Cell-free synthetic biology: a bottom-up approach to discovery by design

The practitioners of the brand of synthetic biology that lies closest to engineering are fond of quoting the phrase Richard Feynman had written on his blackboard: ‘What I cannot create I do not understand’. This phrase captures both a warning about the limitations of analysis in understanding complex systems and an endorsement of the value of design in the quest for discovery. Analysis, modeling, and simulation have a tendency to focus attention on the details of individual elements and components, whereas the reiterative nature of design requires grappling with the trade-offs and compromises required to enable system function. The emergence of this system view from design suggests that redesign (or rewriting in the context of evolved systems) is a promising route for understanding the fundamental principles governing the organization of natural genetic systems. Synthetic biology rewriting efforts have usually followed a strategy of constructing deliberately simplified systems to build an understanding