Animal Rights

$900 Million Mouse Project

| by Dr Ray Greek

Alison Abbott wrote in Nature about the International Mouse Phenotyping Consortium (IMPC). This is $900 million project to:

. . . identify the function of every gene in the mouse genome looks set to provide scientists with the ultimate mouse model of human disease . . . The IMPC aims to take mice of identical genetic background and to create viable strains in which one of the 20,000 or so genes in the mouse genome is knocked out, or deactivated. The knockout strains will then be put through rigorous, systematic phenotypic screens, which will check for physical and behavioural differences. The information will be stored in a purpose-built, open-access database. Scientists would, for example, be able to turn to the database to learn more about an unfamiliar gene signalled in a genome-wide association study in humans as being possibly relevant to a particular disease. (Emphasis added.)

I encourage you to read the entire article.

I must admit the above embodies pretty much all of my criticisms of animal models. (This might explain why my research does not get published in Nature.) My criticisms include the following.

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1. Animal models cannot predict human response to drugs and disease despite what this article states or implies.

2. Animal models cannot predict gene function despite what this article states or implies.

Van Regenmortel 2004:

However, there is probably a more fundamental reason for these failures: namely, that most of these approaches have been guided by unmitigated reductionism. As a result, the complexity of biological systems, whole organisms and patients tends to be underrated (1). Most human diseases result from the interaction of many gene products, and we rarely know all of the genes and gene products that are involved in a particular biological function. Nevertheless, to achieve an understanding of complex genetic networks, biologists tend to rely on experiments that involve single gene deletions. Knockout experiments in mice, in which a gene that is considered to be essential is inactivated or removed, are widely used to infer the role of individual genes. In many such experiments, the knockout is found to have no effect whatsoever, despite the fact that the gene encodes a protein that is believed to be essential. In other cases, the knockout has a completely unexpected effect (2). Furthermore, disruption of the same gene can have diverse effects in different strains of mice (3). Such findings question the wisdom of extrapolating data that are obtained in mice to other species. In fact, there is little reason to assume that experiments with genetically modified mice will necessarily provide insights into the complex gene interactions that occur in humans (Horrobin, 2003).

The disappointing results of knockout experiments are partly caused by gene redundancy and pleiotropy, and the fact that gene products are components of pathways and networks in which genes acting in parallel systems can compensate for missing ones (4). As many factors simultaneously influence the behaviour of a system, one part might function only in the presence of other components. The essential contribution of other genes in achieving a particular function will therefore be missed, which will further encourage the reductionist view that a single gene has adequate explanatory power (5). It remains true that human disease is best studied in human subjects (Horrobin, 2003). (6) (Emphasis added.)

Van Zutphen, in 2000, states that animals can be used to find out which gene causes a disease in humans:

However, results to-date suggest that the predictive value of a candidate gene, established in such an animal model, is rather low: thus far only few genes have been allocated as causative factors for corresponding disorders in man. In fact, it can be questioned whether the use of animal models is the most effective way to detect candidate genes for complex human disorders. Due to the complexity of the genotype-environment interactions, the pathways that lead to an aberrant phenotype often differ between man and animal. (7) (Emphasis added.)

Nijhout, in 2003, comments on the fact that the same genes do different things in different strains:

The importance of context is also illustrated by studies of the effects of “knockouts” of specific genes in mice, a method that completely eliminates the function of a gene’s product. For example, knockout of a retinoblastoma-related gene causes severe abnormalities and embryonic death in one strain of mice, but the same mutation in another strain has no effect. The mutant mice are viable and become fertile adults, as shown by Michael Rudnicki (8) and his colleagues at McMaster University. (9)

Shapiro 2007:

Gene-targeting studies into a1-antitrypsin (a1-AT) and emphysema in mice have demonstrated that the genetic locus for a1-AT in mice is very complex and that the loss of one gene is lethal in embryo lung development. This underlines the differences between mice and humans that limit the ability to translate between systems in some instances. Gene targeting has also highlighted complex roles for transforming growth factor-b in COPD and has been used to determine important molecules and pathways in COPD. (10) (Emphasis added.)

3. Animal–based research is sold to the public as providing future cures.

4. The cost. That $900 million could be used for human-based research into which genes cause or are involved in specific diseases or normal physiologic processes. Or, into gene therapy, which is what scientists actually need to learn how to do in order to correct faulty genes. Or, it could go to fund projects in the basic sciences of physics and chemistry. Or, into clinical research comparing various treatments in order to see which one is best. Or, into one of the myriad other research modalities.

Almost $1 billion! That money will be spread out over time but even so, $900 million could fund a lot of human-based research. Research on the species we are supposedly trying to cure.

(See Animal Models in Light of Evolution for a more in-depth discussion of the concepts alluded to above). 

References

1. D. F. Horrobin, Nat Biotech 19, 1099 (2001).

2. M. Morange, The Biochemist 23, 37 (2001).

3. H. Pearson, Nature 415, 8 (Jan 3, 2002).

4. M. Morange, The misunderstood gene.  (Harvard University Press, Cambridge, 2001).

5. M. H. V. V. Regenmortel, Journal of Molecular Recognition 17, 145 (2004).

6. M. H. Van Regenmortel, EMBO Rep 5, 1016 (Nov, 2004).

7. L. F. van Zutphen, Comp Med 50, 10 (Feb, 2000).

8. J. E. LeCouter, B. Kablar, P. F. Whyte, C. Ying, M. A. Rudnicki, Development 125, 4669 (December 1, 1998, 1998).

9. H. F. Nijhout, American Scientist 91, 416 (2003).

10. S. D. Shapiro, Eur Respir J 29, 375 (Feb, 2007).