Synthetic gene circuits as tools for drug discovery

Within mammalian systems, there exists enormous opportunity to use synthetic gene circuits to enhance phenotype-based drug discovery, to map the molecular origins of disease, and to validate therapeutics in complex cellular systems. While drug discovery has relied on marker staining and high-content imaging in cell-based assays, synthetic gene circuits expand the potential for precision and speed. Here we present a vision of how circuits can improve the speed and accuracy of drug discovery by enhancing the efficiency of hit triage, capturing disease-relevant dynamics in cell-based assays, and simplifying validation and readouts from organoids and microphysiological systems (MPS). By tracking events and cellular states across multiple length and time scales, circuits will transform how we decipher the causal link between molecular events and phenotypes to improve the selectivity and sensitivity of cell-based assays. Synthetic gene circuits enable real-time monitoring of diverse molecular events in live cells.Synthetic circuits provide internal controls to expedite hit validation and facilitate hit prioritization.Synthetic circuits enable on-line validation of induced pluripotent stem cell (iPSC)-derived cells.Synthetic circuits potentiate longitudinal tracking of neurodegenerative-associated phenotypes.