Using a queueing framework to explore the design principles of synthetic circuits in microorganisms

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Survival in environments with limited resources (e.g. nutrients) is a challenge encountered by a variety of microbial systems. Although it has long been appreciated that microbes adapt and evolve to cope with resource limitations, there remains a need to better understand how cellular machinery involved in the processing of finite resources are important in a cell, including molecular machines that control protein production, degradation, and modification. The team of investigators explores the underlying design principles governing synthetic and native biological "circuits" in E. coli that are central to cellular resource allocation processes. In addition to characterizing the resource processing and allocation machinery, the project develops an associated queueing theory (a mathematical study of waiting lines) framework to analyze the system, which will provide a unifying and intuitive framework for biomolecular resource allocation systems. As part of the educational Broader Impacts of the project, investigators will recruit students, including those from underrepresented groups, to participate in synthetic biology research experiences. Additionally, the project will provide professional development workshops for K-12 science teachers to enhance their ability to integrate synthetic biology modules into their classrooms. The cellular machinery involved in crucial processes such as metabolism, transcription, translation, and protein degradation are designed to avoid overloading cellular systems when resources are limited, as overloading could lead to the formation of waiting lines (i.e., biological queueing). To investigate queueing in biomolecular processes, this project combines techniques, such as fluorescence microscopy and microfluidics, with synthetic biology and quantitative modeling to infer theoretical queueing principles behind the dynamics of both synthetic and native biological networks. Focusing on proteolytic pathways in E. coli cells, investigators combine single-cell and high-throughput techniques to quantify and mathematically model crosstalk, or proteolytic bottlenecks, between proteins targeted to and competing for multiple degradation pathways. Results of this project has the potential to advance the use of queueing theory for the analysis of synthetic circuits and enhance our understanding of how native biological processes allocate dynamically varying resources.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.