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 />
in medical <str<strong>on</strong>g>research</str<strong>on</strong>g> to investigate basic biological processes. Many mouse mutants have<br />
arisen sp<strong>on</strong>taneously in col<strong>on</strong>ies maintained specifically for experimental purposes. Some <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
these have been used as models <str<strong>on</strong>g>of</str<strong>on</strong>g> human disease, including diabetes, obesity and<br />
neurodegenerative diseases. 9<br />
‘Forward genetics’<br />
5.17 Other techniques seek to deliberately change the genetic complement <str<strong>on</strong>g>of</str<strong>on</strong>g> <str<strong>on</strong>g>animals</str<strong>on</strong>g>, in order<br />
to observe the c<strong>on</strong>sequences <str<strong>on</strong>g>of</str<strong>on</strong>g> these alterati<strong>on</strong>s. Classical genetic experiments (also called<br />
‘forward genetics’) are performed by inducing random mutati<strong>on</strong>s. <str<strong>on</strong>g>The</str<strong>on</strong>g> <str<strong>on</strong>g>animals</str<strong>on</strong>g> are treated<br />
with mutagens such as X-rays, chemicals that alter genetic informati<strong>on</strong> or viruses that insert<br />
DNA into the host genome. Offspring are screened for abnormal features in development,<br />
physiology or behaviour. <str<strong>on</strong>g>The</str<strong>on</strong>g> advantage <str<strong>on</strong>g>of</str<strong>on</strong>g> this approach is that when a mutated gene is<br />
found, it is likely to be important for the feature that is abnormal in the mutant. <str<strong>on</strong>g>The</str<strong>on</strong>g> mutant<br />
gene can then be identified, by comparing gene sequences from the mutated animal to<br />
those from normal <str<strong>on</strong>g>animals</str<strong>on</strong>g>. This procedure has become much more straightforward since the<br />
genomes <str<strong>on</strong>g>of</str<strong>on</strong>g> a number <str<strong>on</strong>g>of</str<strong>on</strong>g> <str<strong>on</strong>g>animals</str<strong>on</strong>g> have been mapped and sequenced.<br />
5.18 Until recently, these studies were mainly carried out in fruit flies and nematode worms,<br />
organisms which are small, low cost and have rapid generati<strong>on</strong> times. <str<strong>on</strong>g>The</str<strong>on</strong>g>se are crucial<br />
features for large-scale genetic studies that involve many thousands <str<strong>on</strong>g>of</str<strong>on</strong>g> <str<strong>on</strong>g>animals</str<strong>on</strong>g>. Genetic<br />
screens in flies and worms have c<strong>on</strong>tributed to many important advances in our<br />
understanding <str<strong>on</strong>g>of</str<strong>on</strong>g> animal development. Many <str<strong>on</strong>g>of</str<strong>on</strong>g> the genes identified were later shown to be<br />
comm<strong>on</strong> to all <str<strong>on</strong>g>animals</str<strong>on</strong>g>, including humans, and they <str<strong>on</strong>g>of</str<strong>on</strong>g>ten functi<strong>on</strong> in very similar ways. <str<strong>on</strong>g>The</str<strong>on</strong>g><br />
c<strong>on</strong>served functi<strong>on</strong>s <str<strong>on</strong>g>of</str<strong>on</strong>g> particular genes have been dem<strong>on</strong>strated by transferring them, for<br />
example, from humans to worms or flies, and showing that they functi<strong>on</strong> in the same way.<br />
This <str<strong>on</strong>g>research</str<strong>on</strong>g> has revealed a remarkable degree <str<strong>on</strong>g>of</str<strong>on</strong>g> c<strong>on</strong>servati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> genetic informati<strong>on</strong><br />
during evoluti<strong>on</strong>. More recently, large-scale genetic screens have been carried out using<br />
zebrafish and mice, primarily to discover the genes resp<strong>on</strong>sible for a particular<br />
developmental or physiological process. <str<strong>on</strong>g>The</str<strong>on</strong>g> welfare implicati<strong>on</strong>s <str<strong>on</strong>g>of</str<strong>on</strong>g> such experiments are<br />
difficult to predict and, depending <strong>on</strong> the genes involved, could range from no adverse<br />
affects to severe developmental abnormalities and disability (see paragraph 5.13).<br />
‘Reverse genetics’<br />
5.19 Another genetic approach, called ‘reverse genetics’, is mainly applied to mice. Researchers<br />
can alter a specific gene <str<strong>on</strong>g>of</str<strong>on</strong>g> unknown functi<strong>on</strong> either by over-expressi<strong>on</strong> (in transgenic<br />
mice), eliminati<strong>on</strong> (in knock-out mice) or replacement with an altered form <str<strong>on</strong>g>of</str<strong>on</strong>g> the gene (in<br />
knock-in mice). <str<strong>on</strong>g>The</str<strong>on</strong>g> genetic change is then passed <strong>on</strong> from generati<strong>on</strong> to generati<strong>on</strong> in the<br />
new, genetically engineered mouse strain, in which the functi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the gene under study<br />
can be analysed.<br />
CHAPTER 5 THE USE OF ANIMALS IN BASIC BIOLOGICAL RESEARCH<br />
5.20 In order to over-express a gene, DNA is injected into the nucleus <str<strong>on</strong>g>of</str<strong>on</strong>g> a fertilised egg, which is<br />
then implanted into the uterus <str<strong>on</strong>g>of</str<strong>on</strong>g> a surrogate mother. A gene might also be eliminated<br />
(knocked out) or altered (knocked in) in ES cells, which are then injected into an early mouse<br />
embryo so that the cells derived from the modified ES cells develop into the tissues <str<strong>on</strong>g>of</str<strong>on</strong>g> the<br />
developing mouse. If cellular descendents <str<strong>on</strong>g>of</str<strong>on</strong>g> the ES cells form germ cells (sperm or eggs),<br />
these chimeric mice will produce <str<strong>on</strong>g>of</str<strong>on</strong>g>fspring that have the eliminated or altered gene. Further<br />
breeding will produce some mice in which the gene has been completely eliminated or in<br />
which <strong>on</strong>ly the altered form <str<strong>on</strong>g>of</str<strong>on</strong>g> the gene is present (see Box 5.6).<br />
9 See Schuler AM and Wood PA (2002) Mouse models for disorders <str<strong>on</strong>g>of</str<strong>on</strong>g> mitoch<strong>on</strong>drial fatty acid ß-oxidati<strong>on</strong> Inst Lab Anim<br />
Res 43: 57–65.<br />
97