PhD defense by Chengzhe Tian
Decision Making in Biological Systems
This thesis consists of five projects in three topics with a shared theme of understanding cellular decision-making processes with mathematical modeling. In the first topic, we address the possible interaction between bacterial Toxin-Antitoxin (TA) systems and stringent response alarmone guanosine tetra- and pentaphosphate [(p)ppGpp] and examine how this interaction contributes to bacterial persistence. We show that TA systems mediate a negative feedback to early stringent response by reducing the available mRNA. We also show that the redundancy of TA systems can be realized if bacterial growth-dormancy transition is primarily mediated by (p)ppGpp fluctuation.
In the second topic, we discuss the transition paths between two stable steady states. We construct a simple model of coupled bistable gene circuits and demonstrate the possibility of bifurcation of transition path in biology. We then construct a theory to predict whether a general coupled bistable system exhibits bifurcated path or not and verify the theory through numerical simulation. We also show that a primary function of bifurcated paths is to facilitate transition by lowering the associated action.
In the third topic, we discuss the function of extrinsic noises in digital signaling using mammalian NF-κB pathway. We show that when cells are stimulated by one ligand, digital signaling allows one to independently control the fraction of responding cells (population-level response) and temporal profiles of NF-κB activity (individual-level response). We also show that under co-stimulation of two ligands, cells respond to only one input rather than both. We term this behavior "non-integrative processing" and we propose a possible mechanism by introducing an ultrasensitive negative feedback, allowing cells to block signaling pathways upon activation by one ligand.