Identification of optimal strategies for state transition of complex biological networks.

Complex biological networks typically contain numerous parameters, and determining feasible strategies for state transition by parameter perturbation is not a trivial task. In the present study, based on dynamical and structural analyses of the biological network, we optimized strategies for controlling variables in a two-node gene regulatory network and a T-cell large granular lymphocyte signaling network associated with blood cancer by using an efficient dynamic optimization method. Optimization revealed the critical value for each decision variable to steer the system from an undesired state into a desired attractor. In addition, the minimum time for the state transition was determined by defining and solving a time-optimal control problem. Moreover, time-dependent variable profiles for state transitions were achieved rather than constant values commonly adopted in previous studies. Furthermore, the optimization method allows multiple controls to be simultaneously adjusted to drive the system out of an undesired attractor. Optimization improved the results of the parameter perturbation method, thus providing a valuable guidance for experimental design.