2
Biomedical Model Definition

Biomedical models can be of many types—from animal models of human diseases to animal, in vitro, or modelling systems for studying any aspect of human biology or disease. A detailed discussion of various types of models appeared in a National Research Council study, Models for Biomedical Research (NRC 1985), and is appended to this report.

A biomedical model is a surrogate for a human being, or a human biologic system, that can be used to understand normal and abnormal function from gene to phenotype and to provide a basis for preventive or therapeutic intervention in human diseases. For example, characterization of mouse models of various dwarfing syndromes, cloning of mutated genes, and parallel comparative genetic mapping and cloning of genes for similar human syndromes have led to an understanding of various human dwarfing conditions and have suggested therapies based on biologic knowledge, rather than shotgun testing. Mouse models with targeted mutations in the cystic fibrosis gene are providing a means for testing gene therapy delivered by aerosol into the lungs (Dorin and others 1996). The use of nonhuman primates that are genomically similar is beginning to shed light on complex human diseases. Squid giant axons are important model systems in neurobiologic research because their size allows a variety of manipulations not possible with vertebrate axons and because there are 40 years of data on the anatomy, physiology, biophysics, and biochemistry of those neurons. Clams, sea urchins, and fishes are models in developmental biology (for example, for study of transcriptional regulation during early cell differentiation) because they have high fecundity, short generation times, and transparent eggs that develop externally. Those are but a few examples among thousands that illustrate the breadth and utility of comparative models in biomedicine.

A model need not be an exact replica of a human condition or disease. For example, mice with mutations in the homologue of the human Duchenne-Becker muscular dystrophy gene are less severely affected than human patients and can regenerate degenerating muscle (Anderson and others 1988); they have been used successfully to test muscle implantation therapy for this debilitating disease (Ragot and others 1993). Many targeted-mutation (so-called knockout) mice exhibit unexpected phenotype, revealing previously unidentified roles for known genes (Homanics and others 1995 Shastry 1994). Finally, to the extent that biologic processes in living organisms are predictable, computer modelling might be able to predict the outcome of perturbing a metabolic pathway or treating a metabolic disease; this can lead to hypothesis-driven research with an animal model.

This report tends to emphasize genetic models because the dramatic success of the Human Genome Initiative has created a strong bias in biomedical research toward



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Biomedical Models and Resources: Current Needs and Future Opportunities 2 Biomedical Model Definition Biomedical models can be of many types—from animal models of human diseases to animal, in vitro, or modelling systems for studying any aspect of human biology or disease. A detailed discussion of various types of models appeared in a National Research Council study, Models for Biomedical Research (NRC 1985), and is appended to this report. A biomedical model is a surrogate for a human being, or a human biologic system, that can be used to understand normal and abnormal function from gene to phenotype and to provide a basis for preventive or therapeutic intervention in human diseases. For example, characterization of mouse models of various dwarfing syndromes, cloning of mutated genes, and parallel comparative genetic mapping and cloning of genes for similar human syndromes have led to an understanding of various human dwarfing conditions and have suggested therapies based on biologic knowledge, rather than shotgun testing. Mouse models with targeted mutations in the cystic fibrosis gene are providing a means for testing gene therapy delivered by aerosol into the lungs (Dorin and others 1996). The use of nonhuman primates that are genomically similar is beginning to shed light on complex human diseases. Squid giant axons are important model systems in neurobiologic research because their size allows a variety of manipulations not possible with vertebrate axons and because there are 40 years of data on the anatomy, physiology, biophysics, and biochemistry of those neurons. Clams, sea urchins, and fishes are models in developmental biology (for example, for study of transcriptional regulation during early cell differentiation) because they have high fecundity, short generation times, and transparent eggs that develop externally. Those are but a few examples among thousands that illustrate the breadth and utility of comparative models in biomedicine. A model need not be an exact replica of a human condition or disease. For example, mice with mutations in the homologue of the human Duchenne-Becker muscular dystrophy gene are less severely affected than human patients and can regenerate degenerating muscle (Anderson and others 1988); they have been used successfully to test muscle implantation therapy for this debilitating disease (Ragot and others 1993). Many targeted-mutation (so-called knockout) mice exhibit unexpected phenotype, revealing previously unidentified roles for known genes (Homanics and others 1995 Shastry 1994). Finally, to the extent that biologic processes in living organisms are predictable, computer modelling might be able to predict the outcome of perturbing a metabolic pathway or treating a metabolic disease; this can lead to hypothesis-driven research with an animal model. This report tends to emphasize genetic models because the dramatic success of the Human Genome Initiative has created a strong bias in biomedical research toward

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Biomedical Models and Resources: Current Needs and Future Opportunities research on functional genomics. The preponderance of survey and workshop participants were scientists who were using genetic animal models. This emphasis is not intended to downplay the value of nongenetic model systems. The information that we gathered from researchers who were using nongenetic systems strongly suggests that many of the same factors influence their success or failure. The committee recognized the importance of in vitro models, but did not cover them in this report for several reasons. First, in vitro models, including cell culture, bacteria, viruses, and yeasts. are universally used by the scientific community, including those using animal models. In vitro models provide important perspectives on the continuum of biologic processes that ultimately must be investigated at the organismal level. Furthermore, in vitro systems provide a wealth of material for in vivo applications, including vectors, constructs, expression libraries, monoclonal antibodies, infectious agents (including genetically modified agents), and so on. Finally, in vitro models are used by scientists across all NIH institutes, and this committee focused on recommendations that would enhance NCRR's rich tradition of animal model development, maintenance, and support.