恒元物理学讲座（第096期）：Stochasticity and Synchronization of Single-Cell Biological Clocks

讲座内容：Oscillators, by virtue oftheir periodic dynamics, provide a way to tell time, as illustrated by theperiodic movement of a clock’s pendulum. The study of coupled oscillatorsand their mutual synchronization has remained a problem central to physics forcenturies, but has also captured the imagination of biologists in recent times.One example of synchronized oscillators are the circadianbiological clocksfound in living cells. Biological clocks are pervasive in their effects fromgenes to ecosystems. Biological clocks affect the health ofanimals and plantsand they are being engineered for timed delivery of therapeutics, algalbioreactors for biofuel production, and crop improvement. The clock, throughits light entrainment feature, impacts the genetic dynamics of bacterialassemblages in the world’s oceans and hence may affect carbon cyclingin marine ecosystems. Understanding how cell populations synchronize theirclock oscillations, to give rise to a fully functional“biological clock”，is therefore ofsubstantial interest incurrent systems biology research.

In this lecture, Iwillreview our past experimental and modeling studiesof the gene regulatorysystem dynamics of the biological clock in the filamentous fungus Neurosporacrassa at the level of macroscopic cell populations [1,2]. I will then discussrecent micro-fluidics-based experiments on the N. crassa biological clock,andits stochastic modeling,at the single-cell and few-cell level [3].In theseexperiments, one or a few cells are isolated inside small water dropletsimmersed in oil. Time series of fluorescent signals from clock-controlled (CCG)gene products are recorded for each individual cell. Detailed noise propagationanalyses 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 thefew-cell level, statistical analysis of observations from 2-cell to 15-celldroplets demonstrate that the clocks become highly correlated when confined inclose spatial proximity within the same aqueous droplet, suggesting that thesecorrelations may be the precursor to the fully developed coherent clockoscillations observed in large cell populations. Ensemble network simulations(ENS) [4] are performed onstochastic chemical reaction network modelsof single-and multiple-cell systems.The ENS results show that a clock model withGillespie-type stochastic reaction kinetics and a quorum sensing inter-cellcommunications [3] are generally consistent with the experimental single- andfew-cell data. Experimental searches are currently under way to identifypossible diffusible exo-metabolites which could mediatesuchquorum-sensinginter-cell communications. Lastly, I will also discuss the light entrainmenteffects observed insingle cellssubjected to periodic on-off-illumination andtheir relation to the light entrainment seen in macroscopic cell populations.

[1] Y. Yu, W. Dong, C. Altimus, X. Tang, J. Griffith, M. Morello, L.Dudek, J. Arnold & H.-B. Schüttler, Proc. Natl. Acad. Sci. (USA)104, 2809 (2007).

[2] W. Dong, X. Tang, Y. Yu, R. Nilsen, R. Kim, J. Griffith, J. Arnold& H.-B. Schüttler, PLoS ONE 3 (8):e3105 (2008).

[3] Z. Deng, S. Arsenault, C. Caranica, J. Griffith, T. Zhu, A. Al-Omari,H.-B. Schüttler, J. Arnold, L. Mao, Scientific Reports 6, 35828 (2016).

[4] D. Battogtokh, D.K. Asch, M.E.Case, J. Arnold and H.-B. Schüttler, Proc. Natl.Acad. Sci. (USA) 99, 16904 (2002).