The Eukaryotic Cell Cycle as a Test Case for Modeling Cellular Regulation in a Collaborative Problem-Solving Environment

A multi-university team of theoreticians, experimentalists, and computer scientists will develop a collaborative problem-solving environment (PSE) tor studying the eukaryotic cell cycle. The PSE will serve as a paradigm for modeling and simulation of intra-cellular regulatory networks. The cell cycle \vill provide compelling evidence for the power of computational tools. To these ends, the team intends to make the tollowing contributions to the DARPA Bio-SPICE program: 1. Model Kernel. We will develop comprehensive, realistic, predictive, computational models of the molecular machinery that regulates DNA synthesis, mitosis, and cell division in budding yeast, frog eggs, and mammalian cells. These biochemical networks can be described by sets of nonlinear ordinary differential equations. We will use numerical simulation to show quantitative agreement between models and cell physiology, and bifurcation theory to reveal the underlying logic of the control system. By pushing the boundaries of modeling, simulation and analysis, \Ve will provide compelling evidence for the utility of computational tools in cell biology. 2. Experimental Validation. We will measure crucial kinetic and thermodynamic constants that determine the quantitative properties of our yeast cell cycle model. We will also construct and characterize new mutant strains of yeast to test the predictive power of the model. Using frog egg extracts, we expect to verify some striking predictions of the model about hysteresis, Hopf bifurcations and infinite-period limit cycles. 3. Simulation Environment. We will develop a user friendly, web accessible, collaborative problem-solvingenvironment(PSE) for cell cycle modeling. The PSE will provide tools tor model construction, access to experimental databases, simulation management, bifurcation analysis, automated parameter optimization, and expert recommendations about modeling strategies. The PSE will facilitate a close interplay of theory and experiment. Beyond aiding cell cycle modelers, the PSE will contribute crucial simulation and analysis tools to Bio-SprCE. The eukaryotic cell cycle provides an excellent demonstration for Bio-SPICE. The cycle of groWth, DNA synthesis, and division of single cells underlies the development and reproduction of all eukaryotic organisms. Defects in cell cycle regulation are related to serious human maladies, especially cancer and neuro-degenerative diseases. Subtle differences in cell cycle regulation could be exploited to create new pharmaceuticals to combat eukaryotic pathogens. and to promote wound healing and tissue regeneration. Molecular biologists have assembled an extensive parts list of proteins involved in cell cycle regulation, and their interactions. To understand how these molecules ultimately determine the behavior of cells will require powerful and effective software tools for converting "molecular wiring diagrams" into computational models that can reliably predict the physiological consequences of the underlying machinery. The team includes some of the world's leading experts in computational molecular biology (Tyson, Novak and Chen), cell cycle genetics and biochemistry (Cross, Mendenhall and Sible). human-computer interface (Shaffer), high performance computing (Watson), and data mining (Ramakrishnan). By combining all aspects of Bio-Computation (modeling, experiment, and simulation) in one team, we will achieve synergies attainable at few other places in the world.