Theoretical Condensed Matter Physics

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This grant is supported jointly by the Divisions of Materials Research and Molecular and Cellular Biosciences. All multi-celled organisms begin as an undifferentiated single celled egg and use the instructions written in the genome to create the specialized cells and organs of the adult. Recent genome sequencing projects reinforce earlier ideas that form is derived from how genes are regulated and coordinated; and by implication evolution, proceeds more by tinkering with the regulation of genes than creating new genes. The inference of gene regulation from the genome is still in its infancy, and many of the current genome sequencing projects are focused on clusters of related organisms with the intent of using interspecies comparisons as a filter for what is conserved and by implication most important for function. However, we are still largely ignorant of how regulatory information is encoded in the genome and simply comparing sequence may be like comparing the same sentence in two languages. Statistical mechanics is fundamentally concerned with computing the probabilities of patterns and assessing whether a sample is consistent with a model (more technically, the probability of the data giventhe model). The fruit fly has been a model for genetics and development for 100 years, and the genomes of 10 related species will be available in early 2005. Together with a developmental biology lab at Rockefeller University, we will ask whether our earlier successes in computing which regions of the genome control early embryonic patterning, can be made more quantitative by computing the partition function for binding the regulatory proteins to the DNA. The regulation we understand in fly will be mapped onto the other sequenced species, as well as the mosquito, as a test of our understanding and to see how regulation evolves.In a previous project we classified the basic molecular events through which regulatory sequence changes by studying recently diverged fly species. Since regulatory DNA directs gene expression by binding proteins, simulating how this property is preserved under mutation and selection should provide clues about how to decode natural sequence. The goal is to cast evolution as an optimization process and thus make it more a predictive theory, rather than a historical one.Cells have to coordinate many processes to divide and cells must cooperate to form an organism. The networks that accomplish this coordination are an important focus of current biology. The cell division cycle is arguable the basis of life itself, and many of the key genes are preserved between single celled yeast and mammals. Aberrations in the control of cell division and growth lead to cancer.The PI plans to process movies of single yeast cells growing into clusters with custom image processing software to investigate how cell to cell variability is indicative of the control network. Do larger cells divide more rapidly, and does the duration of the various phases of the cell cycle correlate? The cell cycle has to strictly order certain processes, e.g. DNA replication must precede the segregation of chromosomes, we will ask whether the fluctuations provide evidence for sub modules within the cell cycle (e.g. is DNA replication tied to bud emergence, and the expression of certain cyclin genes). A large collection of cell cycle mutants has been derived from screens on populations of cells and one should reexamine their properties at the single cell level. Specifically are certain genes responsible for maintaining the temporal coherence of submodules? As a representative cellular network, are there some aspects of the cell cycle that are better modeled as discrete, binary, systems rather than sets of differential equations?Broader Impacts: Enhance Infrastructure for Research and Education.The PI divides his time between The Rockefeller University, in New York City, and Cornell University, in Ithaca, NY, and collaborates with many individuals in the physical sciences and biology. He is on the thesis committee of many biology students, and the advisory panels for NIH funded centers in quantitative biology and foundations awarding grants for transitional research, where he is often the only quantitative member. This proposal will fund physical science students wanting to move into biology. We make our computational predictions available through customized web sites, and our software packages are distributed freely.