This CREATIV award is partially funded by the Biomolecular Dynamics, Structure and Function and the Networks and Regulation Clusters in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences; the Physics of Living Systems Program in the Division of Physics, the Condensed Matter and Materials Theory Program in the Division of Materials Research, and the Chemistry of Life Processes Program in the Division of Chemistry in the Directorate of Mathematical and Physical Sciences.
The objective of this CREATIV project is to investigate the fundamental question of how intricate protein-based molecular machines can determine cellular-level dynamics for living systems. Specifically, the goal is to create a framework for quantitatively predicting functional consequences of designed changes in protein systems. This project will focus on the decision-making circuitry in Bacillus subtilis as a test case for the thesis that, although biology starts from the molecular scale, it is only at the cellular and multicellular scales that one sees life in action, as a distinct form of matter having goal oriented behavior. This is the level at which evolutionary selective pressures operate. It therefore must be the case that the dynamics at these higher-scales are directly determined by their molecular underpinnings. Exactly how this works has not yet been understood even for simple forms of life such as bacteria. Instead, quantitative systems-biology approaches today remain impoverished of molecular detail and one cannot hope for an understanding of either why things work the way they do, or, often more importantly, how we can intervene at the molecular scale to engineer the system performance. The PIs and their collaborators will apply an integrative approach that combines computational and experimental techniques to bridge this huge gap in our understanding and predictive capability of the quantitative functionality of biological systems. Recent progress on the Bacillus system has for the first time enabled this type of trans-scale approach. At the molecular level, advances in modeling and new ideas utilizing sequence-based data can effectively treat protein-protein interactions and conformational changes associated with chemical function. Cellular-level circuits that govern sporulation and competence have been the subject of much recent interest and there is in place an initial set of ideas regarding the logic implemented therein. Finally, the coupling between each cell's decision-making in overall colony structure is being vigorously studied. This research project is inherently multidisciplinary, combining protein chemistry with signal transduction, combining molecular biology and biophysics with complex pattern-formation physics, and combining non-equilibrium statistical mechanics with synthetic biology. This work is high risk and potentially high pay off. Molecular modelers have stayed away from making predictions as to how specific changes will be manifested at the scale of life, as this was considered to be too hard as compared to explaining in vitro biochemistry data. The results from this project would be transformative, changing how we approach the quantitative analysis of integrated biological systems. It is therefore highly appropriate for the NSF CREATIV program.
The basic knowledge generated from this CREATIV project will be crucial for revolutionizing our ability to control biofilms by molecular manipulation. Biofilm control is crucial for bacteria-based environmental remediation and for modern desalination. This project will provide a fertile ground to expose junior scientists to the challenge of cross-disciplinary research, both theoretical and experimental, which explicitly aims to break down the barriers between different subfields. This will lead to a future workforce better able to face the challenges of modern quantitative biology. Finally, bacterial colony structures and their cellular and molecular underpinnings are a fascinating area with which one can draw the public into contact with the ideas of modern science.
PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH
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P Ghosh, J Mondal, E Ben-Jacob, H Levine. "Mechanically-driven phase separation in a growing bacterial colony," Proceedings of the National Academy of Sciences, v.112, 2015, p. E2166.
Ghosh, Pushpita, Ben-Jaco, Eshel & Levine, Herbert. "Modeling cell-death patterning during biofilm formation," Physical Biology, v.10, 2013, p. 066006.
Daniel Schultz, Mingyang Lu, Trevor Stavropoulos, Jose' Onuchic & Eshel Ben-Jacob. "Turning Oscillations Into Opportunities: Lessons from a Bacterial Decision Gate," Scientific Reports, v.3, 2013, p. 1668.
Mingyang Lu, Mohit Kumar Jolly, Ryan Gomoto, Bin Huang, Jose Onuchic & Eshel BenJacob. "Tristability in Cancer-Associated MicroRNA-TF Chimera Toggle Switch," Journal of Physical Chemistry B, v.117, 2013, p. 13164.
Faruck Morcos, Nicholas P. Schafera, Ryan R. Cheng, Josť N. Onuchic, and Peter G. Wolynes. "Coevolutionary information, protein folding landscapes, and the thermodynamics of natural selection," PNAS, v.111, 2014, p. 12408.
Cheng, Ryan R., Morcos, Faruck, Levine, Herbert & Onuchic, Jose N.. "Toward rationally redesigning bacterial two-component signaling systems using coevolutionary information," Proceedings of the National Academy of Sciences USA, v.111, 2014, p. E563.
Ryan R. Cheng, Mohit Raghunathan, Jeffrey K. Noel, & Jose' N. Onuchic. "Constructing sequence-dependent protein models using coevolutionary information," Protein Science, v.25, 2016, p. 111.
Deborah Schwarcz, Herbert Levine, H (Levine, Eshel Ben-Jacob, and Gil Ariel. "Uniform modeling of bacterial colony patterns with varying nutrient and substrate," PHYSICA D-NONLINEAR PHENOMENA, v.316, 2016, p. 91.