Design Principles for Compartmentalization and Spatial Organization of Synthetic Genetic Circuits

Compartmentalization is a hallmark of cellular systems and an ingredient actively exploited in evolution. It is also being engineered and exploited in synthetic biology, in multiple ways. While these have demonstrated important experimental capabilities, understanding design principles underpinning compartmentalization of genetic circuits has been elusive. We develop a systems framework to elucidate the interplay between the nature of the genetic circuit, the spatial organization of compartments, and their operational state (well-mixed or otherwise). In so doing, we reveal a number of unexpected features associated with compartmentalizing synthetic and template-based circuits. These include (i) the consequences of distributing circuits including trade-offs and how they may be circumvented, (ii) hidden constraints in realizing a distributed circuit, and (iii) appealing new features of compartmentalized circuits. We build on this to examine exemplar applications, which consolidate and extend the design principles we have obtained. Our insights, which emerge from the most basic and general considerations of compartmentalizing genetic circuits, are relevant in a broad range of settings.