ABSTRACT The major events of the cell division cycle, DNA synthesis and mitosis, are triggered by 'cyclin-dependent kinases' (CDK's): a family of enzymes whose activity and specificity depend on their binding to various cyclins. CDK activity is also regulated by phosphorylation and by binding to inhibitory proteins. These regulatory proteins interact with each other in a complex web of biochemical reactions and feedback signals, to generate an orderly progression of the cell cycle. So far, characterization of this regulatory system has been reductionistic: breaking the network into its constituent pieces and determining which pieces interact. Rigorous mathematical methods are being developed to assemble the pieces into a coherent model of the intact regulatory system, so that predictions can be compared qualitatively with experimental observations about the physiology and genetics of the organisms. Using standard methods of dynamical systems theory, the investigators are constructing comprehensive, accurate, and predictive. Mathematical models of the cell cycle in yeast cells and frog embryos. The human genome project promises to deliver a rich stream of information about the genes and proteins that govern all our physiological affairs. Complementing extensive research on the 'informational' aspects of genome analysis (storage and retrieval, sequence comparison, structural predictions) this project addresses a new level of 'dynamical' questions: how do molecules interact with one another in time and space to produce the organized, functional behavior of living cells? Appropriate mathematical and computational tools to answer this question are being developed in the context of a specific physiological problem: cell growth and division. To understand how cell proliferation is regulated would not be only a satisfying achievement of basic science but also a breakthrough for clinical medicine. When the signals that initiate or suppress cell division are understood, the means to restrain the proliferation of cancer cells or to induce the regeneration of nerve cells will become more apparent. This work is being funded by the Computational Biology (BIO), Signal Transduction (BIO), and Mathematical Biology (MPS) Programs.
