Coarse-grained analysis of stochastically simulated cell populations with a positive feedback genetic network...

Among the different computational approaches modelling the dynamics of isogenic cell populations, discrete stochastic models can describe with sufficient accuracy the evolution of small size populations. However, for a systematic and efficient study of their long-time behaviour over a wide range of parameter values, the performance of solely direct temporal simulations requires significantly high computational time. In addition, when the dynamics of the cell populations exhibit non-trivial bistable behaviour, such an analysis becomes a prohibitive task, since a large ensemble of initial states need to be tested for the quest of possibly co-existing steady state solutions. In this work, we study cell populations which carry the lac operon network exhibiting solution multiplicity over a wide range of extracellular conditions (inducer concentration). By adopting ideas from the so-called "equation-free" methodology, we perform systems-level analysis, which includes numerical tasks such as the computation of coarse steady state solutions, coarse bifurcation analysis, as well as coarse stability analysis. Dynamically stable and unstable macroscopic (population level) steady state solutions are computed by means of bifurcation analysis utilising short bursts of fine-scale simulations, and the range of bistability is determined for different sizes of cell populations. The results are compared with the deterministic cell population balance model, which is valid for large populations, and we demonstrate the increased effect of stochasticity in small size populations with asymmetric partitioning mechanisms.