During the first half of the 20th century, biomedical research relied on only a few animal models. The basic biomedical sciences biochemistry, nutrition, pharmacology, physiology, etc. used the rat as the primary model. Mice were used occasionally, and other species were used in specialized fields, e.g., dogs in cardiovascular research and pigeon breast muscle for study of skeletal muscle biochemistry. Selection of a particular species as an animal model was usually based on convenience, e.g., animal availability (pound dogs) or cost and ease of care (rats). Initially, there was minimal knowledge about the models or of human function, so the appropriateness of the model was not considered. As the knowledge base for models and humans increased, primarily during the latter half of the 20th century, questions arose regarding the applicability of particular long-standing models to humans. If the model animal has a major anatomical, biochemical, or physiological difference from the human, then extrapolation of results from the model to humans becomes questionable. Over time, knowledge about other species has accrued so that alternative models may be considered. In the last 30 to 40 years, the biochemistry, nutrition, and physiology of species raised for human food production have been extensively investigated. Consequently, some agricultural species are being used in biomedical research because they are excellent models for humans. For example, the pig is generally a better cardiovascular model than the dog, the classical model species. Some details of human biology extrapolated from classical models are incorrect, and in many cases the newer models are more similar to humans. Nevertheless, the acquisition of the current incredible knowledge base about human biology was possible primarily because of the classical models, e.g., the rat and the dog.

Currently, the mouse is a popular model, not because it is an excellent human model, but because it provides a tool to study specific gene function. Transgenic mice overexpress a particular gene and in some cases overexpress the gene in particular organs. Control of the timing of gene function and tissue-specific expression is becoming feasible, so gene function during development or aging can be examined. In knockout models, specific genes are modified so that they do not function. Mice are also advantageous because they are small, require little special care, and are fecund with a continuous and short breeding cycle. There are transgenic cattle, pigs, and sheep that have special uses in the biomedical community, e.g, production of a specific human protein for use in human medicine. However, the size of these species restricts their general use.

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