Collective Behavior of Cellular Oscillators

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Collective behavior can be observed in a variety of contexts and across biological scales, from the blinking of fireflies, the marching of locusts, the flocking of birds, down to the synchronized behavior of cells in tissues. Single cells have a biological clock, but their synchronized timekeeping is usually only observed at the level of tens of millions of cells. A grand challenge is understanding how cellular clocks in organisms, tissues, and cells become synchronized to keep time. Using a model fungal system, Neurospora crassa, investigators consider two principal theories on the emergence of clock synchronization: (1) through a shared biochemical signal between cellular clocks; (2) through the random switching of clock genes within a cell. In examining these two scientific theories, investigators explore the origin of the biological clock from a single cell perspective, which remains an open challenge since the Nobel Prize winning discoveries of Hall, Young, and Rosbash linking genes to circadian rhythms. As part of the Broader Impact activities investigators develop new projects in the area of biological clock research for two REU site programs in Genomics and Computational Biology and Nanotechnology and Biomedicine, which actively recruits students from Clark Atlanta University. The team will also organize and contribute to the Gordon Conference on Collective Behavior (GRC).In order to understand the synchronization of clocks between cells, there are several challenges that need to be addressed, including: (1) lack of working stochastic network models to describe populations of cellular clocks; (2) lack of a direct test for interrogating the biochemical signals as quorum sensing based synchronization mechanisms; (3) lack of knowledge on what signal(s) synchronize(s) cellular clocks; (4) lack of evidence to determine whether or not stochastic switching in clock genes plays a role in synchronization – the stochastic resonance (coherence) hypotheses; (5) lack of understanding how the clock functions at the predominant life stage of fungi, the filament. The goal of this work is to understand the synchronization of biological clocks between cells and filaments in N. crassa by two mechanisms, quorum sensing vs. Stochastic Resonance (Coherence). The interdisciplinary team will investigate mechanisms of collective behavior using: novel microfluidics platforms to measure phase synchronization of biological clocks on a controlled number of living N. crassa cells, methods from Statistical Physics to test quorum sensing versus Stochastic Resonance theoretical frameworks, and a newly developed Continuous in vivo metabolism-NMR (CIVM-NMR) method to identify and characterize signaling molecules that may be responsible for clock synchronization. The research-driven Broader Impact activities include: (1) Development of interdisciplinary research-centered course, Clock Collaboratorium; (2) Development of undergraduate research projects focused on the central theme of the biological clock, which will be deployed in two NSF REU site programs; and (3) Organization of a collective behavior community that will engage through a new Gordon Research Conference in Newport, RI.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.