Biophysical models of the effect of the physico-chemical environment on genetic networks

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A major challenge in biophysics is to understand how cells cope with stress in their environment. At present, we do not understand the genetic and molecular mechanisms underlying the cellular response to common stressors, including electromagnetic fields (EMFs) and fluctuating chemical conditions, and we lack the quantitative tools needed to study them. The main objective of this interdisciplinary research program is to close this knowledge gap by developing mathematical and yeast model systems, and by performing experiments on genetically engineered yeast cells under a variety of real-world conditions. This work aims to make fundamental advances in the fields of cellular/molecular biophysics and gene network biology, and engineer more robust gene networks for use in basic research and industrial applications in Canada. The theoretical component of this research program will develop biophysical models and computer simulation algorithms based in fundamental physics to predict the effects of EMFs and fluctuating chemical exposure on gene networks. Previously, this approach has been used to make important advances on understanding how gene networks are affected by temperature (Charlebois et al., PNAS, 2018). These multiscale biophysical models and spatial cell population simulation algorithms, which are currently lacking in the field, will guide laboratory experiments on engineered yeast cells. In turn, the data generated from these experiments will be used to develop and validate the mathematical/computational models. The experimental component of this research program will focus on building EMF apparatuses that emulate real-world conditions for living cells and engineered gene networks that mimic natural gene networks. Yeast is an ideal model organism as it has been extensively characterized, grows well in the laboratory, is responsive to genetic manipulation, and yeast biology is highly relevant to other organisms. These EMF apparatuses and engineered yeast strains will allow the function, dynamics, and evolution of gene networks in diverse extracellular conditions to be studied in a more quantitative and controlled manner than is presently possible. The proposed research program has two main goals. First, it aims to fundamentally advance our knowledge of how healthy, living cells respond at the genetic level to cope with stressful conditions using mathematical modeling and experiments on gene networks inside of cells in nonstandard, fluctuating environmental conditions. Second, it aims to provide an inclusive first-rate training opportunity for highly qualified personnel in biophysics. The main expected impacts of this research are the development of new biophysical theories, spatial cell population simulation algorithms, EMF apparatuses for cellular/molecular biophysics, robust engineered gene networks for use in basic research and industrial applications, and a deeper understanding of gene networks and evolution.