Engineering Genetic Controllers to Accelerate Adaptation and Attenuate Cellular Noise

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• Maurice Filo, ETH Zurich
• Thursday 22 May 2025, 14:00-15:00
• JDB Seminar Room, Department of Engineering and online (Zoom).

If you have a question about this talk, please contact Fulvio Forni.

Cells excel at regulating internal processes with speed, precision, and resilience. Inspired by this, synthetic biology increasingly employs feedback control to engineer robust, adaptive behaviors. Yet, molecular noise, saturation, nonlinearities, and structural constraints pose major design challenges. This talk explores molecular feedback controllers that achieve Robust Perfect Adaptation (RPA)—maintaining steady-state output despite persistent disturbances—while improving dynamic response and suppressing intrinsic noise.

We begin with the Antithetic Integral Feedback (AIF) motif, a chemical reaction network (CRN) implementing integral control, and extend it to nonlinear architectures that emulate PID control through biologically feasible feedback circuits. These designs respect strict CRN constraints, introducing unique synthesis and analysis challenges. I also briefly touch on anti-windup strategies that mitigate performance degradation under saturation.

Next, we examine simpler architectures that exploit nonlinearities to realize PI control with minimal complexity—an especially valuable trait for practical implementation in synthetic biology. Despite their simplicity, these controllers deliver RPA , high dynamic performance, and intrinsic noise suppression. I present theoretical results showing these minimal designs outperform standard negative feedback loops, even under non-ideal conditions. Building on these insights, we outline practical guidelines for modifying negative feedback circuits, built with genetic repressors, to improve disturbance rejection, dynamic response, and noise suppression. Finally, I present an experimental implementation using inteins, protein elements that catalyze splicing. The strong alignment between theory and experiment underscores a robust, versatile framework for synthetic feedback control, with applications from therapeutic systems to advanced biotechnologies.

The seminar will be held in JDB Seminar Room, Department of Engineering, and online (zoom): https://newnham.zoom.us/j/92544958528?pwd=YS9PcGRnbXBOcStBdStNb3E0SHN1UT09

This talk is part of the CUED Control Group Seminars series.

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