Nonequilibrium physics of signaling and spatial organization at the cellular scale

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Background The Second Law of Thermodynamics tells us that without energy input, any system will tend towards becoming disordered. For the basic units of life, biological cells, much of the energy consumed is not stored or used to build structures, but is dissipated to pay the cost of maintaining order by directing and coordinating cellular processes. Biological cells are also organized into spatial compartments of a variety of shapes and sizes that have distinct functional roles. The geometry (shape and size) of these compartments changes with health, prevailing conditions, and cell activities, indicating that these compartment geometries are important to biological function. Although a cell may appear relatively static, its constituent molecules and the structures they compose are very dynamic, continuously moving and changing. My long-term objectives are to understand how these cellular dynamics are driven by energy expenditure and influenced by geometry to achieve the many tasks that make a cell alive. This includes probing the physical limits placed by energy consumption and geometric confinement on important cellular processes. Objectives I will use theoretical and computational techniques to work towards three specific short-term objectives: 1) Understand how energy is used by cells to make decisions, such as by labelling cellular components for recycling. How is energy used to influence the dynamic addition and removal of these label molecules to decide to recycle a component at the right time? 2) Develop a quantitative framework for how cells control the spatial distribution of proteins. Cells are able to put specific protein types into certain compartments, without the proteins `knowing' where to go. How do cells spend energy and use geometry to ensure proteins are present where they are needed? 3) Understand how confining proteins to the narrow interiors of cellular compartments affects how signals can be generated within these compartments. Signaling often involves protein clustering or a phase transition in behaviour. How are clustering, phase transitions, and reaction kinetics impacted by geometric confinement to compartment interiors, and what limits does this put on signaling? Impact My research program, which provides valuable training to young scientists and quantitative skillsets for the modern workforce, uses theoretical approaches to understand the physical factors behind the operation of biological cells. This work pushes forward our understanding of the nonequilibrium nature of the mechanisms and rules underlying life, and has potential long term practical application to medicine. Alzheimer's disease, diabetes, and many other human pathologies are thought to originate at the cellular level, and understanding how cells carry out their function and remain healthy is essential to countering disease symptoms and causes.