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