Sloppiness, robustness, and evolvability in systems biology.

The functioning of many biochemical networks is often robust-remarkably stable under changes in external conditions and internal reaction parameters. Much recent work on robustness and evolvability has focused on the structure of neutral spaces, in which system behavior remains invariant to mutations. Recently we have shown that the collective behavior of multiparameter models is most often sloppy: insensitive to changes except along a few 'stiff' combinations of parameters, with an enormous sloppy neutral subspace. Robustness is often assumed to be an emergent evolved property, but the sloppiness natural to biochemical networks offers an alternative nonadaptive explanation. Conversely, ideas developed to study evolvability in robust systems can be usefully extended to characterize sloppy systems.