Simulating the flipping of the bacteriophage lambda genetic switch

Bacteriophage lambda is a virus that infects the bacterium Escherichia coli. It is a paradigm for developmental biology because it has two alternative modes of living - the lysogenic state, in which it integrates its DNA into the E. coli chromosome and lives stably, and the lytic state, where it replicates and kills the E. coli cell. We have  constructed a stochastic simulation model for the genetic regulatory network that controls the transition from lysogeny to lysis. This network is bistable and subject to random fluctuations, but it has been found experimentally to be extremely stable, flipping spontaneously less than once in 10^9 bacterial generations! We have used the Forward Flux Sampling rare event simulation method to calculate the spontaneous flipping rate. Our results highlight the need to consider nonspecific DNA binding, DNA looping and macromolecular crowding in order to get the "right" answer, leading to some general conclusions about stochastic modelling of gene regulatory networks.