Ethics of Research involving animals
The mouse as a model for human disease
7.5 The genetic modification of organisms such as the fruit fly Drosophila, the nematode worm C. elegans, yeast, bacteria and viruses can provide useful information on the fundamental biological role of genes. However, studies in these species cannot address questions that concern the effects of gene modification on the development of organs or physiological disease processes that are only found in vertebrates or mammals. The mouse is therefore increasingly the preferred organism for modelling the genetics of human disease. It is difficult to make an accurate current estimate of the total number of mouse mutant lines available in the world today but estimates suggest that there are more than 3,000.2 There are several approaches that are routinely used for manipulating the mouse genome and generating new GM mice, including:
- gene targeting by using ES cells (see paragraph5.6);
- a mutagenesis programme using chemical mutagens followed by screening to identify relevant disease models (see paragraph 5.18); and
- new approaches, including the use of technologies to inactivate the RNA transcript of agene so that it cannot be translated into a protein (RNA interference, or RNAi).
Depending on the method used to produce mutations (see paragraphs 5.17–5.22), the number of mice that are required to establish a line carrying a specific mutation varies from about 50 animals to several hundred. Additional animals will be required to investigate the phenotypic effects of any scientifically useful mutant that is created. Many large-scale research programmes involving these techniques are in progress at a number of centres around the world. One of the aims of the international community of mouse geneticists is to develop at least one mouse mutant line for every gene in the mouse genome over the next 20 years. The total number of mice that are expected to be used in mutagenesis and phenotyping studies is of the order of several million each year in the UK alone (see paragraph 5.22).3
7.6 This use of GM animals for the study of human disease is rapidly expanding both in capacity and sophistication. A number of ‘mouse clinics’ are being built around the world with the space and tools to begin the analysis of the many thousands of mouse lines that will be developed. Ultimately, it is expected that highly detailed data that relate mutations in genes to different disease processes in the animal will be generated.
7.7 The question arises as to how relevant the information on disease processes in mutant animals, especially the mouse, will be to the genetics of disease processes in humans. There are a number of contrasting points to consider:
i) Comparative anatomy and comparative pathology represent long-established traditions that have made significant contributions to the general understanding of the function of mammalian systems, and therefore to the understanding of disease processes in both humans and mammals. The scientific community also uses genetic models to provide valuable comparative physiological, developmental, biochemical and pathological information across species.
ii) The major differences in the one percent of mouse genes that do not have direct counterparts in humans (see paragraph 7.2) are accounted for by specialist classes of multigene families. These mouse-specific clusters often correspond to only a single gene in the human genome. Most clusters involve genes related to reproduction, immunity and the ability to smell (olfaction). One example is a group of genes in the mouse that is called the vomeronasal receptor family and plays a specialist role in mouse reproduction. In humans, this structure is non-functional.
iii) In evolutionary terms, the mouse and human diverged some 80 million years ago, which explains the significant differences in some areas of their comparative physiology including, for example, longevity and many behavioural adaptations. While there is a very high concordance of genes between the two genomes, it is generally agreed that differences between humans and mice are due to changes in the patterns and timing of gene expression. These changes reflect alterations in the regulation of genes that have occurred since the two species diverged.
7.8 Clearly, the mouse is not a replica of a human, but biomedical scientists maintain that the similarities are sufficient to make informative comparisons. They also take the view that, although the effects of mutations in genes in the mouse might not replicate exactly the effects that they exert in humans, they can provide a robust guide to the function of genes in mammalian species. Given that a large number of mouse mutations is already available, what is the evidence that there have been useful contributions to our understanding of human disease genetics? In the next section we give examples of specific disease models to address this question.
Footnotes1 GM animals were used in a total of 764,000 regulated procedures in 2003 (see paragraph 13.25). This figure comprises 27
percent of all procedures for 2003. Ninety-eight percent of the procedures using GM animals involved rodents. Sixty-eight
percent of the total number of GM animals were used for the maintenance of breeding colonies but not for any further
procedures. See Home Office (2004) Statistics of Scientific Procedures on Living Animals Great Britain 2003 (London: HMSO).
2 Abbott A (2004) Geneticists prepare for deluge of mutant mice Nature 432: 541
3 For further information, see The Comprehensive Knockout Mouse Project Consortium (2004) The Knockout Mouse Project Nat
Genet 36: 921–4.
4 Type II diabetes is a late-onset disease that is not necessarily life-threatening and which does not always require control with
insulin administration.
5 Toye AA, Moir L, Hugill A et al. (2004) A New Mouse Model of Type 2 Diabetes, Produced by N-Ethyl-Nitrosourea
Mutagenesis, Is the Result of a Missense Mutation in the Glucokinase Gene Diabetes 53: 1577–83.