We want to understand how the behavior of living cells is produced by the biochemical interactions of many non-living molecules. We believe that a quantitative theory of how cells work will lead us to better treatments for disease and ultimately the ability to reprogram cells. The lab is currently focused on a bacterial circadian clock that can be rebuilt using a mixture of three proteins (KaiABC). We use a combination of mathematical modeling, biochemical, and advanced microscopy approaches.

Circadian Clocks and Metabolism

Pioneering work from Takao Kondo's lab showed that the KaiABC proteins alone could keep time in a test tube. In a living cell, however, there must be mechanisms that allow the Kai proteins to sense the external environment and learn whether it is day or night. Our attempts to find these mechanisms began with the observation that the activity of the Kai proteins responds to metabolites that mirror the energy and redox state of the cell. Remarkably, the clock time can be reset when metabolism changes, but the period of the clock remains the same.

We've recently found that the clock itself drives rhythms in metabolism, telling the cell to accumulate energy storage molecules it needs for the night. When these rhythms in glycogen storage are disturbed, the clock can no longer reset appropriately. These findings point to a deep connection between clock function and metabolism that we are continuing to unravel.

Biophysical Basis of Circadian Rhythms

Circadian rhythms cycle about once a day, a remarkably slow time compared to the molecular jiggling within proteins. Where does the slow time come from? How can it be so resistant to temperature changes, unlike most biochemical reactions? Is the way the bacterial clock proteins generate rhythms fundamentally similar to or different from the proteins in our cells? The keys to answer these questions must lie in the physical structures of the clock proteins which generate a slow rhythm in multisite phosphorylation. We are developing new biochemical and biophysical approaches to help understand these processes. We've found that the "double doughnut" design of KaiC is key, and that information about time-of-day (stored in protein phosphorylation) causes a cooperative change in the KaiC ring. In collaboration with Andy LiWang's lab, we helped show that a slow refolding of the KaiB structure is needed to allow the clock proteins to form a complex.

Clock Function in Fluctuating Environments

Most studies on the molecular networks that produce biological rhythms are based on experiments where oscillations are allowed to free-run in a constant environment. However, constant laboratory conditions have nothings to do with the challenges that clocks must face in the real world. We are working to study how clocks and cells respond when they live in conditions that fluctuate between day and night, with both seasonal changes and the noisy random fluctuations seen in ecological recordings of light intensity. Our goal is to better define the function of circadian clocks and to understand the role of the signaling networks clocks are embedded in.

Evolution of Circadian Clocks

Cyanobacteria, because they have the simplest known circadian oscillator and a relatively rapid doubling time, present a unique opportunity to study the fitness advantages conferred by a circadian clock. Guided by mathematical models of the cyanobacterial clock, we are working to define environmental conditions where a stable free-running oscillator gives a fitness advantage over simpler proto-circadian systems.

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