In Silico Generation of Alternative Hypotheses Using Causal Mapping (CMAP)

Abstract

Previously, we introduced causal mapping (CMAP) as an easy to use systems biology tool for studying the behavior of biological processes that occur at the cellular and molecular level. CMAP is a coarse-grained graphical modeling approach in which the system of interest is modeled as an interaction map between functional elements of the system, in a manner similar to portrayals of signaling pathways commonly used by molecular cell biologists. CMAP describes details of the interactions while maintaining the simplicity of other qualitative methods (e.g., Boolean networks).In this paper, we use the CMAP methodology as a tool for generating hypotheses about the mechanisms that regulate molecular and cellular systems. Furthermore, our approach allows competing hypotheses to be ranked according to a fitness index and suggests experimental tests to distinguish competing high fitness hypotheses. To motivate the CMAP as a hypotheses generating tool and demonstrate the methodology, we first apply this protocol to a simple test-case of a three-element signaling module. Our methods are next applied to the more complex phenomenon of cortical oscillations observed in spreading cells. This analysis produces two high fitness hypotheses for the mechanism that underlies this dynamic behavior and suggests experiments to distinguish the hypotheses. The method can be widely applied to other cellular systems to generate and compare alternative hypotheses based on experimentally observed data and using computer simulations.

RhoA Regulates Calcium-Independent Periodic Contractions of the Cell Cortex

“…In a previous study, we described the morphological oscillations of spreading cells whose MTs had been depolymerized (1) and built computational models able to produce oscillations (5,6). Our further coarse-grained modeling revealed two competing pathways in which either calcium or RhoA could play a dominant role in producing oscillations (7). In this study, we performed a biochemical investigation to distinguish between these pathways and to begin to characterize the regulatory system that underlies the oscillatory behavior.…”

“…The oscillatory phenomenon presents an example of the analysis of a complex mechanochemical system at the cellular level that serves as a challenge for both systems cell biology approaches and more conventional modeling efforts. We used an advanced CMAP technology termed hypothesis generation to investigate which of many different pathway architectures are capable of producing cortical oscillations (7). The CMAP modeling effort revealed two competing pathways that create the oscillatory phenotype; one in which calcium plays a leading role, the other in which RhoA is predominantly involved.…”

Visinets: A Web-Based Pathway Modeling and Dynamic Visualization Tool

“…The underlying mathematical approach in Visinets (Causal Mapping (CMAP)) is a modeling method that allows for the integration of diverse data into a single model of networks organized in causally linked relationships. Initially applied to model of cortical contraction [ 1 , 9 ], CMAP is a semi-quantitative approach based on a detailed description of all network interactions and is particularly useful when detailed knowledge of those interactions is absent and specific parameter values need to be estimated. CMAP approach lies between coarse-grained (e.g.…”