Practical Application of
Non-Whole Animal Alternatives," Washington, D.C., 1993.

This workshop, cosponsored by several NIH institutes and
centers, other Federal agencies, and private organization, is
intended to help set a course for the scientific approval and
acceptance of non-whole animal alternatives to the Draize eye
test; a report will be prepared.

World Congress on Alternatives and Animal Use in the Life
Sciences: Education, Research, and Testing, Baltimore, Maryland,
1993.

The purpose of the World Congress, supported in part by
several NIH institutes and centers, is to review progress
made toward refining, reducing, and replacing the use of
animals in education, research, and testing; to develop a
realistic understanding of the validity and status of
alternatives; and to create an understanding that in
research, animal studies, together with clinical studies and
in vitro methods, advance science and contribute to the basic
understanding of biology and disease.

Workshops on Implementing Public Health Service Policy for the
Humane Care and Use of Laboratory Animals.

The NIH Office of Laboratory Animal Welfare conducts a
nationwide program of animal welfare education, including
co-sponsorship of multiple, annual regional meetings.
Thirty-six (36) workshops have been presented since their
inception in 1985. Each year one or two of these programs
has focused on nonanimal methods of research and/or the use
of less differentiated animal species in research. Through
this process the NIH has participated in numerous,
broad-ranging discussions of nonanimal research models.


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:


A Request for Applications on "Non-Mammalian species in
Toxicological Testing" was issued by the National Institute of
Environmental Health Sciences in 1986.

A Request for Applications for "Studies on the Etiology of
Neoplasia in Poikilothermic, Aquatic Animals" was issued by the
National Institute of Environmental Health Sciences in 1986.

A Request for Applications for "Developing and Improving
Institutional Animal Resources" was issued by the National Center
for Research Resources in 1989.

A Request for Applications for "Animal Facility Improvement for
Small Research Programs" was issued the National Center for
Research Resources in 1989.
Program Announcements on
"Investigations into Methods that Replace or Reduce Vertebrate
Animals Used in Research, or Lessen Their Pain and Distress" were
issued as Trans-NIH initiatives in 1987, 1988, 1989, and 1991.

A Request for Applications on the "Development of Nonmammalian
Models for Biomedical Research" was issued by the National Center
for Research Resources in 1990.

A Program Announcement encouraging the submission of applications
for grants on the "Development and Utilization of Transgenic
Animal and Cell Models in Studies of Environmental Mutagenesis and
Associated Health Effects" was issued by the National Institute of
Environmental Health Sciences" in 1990.

A Program Announcement encouraging the submission of applications
for grants on "Molecular Approaches to Drug Abuse Research" was
issued by the National Institute on Drug Abuse in 1990.

A Program Announcement encouraging the submission of applications
for grants on "Anticancer Model Development" was issued by the
National Cancer Institute in 1991.

A Program Announcement encouraging the submission of applications
for "Small Grants for the Development of Nonmammalian Models" was
issued as a Trans-NIH initiative in 1991.

A Program Announcement encouraging the submission of applications
for grants on "Development of High Connectivity Nonmammalian
Models" was issued by the National Center for Research Resources
in 1992.

A Small Business Innovative Research Solicitation to "Foster
Research into Methods That Do Not Use Animals" was issued as a
Trans-NIH initiative in 1992.

A Program Announcement encouraging the submission of applications
for grants on "Genetic Studies in Alcohol Research" using
invertebrate models was issued by the National Institute on
Alcohol Abuse and Alcoholism in 1993.

A Request for Proposal for a contract to conduct a "National
Survey of Laboratory Animal Use, Facilities, and Resources" was
issued by the National Center for Research Resources, in 1993.

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:


Evaluate the effectiveness of previous Trans-NIH Program
Announcements to encourage the submission of applications for
investigations into methods that do not require animals, reduce
the numbers of animals, or lessen pain and distress in animals.
Use this evaluation to determine new areas of research that meet
the objectives of the legislation.

This activity explores the use of lower organisms, cultured
tissues and cells, and mathematical and computer simulations
as models for biomedical and behavioral research.

Reissue the National Center for Research Resources' Program
Announcement to encourage the submission of applications for the
development of high connectivity nonmammalian models for
biomedical research.

"High connectivity" can be defined as those models having
well-characterized functions or properties that cross many
species. This activity promotes research on nonmammalian
systems, specifically poikilothermic (cold-blooded)
vertebrates, including fishes and reptiles; invertebrates,
including aquatic species; microorganisms; cell and tissue
cultures; and mathematical, computer, and physical models.

Strengthen and enlarge the Trans-NIH Solicitation for Small
Business Innovation Research (SBIR) projects to develop critical
technologies that promote the understanding of basic biological
mechanisms in accord with the objectives of this legislation. The
final phase of these grants requires commercialization with no
Federal funding. Set-aside funds available for all SBIR grants in
Fiscal Year 1994 will be 1.5% of the NIH budget, increasing to
2.5% in Fiscal Year 1996.

Each awarding component will encourage the development of new
model systems that are integral to its mission.

Issue a Trans-NIH Solicitation to implement a new pilot program
for Small Business Technology Transfer (STTR) projects to develop
critical technologies that promote the understanding of basic
biological mechanisms in accord with the objectives of this
legislation. The final phase of STTR grants requires agreements
between small businesses and research institutions with no Federal
funding. Set-aside funds available in Fiscal Year 1994 for all
STTR grants will be 0.05% of the NIH budget, increasing to 0.15%
in Fiscal Year 1996.

Issue Trans-NIH Program Announcement for Academic Research
Enhancement Awards to encourage educational institutions that have
not been traditional recipients of NIH research funds to develop
critical technologies or model systems that promote the
understanding of basic biological processes in accord with the
goals of this legislation.

Support ongoing NIH research projects and consider issuing new
solicitations for projects that use cell cultures or other in
vitro systems as models for screening prior to animal testing.

Several NIH "Drug Discovery Programs" currently support the
development of in vitro models to screen new compounds for
the treatment and prevention of various diseases.

Continue NIH support for investigator-initiated research projects
to develop new or improved test systems for toxicological testing
of environmental chemicals in accord with the objectives of this
legislation.

In its role to safeguard the public health by preventing
unnecessary exposure to environmental hazards, the National
Institute of Environmental Health Sciences (NIEHS) has become
the principal coordinating agency in the development and
validation of new toxicological testing methodologies.

Continue to support NIH research projects and issue solicitations
for improving laboratory animal resources through the National
Center for Research Resources' Comparative Medicine Program:

(A) to upgrade animal facilities and equipment, improving
facility design; and

(B) to foster the detection, diagnosis, characterization,
treatment, and prevention or control of diseases which may
threaten the health and well-being of laboratory animals; and

(C) to develop, preserve, and make available genetically suitable
stocks of animals (e.g., cryopreservation of embryos).

These awards are intended to assist institutions in promoting
stable, species-specific environments for research animals;
in improving the general health and well-being of animals; in
controlling infectious diseases; and in minimizing genetic
variation. Collectively, such improvements can potentially
reduce the number of animals used by minimizing the
extraneous factors that tend to increase experimental
variables (e.g., environmental stress, diseases, and genetic
drift).

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.

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.

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.

Encourage collaboration between experts in computer science and
health researchers to solve current biomedical and behavioral
research problems using advanced computerized research
technologies.

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.

Continue to support laboratory-cultured aquatic specimens and
disseminate information on their availability and suitability for
biomedical and behavioral research.

The National Center for Research Resources currently supports
resource centers where aquatic species are established as
standard nonmammalian marine models.


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


Establish an Advisory Panel composed of experts from Federal
agencies to review and evaluate new technologies that meet the
objectives of this legislation.

The panel will meet periodically and make recommendations to
the NIH on the potential utility of newly-developed
technologies. Non-Federal employees will be recruited to
serve on as ad hoc consultants.

Continue to search and broaden the circulation of the National
Library of Medicine's (NLM) computerized on-line data bases for
citations relevant to its quarterly annotated bibliography titled:
"Alternatives to the Use of Live Vertebrates in Biomedical
Research and Testing."

This Bibliography is available upon request and at no charge
and helps to keep scientists apprised of articles on existing
and new methodologies to evaluate the toxicologic potential
of chemical, biological, and physical agents. The NLM
continues to solicit comments on the scope of this
publication.

Develop and make accessible computerized data and information
resources with functional capabilities to support the evaluation
and comparison of new toxicological test procedures and allow for
comparison of test results derived from whole animals and other
methodologies.

The National Library of Medicine will continue to advise on
the administrative and technical frameworks needed to support
the development, maintenance, and utility of such data and
information resources.

Continue to develop liaisons with other Federal agencies, industry
and private sector organizations, and foreign authorities to
foster efforts relevant to the validation of promising research
methodologies.

In this regard, the NIH continues to support the efforts
being developed by representatives from the Consumer Product
Safety Commission, the Environmental Protection Agency, and
the Food and Drug Administration. The National Library of
Medicine works closely with this group effort. In addition
to considering "alternatives" to eye irritation test methods,
this group will consider other relevant topics, such as
"alternatives" to dermal irritation and sensitization tests,
and the potential reuse of animals in testing.

Disseminate information about this NIH Plan and subsequent updates
and revisions by publishing them in the NIH Guide for Grants and
Contracts, and various scientific newsletters, such as the Center
for Alternatives to Animal Testing, the Institute of Laboratory
Animal Resources, the Scientists Center for Animal Welfare, the
Research Resources Reporter, and the Alternatives Report, and by
reporting progress at national and international meetings.

Continue NIH support for symposia, workshops, and consensus
conferences in accord with the objectives of this
legislation; disseminate relevant publications (e.g.,
monographs) resulting from these meetings to encourage
acceptance of valid and reliable methods by the scientific
community.

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

Incorporate training in new and diverse technologies into
interdisciplinary training programs (e.g., mathematics and
computer sciences) in accord with the objectives of this
legislation.

These training programs can be incorporated into NIH training
grants awarded to eligible institutions and into predoctoral
and postdoctoral fellowships to prepare future scientists for
careers in biomedical and behavioral research.

Promote the training of scientists who use research animals in the
humane care and use of laboratory animals in accord with
objectives of this legislation; and promote the training of animal
researchers and members of animal care and use committees of the
importance of power and sample size planning in research design.

Programs to foster the humane treatment of animals used in
research will be incorporated into the NIH Office for
Protection from Research Risks'(OPRR) series of regional
workshops given several times a year at selected sites across
the Nation. In addition, the OPRR plans to develop a
videotape for broad distribution to investigators and members
of animal care committees to illustrate the impetus for the
reduction, refinement, and replacement inherent in the U.S.
Government Principles for the Utilization and Care of
Vertebrate Animals Use in Testing, Research, and Training.

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:

Establish a process to identify and review the scientific content
of awards for research projects that meet the objectives of this
legislation. Using an indexing vocabulary that will be further
refined, the Committee will examine projects contained in the
Computer Retrieval of Information of Scientific Projects (CRISP)
System, a database containing information on all NIH-funded
research projects for current and previous fiscal years.

A subcommittee has been appointed to develop a coding manual
and computer software to facilitate the identification of the
projects.

Establish a database to identify and review published
literature on research models and maintain a current
bibliography that meet the objectives of this legislation.
Many biomedical and behavioral research articles appearing in
refereed journals represent the endproducts of research
conducted and supported by the NIH.

A subcommittee has been appointed to consider the feasibility
of online searching of a variety of databases available from
public and private sector vendors, including the files
available through National Library of Medicine's database of
biomedical and behavioral research articles. This also
requires indexing key words and appropriate modification of
search strategies to identify relevant citations.

APPENDIX A: INTERAGENCY COORDINATING COMMITTEE ON THE USE OF
ANIMALS IN RESEARCH



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 of Laboratory Animal Welfare

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

(a) 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. (a) 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-

(A) methods of biomedical research and experimentation that
do not require the use of animals;

(B) methods of such research and experimentation that reduce
the number of animals used in such research;

(C) methods of such research and experimentation that produce
less pain and distress in such animals;and

(D) methods of such research and experimentation that involve
the use of marine life (other than marine mammals);

(2) for establishing the validity and reliability of the method
described in paragraph (1);

(3) for encouraging the acceptance by the scientific community of
such methods that have been found to be valid and reliable ;and

(4) for training scientists in the use of such methods that have
been found to be valid and reliable.

(b) 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.

(c) 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.

(d) 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).

(e)(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').

(2) The committee shall provide advice to the Director of NIH on
the preparation of the plan required in subsection (a).

(3) The committee shall be composed of

(A) 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

(B) 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.

(b) 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 prepared 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.

- What are the strengths and limitations of mathematical and
physical modeling in solving problems in diabetes, and
cardiovascular/pulmonary function? What is the general potential of
such models in biomedical research, and can principles be derived for
broader applications?

- What are the strengths and limitations of nonmammalian models in
solving problems in diabetes and cardiovascular/pulmonary function?
What is the general potential of such models in biomedical research,
and are there principles to be derived for broader applications?

- What types of problems in diabetes and cardiovas-
cular/pulmonary function are best studied using mammalian or vertebrate
models? What are the strengths and limitations of these models? Are
there principles that can be derived for broader applications?

- To solve current and future biomedical problems, are there
recommendations that should be mode to encourage development and use of
particular types of models in the entire spectrum from purely
mathematical to human?

Responses were to include an assessment of the strengths,
limitations, and potential of each type of model in biomedical
research. In addition, recommendations were requested from the panel
regarding the particular types of models that should be developed in
aid of solving current and future biomedical problems.

SUMMARY OF CONCLUSIONS

1. 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.

II. Conclusions on Specific Models

A. 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.

B. 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.

C. 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.

D. 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

I. 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 modeling 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.

II. 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:

- Research mammals are indispensable for the progress of human and
veterinary medicine and the maintenance of human and animal
health.

- Although the numbers of such animals needed in the near term for
research may not rise, neither are they likely to fall
significantly.

- The advance of modeling and model systems enhances science; it
will not substitute for animal research and testing.

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

Sándor J. Kovács 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 Physics
Washington University
St. Louis, Missouri

Horold J. Morowitz, Ph.D.
Clarence J. Robinson Professor of Biology and Natural
Philosophy
George Mason University
Fairfax, Virginia

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

SPEAKERS

Julien I.E. Hoffman, M.D,
The Uses and Abuses of Models
Samuel A. Wickline, M.D., F.A.C.C.
"Ultrasonic Characterization of Cardiovascular Tissue"

Stephen M. Factor, M.D., and Richard S. Chadwick, Ph.D.
"The Effects of the Myocardial Connective Tissue Matrix on Cardiac
and Theoretical Biomechanics''

Robert R. Ruffolo, Jr., Ph.D.
"The Use of Animal Model Systems in the Development of
Cardiovascular Drugs"

Norman C. Staub, M.D.
"Interdependence of Animal Experiments and Mathematical Models"

M.A. Gimbrone, Jr., M.D., and C.F. Dewey, Jr., Ph.D.
"Physical and Biological Models of Flow Cell lnteractions"

Charles S. Peskin, Ph.D.
"Biomedical Applications of a Computer Model of the Heart:
Physiology, Pathophysiology, and Prosthetic Valve Design"

Kenneth R. Brown, M.D., and Richard T. Robertson, Jr., Ph.D.
"The Preclinical and Clinical Development of Ivermectin (Mectizan)
for the Treatment of Onchocerciasis"

APPENDIX D: MODEL SYSTEMS

Living Systems

In vivo models (in the living body)

Clinical studies (epidemiological studies in humans)

Higher vertebrates (mammals)

Lower vertebrates (warm-and cold-blooded)

Invertebrates (e.g., roundworms, aquatic spp.)

Microorganisms (e.g., bacteria, protozoa, yeasts)

Higher Plants

In vitro models

Organ, tissue, cell cultures derived from human and
animal species

Non-living systems

Mathematical modeling (including better experimental
design)

Computer simulation

Imaging technologies (e.g., nuclear magnetic
resonance)

AWIC

Animal Welfare Information Center
United States Department of Agriculture
National Agricultural Library

USDA Cooperative Agreement No. 58-0520-5-076 - July, 1995