A synchronized quorum of genetic clocks

Abstract

The engineering of genetic circuits with predictive functionality in living cells represents a defining focus of the expanding field of synthetic biology. This focus was elegantly set in motion a decade ago with the design and construction of a genetic toggle switch and an oscillator, with subsequent highlights that have included circuits capable of pattern generation, noise shaping, edge detection, and event counting. Here, we describe an engineered gene network with global intercellular coupling that is capable of generating synchronized oscillations in a growing population of cells. Using microfluidic devices tailored for cellular populations at differing length scales, we investigate the collective synchronization properties along with spatiotemporal waves occurring on millimeter scales. We use computational modeling to quantitatively describe the observed dependence of the period and amplitude of the bulk oscillations on the flow rate. The synchronized genetic clock sets the stage for the use of microbes in the creation of a macroscopic biosensor with an oscillatory output. In addition, it provides a specific model system for the generation of a mechanistic description of emergent coordinated behavior at the colony level.

Design principles for robust oscillatory behavior

“…Synthetic functional circuits incorporating oscillators as time-keepers have also been developed (Danino et al 2010;Mondragon-Palomino et al 2011;Franco et al 2011;Khalil and Collins 2014). Still, there is not yet a thorough and comprehensive set of guidelines for engineering robust oscillators.…”

Synthetic biology – the state of play

“…However, for oscillators to be really useful, in the context of human-designed biological devices, they must be controllable and stable in terms of frequency and amplitude, and have a high signal to noise ratio. Since the Repressilator there have been various attempts to achieve this objective; for example, by the use of Lotka-Volterra dynamics [38] and a tuneable synthetic gene oscillator [39] -and, more recently, be using a synchronised quorum clock approach [40]. A recent example of the use of biological oscillators in another area relates to their application to liquid crystal displays [41].…”

Synthetic circuits, devices and modules

“…The construction of such higher-order genetic circuits and devices has allowed the synthetic biologists to challenge more difficult works, such as output of specific signal mode (Kemmer et al, 2010), noise control (Hooshangi et al, 2005;Murphy et al, 2010), biological counters (Friedland et al, 2009) and circadian clocks (Danino et al, 2010). Given the broad applications of these genetic circuits and devices, it is crucial to develop more useful devices that operate effectively inside living cells.…”