Role of Spatial Structure in Decision Making Grant uri icon

abstract

  • Phages are a form of viruses that infect bacterial cells. Upon infecting an E. coli cell, phage lambda can make different choices in its fate. It can either go to the lytic (virulent) pathway where ~100 progeny particles are produced and released upon lysis of the cell, or go to the lysogenic (dormant) pathway in which phage DNA is integrated into the host chromosome where it gets replicated. Current data suggests that infecting phages inside the cell can individually ?vote? for lysis or lysogeny and depending on the outcome, phages exhibit different interactions to propagate through an interplay of competition with cooperation. We have an incomplete quantitative understanding of the subcellular workings of the phage system. This project will investigate the heretofore unexplored idea that spatial organization of the phage-host system may be a pivotal ?hidden variable? in determining cell fate. The overarching goal of this project is to construct a quantitative picture of phage lambda decision making with single-cell accuracy. This project will set up a benchmark and generate a framework for studying other phage systems via quantitative experiments and modellings, and shed important light on decision-making processes in other phage-host systems and perhaps also to contribute to how other viruses operate in higher organisms. The Broader Impacts of the project will involve integrating quantitative modellings into the course curricula at both the undergraduate and graduate levels in the university, and therefore, help build a modern biophysics and quantitative biology program. Additional outreach efforts will involve providing images and videos for educational purposes nationwide and worldwide. The subcellular lambda decision making will be studied through high-resolution, super-resolution microscopy and multi-scale spatial stochastic modeling. Specifically, this project has two objectives. Objective 1 is to investigate the role of subcellular spatial structure in decision making by fluorescence microscopy, focusing on quantifying individual phage gene expression in space and time and on examining the subcellular locations of relevant biomolecules to correlate them with the final phage/cell fate. Objective 2 is to formulate a spatial stochastic dynamics model. Spatial degrees of freedom at subcellular level will be addressed for the first time in the constructed stochastic model to account for the spatial effect in multi-scale stochastic modeling of the lambda system. Through the studies, the understanding of the following aspects regarding phage decision making will be advanced: 1) role of protein diffusivity/locality in individual viral decision making in cell decision process; 2) precise measurements of biomolecules within phage compartments; 3) phage-host spatial interaction in decision making and development; and 4) integration of noise with spatial structure to a more accurate account of stochasticity. Upon the completion of this project, the prediction of lambda decision making will be expected to be achieved with single-cell resolution. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

date/time interval

  • 2020 - 2023