Dynamics and Bifurcations of Population Structures Induced by Cell Cycle Feedback

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DESCRIPTION (provided by applicant): Quorum, density or efficiency sensing, as well as other forms of inter-cellular communication, have been found to impact many of the physiological processes that are important in biology, medicine and human health. Working in yeast we have shown that cell cycle dependent feedback of a non-local form can produce an oscillating population density. The mathematical results, observed across a wide range of models, with and without randomness, suggest that the phenomena is robust. The phenomenon is observed when cells in one part of the cell cycle (G0,G1,S,G2,M) communicate with cells in another via metabolites and/or pheromones, with the consequence that the later population experiences advances and/or delays in their growth rate. The outcome of the advances or delays is that the population density becomes multi-modal and clustered. (Consider how traffic lights produce clusters of cars.) Experimental data support the observation that feedback of this form produces clusters of pseudo-synchronized cells that traverse the cell cycle in unison. Our prior work shows that the size and location of signaling and responsive regions within the cell cycle, and cell age, influences the integer number of emergent clusters. These factors suggests a picture in which the geometry of the cell cycle is more influential than the explicit form and strength of the feedback. By (1) focusing narrowly on phenomenological models of feedback that involve density dependence and the geometry of the cell cycle, and (2) tightly coupling measurement with modeling and analysis, we will make progress toward understanding the phenomenon of clustered populations and lay the foundations of a bifurcation theory in this setting that describes how the number of clusters can and will respond to external and genetic variation. Oscillating population density can be exploited in the laboratory and the clinic to prolong cell cycle synchrony or to reduce the cost of protein purification. Cell cycle dependence can con found virtually any assay involving populations of proliferating cells, from diagnostic measurements of bio molecules and biomarkers to metabolic studies of tumor progression. Models that can predict and de convolve the effects of population structure are likely to be useful across systems biology and biomedicine.