What Blonde Hair Tells Us About Animal Models

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Convergent evolution, the acquisition of the same trait in species with different evolutionary ancestors, is one reason inter-species extrapolation is problematic. The classic example of convergent evolution is the trait of flight in bats, birds, and insects. Even though the trait evolved through different mechanisms, the outcome, the ability to fly, is shared by all. Another example is the eye of cephalopods, for example the octopus, and the eye of vertebrates. Same outcome, but very different mechanisms. Another example was provided last week. It seems that blonde hair evolved in Melanesians by a different mechanism than it did in Europeans.(Kenny et al. 2012)

There are many reasons besides convergent evolution to explain the fact that animal models are not predictive for human response to drugs and disease. Animals and humans vary in their genetic makeup, for example, the way the same genes are regulated and expressed, mutations, and pleiotropy among others. These differences are sufficient to justify the expectation for different outcomes in terms of drugs and disease. But there are more reasons. The fact that animals and humans are complex systems should raise red flags for anyone considering using an animal to predict human response to any perturbation that affects different levels of organization or that acts on a system wide level. Drugs and disease do both. Differences in genetic makeup between complex systems also explain intra-human variation in response to drugs and disease.

In keeping with this concept, research at Yale revealed that human embryonic stem cells organize development differently than mouse embryonic stem cells. Co-author of the study Natalia Ivanova stated: “It is difficult to deduce from the mouse how these cells work in humans. Human networks organize themselves quite differently.” Three genes that both species have in common but that act differently appear responsible for the differences: Nanog, Oct 4, and Sox 2. From e!Science:

The new study shows that human embryonic cells operate in fundamentally different ways in humans than in mouse cells. In humans, for instance, Nanog pairs with Oct 4 to regulate differentiation of so-called neuro-ectoderm cells, a lineage that gives rise to neurons and other central nervous system cells. Sox 2, by contrast, inhibits the differentiation of mesoderm -- a lineage that gives rise to muscles and many other tissue types. Oct 4 cooperates with the other genes and is crucial in the regulation of all four early cell lineages: ectoderm, mesoderm, and endoderm -- which gives rise to gut and glands such as liver and pancreas -- as well as the creation of new stem cells. The self-renewal of stem cells has been implicated in several forms of cancer. (e! Science News 2012)

The study was published in Cell Stem Cell. (Wang et al. 2012)

Things as simple as the fact that chocolate is toxic to dogs and that blonde hair can arise by different mechanisms can inform us about the ability of animal models to predict human response to drugs and disease. But science is about looking deeper for explanations and when do we discover that evolutionary biology and complexity science explain why different species and even different humans respond so differently to the same drug or disease. We ignore such knowledge at our own peril.

For more on this theme, see Animal models in an age of personalized medicine.


e! Science News. 2012. Yale researchers show how embryonic stem cells orchestrate human development. e! Science News, April 6 2012 [cited April 9 2012]. Available from http://esciencenews.com/articles/2012/04/06/yale.researchers.show.how.embryonic.stem.cells.orchestrate.human.development?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+eScienceNews%2Fpopular+%28e!+Science+News+-+Popular%29.

Kenny, Eimear E., Nicholas J. Timpson, Martin Sikora, Muh-Ching Yee, Andrés Moreno-Estrada, Celeste Eng, Scott Huntsman, Esteban González Burchard, Mark Stoneking, Carlos D. Bustamante, and Sean Myles. 2012. Melanesian Blond Hair Is Caused by an Amino Acid Change in TYRP1. Science 336 (6081):554.

Wang, Zheng, Efrat Oron, Brynna Nelson, Spiro Razis, and Natalia Ivanova. 2012. Distinct Lineage Specification Roles for NANOG, OCT4, and SOX2 in Human Embryonic Stem Cells. Cell Stem Cell 10 (4):440-454.


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