Genetically Engineered Proportional-Integral Feedback Controllers for Robust Perfect Adaptation in Mammalian Cells

To support their survival, cells adapt to environmental disturbances by maintaining a constant internal milieu. Robust perfect adaptation is a strategy that utilizes integral feedback to promote adaptation by robustly driving regulated physiological variables to their pre-disturbance levels. Present in natural systems, this stringent regulatory strategy promises to enable the engineering of sophisticated genetic programs with diverse applications. Here, we present the first synthetic implementations of integral and proportional-integral feedback controllers in mammalian cells. We show that the integral controller robustly and precisely maintains a desired level of a transcription factor, in spite of induced disturbances and network perturbations. Augmenting proportional feedback reduces stochastic variability while maintaining robust perfect adaptation. We demonstrate the benefits of these controllers in mitigating the impact of resource burden and investigate their use in cell therapy. The synthetic biological realization of robust perfect adaptation holds promise for substantial advances in industrial biotechnology and cell-based therapies.