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Section: Research Program

Modeling of Phenotypic Heterogeneity in Cellular Processes

Since nearly two decades, a significant interest has grown for getting a quantitative understanding of the functioning of biological systems at the cellular level. Given their complexity, proposing a model accounting for the observed cell responses, or better, predicting novel behaviors, is now regarded as an essential step to validate a proposed mechanism in systems biology. Moreover, the constant improvement of stimulation and observation tools creates a strong push for the development of methods that provide predictions that are increasingly precise (single cell precision) and robust (complex stimulation profiles).

It is now fully apparent that cells do not respond identically to a same stimulation, even when they are all genetically-identical. This phenotypic heterogeneity plays a significant role in a number of problems ranging from cell resistance to anticancer drug treatments to stress adaptation and bet hedging.

Dedicated modeling frameworks, notably stochastic modeling frameworks, such as chemical master equations, and statistic modeling frameworks, such as ensemble models, are then needed to capture biological variability.

Appropriate mathematical and computational should then be employed for the analysis of these models and their calibration to experimental data. One can notably mention global optimization tools to search for appropriate parameters within large spaces, moment closure approaches to efficiently approximate stochastic models (Moment-based inference predicts bimodality in transient gene expression, C. Zechner C, J. Ruess, P. Krenn, S. Pelet, M. Peter, J. Lygeros, and H. Koeppl, Proceedings of the National Academy of Sciences USA, 9(5):109(21):8340-5, 2012), and (stochastic approximations of) the expectation maximization algorithm for the identification of mixed-effects models (What population reveals about individual cell identity: estimation of single-cell models of gene expression in yeast, A. Llamosi, A.M. Gonzalez-Vargas, C. Versari, E. Cinquemani, G. Ferrari-Trecate, P. Hersen, and G. Batt, PLoS Computational Biology, 9(5): e1003056, 2015).