Investigating the systems complexity of cellular information processing at and across different levels: Biochemical modification systems, cellular networks, and populations
File(s)
Author(s)
Ramesh, Vaidhiswaran
Type
Thesis
Abstract
Cells continuously process information, simultaneously reacting to environmental cues, interacting with other cells and maintaining the numerous intra-cellular processes required to function and sustain life. The cell undertakes this task by leveraging internal reaction networks whose defining feature is their multi-level and multi-functional nature. These factors present formidable systems challenges. We aim to address these systems challenges associated with information processing at and across different levels by focussing on the following key studies, 1. Exploring intrinsic information processing capabilities of substrate modification systems, 2. Dissecting multi-level interactions between network regulation and substrate modification systems, 3. Understanding the collective behavior of cells (with their internal networks) and populations. We first focus on the complexities within a given level. Substrate modification provides functionality to a protein and such modifications ubiquitous within a cell. We studied their intrinsic information processing capacity by, 1. Using the new vista of symmetry in reaction kinetics to explore symmetry breaking and its associated features, and 2. Building an unified approach to study their propensity to enable biphasic dose responses. Such modification systems however are seldom modular and often interact with the wider cellular network. Building on work by Dr. Thapanar Suwanmajo, we then study the behavior of these networks across levels, focusing on their interplay with canonical network regulation such as feedback and feedforward. Finally, beyond the cell, we study the role of multi-level cross-population interactions in enabling the collective behavior of cells and populations at different levels. Throughout we utilize a consolidated methodology (computational, analytical and semi-analytical approaches), that allows us to tackle these systems challenges and characterize the effect of parameters. We provide strict characterization (as a function of parameters) of multiple emergent behaviors, trace transitions and origins of behavior, and provide guarantees for presence/absence of behavior. Our analysis provides multiple evidences of novel behavior arising from the multilevel and systems interplay. At the substrate modification level, we show symmetry breaking leading to multistability and absolute concentration robustness of different kinds, and our unified approach to biphasic doses, reveals how various systems can present enzyme or substrate biphasic or a combination of both. Across levels we show substrate modification together with network regulation can present novel behavior (multistability from negative feedback) and the interplay can subvert expected response from each level. At the level of cells and populations, we show collective behavior arising from multi-level and multi-population interactions, that cannot be attributed or realized from one level or one population. Together, these studies represent a first step in tackling the complexity of multi-level cellular information processing.
Version
Open Access
Date Issued
2022-10-18
Date Awarded
01/12/2022
License URL
Advisor
Krishnan, J
Sponsor
Imperial College London
Publisher Department
Chemical Engineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)