Animal Rights

Another Misrepresentation from the Vested Interest Groups

| by Dr Ray Greek

A May 29, 2011 press release from the University of North Carolina School of Medicine states the following:

Laboratory research has always been limited in terms of what conclusions scientists can safely extrapolate from animal experiments to the human population as a whole. Many promising findings in mice have not held up under further experimentation, in part because laboratory animals, bred from a limited genetic foundation, don't provide a good representation of how genetic diversity manifests in the broader human population.

Now, thanks to an in-depth analysis by a team led by Fernando Pardo-Manuel de Villena, PhD, in the UNC Department of Genetics and Gary Churchill, PhD, at The Jackson Laboratory in Bar Harbor, Maine, researchers will be able to use an online resource dubbed the Mouse Phylogeny Viewer to select from among 162 strains of laboratory mice for which the entire genome has been characterized. Phylogeny refers to the connections among all groups of organisms as understood by ancestor/descendant relationships. Pardo-Manuel de Villena is also a member of UNC Lineberger Comprehensive Cancer Center and the Carolina Center for Genome Sciences. . . .

"As scientists use this resource to find ways to prevent and treat the genetic changes that cause cancer, heart disease, and a host of other ailments, the diversity of our lab experiments should be much easier to translate to humans," he [Pardo-Manuel de Villena] noted.

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A similar press release is available from Jackson Laboratory.

Apparently the vested interest groups have failed to notice the past two decades of research in evo devo, complex systems, and genetics. The same gene can function in very different ways depending on the species and strain. Gene regulation, alternative splicing, background genes, and modifier genes have significant affects on what genes do in various species. Genes are not like pistons in a particular model of car, which are interchangeable to a large degree. This is one reason transgenic mice have not predicted human response to drugs and disease.

Lynch 2009:

However, the assumption that gene functions and genetic systems are conserved between models and humans is taken for granted, often in spite of evidence that gene functions and networks diverge during evolution. (Lynch 2009)

Oti and Brunner 2007:

This situation is further complicated by the fact that there is not a one-to-one relationship between syndromes and genes. Typically, multiple syndromes can be caused by mutations in the same gene, and a single disorder can be caused by mutations in different genes (5). The existence of phenotypic variability is not surprising given that genes work in concert to form and maintain the human body. Different alleles of different genes in different individuals integrate differently with each other to create different final phenotypes. This is the basis of human phenotypic diversity and an important factor contributing to the fact that no two individuals are identical. (Oti and Brunner 2007)

Miklos:

There is enormous phenotypic variation in the extent of human cancer phenotypes, even among family members inheriting the same mutation in the adenomatous polyposis coli (APC) gene believed to be causal for colon cancer. In the experimental mouse knockout of the catalytic gamma subunit of the phosphatidyl-3-OH kinase, there can be a high incidence of colorectal carcinomas or no cancers at all, depending on the mouse strain in which the knockout is created, or into which the knockout is crossed. (Miklos 2005)

Gene expression varies greatly intra- and inter-species, in humans (Morley et al. 2004; Rosenberg et al. 2002; Storey et al. 2007; Zhang et al. 2008) and in animals (Pritchard et al. 2006; Rifkin, Kim, and White 2003; Sandberg et al. 2000; Suzuki and Nakayama 2003).

The fact that monozygotic twins do not always respond the same to drugs and disease calls into question using mice to search for cures to cancer and heart disease. While mapping mouse genomes will be a boon to mouse researchers and people and companies that sell mice, it is highly unlikely to have positive effects for sick humans.

References

Lynch, V. J. 2009. Use with caution: developmental systems divergence and potential pitfalls of animal models. Yale J Biol Med 82 (2):53-66.

Miklos, G L Gabor. 2005. The human cancer genome project--one more misstep in the war on cancer. Nat Biotechnol 23 (5):535-7.

Morley, M., C. M. Molony, T. M. Weber, J. L. Devlin, K. G. Ewens, R. S. Spielman, and V. G. Cheung. 2004. Genetic analysis of genome-wide variation in human gene expression. Nature 430 (7001):743-7.

Oti, M., and H. G. Brunner. 2007. The modular nature of genetic diseases. Clin Genet 71 (1):1-11.

Pritchard, C., D. Coil, S. Hawley, L. Hsu, and P. S. Nelson. 2006. The contributions of normal variation and genetic background to mammalian gene expression. Genome Biol 7 (3):R26.

Rifkin, S. A., J. Kim, and K. P. White. 2003. Evolution of gene expression in the Drosophila melanogaster subgroup. Nat Genet 33 (2):138-44.

Rosenberg, N. A., J. K. Pritchard, J. L. Weber, H. M. Cann, K. K. Kidd, L. A. Zhivotovsky, and M. W. Feldman. 2002. Genetic structure of human populations. Science 298 (5602):2381-5.

Sandberg, R., R. Yasuda, D. G. Pankratz, T. A. Carter, J. A. Del Rio, L. Wodicka, M. Mayford, D. J. Lockhart, and C. Barlow. 2000. Regional and strain-specific gene expression mapping in the adult mouse brain. Proc Natl Acad Sci U S A 97 (20):11038-43.

Storey, J. D., J. Madeoy, J. L. Strout, M. Wurfel, J. Ronald, and J. M. Akey. 2007. Gene-expression variation within and among human populations. Am J Hum Genet 80 (3):502-9.

Suzuki, Y., and M. Nakayama. 2003. Differential profiles of genes expressed in neonatal brain of 129X1/SvJ and C57BL/6J mice: A database to aid in analyzing DNA microarrays using nonisogenic gene-targeted mice. DNA Res 10 (6):263-75.

Zhang, W., S. Duan, E. O. Kistner, W. K. Bleibel, R. S. Huang, T. A. Clark, T. X. Chen, A. C. Schweitzer, J. E. Blume, N. J. Cox, and M. E. Dolan. 2008. Evaluation of genetic variation contributing to differences in gene expression between populations. Am J Hum Genet 82 (3):631-40.