Understanding the robustness of cell cycles

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Project Summary Biological oscillators are essential to a variety of cyclic processes in cells and development. These include cell divisions, heartbeats, and somitogenesis. Impaired biological oscillators may cause diseases from insomnia to cancer. It is thus crucial for an oscillator to develop the ability to maintain a stable function against the changes in environmental conditions. The architecture of many oscillators is highly conserved among species, despite that the actual molecules may vary from species to species. This highlights the important role of network topology in the functions of biological oscillators. How the network structure is linked to the certain functions of biological oscillators is still an open challenging question in systems and synthetic biology. The goal of this proposal is to identify the fundamental principles underlying the robust functioning of clock networks. To achieve the goal, a systematic computational approach will be applied to analyze all topological modifications that significantly impact the robustness and tunability of clock networks. As a comparison to computational studies, this proposal will experimentally investigate the possible mechanisms by which cell cycles retain robust oscillations. The proposed experiments make use of a droplet-based microfluidic system, where cell-free extracts are encapsulated in droplets to mimic single cells that undergo mitotic cycles. This artificial cell system will be integrated with live embryo imaging and stochastic modeling, to track and analyze many single oscillators simultaneously, and thereby quantify the robustness of the mitotic cycles to environmental changes and molecular stochasticity. To study the role of network structure in the robustness of the clock, results from intact oscillators will be compared with the ones whose sub-networks are compromised. The results from the mitotic clock may apply to a broad set of other clocks that share similar topological cores. The results should also provide valuable insights on how to design a robust synthetic clock.