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T h e e t h i c s o f r e s e a r c h i n v o l v i n g a n i m a l s Zebrafish and rats as disease models 7.11 Both the zebrafish and the rat play a role as disease models in the investigation <strong>of</strong> the genetics <strong>of</strong> human disease. Each occupies a narrower niche than the mouse for several reasons. Zebrafish 7.12 <strong>The</strong>re has been a very significant increase in the use <strong>of</strong> zebrafish for the study <strong>of</strong> disease processes in humans. Zebrafish reproduce easily and quickly and have morphological and physiological similarities to mammals. Those who study zebrafish hope that use <strong>of</strong> the species will lead to progress in several aspects <strong>of</strong> the drug development process, including target identification, disease modelling, lead discovery and toxicology (see paragraphs 8.6–8.16). 20 <strong>The</strong> study <strong>of</strong> the zebrafish genome is relatively well advanced and a complete genome sequence will soon be available. 21 It has been the focus <strong>of</strong> several major forward genetic screens (see paragraphs 5.17-5.18) for a variety <strong>of</strong> diseases and other phenotypes. Zebrafish models have been developed for several human diseases, including blood disorders, diabetes, muscular dystrophy and neurodegenerative diseases. 22 <strong>The</strong> transparency <strong>of</strong> the developing zebrafish embryo has enhanced its usefulness for studying the genetics <strong>of</strong> development. One area where much progress has been made is in the study <strong>of</strong> the genetics <strong>of</strong> the development <strong>of</strong> the heart and vascular system. Increased understanding about the genes involved has also contributed to understanding <strong>of</strong> these processes in vertebrates. Rat 7.13 Research <strong>involving</strong> the rat has for many years lagged behind that <strong>of</strong> the mouse in terms <strong>of</strong> developing the techniques for manipulating its genetic systems. This, coupled with the expense <strong>of</strong> producing mutations in the rat, has been the primary reason for it having been used less widely than the mouse for the study <strong>of</strong> the genetics <strong>of</strong> disease processes. Although a complete genome sequence has recently been published, 23 the relative lack <strong>of</strong> 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 <strong>of</strong> 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 <strong>of</strong> the technologies available for the measurement <strong>of</strong> phenotypes such as blood pressure. Comparisons between inbred lines have revealed a significant amount <strong>of</strong> 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 <strong>of</strong> hypertension is a major area for study in the rat and a number <strong>of</strong> genes have been identified that are involved in determining blood pressure. 24 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 <strong>of</strong> 2005. See <strong>The</strong> Wellcome Trust Sanger Institute (2005) <strong>The</strong> 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 <strong>of</strong> 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. 128
T h e e t h i c s o f r e s e a r c h i n v o l v i n g a n i m a l s Summary 7.14 This chapter has described the use <strong>of</strong> GM <strong>animals</strong> in the study <strong>of</strong> human disease. <strong>The</strong> vast majority <strong>of</strong> <strong>animals</strong> that are genetically modified for this purpose are mice, rats and zebrafish. Although an animal model cannot be considered as an exact replica <strong>of</strong> a human disease, scientists working in the field have found that there are <strong>of</strong>ten sufficient similarities to make informative comparisons. Even when <strong>animals</strong> do not present disease symptoms that are similar to those <strong>of</strong> humans, useful information may still be discovered regarding gene function. For example, individual genes can be identified that are involved in specific facets <strong>of</strong> even complicated disease processes. 7.15 <strong>The</strong> number <strong>of</strong> <strong>animals</strong> required to establish an individual genetic line carrying a particular mutation currently ranges from 50 to several hundred. Over the next 20 years, a major increase in the production <strong>of</strong> GM <strong>animals</strong> is expected. <strong>The</strong> total number <strong>of</strong> mice used in mutagenesis and phenotyping studies in the UK is likely to be <strong>of</strong> the order <strong>of</strong> several million each year. 7.16 As with all <strong>animals</strong> kept in laboratories, the welfare <strong>of</strong> GM <strong>animals</strong> depends to a considerable degree on non-experimental conditions such as housing and handling. Specific issues relating to the way the <strong>animals</strong> are produced may be raised because <strong>of</strong> the large numbers involved. Care needs to be taken to create environments that are appropriate for the <strong>animals</strong> with regard to their basic species-specific needs, particularly concerning space, enrichments and interactions with other <strong>animals</strong>. Welfare issues may also be raised by the particular genetic modification. <strong>The</strong>se may be severe if the <strong>animals</strong> are affected by, for example, a neurodegenerative disease. We have also described genetic modifications that have yielded useful results with regard to human disease but which do not appear to produce adverse effects on animal welfare. <strong>The</strong> main problems in assessing the welfare <strong>of</strong> GM <strong>animals</strong> are that (i) in most cases <strong>of</strong> forward or reverse genetic screens, the implications for welfare cannot be predicted (see paragraph 4.57); and (ii) it can sometimes be difficult to detect and measure more subtle adverse welfare effects (see paragraphs 4.3-4.7, 4.18 and 7.10). CHAPTER 7 GENETICALLY MODIFIED ANIMALS IN THE STUDY OF HUMAN DISEASE 129
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The ethics
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The ethics
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Foreword The issue
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Table of contents
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Stages 1-2: discovery and selection
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Conclusions and recommendations ...
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Terms of reference
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T h e e t h i c s o f r e s e a r c
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Chapter 1 Introduction
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Chapter 2 The cont
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Chapter 3 Ethical issues raised by
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Chapter 4 The capa
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Section 3 Alternatives
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Section 4 Legal, ethical and policy
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Chapter 14 Discussion of</s
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Appendices
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Genetic screening: ethical issues P
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