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Knockout

Gene knockouts are genetically engineered animals in which a specific gene is disrupted so that the gene product is no longer produced. The absence of the gene often leads to some observable effects in terms of animal physiology, behavior, or other characteristics. Any abnormalities that result from knocking out a gene serve as valuable clues regarding the gene's actual function. Usually, knockout technology is applied to mice, because mice are genetically quite similar to humans—and therefore, serve as good models of human disorders—and are relatively convenient to study. Knockout technology has many medical applications. For instance, researchers can disrupt a gene that is involved in a particular disease in order to examine the physiology surrounding that disease. Similarly, knockout mice are useful in testing prospective drugs for safety and efficacy.

Medical Applications of Gene Knockouts

An example of the usefulness of gene knockouts is in the study of neurological disorders. A deficiency of the neurotransmitter dopamine is involved in a number of neurological/psychiatric illnesses, including Parkinson's disease and schizophrenia. To study these diseases, scientists have knocked out dopamine transporters and dopamine receptors. These knockout mice have provided insight into the role of dopamine and possible therapies for diseases that involve this neurotransmitter. In a similar manner, knockout mice have been created to serve as models of a variety of human diseases, ranging from cancer to metabolic diseases to behavioral disorders.

In addition to serving as disease models, knockout mice are utilized for testing potential drugs. In some cases, the safety of a drug is examined by knocking out the gene targeted by the drug and determining the extent of the negative effect. Conversely, drugs are sometimes given to knockout mice to determine whether the abnormalities of these mice can be alleviated.

Difficulties Associated with Knockouts

Some genes are essential for normal embryonic development, and knockout of one of these genes results in death during gestation. It is difficult to study the functions of the gene in this case, because the defects are so severe. To overcome this problem, techniques have been developed for knocking out a gene only in a particular cell type or at a particular stage in development.

Moreover, even if a gene can be studied in mice, this does not necessarily mean that its functions in humans and mice are exactly the same. Mice are useful models, but they are not identical to humans. As a result, therapies that are developed based on a mouse model of a disease may not be effective against the disease in humans. Consequently, knockouts are an excellent starting point for biomedical research, but discoveries must be followed up in human clinical trials.

  • genes
  • knockout
  • disease
KevinShenderovNew York University
http://dx.doi.org/10.4135/9781412963855.n680
See Also:

Bibliography

ErnestoBockamp, et al., “Of Mice and Models: Improved Animal Models for Biomedical Research,”Physiological Genomics (v.11/3, 2002)
Helen V.Firth, Judith G.Hall and Jane AHurst, eds. Oxford Desk Reference Clinical Genetics (Oxford University Press, 2005)
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