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 />
Box 10.2: A recent retrospective study <str<strong>on</strong>g>of</str<strong>on</strong>g> the<br />
potential value <str<strong>on</strong>g>of</str<strong>on</strong>g> knock-out mouse models*<br />
in pharmaceutical discovery and development<br />
<str<strong>on</strong>g>The</str<strong>on</strong>g> study aimed to address ‘comm<strong>on</strong> and<br />
varied…questi<strong>on</strong>s c<strong>on</strong>cerning the value <str<strong>on</strong>g>of</str<strong>on</strong>g> mouse<br />
genetics for drug discovery’, including the following.<br />
■ What is the correlati<strong>on</strong> between mouse and human<br />
physiology and hence the relevance <str<strong>on</strong>g>of</str<strong>on</strong>g> knock-out<br />
models in developing small-molecule drugs?<br />
■ Does gene compensati<strong>on</strong> (when the expressi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
another gene alters to compensate for the loss <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
another during development) prevent identificati<strong>on</strong><br />
<str<strong>on</strong>g>of</str<strong>on</strong>g> the true functi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the genes that have been<br />
knocked out?<br />
■ Since current technology means that the genes are<br />
usually knocked out very early in development, in<br />
what sense are the effects <str<strong>on</strong>g>of</str<strong>on</strong>g> the lack <str<strong>on</strong>g>of</str<strong>on</strong>g> a particular<br />
gene throughout development relevant to the<br />
functi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the gene in adult <str<strong>on</strong>g>animals</str<strong>on</strong>g>?<br />
■ How far is the embry<strong>on</strong>ic or ne<strong>on</strong>atal death <str<strong>on</strong>g>of</str<strong>on</strong>g> some<br />
knock-out mouse lines likely to prevent the<br />
identificati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> many <str<strong>on</strong>g>of</str<strong>on</strong>g> the best drug targets in<br />
future?<br />
In light <str<strong>on</strong>g>of</str<strong>on</strong>g> such questi<strong>on</strong>s, the study dem<strong>on</strong>strated that<br />
the 100 best-selling human pharmaceutical medicines<br />
between them have 43 human biochemical targets, the<br />
genes for 34 <str<strong>on</strong>g>of</str<strong>on</strong>g> which have now been knocked out in<br />
mice. A literature review revealed that, <str<strong>on</strong>g>of</str<strong>on</strong>g> these 34<br />
knock-out models, 29 (85 percent) provide a direct<br />
correlati<strong>on</strong> with the therapeutic effect <str<strong>on</strong>g>of</str<strong>on</strong>g> the relevant<br />
medicine. In the remaining five cases, early (e.g.<br />
embry<strong>on</strong>ic or ne<strong>on</strong>atal) lethality or unrelated<br />
abnormalities meant that the knock-out mice were not<br />
useful models for humans.†<br />
It might be argued that such a finding is not surprising<br />
since the knock-out mice were generated after the<br />
medicines were developed, when the mechanism <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
acti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the medicines was already known. However, the<br />
authors also assert that more ‘prospective’ use <str<strong>on</strong>g>of</str<strong>on</strong>g> knockout<br />
mouse models is currently yielding benefits. A<br />
number <str<strong>on</strong>g>of</str<strong>on</strong>g> new pharmaceuticals are being developed<br />
against human biochemical targets the functi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> which<br />
has been determined using genetic <str<strong>on</strong>g>research</str<strong>on</strong>g> <str<strong>on</strong>g>involving</str<strong>on</strong>g><br />
mice, including treatments for osteoporosis and obesity.‡<br />
* That is, mice in which <strong>on</strong>e or a few genes have been deleted,<br />
or otherwise disrupted, so as to prevent their expressi<strong>on</strong>.<br />
† Zambrowicz B and Sands A (2003) Knockouts model the 100<br />
best-selling drugs – will they model the next 100? Nat Rev<br />
Drug Disc 2: 38–51.<br />
‡ Zambrowicz B and Sands A (2003) Knockouts model the 100<br />
best-selling drugs – will they model the next 100? Nat Rev<br />
Drug Disc 2: 38–51.<br />
10.39 <str<strong>on</strong>g>The</str<strong>on</strong>g> study described in Box 10.2 is an example <str<strong>on</strong>g>of</str<strong>on</strong>g> a systematic attempt to evaluate the scientific<br />
validity <str<strong>on</strong>g>of</str<strong>on</strong>g> using <str<strong>on</strong>g>animals</str<strong>on</strong>g> as models for humans, by directly comparing findings in <str<strong>on</strong>g>animals</str<strong>on</strong>g> with<br />
the results <str<strong>on</strong>g>of</str<strong>on</strong>g> corresp<strong>on</strong>ding clinical studies. <str<strong>on</strong>g>The</str<strong>on</strong>g>re have also been two recent meta-analyses <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
such systematic reviews. One was c<strong>on</strong>ducted ‘to find out how animal <str<strong>on</strong>g>research</str<strong>on</strong>g> had informed<br />
ensuing clinical <str<strong>on</strong>g>research</str<strong>on</strong>g>’, 19 the other to assess the value <str<strong>on</strong>g>of</str<strong>on</strong>g> pre-clinical animal studies in<br />
permitting safe and effective first-dose studies <str<strong>on</strong>g>of</str<strong>on</strong>g> potential new medicines in humans. 20<br />
10.40 <str<strong>on</strong>g>The</str<strong>on</strong>g> first paper, by Pound et al. (2004), examined six reviews, each <str<strong>on</strong>g>of</str<strong>on</strong>g> which compared animal<br />
and clinical findings in a specific and problematic therapeutic area (heart disease, stroke,<br />
wound healing). <str<strong>on</strong>g>The</str<strong>on</strong>g> authors c<strong>on</strong>cluded that these six reviews provide little evidence to support<br />
the view that animal <str<strong>on</strong>g>research</str<strong>on</strong>g> has c<strong>on</strong>tributed to the treatment <str<strong>on</strong>g>of</str<strong>on</strong>g> human disease. <str<strong>on</strong>g>The</str<strong>on</strong>g> study<br />
has been used to support claims that there is ‘no-evidence base for animal <str<strong>on</strong>g>research</str<strong>on</strong>g>’. 21 But it has<br />
also been str<strong>on</strong>gly criticised, in particular for its selectivity, given that other systematic reviews<br />
were identified by the team but were excluded from the analysis. Of the six reviews discussed<br />
in the paper, five were initiated following lack <str<strong>on</strong>g>of</str<strong>on</strong>g> success in clinical trials, which could have been<br />
predicted from better analysis <str<strong>on</strong>g>of</str<strong>on</strong>g> the relevant animal studies. <str<strong>on</strong>g>The</str<strong>on</strong>g> sixth was initiated because <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
difficulties in establishing an animal model <str<strong>on</strong>g>of</str<strong>on</strong>g> the relati<strong>on</strong>ship between social status and<br />
cor<strong>on</strong>ary heart disease. Nevertheless, the study has served to highlight cases in which there<br />
were some methodological problems in the animal studies and/or in which full analysis <str<strong>on</strong>g>of</str<strong>on</strong>g> the<br />
animal results available would have predicted the ineffectiveness <str<strong>on</strong>g>of</str<strong>on</strong>g> the treatment, had such an<br />
analysis been d<strong>on</strong>e before clinical work started. 22<br />
19 Pound P, Ebrahim S, Sandercock P et al. (2004) Where is the evidence that animal <str<strong>on</strong>g>research</str<strong>on</strong>g> benefits humans? BMJ 328:<br />
514–7.<br />
20 Greaves P, Williams A and Eve M (2004) First dose <str<strong>on</strong>g>of</str<strong>on</strong>g> potential new medicines to humans: how <str<strong>on</strong>g>animals</str<strong>on</strong>g> can help Nat Rev<br />
Drug Disc 3: 226–36.<br />
21 See, for example, rapid resp<strong>on</strong>se letters to the British Medical Journal.<br />
22 See for example Blakemore C and Peatfield T (2004) Missing evidence that animal <str<strong>on</strong>g>research</str<strong>on</strong>g> benefits humans BMJ 328: 1017-8<br />
182