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

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Final rept. Sep 2001-Sep 2006

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The purpose of DARPAs BioSPICE Program was to provide a new and useful set of software tools for modeling biochemical pathways and molecular regulatory networks within living cells. Using nonlinear ordinary differential equations to capture the temporal dynamics of molecular control systems, the modeling team built successful computer models of cell cycle regulation in a variety of organisms, including yeast cells, amphibian embryos, bacterial cells and human cells. These models accurately reproduce the physiological properties of normal cell division, and the bizarre properties of 200 mutant cells that have been studied. The models predict phenotypes of novel mutants and unintuitive properties of the cell cycle machinery, which have been confirmed by the experimental teams on the project. The theorists used one- and two-parameter bifurcation diagrams to link gene-protein interaction networks to the physiological properties of cells. The Software Team developed tools for building mathematical models from a chemical reaction network, for associating experimental data with a model, for managing simulations of the data by the model, for evaluating how well the simulation fits the data, and for automatic parameter estimation. In addition a powerful tool for numerical bifurcation analysis was created. The major accomplishments of the Virginia Tech Consortium are 1 a set of downloadable, open-source computer programs that embody a Problem Solving Environment for dynamic modeling of macromolecular regulatory networks in living cells, and 2 an integrated set of models of cell cycle regulation in bacteria, yeasts, and metazoans that are accurate, predictive and informative. The models are described in the peer-reviewed literature and are freely available from web sites maintained at Virginia Tech. Some of the experimental tests carried out by the group are cited as classic examples of modern molecular systems biology.

Subject Categories:

  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Anatomy and Physiology
  • Operations Research
  • Computer Programming and Software

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