Designing customized cell signalling circuits

Abstract

Efforts to engineer cells with customized signalling circuits will teach us about the design principles underlying natural signalling networks and could lead to important applications in medicine and biotechnology, such as specialized anti-cancer cells. There have been exciting recent developments in engineering synthetic or modified sensors and receptors that allow novel inputs to control complex natural responses or allow natural inputs to control novel responses. Engineered sensors have also been developed that allow small molecules or light to precisely control biological responses. Engineering highly diverse sensors remains a big challenge in synthetic biology. However, some examples, such as chimeric T cell receptors that incorporate a single-chain antibody as the extracellular domain, offer a strategy for custom receptor design. The modularity of intracellular signalling proteins can be exploited to generate diverse signal processing circuits. Many protein circuits are dependent on the organization of key proteins into specific complexes and assemblies. Thus, recombination and reorganization of specific catalytic domains with different interaction domains provides a way for both evolution and engineering to generate novel circuit wiring. The modification of spatially controlled signalling circuits can lead to cells with new morphological behaviours. Advances that may facilitate the engineering of customized signalling include improved molecular tool kits that are optimized for predictability, and incorporation of combinatorial library design into the engineering process.