Sequential Control of Boolean Networks with Temporary and Permanent Perturbations

Direct cell reprogramming makes it feasible to reprogram abundant somatic cells into desired cells. It has great potential for regenerative medicine and tissue engineering. In this work, we study the control of biological networks, modelled as Boolean networks, to identify control paths driving the dynamics of the network from a source attractor (undesired cells) to the target attractor (desired cells). Instead of achieving control in one step, we develop attractor-based sequential temporary and permanent control methods (AST and ASP) to identify a sequence of interventions that can alter the dynamics in a stepwise manner. To improve their feasibility, both AST and ASP only use biologically observable attractors as intermediates. They can find the shortest sequential paths and guarantee 100% reachability of the target attractor. We apply the two methods to several real-life biological networks and compare their performance with the attractor-based sequential instantaneous control (ASI). The results demonstrate that AST and ASP have the ability to identify a richer set of control paths with fewer perturbations than ASI, which will greatly facilitate practical applications.