Watch the clock—engineering biological systems to be on time

Inspired by natural time-keeping devices controlling the circadian clock, managing information processing in the brain and coordinating physiological activities on a daily (feeding and sleeping) or seasonal timescale (reproductive activity or hibernation), synthetic biologists have successfully assembled functional synthetic clocks from cataloged genetic components with standardized activities and arranging them in transcription circuits containing positive and negative feedback loops with integrated time-delay dynamics. While the positive feedback loop drives the clock like the (balance) spring in a mechanical watch the negative time-delay circuit represents the pulse generator defining a minimal time unit and precision of the clock like the pendulum fallback or the movement of the balance wheel in a classical mechanic watch. This basic design principle enabled the construction of a variety of synthetic oscillators whose design details are concisely covered in this review.