Carlos Lopez, Harvard Medical School, "Exploring multiple apoptosis signaling mechanisms and their role in cancer biology using models as executable algorithms"

Abstract: Experiments often result in observations that suggest conflicting biochemical mechanisms in signaling networks. Mathematical modeling of biological systems is a method used to probe such experimental observations and provide a consensus among seemingly discordant observations. However, probing multiple mechanistic hypotheses in biological modeling often involves the instantiation of complex systems of equations, which despite their usefulness, makes model revision, extension, and sharing extremely challenging. To address these modeling barriers,, we have developed a modeling framework that brings a process-based approach to biological modeling. In our approach, biological models are written as programs that encode biological functions as needed. Our modeling framework, developed in the Python language, offers access to a large set of existing numerical and programming methods to biological systems modeling. Given our choice of programming language, the resulting models are easier to share, distribute, extend, and revise, adding transparency to the model-creation and execution process. We demonstrate our approach by exploring three competing mechanisms that describe the interactions among the Bcl-2 family of proteins and their contributions to mitochondrial outer membrane permeabilization in extrinsic apoptosis. We used our modeling framework to systematically explore these three proposed mechanisms resulting in the instantiation of sixteen biochemical model topologies for numerical exploration. Our preliminary results, based on simulations calibrated to experimental data, suggest that the so-called indirect mechanism does not accurately reproduce experimental observations. Results from simulations of the so-called direct and indirect mechanisms suggest that the latter model more accurately correlates with the experimental data. Despite these observations, further topology- and numerical-based characterization of the models biochemical connectivity and physicochemical parameter-space is being carried out to more accurately understand the role of these Bcl-2 proteins in apoptosis. We aim to formulate hypotheses, testable through experiments, about the interaction among these proteins and their role in Bcl-2 cancer biology.