RoL: FELS: RAISE: Principles of Modular Organization in Resource-Limited Biological Circuits

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Biological circuits control the way in which cells sense and respond to their environment, from microbes to mammals. Despite the fact that these circuits share and trade common cellular resources, they are surprisingly able to maintain separate (highly decoupled) functionalities. How can biological circuits be connected yet be decoupled? This project seeks to address this puzzling question. This research will improve our current understanding of natural systems and help create new biological circuits that control cellular behavior for energy, environment, and medical applications. Currently, human-engineered biological circuits are unpredictable and not sufficiently reliable for practical use. The biological discoveries of this project may serve to develop engineering solutions that decouple synthetic biological circuits from each other for predictable and reliable behavior. The research conducted under this project requires synergy between theory and experiments and between biology and engineering. As such, a new generation of interdisciplinary researchers will be trained, with cross-disciplinary expertise. This project will develop new educational curricula that cross department boundaries. The researchers will organize workshops and invited sessions at national and international conferences on the problems addressed in this project and will present the research at the Cambridge Science Festival and at its satellite event "Science on the Street". Teaching materials will be further disseminated to the broader community through MIT's OpenCourseWare and edX.Modularity dictates that the input/output behavior of a system is practically independent of its context, thus allowing a bottom-up compositional approach to predict the behavior of complex systems. Today, a key challenge when creating biological circuits is that the input/output properties of a module changes unpredictably when the module is in a different context. While many elements contribute to dependence of modules on context, sharing limited cellular resources such as those required for gene expression remains a major unresolved cause of lack of modularity. This project will elucidate general rules to predict the emergent behavior of a circuit from the composition of intended regulatory links and indirect retroactivity arising from resource sharing. This will lead to formulate the breakdown of modularity as the control-theoretic problem of attenuating indirect retroactivity, which will be addressed with a decentralized feedback control solution inspired from nature. The experimental implementation of this solution will elucidate how natural feedback motifs keep homeostasis while working in orchestration and may substantially enhance our ability to create predictable systems in synthetic biology.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.