Ethics of Research involving animals
Zebrafish and rats as disease models
7.11 Both the zebrafish and the rat play a role as disease models in the investigation of the genetics of human disease. Each occupies a narrower niche than the mouse for several reasons.
Zebrafish
7.12 There has been a very significant increase in the use of zebrafish for the study of disease processes in humans. Zebrafish reproduce easily and quickly and have morphological and physiological similarities to mammals. Those who study zebrafish hope that use of the species will lead to progress in several aspects of the drug development process, including target identification, disease modelling, lead discovery and toxicology (see paragraphs 8.6–8.16).20 The study of the zebrafish genome is relatively well advanced and a complete genome sequence will soon be available.21 It has been the focus of several major forward genetic screens (see paragraphs 5.17-5.18) for a variety of diseases and other phenotypes.
Zebrafish models have been developed for several human diseases, including blood disorders, diabetes, muscular dystrophy and neurodegenerative diseases.22 The transparency of the developing zebrafish embryo has enhanced its usefulness for studying the genetics of development. One area where much progress has been made is in the study of the genetics of the development of the heart and vascular system. Increased understanding about the genes involved has also contributed to understanding of these processes in vertebrates.
Rat
7.13 Research involving the rat has for many years lagged behind that of the mouse in terms of developing the techniques for manipulating its genetic systems. This, coupled with the expense of producing mutations in the rat, has been the primary reason for it having been used less widely than the mouse for the study of the genetics of disease processes. Although a complete genome sequence has recently been published,23 the relative lack of tools for forward and reverse mutagenesis (see paragraphs 5.16-5.20) in the rat will continue to limit its utility. Nevertheless, several inbred rat lines have been developed. Many of these have been characterised for diseases such as diabetes and hypertension for which the rat is a particularly tractable model. Rats are the preferred species for these diseases because their large size is more suitable for the use of the technologies available for the measurement of phenotypes such as blood pressure. Comparisons between inbred lines have revealed a significant amount of variation in disease phenotypes. Genetic crosses between them show significant phenotypic differences and allow the genetic regions involved to be mapped and ultimately identified. For example, the genetics of hypertension is a major area for study in the rat and a number of genes have been identified that are involved in determining blood pressure.24
Table 7.1: A summary of the contribution
20 Zon LI and Peterson RT (2005) In vivo drug discovery in the zebrafish Nat Rev Drug Discov 4: 35–44.
21 It is expected that the zebrafish genome sequence will be provided by the end of 2005. See The Wellcome Trust Sanger
Institute (2005) The Danio Rerio Sequencing Project, available at:
http://www.sanger.ac.uk/Projects/D_rerio/faqs.shtml#factsnine. Accessed on: 28 Apr 2005.
22 Rubinstein AL (2003) Zebrafish: from disease modeling to drug discovery Curr Opin Drug Discov Devel 6: 218–23.
23 Gibbs RA, Weinstock GM, Metzker ML et al. (2004) Genome sequence of the Brown Norway rat yields insights into
mammalian evolution Nature 428: 493–521.
24 Herrera VL and Ruiz-Opazo N (2005) Genetic studies in rat models: insights into cardiovascular disease Curr Opin Lipidol 16:
179–91.