Laboratory Animal Medicine (Third Edition)
Chapter 32 - Genetically Modified Animals
For most of the 20th century, increasing numbers of genetically defined laboratory mice have been described and incorporated into biological research; this trend has accelerated in the 21st century. Initially, research using inbred strains was limited mostly to basic genetic studies in which biochemical or visual phenotypic expression patterns were observed. With the advent of molecular genetics in the 1960s, laboratory mice developed into critical research tools in which the genomic basis of disease and mutation could be examined at the level of individual genes. By the 1970s, the prospect of intentionally modifying the murine genome by the addition of new functional DNA was at hand (Jaenisch, 1976; Jaenisch and Mintz, 1974). By the early 1980s, the persistence of microinjected laboratory-derived DNA within the cells of live-born mice (Gordon and Ruddle, 1981) and the functional expression of transgenes in mice (Brinster et al., 1981; Costantini and Lacy, 1981) were reported. Within a few years, major universities, medical schools, and pharmaceutical and biotechnology companies had created in-house transgenic mouse laboratories and genetic modification technologies had been expanded to other species. Genetically modified C. elegans, Drosophila, zebrafish, mice, and rats have been used in biomedical research for studies of basic genetics and gene function, as well as for modeling human disease. Genetically modified cattle, goats, and sheep have been used to produce proteins in milk (Schnieke et al., 1997), while genetically modified pigs have been used as large animal models of certain diseases and as potential xenotransplantation donors (Lai et al., 2002). The mouse remains the primary choice for transgenic experimentation due to the relative ease of embryo and adult manipulation and the unparalleled depth of murine genetic knowledge, although rats may have more utility for some purposes (Zheng et al., 2012). Today, genetically modified mice are produced as models of human disease, to study basic gene function and regulation, and as in vivo systems in which mammalian (and nonmammalian) genetic expression may be investigated.
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Genetically Engineered Animal Models in Toxicologic Research
2021, Haschek and Rousseaux's Handbook of Toxicologic Pathology: Volume 1: Principles and Practice of Toxicologic PathologyGenetically engineered animals enable the study of gene function and disease pathophysiology in efficient, precise, and complex ways. Detailed genomic information for numerous laboratory mouse and rat strains is in the public domain, and international, multilaboratory consortia have made significant headway in characterizing the phenotypic outcomes of mutating every protein-encoding gene in the mouse. The number of engineered models resulting from random insertion as well as targeted deletion or replacement of specific genes is ever expanding. The discovery and development of new products, especially medical therapies, rely on genetically modified animal models to define new targets, elucidate mechanisms of disease and toxicity, and screen products for efficacy and safety. Engineered models for use in drug development include mouse models of human metabolism, mouse models for mutagenicity testing and carcinogenicity assessment, and genetically immunodeficient mice and rats that support the growth of human tissue xenografts suitable for in vivo studies of cancer treatments and nonclinical safety assessment of human cell-based products. Genetically engineered livestock are used as bioreactors to produce therapeutic proteins (“biopharming”); as donors for cell, organ, and tissue xenotransplantation; and increasingly as a source of food products. Toxicologic pathology assessments of genetically modified animals and their products employ the same endpoints that are used in conventional nonclinical safety assessment studies for biomolecules, chemicals, drugs, and cell products. Additional factors that must be considered when analyzing genetically engineered animals include knowledge of the induced mutation and the caveats of the method used in generating a given model, the potential for species-specific molecular mechanisms (where the responses of animals to inserted human gene products often do not recapitulate the human responses), and the possible introduction and propagation of animal pathogens into humans by xenografting infected cells or organs.