The ethics of research involving animals - Nuffield Council on ...

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.
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