Nonequilibrium Dynamics and Thermodynamics of the Cell Cycle

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Jin Wang of Stony Brook University is supported by the Chemistry of Life Processes Program in the Division of Chemistry to develop integrated theoretical and computational methods for exploring the cell cycle of eukaryotic organisms, using budding yeast as a model system. The Physics of Living Systems Program in the Division of Physics, the Cellular Dynamics and Function Cluster in the Division of Molecular and Cellular Biosciences, and the Systems and Synthetic Biology Cluster in the Division of Molecular and Cellular Biosciences also contribute to this award. The cell cycle is critical to the replication and division of a cell. It governs cellular proliferation and development---the basis of life. This project is utilizing a unique combination of approaches to understand the origin and driving forces of the cell cycle. Key genes and regulators of the cell cycle process, critical to guaranteeing normal cellular function, are identified through computational analysis, for comparison with experimental data. Professor Wang's work may lead to a new understanding of the biological functions of the cell, with implications for the maintenance of normal cell function, critical to human health and prevention of disease. A new teaching module, based on research from the project, is integrated into the departmental systems biology course. The interdisciplinary nature of the research is providing opportunities for training students from different backgrounds in a mutual learning, collaborative environment, preparing them to tackle problems at the nexus of these fields.The study of the cell cycle is essential to understanding the life of a single cell, the basic unit of living systems. The global dynamical theory that Professor Wang and his group are developing models the underlying gene regulatory network of the cell as a chemical reaction network, with gene expression levels playing the role of chemical state concentrations. The driving forces for transitions between gene expression states originate in a combination of a nonequilibrium effective potential determined by the steady state probability and the rotational steady state flux between states of the system. The steady state probability flux quantifies the extent of nonequilibriumness and irreversible behavior, and provides the bridge for describing the thermodynamics of the system in terms of its dynamics. The project is investigating the development of a dynamical systems model of the cell cycle in terms of the gene regulatory network. Researchers are also developing a nonequilibrium thermodynamic theory of the cell cycle in terms of energy input, energy cost, and entropy production. The team also couples the dynamical systems and nonequilibrium dynamics models to enable predictions of biological observables such as cell cycle speed, coherence, with utilization of sensitivity analysis to identify key genes and regulators. Model predictions are being compared against time-dependent in vivo fluorescence measurements of gene expression dynamics and correlations from experimental collaborator Jie Xiao. The nonequilibrium dynamics and thermodynamic theory is general and can be applied to cell cycle processes in different organisms and associated underlying regulatory networks. This project is enabling a deeper, quantitative understanding of the cell cycle, with applications to normal function maintenance and disease prevention. Educational activities include organization of a workshop, month-long program of visiting scholars, and seminars on the interdisciplinary topics of the project. Students are trained in theory and modeling techniques from chemistry, dynamical systems theory, and physics, with applications to cell biology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.