The dynamic systems approach to control and regulation of intracellular networks

Systems theory and cell biology have enjoyed a long relationship that has received renewed interest in recent years in the context of systems biology. The term 'systems' in systems biology comes from systems theory or dynamic systems theory: systems biology is defined through the application of systems- and signal-oriented approaches for an understanding of inter- and intra-cellular dynamic processes. The aim of the present text is to review the systems and control perspective of dynamic systems. The biologist's conceptual framework for representing the variables of a biochemical reaction network, and for describing their relationships, are pathway maps. A principal goal of systems biology is to turn these static maps into dynamic models, which can provide insight into the temporal evolution of biochemical reaction networks. Towards this end, we review the case for differential equation models as a 'natural' representation of causal entailment in pathways. Block-diagrams, commonly used in the engineering sciences, are introduced and compared to pathway maps. The stimulus-response representation of a molecular system is a necessary condition for an understanding of dynamic interactions among the components that make up a pathway. Using simple examples, we show how biochemical reactions are modelled in the dynamic systems framework and visualized using block-diagrams.     

Robustness analysis identifies the plausible model of the Bcl-2 apoptotic switch

In this paper two competing models of the B-cell lymphoma 2 (Bcl-2) apoptotic switch were contrasted by mathematical modeling and robustness analysis. Since switch-like behaviors are required for models that attempt to explain the all-or-none decisions of apoptosis, ultrasensitivity was employed as a criterion for comparison. Our results successfully exhibit that the direct activation model operates more reliably to achieve a robust switch in cellular conditions. Moreover, by investigating the robustness of other important features of the Bcl-2 apoptotic switch (including low Bax basal activation, inhibitory role of anti-apoptotic proteins and insensitivity to small perturbations) the direct activation model was further supported. In all, we identified the direct activation model as a more plausible explanation for the Bcl-2 apoptotic switch.