Minimally perturbing a gene regulatory network to avoid a disease phenotype: the glioma network as a test case

Background: Mathematical modeling of biological networks is an essential part of Systems Biology. Developing and using such models in order to understand gene regulatory networks is a major challenge. Results: We present an algorithm that determines the smallest perturbations required for manipulating the dynamics of a network formulated as a Petri net, in order to cause or avoid a specified phenotype. By modifying McMillan's unfolding algorithm, we handle partial knowledge and reduce computation cost. The methodology is demonstrated on a glioma network. Out of the single gene perturbations, activation of glutathione S-transferase P (GSTP1) gene was by far the most effective in blocking the cancer phenotype. Among pairs of perturbations, NFkB and TGF-beta had the largest joint effect, in accordance with their role in the EMT process. Conclusion: Our method allows perturbation analysis of regulatory networks and can overcome incomplete information. It can help in identifying drug targets and in prioritizing perturbation experiments.