Predicting Cellular Regulation from Natural Selection, Thermodynamics and Control Theory

Predicting cellular regulation is a grand challenge in biology. This challenge can be successfully addressed by taking advantage of the fact that natural selection selects for the most fit or optimal individuals out of all solutions. Fitness is a non-equilibrium thermodynamic emergent property and cab be formulated from a thermodynamic perspective to obtain the most likely kinetic parameters, and then information derived from data can be used to constrain the solution space. For instance, data on metabolite levels shows that metabolites rarely exceed 20 mM, arguably because the cytoplasm otherwise becomes too viscous for diffusion to occur. Likewise, data shows that proteins are expressed only as much as needed, because otherwise the cell is wasting precious resources and energy. This information is thermodynamic in nature, and these thermodynamic principles can be exploited to predict regulation based on fitness. We provide examples in both bacteria and fungi.