Modeling Human Drug Response

In humans, any approach to assess genetic causation of a pharmacogeneic trait is necessarily indirect. However, a convincing experimental model can often help dissect the genetic basis of the trait, or provide insight into mechanisms responsible for the trait, and may disclose its biological significance under experimental conditions that cannot be met in human experimentation for ethical or methodological reasons. Responders of known genotypes and phenotypes to a toxic chemical can be examined under carefully controlled conditions that reveal the pharmacological and toxicological consequences of a given trait. Even models that may be unsuitable for assessing new drug therapy may yet be excellent for elucidating the molecular basis and physiological mechanisms of human traits. Such studies can turn our thinking toward previously unsuspected pathways and mechanisms, and thereby direct attention toward the acquisition of information that advances our understanding of the human condition. Of course, the findings in any nonhuman model system must be assessed in humans to assess their applicability to the human condition.

Until recently, chance observations of spontaneous mutations in naturally occurring populations of domesticated species or laboratory stocks were the primary source of animal models for genetic research. But there are several disadvantages associated with naturally occurring models of human genetic traits that limit their usefulness for genetic analysis. Frequently, the mutation is rare, making it difficult to find the appropriate model, and the specific genetic defect may be difficult to identify and compare with its human counterpart. Because many domesticated species as well as some of the laboratory species are difficult to breed, and because maturation times may be lengthy, they become very expensive to maintain.

Some of these problems can be avoided by a proper choice of species and strains of laboratory animals to find traits that mimic those of humans. For many years, geneticists have relied mainly on inbred strains, including recombinant, congenic, and recombinant congenic strains for the development of genetic models of human hereditary traits because of the long-term stability of strain characteristics, genetic authenticity, phenotypic uniformity, and the unique combinations of genetic material that occur in individual strains. Most of these desirable features are a result of the homozygosity and isogenicity that is achieved at nearly every gene locus through prolonged inbreeding. Moreover, inbred strains can provide an unlimited supply of replicate genotypes and can be bred to yield new combinations of genes that do not occur in nature.

Many highly inbred strains of mice, rats, hamsters, guinea pigs, and pigeons are commercially available. Additional inbred stocks of laboratory species are maintained independently at universities, research institutes, and governmental laboratories by investigators who are usually willing to supply mating pairs of specialized strains on request at no charge or at nominal cost. Although human and mouse genomes have dominated genome science, the annotation of genomic sequences of several nonmammalian eukaryotic organisms (yeast, fruit fly, nema-tode, zebrafish) provides additional opportunities to use comparative genomics for pharmacogenomics analysis and therapeutics.

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