Robust tunable in vitro transcriptional oscillator networks

Synthetic biology is facilitating novel methods and components to build in vivo and in vitro circuits to better understand and re-engineer biological networks. Circadian oscillators serve as molecular clocks that govern several important cellular processes such as cell division and apoptosis. Hence, successful demonstration of synthetic oscillators have become a primary design target for many synthetic biology endeavors. Recently, three synthetic transcriptional oscillators were demonstrated by Kim and Winfree utilizing modular architecture of synthetic gene analogues and a few enzymes. However, the periods and amplitudes of synthetic oscillators were sensitive to initial conditions and allowed limited tunability. In addition, it being a closed system, the oscillations were observe to die out after a certain period of time. To increase tunability and robustness of synthetic biochemical oscillators in the face of disturbances and modeling uncertainties, a control theoretic approach for realtime adjustment of oscillator behaviors would be required. In this paper, assuming an open system implementation is feasible, we demonstrate how dynamic inversion techniques can be used to synthesize the required controllers.