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 />
7.7 <str<strong>on</strong>g>The</str<strong>on</strong>g> questi<strong>on</strong> arises as to how relevant the informati<strong>on</strong> <strong>on</strong> disease processes in mutant<br />
<str<strong>on</strong>g>animals</str<strong>on</strong>g>, especially the mouse, will be to the genetics <str<strong>on</strong>g>of</str<strong>on</strong>g> disease processes in humans. <str<strong>on</strong>g>The</str<strong>on</strong>g>re<br />
are a number <str<strong>on</strong>g>of</str<strong>on</strong>g> c<strong>on</strong>trasting points to c<strong>on</strong>sider:<br />
i) Comparative anatomy and comparative pathology represent l<strong>on</strong>g-established traditi<strong>on</strong>s<br />
that have made significant c<strong>on</strong>tributi<strong>on</strong>s to the general understanding <str<strong>on</strong>g>of</str<strong>on</strong>g> the functi<strong>on</strong><br />
<str<strong>on</strong>g>of</str<strong>on</strong>g> mammalian systems, and therefore to the understanding <str<strong>on</strong>g>of</str<strong>on</strong>g> disease processes in both<br />
humans and mammals. <str<strong>on</strong>g>The</str<strong>on</strong>g> scientific community also uses genetic models to provide<br />
valuable comparative physiological, developmental, biochemical and pathological<br />
informati<strong>on</strong> across species.<br />
ii)<br />
<str<strong>on</strong>g>The</str<strong>on</strong>g> major differences in the <strong>on</strong>e percent <str<strong>on</strong>g>of</str<strong>on</strong>g> mouse genes that do not have direct<br />
counterparts in humans (see paragraph 7.2) are accounted for by specialist classes <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
multigene families. <str<strong>on</strong>g>The</str<strong>on</strong>g>se mouse-specific clusters <str<strong>on</strong>g>of</str<strong>on</strong>g>ten corresp<strong>on</strong>d to <strong>on</strong>ly a single gene<br />
in the human genome. Most clusters involve genes related to reproducti<strong>on</strong>, immunity<br />
and the ability to smell (olfacti<strong>on</strong>). One example is a group <str<strong>on</strong>g>of</str<strong>on</strong>g> genes in the mouse that<br />
is called the vomer<strong>on</strong>asal receptor family and plays a specialist role in mouse<br />
reproducti<strong>on</strong>. In humans, this structure is n<strong>on</strong>-functi<strong>on</strong>al.<br />
iii) In evoluti<strong>on</strong>ary terms, the mouse and human diverged some 80 milli<strong>on</strong> years ago, which<br />
explains the significant differences in some areas <str<strong>on</strong>g>of</str<strong>on</strong>g> their comparative physiology<br />
including, for example, l<strong>on</strong>gevity and many behavioural adaptati<strong>on</strong>s. While there is a<br />
very high c<strong>on</strong>cordance <str<strong>on</strong>g>of</str<strong>on</strong>g> genes between the two genomes, it is generally agreed that<br />
differences between humans and mice are due to changes in the patterns and timing <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
gene expressi<strong>on</strong>. <str<strong>on</strong>g>The</str<strong>on</strong>g>se changes reflect alterati<strong>on</strong>s in the regulati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> genes that have<br />
occurred since the two species diverged.<br />
7.8 Clearly, the mouse is not a replica <str<strong>on</strong>g>of</str<strong>on</strong>g> a human, but biomedical scientists maintain that the<br />
similarities are sufficient to make informative comparis<strong>on</strong>s. <str<strong>on</strong>g>The</str<strong>on</strong>g>y also take the view that,<br />
although the effects <str<strong>on</strong>g>of</str<strong>on</strong>g> mutati<strong>on</strong>s in genes in the mouse might not replicate exactly the<br />
effects that they exert in humans, they can provide a robust guide to the functi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> genes<br />
in mammalian species. Given that a large number <str<strong>on</strong>g>of</str<strong>on</strong>g> mouse mutati<strong>on</strong>s is already available,<br />
what is the evidence that there have been useful c<strong>on</strong>tributi<strong>on</strong>s to our understanding <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
human disease genetics? In the next secti<strong>on</strong> we give examples <str<strong>on</strong>g>of</str<strong>on</strong>g> specific disease models to<br />
address this questi<strong>on</strong>.<br />
Disease models in the mouse<br />
7.9 Gene dysfuncti<strong>on</strong> is at the root <str<strong>on</strong>g>of</str<strong>on</strong>g> all genetically determined disease processes. Not all gene<br />
dysfuncti<strong>on</strong>s are heritable as gene expressi<strong>on</strong> is also influenced by injury, infecti<strong>on</strong>, ageing,<br />
cancer, neural degenerati<strong>on</strong> and neural regenerati<strong>on</strong>. By asking how <str<strong>on</strong>g>of</str<strong>on</strong>g>ten mouse mutants<br />
reproduce the effect <str<strong>on</strong>g>of</str<strong>on</strong>g> mutati<strong>on</strong>s in the corresp<strong>on</strong>ding human gene, it is possible to assess<br />
the utility and relevance <str<strong>on</strong>g>of</str<strong>on</strong>g> disease models. We illustrate this below with several examples<br />
(see also Table 7.1), which also show that the implicati<strong>on</strong>s for the welfare <str<strong>on</strong>g>of</str<strong>on</strong>g> <str<strong>on</strong>g>animals</str<strong>on</strong>g> involved<br />
in such <str<strong>on</strong>g>research</str<strong>on</strong>g> are wide ranging.<br />
CHAPTER 7 GENETICALLY MODIFIED ANIMALS IN THE STUDY OF HUMAN DISEASE<br />
i) Diabetes: Mutati<strong>on</strong>s in the glucokinase gene in humans lead to a form <str<strong>on</strong>g>of</str<strong>on</strong>g> type II diabetes 4<br />
that manifests itself in the young, called maturity-<strong>on</strong>set diabetes <str<strong>on</strong>g>of</str<strong>on</strong>g> the young (MODY).<br />
Mutati<strong>on</strong>s in the glucokinase gene in the mouse also develop a type II diabetes, very<br />
similar to that seen in human MODY patients. 5 <str<strong>on</strong>g>The</str<strong>on</strong>g>se mutants provide a useful model <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
4 Type II diabetes is a late-<strong>on</strong>set disease that is not necessarily life-threatening and which does not always require c<strong>on</strong>trol with<br />
insulin administrati<strong>on</strong>.<br />
5 Toye AA, Moir L, Hugill A et al. (2004) A New Mouse Model <str<strong>on</strong>g>of</str<strong>on</strong>g> Type 2 Diabetes, Produced by N-Ethyl-Nitrosourea<br />
Mutagenesis, Is the Result <str<strong>on</strong>g>of</str<strong>on</strong>g> a Missense Mutati<strong>on</strong> in the Glucokinase Gene Diabetes 53: 1577–83.<br />
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