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The Complexity of Genetic Composition

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Because the use of animal models to predict human response to drugs and diseases has its foundations in a creationist view of origins [1-3], animal modelers tend to view humans and animals as simple systems. The fact that each is an evolved complex system that differs from other evolved complex systems complicates their mythical view of animal models. Nowhere is this more evident than when considering the role of regulatory genes in evolution.

Arbiza et al state, in Nature Genetics:

For decades, it has been hypothesized that gene regulation has had a central role in human evolution, yet much remains unknown about the genome-wide impact of regulatory mutations. Here we . . . demonstrate that natural selection has profoundly influenced human transcription factor binding sites since the divergence of humans from chimpanzees 4–6 million years ago. . . . We find that, on average, transcription factor binding sites have experienced somewhat weaker selection than protein-coding genes. However, the binding sites of several transcription factors show clear evidence of adaptation. Several measures of selection are strongly correlated with predicted binding affinity. Overall, regulatory elements seem to contribute substantially to both adaptive substitutions and deleterious polymorphisms with key implications for human evolution and disease. [4]

This means that the human-chimpanzee split was due largely to changes in regulatory genes as opposed to structural genes—the genes that actually build the body. This is consistent with the fact that humans and chimpanzees share ~99% of their genes. “The researchers showed that the number of evolutionary adaptations to the part of the machinery that regulates genes, called transcription factor binding sites, may be roughly equal to adaptations to the genes themselves.” Humans and chimpanzees share many structural genes, but when and for how long these structural genes are turned on varies. Think of the keys on a piano as the structural genes and the sheet music as the regulatory genes. The sheet music dictates when the keys are played and for how long. You can play very different music on the same set of piano keys. You cannot simply cite similarity of the keys and predict the next selection a pianist is going to play. “The regulatory machinery works when proteins called transcription factors bind to specific short sequences of DNA that flank the gene, called transcription factor binding sites, and by doing so, switch genes on and off.”

This again reveals that two species may share a vast majority of their structural genes but still demonstrate very different responses to perturbations like drugs and disease.

Another reason for differences in response is convergent evolution. Convergent evolution occurs when species in two different lineages acquire the same trait. Examples include vision in the form of a camera eye, wings for flight, and “antifreeze” in fish. The mechanism whereby the organism acquired the trait, the genes responsible for the trait, and the “wiring” of the trait may vary considerably. This means that the way the organism responds to perturbations involving the trait may differ dramatically.

Examples of convergent evolution were recently discussed by scientists in the UK. [5-7] Many species need more oxygen under specific circumstances. Elephant seals, for example, store oxygen in their muscle tissue and extract it when diving. Myoglobin in the muscles of whales and other sea mammals have a higher charge than the myoglobin of land mammals. This allows access to oxygen that they otherwise would not have access to. But this mechanism differs from that of ray-finned fish and that of deer mice, who also need more oxygen occasionally. [5-7] Just because an animal modeler discovers a mechanism for a trait in an animal does mean the mechanism for that same trait, or a similar trait in humans or other animals, will be the same. It is therefore ironic that animal modelers harp on mechanisms when asked to defend their profession.

All of the above is not to imply that differences in structural genes are unimportant. Scientists at the University of Chicago Medical Center discovered that African-American women are more likely to carry certain mutations that predispose them to triple negative breast cancer. It was already know that African-American women are at higher risk for triple negative breast cancer than Caucasian women. There are many more differences among humans; for example, the anatomy of the brains of patients with dyslexia may differ between the sexes. [8]

Considering the dramatic intra-human variation in response to drugs and disease, pretending that animal models have predictive value reveals a child-like view of reality. That, or a vested interest in the paradigm. Genetic composition is not the sole determining factor in how we think, act, and react to drugs and disease. Environment plays a big role as well. But just considering the complexity of genetic make-up, including regulatory genes, a strong case could be made that the predictive value of animal models for human response to drugs and disease should be minimal. And that is exactly what the empirical evidence shows.

When Galileo offered a representative of the pope the opportunity to view the four moons of Jupiter through his telescope, thus challenging the Ptolemaic view of the universe, the representative stated: “I refuse to look at something which my religion tells me cannot exist.” Vivisection activists manifest the same attitude regarding empirical evidence, complexity science, and genetic composition when discussing the predictive value of animal models.

Finally, just FYI.

Our Hen House has published an essay from me, which is available at http://www.ourhenhouse.org/2013/05/how-to-argue-against-vivisection-in-the-21st-century-by-ray-greek-m-d/

The Vegan Sprout has published an interview with me and it is available at:

http://thevegansprout.com/2013/06/19/people-to-know-dr-ray-greek/

References

1.         Bernard, C., An Introduction to the Study of Experimental Medicine. 1865. 1957, New York: Dover. 125.

2.         Elliot, P., Vivisection and the Emergence of Experimental Medicine in Nineteenth Century France, in Vivisection in Historical Perspective, N. Rupke, Editor. 1987, Croom Helm: New York. p. 48-77.

3.         LaFollette, H. and N. Shanks, Animal Experimentation: The Legacy of Claude Bernard. International Studies in the Philosophy of Science, 1994. 8(3): p. 195-210.

4.         Arbiza, L., et al., Genome-wide inference of natural selection on human transcription factor binding sites. Nat Genet, 2013. advance online publication. http://dx.doi.org/10.1038/ng.2658

5.         Natarajan, C., et al., Epistasis among adaptive mutations in deer mouse hemoglobin. Science, 2013. 340(6138): p. 1324-7. http://www.ncbi.nlm.nih.gov/pubmed/23766324

6.         Rummer, J.L., et al., Root effect hemoglobin may have evolved to enhance general tissue oxygen delivery. Science, 2013. 340(6138): p. 1327-9. http://www.ncbi.nlm.nih.gov/pubmed/23766325

7.         Mirceta, S., et al., Evolution of mammalian diving capacity traced by myoglobin net surface charge. Science, 2013. 340(6138): p. 1234192. http://www.ncbi.nlm.nih.gov/pubmed/23766330

8.         Evans, T., et al., Sex-specific gray matter volume differences in females with developmental dyslexia. Brain Structure and Function, 2013: p. 1-14. http://dx.doi.org/10.1007/s00429-013-0552-4

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