The most striking success of 20th century biology was the identification and characterization of the molecules of life. A major challenge for 21st century biology will be to understand how these molecules interact to produce the complex biological processes that ultimately create living cells. What do we need to know to have this understanding? To what degree can detailed knowledge of individual molecules and their interactions provide predictive understanding of a complex biological process as it occurs in a living cell? To what degree will it be necessary to incorporate emergent properties of complex systems, those evident only in intact cell? The Chemotaxis Glue Grant Consortium proposes to address these questions in a Large Scale Collaborative Project by using chemotaxis in Escherichia coli as a test case. Chemotaxis is of the very best characterized examples of cellular behavior and signaling in biology. There are few other cellular processes in any species for which we have the comparable depth and breadth of molecular and mechanistic information. We propose to take advantage of this in a concerted effort to assemble a comprehensive description of chemotactic behavior and signal transduction. This will be done by an intimate interdigitation of computer simulation and experimental manipulation. We will employ multiple strategies to effect this interdigitation, but we will emphasize sustained personal contact, exchange residencies between modeling and experimental laboratories, and nurturing of individuals adept at both modeling and experiment. Obtaining the necessary additional information will require development, standardization and coordination of materials, assays and data across the interactive community of chemotaxis researchers. It will require recruitment of new approaches and new expertise to the problem, and collection of crucial structural information about challenging multi-protein complexes that is currently lacking. Finally, it will involve several mechanisms for establishing and encouraging communication, interaction and mutual education across the community of researchers interested in the issues to be addressed. We know no biological phenomenon of comparable complexity for which such a task has been undertaken and few, if any, for which it would be feasible. The output of our efforts will be mathematical and structural models, based on specific experimental data that mimic and predict the behavior of the organism and the detailed functioning of various aspects of the chemosensory system of E. coli. The intense effort and coordination of different expertise necessary to create such models should also produce benefits in the course of the process, providing new insights and revealing new fundamental properties that occur not only in E. coli chemotaxis but in signaling systems throughout biology. In this Phase I application, we ask for funds to continue and complete planning for this Large Scale Collaborative Project.
