Closed-loop Optogenetic Control in a Microplate Reader

Living cells sense diverse molecules and synthesize complex compounds, but their responses are slow and context dependent, which makes precise control difficult. Electronic systems excel at fast computation, communication, and control, but their direct access to biochemistry is limited. These two classes can be integrated through optogenetics to form cell-silicon systems for sensing and biomanufacturing. However, prototyping these systems remains nontrivial: current tools either pair high-accuracy sensing with robotic sample transfer that requires extensive setup, or avoid transfers by using custom sensors with limited accuracy and dynamic range that compromise performance. Here we present LEMOS, a low-cost LED-embedded microplate that operates inside a commercial microplate reader, keeping cultures in the reader for the entire experiment while synchronizing illumination with measurement. Using LEMOS and a growth-aware multiscale model, we rapidly executed the design–build–test–learn cycle to diagnose and correct closed-loop overshoot in gene-expression setpoint tracking. We demonstrate closed-loop gene-expression control in batch culture within a standard plate reader and show that growth state is a key design variable for controller choice and tuning. By combining accessible hardware with a predictive model, LEMOS lowers the barrier to model-informed DBTL, shortens iteration, and provides a path to portable control strategies that extend to other hosts and optogenetic systems.