Network nonlinearities in drug treatment

Despite major achievements in the understanding of human disease, there is a general perception that the drug development industry has failed to meet the expectations that recent advances in biotechnology should drive. One of the potential sources of failure of many next generation drugs is that their targets are embedded in highly nonlinear signaling pathways and gene networks with multiple negative and positive feedback loops of regulation. There is increasing evidence that this complex network shapes the response to external perturbations in the form of drug treatment, originating bistability, hypersensitivity, robustness, complex dose-response curves or schedule dependent activity. This review focuses on the effect of nonlinearities on signaling and gene networks involved in human disease, using tools from Nonlinear Dynamics to discuss the implications and to overcome the effects of the nonlinearities on regulatory networks.