CAREER: Tunable Dynamics from Interlinked Feedback Loops in Synthetic and Natural Gene Circuits

Trustees Of Boston University, Boston

Investigators

Abstract

ABSTRACT Intellectual Merit: Organisms must cope with a wide range of time-varying stresses, owing to fluctuations in nutrient availability, chemical stressors, and environmental changes. Genetically identical populations of cells can use random, stochastic expression of genes to diversify their response and hedge against this uncertainty. However, when environmental changes are slow and can be sensed and responded to, there is little need for a diversified response. This raises a fundamental question as to how cells reconcile these two potentially contradictory demands: the need to use phenotypic diversity to anticipate stress and also employ well-defined deterministic responses. Achieving this requires gene regulatory networks that are tunable, switching between stochastic and deterministic responses depending on environmental conditions. Recent theoretical studies have suggested that interlinked positive and negative feedback ("mixed feedback") networks, can provide this type of tunable response. Using single-cell time-lapse microscopy and microfluidic experiments supported by mathematical modeling, this project will quantify the tunability of synthetic and natural mixed feedback circuits and will test how cells handle time-varying environments. This work is significant because it will reveal genetic mechanisms that allow otherwise identical cells to choose random fates in some circumstances and exhibit deterministic responses in others, allowing organisms to cope with environmental uncertainty. Broader Impacts: The research plan is integrated with an outreach program focused on systems and synthetic biology education at the community, high school, and undergraduate levels: First, through a partnership with ECHO Science Center in Burlington, Vermont, the PI will produce a special summer exhibit and talk aimed at communicating cutting-edge systems and synthetic biology topics to community audiences. Second, the PI will host undergraduate Barrett Scholars in her research group and will provide mentorship for student presentations to high school students in the Governor's Institute in Engineering. Third, the PI will introduce systems and synthetic biology examples into two core engineering courses that currently focus on traditional mechanical and electrical engineering applications.