Control Theory for Engineering Biology

Abstract

Genetic circuits control every aspect of life and thus the ability to engineer them de-novo opens exciting possibilities, from revolutionary drugs and green energy to bugs that recognize and kill cancer cells. The robustness of natural gene networks is the result of a million years of evolution and is in contrast with the fragility of today’s engineered circuits. A genetic module’s input/output behavior changes in unpredictable ways upon inclusion into a larger system. Therefore, each component of a system is usually redesigned every time a new piece is added. Rather than relying on such ad-hoc design procedures, control theoretic approaches may be used to engineer “insulation” of circuit components from context, thus enabling modular composition through specified input/output connections. In this talk, I will give an overview of modularity failures in genetic circuits, focusing on problems of loads, and introduce a control-theoretic framework, founded on the concept of retroactivity, to address the insulation question. Within this framework, insulation can be mathematically formulated as a disturbance rejection problem; however, classical solutions are not directly applicable due to biophysical constraints. I will thus introduce solutions relying on time-scale separation, a key feature of biomolecular systems, which were used to build two devices: the load driver and the resource decoupler. These devices aid modularity, facilitate predictable composition of genetic circuits and show that control-theoretic approaches may be suitable to address pressing challenges in engineering biology.