Functional Constraints on the Acquisition of Novel Metabolic Controls

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This project addresses a fundamental question about the evolution of the complex systems that are used by organisms to control their essential activities such as gene expression and metabolism (the chemistry of life); To what degree have naturally-occurring control systems evolved to minimize the costs to the organism of operating the control systems themselves? The project will utilize synthetic biology approaches to construct a new metabolic pathway in a bacterium (E. coli) with distinct RNA regulatory mechanisms that can be experimentally authenticated. The research will employ iterative cycles of experiment and computational modeling and will not only provide insight into the benefits and costs of RNA-based regulation, but also serve as a platform for designing more efficient regulatory systems of microbial metabolic processes in biomanufacturing. This project is integrated with a formal teaching program and outreach efforts to inspire more women, underrepresented minority groups, and first-generation college students to consider careers in science and engineering. Workforce training and development will be provided to young career scientists through an interdisciplinary research and education experience in mathematical modeling, computational biology and genetic engineering. High school and incoming college students will be introduced to science and engineering through hosted research experiences that connect familiar real-world problems in energy and medicine to basic concepts in synthetic biology. Investigating functional constraints of metabolic control circuitry is an essential aspect of understanding the design limits that shape the evolution of complex regulatory networks. The goal of this project is to apply synthetic biology approaches (an engineered p-amino-cinnamic acid pathway in E coli) to address the hypothesis that RNA regulatory networks have evolved to minimize the energetic and metabolic costs of the control system itself. This project will integrate computational design space analysis, quantitative RNA device engineering and metabolic pathway construction to investigate the constraints of dynamic RNA-based metabolic control systems. Specifically, this will involve: (1) assessing the cost of acquiring novel metabolic functionality; (2) assessing the cost of acquiring novel RNA-based control functions; and (3) performing model-driven quantitative assessments of metabolic control system functions. This work is expected to shed light on whether RNA-based metabolic control mechanisms in microbes are the result of historical happenstance, are remnants of an RNA World, or whether they might be uniquely suited to provide control with low metabolic burden. These efforts will result in new theoretical and experimental frameworks for both studying and engineering complex metabolic systems that can be used for metabolic engineering purposes.This award is funded jointly by the Systems and Synthetic Biology Program in the Division of Molecular and Cellular Biosciences and the Biomedical Engineering Program in the Division of Chemical, Bioengineering, Environmental and Transport Systems.