ABSTRACT

This INSPIRE project is co-funded by the Chemistry of Life Processes Program in the Chemistry Division in the Directorate for Mathematical and Physical Sciences, the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences, the Physics of Living Systems Program in the Physics Division in the Directorate for Mathematical and Physical Sciences and the Office of Integrative Activities in the Directorate for Mathematical and Physical Sciences.

The two fundamental characteristics of living systems are their ability to replicate with precision and adapt to changing environmental conditions. The discovery of the structure of DNA, the molecule that carries genetic information, provided only a framework for describing how the genetic code is copied. However, focusing on DNA in isolation does not provide insights into how the entire machinery, needed to sustain the viability of the cell, is conveyed from the mother to the daughter cell. This is accomplished by networks of other protein molecules that transmit information through chemical reactions both in the process of replication, cell division, and adaptation. How do theses individual molecular components interact and function in a system that is capable of replicating, adapting to changing environment, and operating robustly in noisy crowded milieu? What is the minimum level of complexity needed for a living cell to function? What sets the length scale of such a living system in terms of the molecular constituents? The goal is to develop a quantitative conceptual framework to answer these questions so that the ability to process signals, adapt, and replicate with high fidelity can be described using the laws of physics and chemistry and using a bacterium as a case study. The interdisciplinary approach to this research involves integrating physics, chemistry, and information theory concepts, and is expected to provide a versatile training ground for students and postdoctoral fellows with diverse backgrounds.

In order to achieve the major objectives of the proposed research it is necessary to break new ground by creating new models and ideas coming from a variety of fields. An integrated approach will be developed by combining coarse-grained models of enzymatic reactions, ways of coupling feedback effects due to synthesis of small molecules and proteins, and accounting for non-equilibrium processes. These ideas will be used to explore the organization principles for adaptation to environmental fluctuations, cell size control, and competition between various factors that promote homeostasis. These new concepts will be used to provide a new framework on how a simple bacterium is versatile enough to respond to harsh environmental fluctuations (high salinity or osmolarity) and adapt in a noisy environment. Analyzing such behavior will require combining control theory and the underlying stochastic aspects of signal transmission achieved through chemical reaction networks. In addition, the key question of how cell shape and size (on the order of a micron) emerge will be explored based on the notion that they use feedback to maintain proteostasis and keep the concentrations of metabolites in check. The questions raised here are fundamental and even if answered partially could have far-reaching implications in our understanding of how living systems function. An overarching long term goal of these studies is to begin to provide the framework to eventually design and control macroscopic cell behavior in terms of its underlying components.

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