Gao, X. J. et al. Science 361, 1252–1258 (2018).
Bestowing new functions on cells is a key goal of synthetic biology. Researchers most commonly seek to engineer new circuits at the transcriptional level, for example, by expressing transcription factors; cells, in contrast, often regulate their pathways at the protein level. Gao et al. decided to follow nature’s lead and designed CHOMP (circuits of hacked orthogonal modular proteases), which uses viral proteases for circuit design. They first showed that three different viral proteases can be used to increase or decrease the expression of reporter genes, by cleaving a degradation signal and by exposing a destabilizing domain after cleavage, respectively. Then they used these principles to design two-input logic OR, AND and NOR gates, analog filter processing and regulatory cascades. They engineered a circuit that responds to upstream activators of Ras by activating a protease that in turn switches on caspase-3 and thus induces death in cells with elevated Ras levels, a hallmark of many cancer cells.