Synthetic Biology: Building to learn so that we might learn to build

Synthetic Biology can be broadly parsed into the “top-down creation” of entire genomes and the “bottom-up engineering” of relatively small genetic circuits. A defining component of the gene circuit approach is the development of theory that can serve as the foundation for a new type of cellular engineering. This talk will be anchored by my quest to build genetic oscillators in cells, with a particular focus on the utility of mathematical modeling in determining general design principles. I’ll first describe the design and construction of an intracellular circuit that cycles over a wide range of environmental conditions (http://biodynamics.ucsd.edu/Intracellular.mov). The large space of observed oscillatory behavior drove a revision of model equations that revealed unanticipated coupling of the clock to native cellular processes. More generally, the necessity of the model revision led to our ongoing exploration of biochemical networks that act as queues that can be balanced at a type of critical point. In terms of engineering, the clock was not of the Swiss variety; the period and amplitude exhibited large intracellular variability. However, viewed through the lens of dynamical systems theory, the noisy oscillator provided a benchmark for the development of general synchronization strategies that can restore determinism. This led to three studies describing (i) how quorum sensing can be used to couple clocks between cells (biodynamics.ucsd.edu/Intercellular.mov), (ii) how redox signaling can combine with quorum sensing to couple colonies at centimeter length scales (biodynamics.ucsd.edu/Intercolony.mov), and (iii) how intra- and inter-cellular dynamics can be rapidly coupled and used to encode information (biodynamics.ucsd.edu/Multiplexing.mp4). I’ll conclude with a brief description of current applications that have arisen from our progress in traversing the scales from mathematical design in single cells to observable dynamics at the macroscopic level.