Modeling, Analysis, and Control of Heterogeneous Multicellular Oscillators


No two cells in a population are identical to each other. Cell populations are almost universally heterogeneous, with their heterogeneity or variability often underlying complex emergent behavior and phenotypes. Heterogeneity presents a challenge to the discovery, characterization, and control of multicellular systems. Heterogeneity exists across multiple scales, ranging from the molecular or subcellular level to the population level, and deriving from multiple sources. To better understand how heterogeneity propagates and affects system level function, it is essential to characterize it effectively. In my thesis, I develop methods to characterize heterogeneity and analyze its functional consequences on the core circadian clock in eukaryotes, a system of vital importance to the animal's health and viability. The first part of the thesis is focused on the characterization of heterogeneity and investigating its downstream effects on the natural behavior of the circadian clock, while the latter part focuses on studying how heterogeneity affects our ability to control this multicellular system. The results from my work indicate that a certain level of heterogeneity is beneficial to the system, providing increased robustness to environmental perturbations, as well as making the system easier to control through the use of external inputs. These insights impact the control of such multicellular systems, as well as inform the design of synthetic or engineered biological systems. I conclude this thesis by making a case for incorporating heterogeneity as a key consideration in the analysis and design of complex dynamical systems.

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