Multi-input biocomputer gene circuits for therapeutic application

Clinical approvals of gene and cell therapies in recent years, and advances in our ability to engineer complex cellular functions using synthetic biology have fueled interest in merging these two approaches to develop and deploy ever more sophisticated treatments. One area of interface between synthetic biology tools and therapeutics comprises synthetic gene circuits that ‘compute’ a response in a programmable fashion using multiple biomolecular inputs. The potential therapeutic utility of such circuits hinges on their ability to perform logical integration of inputs linked to the human cell phenotype. AND logic increases response specificity, OR logic enables targeting heterogeneous cell populations, and NOT logic provides additional safety. We review recent efforts to implement input sensing and logical integration capabilities in cell, gene, RNA, and microbiome-based therapies. With therapeutic candidates using biomolecular computation already in clinical trials, the approach is poised to revolutionize the field of advanced therapies in the years to come.