Monday, March 22, 2010

Mining Evolution

Can a worm get breast cancer? And how would you know if it did (since it doesn't have breasts)?

Biomedical research has made great use of "disease models": conditions in lab organisms that resemble the human diseases that the researchers really want to learn about. By seeing how a model condition develops and how it responds to drugs or other changes, researchers can make better guesses about what might help people. But finding such disease models usually requires some obvious similarity between the outward manifestations of the disease in humans and the animal subjects.

In the Proceedings of the National Academy of Sciences, a team from the University of Texas in Austin led by Edward Marcotte use the underlying molecular relationships to find connections between disorders with no such obvious relationship. In addition to a worm analog of breast cancer, they found an amazing connection between plant and human disorders. The analysis of plants' failure to respond to gravity led them to human genes related to Waardenburg syndrome. This syndrome includes an odd constellation of syndromes resulting from defects in the development of neural crest cells.

I saw Marcotte speak about this fascinating work at the conference I attended last December in Cambridge, Massachusetts. My writeup should be posted soon by the New York Academy of Sciences.

Biologists have repeatedly found that the networks of interacting molecules are organized into modules. Over the course of evolution, these modules can be re-used, often for purposes quite different from their original function. This much is well known, although seeming the persistence of modules over the vast evolutionary separation of plants and people is very dramatic.

What the Austin team did was to devise a methodology to identify related molecular modules in different species even without relying on similar outward manifestations, or phenotypes. They combed the known molecular networks of different species for modules that had a lot of "orthologous" genes: those that had retained similarity--and similar relationships--through evolution. They call the particular traits associated with these genes "orthologous phenotypes," or "phenologs." "We're identifying ancient systems of genes that predate the split of these organisms, that in each case retain their functional coherence," Marcotte said at the conference.

The importance of this scheme is that many molecular networks are poorly mapped, especially in humans. But if a particular gene is part of the network underlying a phenotype in another species--such as poor response of a plant to gravity--it's a good guess that the corresponding gene may be active in the orthologous phenotype in people. The researchers in fact confirmed many of these predicted relationships. Some of these genes were previously known to relate to disease, while others were new. The researchers created a list of hundreds more that they still hope to check.

These genes could give researchers many potential new targets for drugs or other interventions in diseases. So evolution is not just helping us to understand the biologic world we live in, but helping us devise ways to improve human health.

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