Towards a coherent theory for stochastic kinetics in biology

Harvard University, Cambridge MA

Investigators

Abstract

Many genes, RNAs and proteins are present in such low numbers per cell that random births and deaths of individual molecules cause significant 'noise' in concentrations. Such fluctuations cause a wide range of human disorders, and many cellular control circuits are best understood in terms of how they tolerate, exploit, or eliminate the threat of randomization. However, studies of noise have been difficult to interpret due to a lack of comprehensive conceptual frameworks. We will extend the existing frameworks in several ways, by: 1) Determining the applicability of the fluctuation-dissipation theorem (FDT) to genetic networks with nonlinear rate functions. 2) Extending the FDT to higher moments and better approximations, systematically rewriting mathematical theorems in terms of biological observables. 3) Analyzing how the gradual aging of molecules affect random fluctuations between cells. 4) Evaluating and extending a common approximation where dilution of components in growing cells is modeled by degradation. In all cases, we compare the results with experimental findings for single cells. Fluctuations in concentrations arise spontaneously in cells due to 'molecular chaos' where individual molecules randomly collide before reacting. This randomness is particularly pronounced at the extremely low levels of many crucial cellular components, where individual chemical events have large relative effects. Many experimental studies have measured the resulting variation, but the results are difficult to interpret because the conventional mathematical frameworks are poorly suited to cells. Using concepts from statistical physics, we will extend previous methods to create a more effective framework to analyze and interpret fluctuations. This will help explore the physical conditions in the cell, and better understand the basis of physiological disorders that result from an incapacity to correct perturbations.