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Animal Models, Proteins, and the Environment

We state in Animal Models in Light of Evolution:

Our position can be summarized as follows: Living complex systems belonging to different species, largely as a result of the operation of evolutionary mechanisms over long periods of time, manifest different responses to the same stimuli due to: (1) differences with respect to genes present; (2) differences with respect to mutations in the same gene (where one species has an ortholog of a gene found in another); (3) differences with respect to proteins and protein activity; (4) differences with respect to gene regulation; (5) differences in gene expression; (6) differences in protein-protein interactions; (7) differences in genetic networks; (8) differences with respect to organismal organization (humans and rats may be intact systems, but may be differently intact); (9) differences in environmental exposures; and last but not least; (10) differences with respect to evolutionary histories. These are some of the important reasons why members of one species often respond differently to drugs and toxins, and experience different diseases. Immense empirical evidence supports this position. (p358) (Emphasis added.)

The importance of the environment influencing the same genes in different ways cannot be overstressed. Cohen et al studied yeast (a less complex organism than humans or mammals in general) in order to assess the effects of the environment on genes for producing spores. They discovered that small changes to the environment produced dramatically different results in spore production. Importantly they found that the effects of one environment on spore production did not predict the effects for other environments. If such dramatic changes can occur in less complex organisms, the effects of environments on complex organisms will be even greater.

"Having a particular combination of SNPs [single nucleotide polymorphisms] was never a great predictor," Cohen says. "If we didn't know the environment in which the yeast were grown, we could not accurately predict the effect of the SNPs on producing spores. And if we can't make accurate predictions about the way environment influences complex traits in yeast, then it will be exceedingly difficult to do so in people." The paper is published in PLoS Genetics. (Gerke et al. 2010)

The same is true of protein-protein interactions. This has been known for decades but Cheung and Gruebele have revealed a new facet. Proteins exist in cells and in order to be studied are usually isolated from the other proteins. This is classic biochemistry. In what has been called anti-biochemistry, it turns out that proteins are actually jam-packed into cells and a protein’s structure, activity, synthesis, folding, binding, and function are affected by the other proteins surrounding it in the cell. (Arnaud 2010) (Dhar, Samiotakis et al. 2010) (Dhar, Ebbinghaus et al. 2010)

As different organisms have different proteins, these protein-protein interactions will differ. In a complex system these differences can be significant.

As I have pointed out many times, the empirical evidence strongly supports the position that animal models cannot predict human response to drugs and disease. For clinicians, this is all one really needs. But the empirical evidence must be set in the context of theory, in this case evolution and complex systems. It is here that the notion that animal models can predict human response to drugs and disease meets its ultimate end. As science learns more about the cell, the genome, and environmental influences the fact that animals cannot predict human response will be even more strongly established.

Just FYI. In July 2010, I had an article published in the magazine SOUTHASIA. The article “No Tail!” can be accessed though the link. A second article, “The Animal Question” was published in the November issue. Check the SOUTHASIAwebsite for availability.


Arnaud, Celia. 2010. Close Quarters. Chemical & Engineering News 88 (48):9-13.

Dhar, Apratim, Simon Ebbinghaus, Zhen Shen, Tripta Mishra, and Martin Gruebele. 2010. The Diffusion Coefficient for PGK Folding in Eukaryotic Cells. Biophysical journal 99 (9):L69-L71.

Dhar, Apratim, Antonios Samiotakis, Simon Ebbinghaus, Lea Nienhaus, Dirar Homouz, Martin Gruebele, and Margaret S. Cheung. 2010. Structure, function, and folding of phosphoglycerate kinase are strongly perturbed by macromolecular crowding. Proceedings of the National Academy of Sciences 107 (41):17586-91.

Gerke, Justin, Kim Lorenz, Shelina Ramnarine, and Barak Cohen. 2010. Gene-Environment Interactions at Nucleotide Resolution. PLoS Genet 6 (9):e1001144.


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