Collins Conference Room
  US Mountain Time

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Marc Kirschner (Harvard Medical School)

Abstract.  The questions of “How and Why” have underlain biological investigation since the Greeks.  Darwin’s answer, largely on the anatomical, physiological and behavioral level, was his theory of evolution by natural selection.  Yet for natural selection to be completely satisfactory, we needed to understand genetic variation and phenotypic variation in addition to selection. Though we can easily rationalize the value of a prehensile tail, we are still far from understanding how many steps and of what difficulty were needed to achieve it.  The Darwinian explanation looks messier at the molecular level, where it is hard to rationalize why molecular pathways are either as complicated as they are or as unchanging as they often seem to be.  The strange properties of molecular pathways have fueled speculation as to whether the selected properties of biological systems can in part be understood in terms of evolvability.  John Gerhart and I have written about the molecular features of evolvability, which include compartmentalization such as HOX genes, stabilization of physiological variation, as discussed extensively by Schmalhausen and West-Eberhard, exploratory processes like adaptive immunity or nerve cell growth, and specifically about a property we call weak linkage.  Weak linkage is the capacity for molecules or complexes to readily change their interaction partners in evolution while maintaining their core functions.  Most examples of weak linkage are involved in regulation.  In transcription, allosteric enzymes, or developmental signaling,  small evolutionary changes can lead to profound phenotypic change. We wondered why systems seem to have evolved to be so fragile – so receptive to change.  In protein degradation very small protein sequences determine recognition by the ubiquitin pathway. Simple (highly degenerate) sequences on their own have low specificity, and can be inhibited by similar sequences on other proteins. Is this situation selected to make evolution easier or for some other reason? If so it seems like a big price to pay.  Why not evolve larger recognition sequences of more specificity?  The answer is that the more specific binding to the target would slow down a process.  Short redundant sequences give you low specificity but high efficiency; long sequences give high specificity and low efficiency.  There is no free lunch, but there is a way to eat more cheaply. To improve the tradeoff of efficiency and specificity nature has evolved rather complex energy consuming pathways to sweeten the compromise. Thus, in these examples of weak linkage and maybe many others, evolvability emerges as a byproduct of maximizing efficiency and specificity.

Research Collaboration
SFI Host: 
Jerry Sabloff