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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 5.21 A specific gene can also be altered, over-expressed or deleted in particular cell types or at specific times, providing even more precise ways <strong>of</strong> studying gene function in <strong>animals</strong>. <strong>The</strong>re Box 5.6: Common techniques for creating transgenic <strong>animals</strong> Pro-nuclear injection DNA construct fertilised egg surrogate mother non-transgenic <strong>of</strong>fspring transgenic <strong>of</strong>fspring (‘founder’ animal) Embryonic stem cells DNA construct: gene addition ES cells host blastocyst (early stage embryo) surrogate mother chimera with reproductive cell modification inbreeding transgenic <strong>of</strong>fspring GM followed by nuclear transfer egg cell with nucleus removed nuclear transfer implantation DNA construct: gene addition somatic cell (e.g. skin cell) surrogate mother cloned transgenic <strong>of</strong>fspring Pro-nuclear injection In the 1980s the first transgenic <strong>animals</strong> were created by pro-nuclear injection, which allowed only random introduction <strong>of</strong> new DNA sequences into the genome.* DNA is injected into a fertilised egg that is then transferred to a recipient female. Only a small proportion <strong>of</strong> the injected eggs will produce a firstgeneration (‘founder’) transgenic animal containing the gene <strong>of</strong> interest. <strong>The</strong>refore the resulting <strong>of</strong>fspring need to be selectively bred in order to obtain a line <strong>of</strong> <strong>animals</strong> all with the desired traits. This method has been used in Continued 98
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 mice, rats, pigs, sheep, cattle and goats. <strong>The</strong> efficiency is low as approximately three to five percent <strong>of</strong> the <strong>animals</strong> born as a result carry the transgene.* Embryonic stem cells ES cells can be used to modify the <strong>animals</strong>’ own genes in a targeted way, although as yet this has only been successfully carried out in mice. DNA is manipulated in the ES cells before they are transferred to developing embryos. <strong>The</strong> technique allows for specific gene targeting, enabling the precise deletion or modification <strong>of</strong> specific genes. Correctly modified ES cells are identified and injected into a host blastocyst (an embryo at an early stage <strong>of</strong> development). This will develop into a chimeric animal consisting <strong>of</strong> both the host’s original cells and the modified ES cells. Chimeric mice whose reproductive cells (sperm and egg cells) have arisen from the modified ES cells are then used as founder <strong>animals</strong> in selective breeding.* Nuclear transfer Nuclear transfer techniques (or ‘reproductive cloning’, see Figure 5.1) have been adapted to allow more precise modifications <strong>of</strong> the genome, allowing <strong>research</strong>ers to target specific genes. GM is carried out in a cultured cell before nuclear transfer. <strong>The</strong> nucleus from the modified cell is transferred to an oocyte (immature egg cell) which has had its nucleus removed. <strong>The</strong> oocyte and modified nucleus are combined through a process called ‘cell fusion’ and the resulting cell transferred to a recipient female. Viability and survival rates <strong>of</strong> embryos generated by nuclear transfer are low and it is estimated that less than three percent <strong>of</strong> the nuclear transfer embryos result in live <strong>of</strong>fspring† (see paragraphs 5.28-5.29). A relatively new technique <strong>involving</strong> the use <strong>of</strong> viruses to transfer DNA into the genome has the potential for much higher efficiency. It has been reported that 80–100% <strong>of</strong> the mice born following this technique are transgenic.* * See Clark J and Whitelaw B (2003) A future for transgenic livestock Nat Rev Genet 4: 825–33. † Roslin Institute (2002) Somatic Cell Nuclear Transfer (Cloning) Efficiency, available at: http://www.roslin.ac.uk/public/webtablesGR.pdf. Accessed on: 25 Apr 2005. are between 22,000 and 25,000 genes in the mouse genome, and several hundred have already been specifically eliminated in mice. In principle, all <strong>of</strong> the remaining genes could be deleted in further studies, alone or in combination with other genes. Not all <strong>of</strong> these procedures would result in viable <strong>of</strong>fspring, as the elimination <strong>of</strong> some genes would lead to the death <strong>of</strong> the developing embryo. However, more sophisticated techniques have been developed, such as producing ‘conditional knock-out’ <strong>animals</strong>, in which the gene deletion is only triggered for experimental purposes or in specific tissues. 10 5.22 <strong>The</strong> welfare implications for <strong>animals</strong> used in these kinds <strong>of</strong> experiments cannot be predicted because it is not known beforehand what type <strong>of</strong> defect may be produced by the genetic modification (see paragraph 4.57). As we have said, licences require that <strong>research</strong> is stopped and <strong>animals</strong> are killed humanely if defined thresholds <strong>of</strong> pain or suffering are exceeded (paragraphs 5.13 and 12.21). Although many <strong>of</strong> the mice created have no obvious abnormality, others have severe developmental defects. For example, mice in which a growth factor receptor gene was knocked out had severe abnormalities including skeletal defects and pr<strong>of</strong>ound deafness. 11 <strong>The</strong> methods by which GM <strong>animals</strong> are produced also have the potential to be painful and distressing (paragraph 4.58). Large numbers <strong>of</strong> <strong>animals</strong> are used to produce a single GM strain due to the relatively low efficiency <strong>of</strong> the methods used to achieve genetic modification. Usually, the majority <strong>of</strong> the <strong>animals</strong> that are produced do not have the desired genetic traits and are usually euthanised (see Box 5.6). More efficient methods would be desirable. Many strains <strong>of</strong> GM <strong>animals</strong> are expected to be established in the future. For example, it has been predicted that 300,000 new genetic lines <strong>of</strong> mice could be created over the next two decades. 12 CHAPTER 5 THE USE OF ANIMALS IN BASIC BIOLOGICAL RESEARCH Study <strong>of</strong> protein and cellular function 5.23 Genetic modification can also be used to produce mice that express a fluorescent form <strong>of</strong> a particular protein under study. This intervention allows <strong>research</strong>ers to observe the location 10 For a review, see Cohen-Tannoudji M and Babinet C (1998) Beyond ‘knock-out’ mice: new perspectives for the programmed modification <strong>of</strong> the mammalian genome Mol Hum Reprod 4: 929–38. 11 Colvin JS, Bohne BA, Harding GW, McEwen DG and Ornitz DM (1996) Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3 Nat Genet 12: 390–7. 12 Abbot A (2004) Geneticists prepare for deluge <strong>of</strong> mutant mice Nature 432: 541. 99
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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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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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