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National Institutes of Health (US). Office for Medical Applications of Research. NIH State of the Science Statements [Internet]. Bethesda (MD): National Institutes of Health (US); 1983-2002.

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This publication is provided for historical reference only and the information may be out of date.

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4Modeling in Biomedical Research: An Assessment of Current and Potential Approaches: Applications to Studies in Cardiovascular/Pulmonary Function and Diabetes

Technology Assessment May 1-3, 1989

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 National 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 the 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 cardiovascular/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 made 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

I. General Conclusions

The panel members agreed with the conclusions of the extensive 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 humans. These general conclusions are developed in more detail for various models in the following paragraphs.

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 allow 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 analogs, 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 to represent is often displayed more simply and directly than in higher animals.
  • Their tissues and organs are more accessible and may lend themselves more easily 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 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 have 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 to 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 reperfusion, as well as a markedly lower incidence of reocclusion.

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 evaluation 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 long-term 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 data 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 analysis 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 of 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 shear 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 play 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 (non-insulin-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 type 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 part of the literature of endocrinology provide a broad 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 immunosuppressive 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 have an absolute insulin deficiency. The OB/OB and the db/db mice have been studied because they exhibit tissue resistance to the action of insulin and do not have 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 have 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 liver 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 hepatocytes 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 relatively 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 and 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 diabetes--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 combination of 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 part 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 humans.

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 goad 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 research depends on an 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 past 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 appropriate 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 decade ahead, the tools of most biomedical research groups. 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 to 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.

Technology Assessment Panel

  • Gordon H. Sato, Ph.D.
  • Panel and Conference Chairperson
  • Director
  • W. Alton Jones Cell Science Center, Inc.
  • Lake Placid, New York
  • Henry T. Bahnson, M.D.
  • Chief
  • Division of Cardiothoracic 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 Investigator
  • Veterans Administration Medical Center
  • Acting Instructor
  • Division of Metabolism, Endocrinology, and Nutrition
  • Department of Medicine
  • University of Washington
  • Seattle, Washington
  • Sandor J. Kovacs, 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 at Washington University Medical Center
  • Adjunct Assistant Professor of Physics
  • Washington University
  • St. Louis, Missouri
  • Harold 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

  • Richard N. Bergman, Ph.D.
  • "Impact of Mathematical Modeling to Assess Factors Regulating Glucose Tolerance in Animals and Man"
  • Professor
  • Department of Physiology and Biophysics
  • University of Southern California School of Medicine
  • Los Angeles, California
  • Kenneth R. Brown, M.D.
  • "The Preclinical and Clinical Development of Ivermectin (Mectizan) for the Treatment of Onchocerciasis"
  • Group Director, Regulatory Affairs
  • Merck Sharp & Dohme Research Laboratories
  • Associate Professor of Medicine
  • University of Pennsylvania
  • Lansdale, Pennsylvania
  • Richard S. Chadwick, Ph.D.
  • "The Effects of the Myocardial Connective Tissue Matrix on Cardiac Mechanics: Anatomy, Phylogeny, and Theoretical Biomechanics"
  • Head
  • Theoretical Biomechanics Group, MES
  • Biomedical Engineering and Instrumentation Branch
  • Division of Research Services
  • National Institutes of Health
  • Bethesda, Maryland
  • C. F. Dewey, Jr., Ph.D.
  • "Physical and Biological Models of Flow-Cell Interactions"
  • Professor of Mechanical Engineering
  • Mechanical Engineering Department
  • Massachusetts Institute of Technology
  • Cambridge, Massachusetts
  • Stephen M. Factor, M.D.
  • "The Effects of the Myocardial Connective Tissue Matrix on Cardiac and Theoretical Biomechanics"
  • Professor of Pathology and Medicine
  • Albert Einstein College of Medicine
  • Director of Pathology
  • Bronx Municipal Hospital Center
  • Bronx, New York
  • John N. Fain, Ph.D.
  • "Effects of Insulin and Other Hormones on Regulation of Metabolism in Model Systems From Vertebrates and Invertebrates"
  • Van Vleet Professor and Chairman
  • Department of Biochemistry
  • University of Tennessee at Memphis
  • Memphis, Tennessee
  • M.A. Gimbrone, Jr., M.D.
  • "Physical and Biological Models of Flow-Cell Interactions"
  • Elsie T. Friedman Professor of Pathology
  • Harvard Medical School
  • Director
  • Vascular Research Division
  • Department of Pathology
  • Brigham and Women's Hospital
  • Boston, Massachusetts
  • Douglas Greene, M.D.
  • "Animal and In Vitro Models for the Study of Diabetic Complications"
  • Professor of Internal Medicine
  • Director
  • Michigan Diabetes Research and Training Center
  • University of Michigan
  • Ann Arbor, Michigan
  • Gerald Grodsky, Ph.D.
  • "Modeling of Insulin Synthesis, Processing, and Secretion"
  • Professor Biochemistry, Biophysics, and Medicine
  • Associate Research Director
  • Metabolic Research Unit
  • University of California at San Francisco
  • San Francisco, California
  • Julien I.E. Hoffman, M.D.
  • "The Uses and Abuses of Models"
  • Professor of Pediatrics
  • Senior Staff Member
  • Cardiovascular Research Institute
  • University of California at San Francisco
  • San Francisco, California
  • Paul E. Lacy, M.D., Ph.D.
  • "Transplantation"
  • Robert L. Kroc Professor of Pathology
  • Washington University School of Medicine
  • St. Louis, Missouri
  • Charles S. Peskin, Ph.D.
  • "Biomedical Applications of a Computer Model of the Heart: Physiology, Pathophysiology, and Prosthetic Valve Design"
  • Professor of Mathematics
  • Courant Institute of Mathematical Sciences
  • New York, New York
  • Richard T. Robertson, Jr., Ph.D.
  • "The Preclinical and Clinical Development of Ivermectin (Mectizan) for the Treatment of Onchocerciasis"
  • Senior Director, Safety Assessment
  • Merck Sharp & Dohme Research Laboratories
  • West Point, Pennsylvania
  • Ora M. Rosen, M.D.
  • "Biological Models for Study in Insulin Action"
  • Professor
  • Department of Molecular Biology
  • Member
  • Memorial Sloan-Kettering Cancer Center
  • New York, New York
  • Aldo A. Rossini, M.D.
  • "The Use of Animal Models to Study Human Insulin-Dependent Diabetes"
  • Director
  • Division of Diabetes
  • Professor of Medicine
  • University of Massachusetts Medical School
  • Worcester, Massachusetts
  • Jesse Roth, M.D.
  • "Diabetes Mellitus: A Global Problem in Search of Solutions"
  • Intramural Research Program
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institutes of Health
  • Bethesda, Maryland
  • Robert R. Ruffolo, Jr., Ph.D.
  • "The Use of Animal Model Systems in the Development of Cardiovascular Drugs"
  • Group Director
  • Department of Pharmacology
  • Smith, Kline, & French Laboratories
  • King of Prussia, Pennsylvania
  • Norman C. Staub, M.D.
  • "Interdependence of Animal Experiments and Mathematical Models"
  • Professor of Physiology
  • Cardiovascular Research Institute
  • University of California at San Francisco
  • San Francisco, California
  • Samuel A. Wickline, M.D., F.A.C.C.
  • "Ultrasonic Characterization of Cardiovascular Tissue"
  • Assistant Professor of Medicine
  • Cardiovascular Division
  • Washington University School of Medicine
  • St. Louis, Missouri

Planning Committee

  • Richard S. Chadwick, Ph.D. (Chairman)
  • Head
  • Theoretical Biomechanics Group, MES
  • Biomedical Engineering and Instrumentation Branch
  • Division of Research Services
  • National Institutes of Health
  • Bethesda, Maryland
  • Richard N. Bergman, Ph.D.
  • Professor
  • Department of Physiology and Biophysics
  • University of Southern California School of Medicine
  • Los Angeles, California
  • Christina A. Blakeslee
  • Program Analyst
  • Division of Legislative Analysis
  • Office of the Director
  • National Institutes of Health
  • Bethesda, Maryland
  • Linda Blankenbaker
  • Program Analyst
  • Office of Medical Applications of Research
  • National Institutes of Health
  • Bethesda, Maryland
  • James Doherty
  • Information Officer
  • Division of Research Services
  • National Institutes of Health
  • Bethesda, Maryland
  • Murray Eden, Ph.D.
  • Chief
  • Biomedical Engineering and Instrumentation Branch
  • Division of Research Services
  • National Institutes of Health
  • Bethesda, Maryland
  • John L. Fakunding, Ph.D.
  • Special Assistant to the Director
  • Division of Heart and Vascular Diseases
  • National Heart, Lung, and Blood Institute
  • National Institutes of Health
  • Bethesda, Maryland
  • John H. Ferguson, M.D.
  • Director
  • Office of Medical Applications of Research
  • National Institutes of Health
  • Bethesda, Maryland
  • W. Gary Flamm, Ph.D., M.S.
  • Principal Health Science Solutions
  • Reston, Virginia
  • Michael Fluharty
  • Acting Public Affairs Officer
  • Office of Science and Health Reports
  • Division of Research Resources
  • National Institutes of Health
  • Bethesda, Maryland
  • Elaine C. Grose, Ph.D.
  • Acting Director
  • Environmental Toxicology Division
  • Health Effects Research Laboratory
  • U.S. Environmental Protection Agency
  • Research Triangle Park, North Carolina
  • Joan T. Harmon, Ph.D.
  • Director
  • Diabetes Research Program
  • Diabetes Programs Branch
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institutes of Health
  • Bethesda, Maryland
  • J. Woodland Hastings, Ph.D.
  • Conference and Panel CoChairperson
  • Professor of Biology
  • Department of Cellular and Developmental Biology
  • Harvard University
  • Cambridge, Massachusetts
  • Karen S. Hoffman, M.P.A.
  • Program Analyst
  • Office of Program Planning and Evaluation
  • National Institute of Environmental Health Sciences
  • National Institutes of Health
  • Research Triangle Park, North Carolina
  • John J. McGowan, Ph.D.
  • Chief
  • Developmental Therapeutics Branch
  • AIDS Program
  • National Institute of Allergy and Infectious Diseases
  • National Institutes of Health
  • Bethesda, Maryland
  • Harold J. Morowitz, Ph.D.
  • Clarence J. Robinson Professor of Biology and Natural Philosophy
  • George Mason University
  • Fairfax, Virginia
  • Bellur S. Prabhakar, Ph.D., M.Sc.
  • Research Microbiologist
  • Laboratory of Oral Medicine
  • National Institute of Dental Research
  • National Institutes of Health
  • Bethesda, Maryland
  • Louise Ramm, Ph.D.
  • Biological Models and Materials Resource Section
  • Division of Research Resources
  • National Institutes of Health
  • Bethesda, Maryland
  • Barbara A. Rapp, Ph.D.
  • Operations Research Analyst
  • Office of Program Planning and Evaluation
  • National Library of Medicine
  • National Institutes of Health
  • Bethesda, Maryland
  • Stephen L. Rawlins, Ph.D.
  • National Program Leader for Soil Erosion/Systems
  • National Programs Staff
  • U.S. Department of Agriculture/ARS
  • Beltsville, Maryland
  • Walter G. Rosen, Ph.D.
  • Consultant
  • Board on Biology
  • National Research Council
  • Washington, D.C.
  • Jesse Roth, M.D.
  • Director
  • Intramural Research Program
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institutes of Health
  • Bethesda, Maryland
  • Gordon H. Sato, Ph.D.
  • Panel and Conference Chairperson
  • Director
  • W. Alton Jones Cell Science Center, Inc.
  • Lake Placid, New York
  • Robert E. Silverman, M.D., Ph.D., F.A.C.P.
  • Chief
  • Diabetes Programs Branch
  • Division of Diabetes, Endocrinology, and Metabolic Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institutes of Health
  • Bethesda, Maryland
  • Richard Skalak, Ph.D.
  • Professor of Bioengineering
  • Department of Applied Mechanics and Engineering Sciences
  • University of California at San Diego
  • La Jolla, California
  • Bruce L. Umminger, Ph.D.
  • Acting Division Director
  • Division of Cellular Biosciences
  • National Science Foundation
  • Washington, D.C.
  • Carol E. Vreim, Ph.D.
  • Associate Director for Scientific Program Operations
  • Division of Lung Diseases
  • National Heart, Lung, and Blood Institute
  • National Institutes of Health
  • Bethesda, Maryland
  • Susan Wallace, M.F.A.
  • Conference Coordinator
  • Prospect Associates
  • Rockville, Maryland
  • Robert A. Whitney, Jr., D.V.M.
  • Director
  • Division of Research Services
  • Acting Director
  • Division of Research Resources
  • National Institutes of Health
  • Bethesda, Maryland
  • James D. Willett, Ph.D.
  • Chief
  • Biological Models and Materials Resource Section
  • Chief
  • Office of Program Planning and Evaluation
  • Division of Research Resources
  • National Institutes of Health
  • Bethesda, Maryland

Conference Sponsors

  • Division of Research Resources, NIH
  • Division of Research Services, NIH
  • Office of Medical Applications of Research, NIH

About the NIH Technology Assessment Program

NIH Technology Assessment Conferences and Workshops are convened to evaluate available scientific information related to a biomedical technology when topic selection criteria for a Consensus Development Conference are not met. The resultant NIH Technology Assessment Statements are intended to advance understanding of the technology or issue in question and to be useful to health professionals and the public.

Some Technology Assessment Conferences and Workshops adhere to the Consensus Development Conference format because the process is altogether appropriate for evaluating highly controversial, publicized, or politicized issues. Other Conferences and Workshops are organized around unique formats. In this format, NIH Technology Assessment Statements are prepared by a nonadvocate, nonfederal panel of experts, based on: (1) presentations by investigators working in areas relevant to the consensus questions typically during a 1-1/2-day public session; (2) questions and statements from conference attendees during open discussion periods that are part of the public session; and (3) closed deliberations by the panel during the remainder of the second day and morning of the third. This statement is an independent report of the panel and is not a policy statement of the NIH or the Federal Government.

Preparation and distribution of these reports are the responsibility of the Office of Medical Applications of Research, National Institutes of Health, Federal Building, Room 618, Bethesda, MD 20892.

Footnotes

1

Although it was not directly pertinent to cardiovascular health or diabetes, one presentation at 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 affecting livestock and causing river blindness in man. This drug was first tested in infected mice and found to have only 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 species, there would have been no way to establish 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.

This statement was originally published as: Modeling in biomedical research: An assessment of current and potential approaches: Applications to studies in cardiovascular/pulmonary function and diabetes. Workshop summary; 1989 May 1-3. Bethesda (MD): National Institutes of Health, Office of Medical Applications of Research; [1989].

For making bibliographic reference to the statement in the electronic form displayed here, it is recommended that the following format be used: Modeling in biomedical research: An assessment of current and potential approaches. NIH Technol. Assess Statement Online 1989 May 1-3 [cited year month day]; (4):19.

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