Stochastic and spatio-temporal modeling in systems biology

The post genome era of systems biology is marked by the need to develop models that explain the emergent behavior of biological systems different from the functioning of the individual parts of their constituents. Models should not only explain the observed experimental findings but should also be able to predict under outcomes that are not currently experimentally amenable.; This thesis attempts to address this need for better models by studying in detail two important regulatory systems. First, the genetic toggle is the simplest bistable network showing multiple steady states. It is therefore an important model system in synthetic biology for studying the cellular differentiation and cell cycle networks. A detailed kinetic model was developed to quantify the kinetic parameter ranges when the toggle may behave as a two way switch opposed to a one way switch. A stochastic model taking into account the small number of molecules was developed to explain reversibility (two way switching).; The second system chosen for study is the spatio-temporal regulation of the yeast pheromone pathway. At high enough levels Ste5, the molecular scaffold for the pathway can activate signaling in the absence of the ligand. To prevent this, nature has devised the nuclear shuttling of the molecular scaffold, whereupon only those scaffold molecules that have been exported out of the nucleus are able to activate the pathway. A 2-compartment spherical co-ordinate system model of the yeast cell with relevant nuclear translocation fluxes was developed to quantify the system. The resulting model is the first quantitative model to explain spatio-temporal control of pathway activation.