Engineering of synthetic intercellular communication systems

The introduction of synthetic devices that provide precise fine-tuning of transgene expression has revolutionized the field of biology. The design and construction of sophisticated and reliable genetic control circuits have increased dramatically in complexity in recent years. The norm when creating such circuits is to program the whole network in a single cell. Although this has been greatly successful, the time will soon come when the capacity of a single cell is no longer adequate. Therefore, synthetic biology-inspired research has started to shift towards a multicellular approach in which specialized cells are constructed and then interconnected, enabling the creation of higher-order networks that do not face the same limitations as single cells. This approach is conceptually appealing in many respects. The fact that overall workload can be easily divided between cells eliminates the problem of limited program capacity of a single cell. Furthermore, engineering of specialized cells will enable a plug-and-play approach in which cells are combined into multicellular consortia depending on the requested task. Recent advances in synthetic biology to implement intercellular communication and multicellular consortia have demonstrated an impressive arsenal of new devices with novel functions that are unprecedented even in engineered single cells. Engineering of such devices have been achieved in bacteria, yeast and mammalian cells, all of which is covered in this review. The introduction of synthetic intercellular communication into the cell engineering toolbox will open up new frontiers and will greatly contribute to the future success of synthetic biology and its clinical applications.

► Engineered ligand-responsive gene circuits sets the basis for synthetic biology. ► Such circuits are used to build complex synthetic regulatory networks. ► A single cell will no longer be adequate to perform complex regulatory tasks. ► Intercellular communication (IC) allows division of the metabolic workload. ► Multicellular systems implementing IC opens new frontiers for synthetic biology.