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 ...
You also want an ePaper? Increase the reach of your titles
YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.
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 />
there is not yet a model which c<strong>on</strong>tains all <str<strong>on</strong>g>of</str<strong>on</strong>g> the relevant features that characterise the<br />
pathology <str<strong>on</strong>g>of</str<strong>on</strong>g> Alzheimer’s disease, the models available are nevertheless <str<strong>on</strong>g>of</str<strong>on</strong>g> great interest<br />
to <str<strong>on</strong>g>research</str<strong>on</strong>g>ers. 10 A variety <str<strong>on</strong>g>of</str<strong>on</strong>g> approaches, including histopathological, imaging,<br />
electrophysiological and molecular genetic techniques have been particularly helpful for<br />
mapping the progressi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> neurodegenerative disorders in mouse models as well as<br />
determining the effects <str<strong>on</strong>g>of</str<strong>on</strong>g> several <str<strong>on</strong>g>of</str<strong>on</strong>g> the mutati<strong>on</strong>s.<br />
With regard to welfare implicati<strong>on</strong>s, mouse models <str<strong>on</strong>g>of</str<strong>on</strong>g> neurodegenerative disease may<br />
show a variety <str<strong>on</strong>g>of</str<strong>on</strong>g> neurological impairments including, for example, tremors and ataxia<br />
(loss <str<strong>on</strong>g>of</str<strong>on</strong>g> full c<strong>on</strong>trol <str<strong>on</strong>g>of</str<strong>on</strong>g> bodily movements). <str<strong>on</strong>g>The</str<strong>on</strong>g>se symptoms <str<strong>on</strong>g>of</str<strong>on</strong>g>ten have significant effects<br />
<strong>on</strong> fecundity and viability and require careful m<strong>on</strong>itoring. <str<strong>on</strong>g>The</str<strong>on</strong>g> diseases may also affect a<br />
mouse’s ability to interact with other <str<strong>on</strong>g>animals</str<strong>on</strong>g>, and to carry out behaviours such as play,<br />
running and climbing.<br />
v) Lesch–Nyhan disease: Mutati<strong>on</strong>s in the Hprt gene, which encodes an enzyme involved in<br />
metabolism (hypoxanthine-guanine phosphoribosyltransferase), lead to a rare but very<br />
severe neurological syndrome in humans known as Lesch–Nyhan disease, the most<br />
characteristic feature <str<strong>on</strong>g>of</str<strong>on</strong>g> which is self-destructive biting. One <str<strong>on</strong>g>of</str<strong>on</strong>g> the earliest targeted<br />
mutati<strong>on</strong>s developed in the mouse, applying the reverse genetic approach (see<br />
paragraphs 5.19–5.22), resulted in the disrupti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the Hprt gene. However, Hprt mouse<br />
mutants show n<strong>on</strong>e <str<strong>on</strong>g>of</str<strong>on</strong>g> the phenotype characteristics <str<strong>on</strong>g>of</str<strong>on</strong>g> Lesch–Nyhan syndrome.<br />
Researchers found that in the mouse an alternative enzyme pathway ameliorated the<br />
effect <str<strong>on</strong>g>of</str<strong>on</strong>g> the Hprt mutati<strong>on</strong>, and obvious adverse effects <strong>on</strong> animal welfare from the<br />
generati<strong>on</strong> and study <str<strong>on</strong>g>of</str<strong>on</strong>g> the mutant model have not been detected.<br />
vi) Cancer: Prior to the sequencing <str<strong>on</strong>g>of</str<strong>on</strong>g> the mouse genome, investigating sp<strong>on</strong>taneous<br />
mutati<strong>on</strong>s in genes involved in cancer required approximately 1,000 mice for crossbreeding<br />
in order to map a gene to a specific chromosomal regi<strong>on</strong>. This regi<strong>on</strong> would<br />
usually c<strong>on</strong>tain several genes, all <str<strong>on</strong>g>of</str<strong>on</strong>g> which needed to be sequenced to determine which<br />
<strong>on</strong>e c<strong>on</strong>tained the mutati<strong>on</strong>. As a result, it would have taken 15 years to identify ten<br />
possible genes that were involved in cancer, whereas this step can now be achieved in<br />
m<strong>on</strong>ths. Moreover, comparis<strong>on</strong>s between the mouse and human genomes help<br />
<str<strong>on</strong>g>research</str<strong>on</strong>g>ers to find related human genes encoding proteins that could be candidates for<br />
the development <str<strong>on</strong>g>of</str<strong>on</strong>g> new medicines. <str<strong>on</strong>g>The</str<strong>on</strong>g> recent development <str<strong>on</strong>g>of</str<strong>on</strong>g> a library <str<strong>on</strong>g>of</str<strong>on</strong>g> some 60,770<br />
full-length cDNAs 11 provides <str<strong>on</strong>g>research</str<strong>on</strong>g>ers with a functi<strong>on</strong>al copy <str<strong>on</strong>g>of</str<strong>on</strong>g> every mouse gene that<br />
can be readily genetically modified. 12 This library is especially useful for studying human<br />
cancers or the role <str<strong>on</strong>g>of</str<strong>on</strong>g> other human genes involved, where the identity and locati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the<br />
mouse homologue is unknown. With regard to animal welfare, mouse models <str<strong>on</strong>g>of</str<strong>on</strong>g> cancer<br />
usually dem<strong>on</strong>strate an increased incidence <str<strong>on</strong>g>of</str<strong>on</strong>g> tumours and an increased morbidity that<br />
will require careful m<strong>on</strong>itoring.<br />
7.10 In assessing the usefulness, relevance and validity <str<strong>on</strong>g>of</str<strong>on</strong>g> the large amount <str<strong>on</strong>g>of</str<strong>on</strong>g> data that are<br />
already available from studies <str<strong>on</strong>g>of</str<strong>on</strong>g> GM mice, advocates note that it is important to c<strong>on</strong>sider a<br />
number <str<strong>on</strong>g>of</str<strong>on</strong>g> features that characterise the investigati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> mouse models, and which apply<br />
more generally to the analysis <str<strong>on</strong>g>of</str<strong>on</strong>g> any genetic animal model <str<strong>on</strong>g>of</str<strong>on</strong>g> human disease:<br />
CHAPTER 7 GENETICALLY MODIFIED ANIMALS IN THE STUDY OF HUMAN DISEASE<br />
10 See, for example, Lee VM, Keny<strong>on</strong> TK and Trojanowski JQ (2005) Transgenic animal models <str<strong>on</strong>g>of</str<strong>on</strong>g> tauopathies Biochim Biophys<br />
Acta 1739: 251–9.<br />
11 Complementary DNA: DNA produced from RNA sequences, which means that it c<strong>on</strong>tains <strong>on</strong>ly the sequences that code for<br />
proteins.<br />
12 <str<strong>on</strong>g>The</str<strong>on</strong>g> number <str<strong>on</strong>g>of</str<strong>on</strong>g> mouse cDNAs identified greatly exceeds the number <str<strong>on</strong>g>of</str<strong>on</strong>g> genes as some do not in fact code for proteins. See<br />
Suzuki M and Hayashizaki Y (2004) Mouse-centric comparative transcriptomics <str<strong>on</strong>g>of</str<strong>on</strong>g> protein coding and n<strong>on</strong>-coding RNAs<br />
Bioessays 26: 833–43.<br />
125