Although central architectures drive robust oscillations, biological clock networks containing the same core vary drastically in their potential to oscillate. What peripheral structures contribute to the variation of oscillation behaviors remains elusive. We computationally generated an atlas of oscillators and found that, while certain core topologies are essential for robust oscillations, local structures substantially modulate the degree of robustness. Strikingly, two key local structures, incoherent inputs and coherent inputs, can modify a core topology to promote and attenuate its robustness, additively. These findings underscore the importance of local modifications besides robust cores, which explain why auxiliary structures not required for oscillation are evolutionarily conserved. We further apply this computational framework to search for structures underlying tunability, another crucial property shared by many biological timing systems to adapt their frequencies to environmental changes.
Experimentally, we developed an artificial cell system to reconstitute mitotic oscillatory processes in water-in-oil microemulsions. With a multi-inlet pressure-driven microfluidic setup, these artificial cells are flexibly adjustable in sizes, periods, various molecular and drug concentrations, energy, and subcellular compartments. Using long-term time-lapse fluorescence microscopy, this system enables high-throughput, single-cell analysis of clock dynamics, functions, and stochasticity, key to elucidating the topology-function relation of biological clocks.
We also investigate how multiple clocks coordinate via biochemical and mechanical signals in the essential developmental processes of early zebrafish embryos (e.g., mitotic wave propagation, synchronous embryo cleavages, and somitogenesis). To pin down the physical mechanisms that give rise to these complex collective phenomena, we integrate mathematical modeling, live embryo and explant imaging, nanofabrication, micro-contact printing, and systems and synthetic biology approaches.