Reinforcement Learning for Robust Dynamic Metabolic Control

Dynamic metabolic control allows key metabolic fluxes to be modulated in real time, enhancing bioprocess flexibility and expanding available optimization degrees of freedom. This is achieved, for example, via targeted modulation of metabolic enzyme expression. However, identifying optimal dynamic control policies is challenging due to the generally high‐dimensional solution space and the need to manage metabolic burden and cytotoxic effects arising from inducible enzyme expression. The task is further complicated by stochastic dynamics, which reduce bioprocess reproducibility. We propose a reinforcement learning framework to derive optimal policies by allowing an agent (the controller) to interact with a surrogate dynamic model. To promote robustness, we apply domain randomization, enabling the controller to generalize across uncertainties. When transferred to an experimental system, the agent can in principle continue fine‐tuning the policy. Our framework provides an alternative to conventional model‐based control such as model predictive control, which requires model differentiation with respect to decision variables; often impractical for complex stochastic, nonlinear, stiff, and piecewise‐defined dynamics. In contrast, our approach relies on forward integration of the model, thereby simplifying the task. We demonstrate the framework in two Escherichia coli bioprocesses: dynamic control of acetyl‐CoA carboxylase for fatty‐acid synthesis and of adenosine triphosphatase for lactate synthesis.