Stochasticity and Synchronization of Single-Cell Biological Clocks
报 告 人：
Prof. Bernd Schüttler (University of Georgia)
Oscillators, by virtue of their periodic dynamics, provide a way to tell time, as illustrated by the periodic movement of a clock’s pendulum. The study of coupled oscillators and their mutual synchronization has remained a problem central to physics for centuries, but has also captured the imagination of biologists in recent times. One example of synchronized oscillators are the circadianbiological clocks found in living cells. Biological clocks are pervasive in their effects from genes to ecosystems. Biological clocks affect the health ofanimals and plants and they are being engineered for timed delivery of therapeutics, algal bioreactors for biofuel production, and crop improvement. The clock, through its light entrainment feature, impacts the genetic dynamics of bacterial assemblages in the world’s oceans and hence may affect carbon cycling in marine ecosystems. Understanding how cell populations synchronize their clock oscillations, to give rise to a fully functional“biological clock”, is therefore ofsubstantial interest incurrent systems biology research.
In this lecture, I willreview our past experimental and modeling studiesof the gene regulatory system dynamics of the biological clock in the filamentous fungus Neurospora crassa at the level of macroscopic cell populations [1,2]. I will then discuss recent micro-fluidics-based experiments on the N. crassa biological clock,and its stochastic modeling,at the single-cell and few-cell level .In these experiments, one or a few cells are isolated inside small water droplets immersed in oil. Time series of fluorescent signals from clock-controlled (CCG) gene products are recorded for each individual cell. Detailed noise propagation analyses of these time seriesreveal that the biological clock module of single, isolated cells is strongly stochastic, with a broad power spectrum (periodogram) peaked at near-circadian (~22h) oscillation periods. At the few-cell level, statistical analysis of observations from 2-cell to 15-cell droplets demonstrate that the clocks become highly correlated when confined in close spatial proximity within the same aqueous droplet, suggesting that these correlations may be the precursor to the fully developed coherent clock oscillations observed in large cell populations. Ensemble network simulations (ENS)  are performed onstochastic chemical reaction network modelsof single- and multiple-cell systems.The ENS results show that a clock model with Gillespie-type stochastic reaction kinetics and a quorum sensing inter-cell communications  are generally consistent with the experimental single- and few-cell data. Experimental searches are currently under way to identify possible diffusible exo-metabolites which could mediatesuchquorum-sensing inter-cell communications. Lastly, I will also discuss the light entrainment effects observed insingle cellssubjected to periodic on-off-illumination and their relation to the light entrainment seen in macroscopic cell populations.
 Y. Yu, W. Dong, C. Altimus, X. Tang, J. Griffith, M. Morello, L. Dudek, J. Arnold & H.-B. Schu?ttler, Proc. Natl. Acad. Sci. (USA)104, 2809 (2007).
 W. Dong, X. Tang, Y. Yu, R. Nilsen, R. Kim, J. Griffith, J. Arnold & H.-B. Schu?ttler, PLoS ONE 3 (8):e3105 (2008).
 Z. Deng, S. Arsenault, C. Caranica, J. Griffith, T. Zhu, A. Al-Omari, H.-B. Schu?ttler, J. Arnold, L. Mao, Scientific Reports 6, 35828 (2016).
 D. Battogtokh, D.K. Asch, M.E.Case, J. Arnold and H.-B. Schu?ttler, Proc. Natl. Acad. Sci. (USA) 99, 16904 (2002).