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Title: Computational methods for multi-omic models of cell metabolism and their importance for theoretical computer science
Author: Angione, Claudio
ISNI:       0000 0004 5372 1389
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2015
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To paraphrase Stan Ulam, a Polish mathematician who became a leading figure in the Manhattan Project, in this dissertation I focus not only on how computer science can help biologists, but also on how biology can inspire computer scientists. On one hand, computer science provides powerful abstraction tools for metabolic networks. Cell metabolism is the set of chemical reactions taking place in a cell, with the aim of maintaining the living state of the cell. Due to the intrinsic complexity of metabolic networks, predicting the phenotypic traits resulting from a given genotype and metabolic structure is a challenging task. To this end, mathematical models of metabolic networks, called genome-scale metabolic models, contain all known metabolic reactions in an organism and can be analyzed with computational methods. In this dissertation, I propose a set of methods to investigate models of metabolic networks. These include multi-objective optimization, sensitivity, robustness and identifiability analysis, and are applied to a set of genome-scale models. Then, I augment the framework to predict metabolic adaptation to a changing environment. The adaptation of a microorganism to new environmental conditions involves shifts in its biochemical network and in the gene expression level. However, gene expression profiles do not provide a comprehensive understanding of the cellular behavior. Examples are the cases in which similar profiles may cause different phenotypic outcomes, while different profiles may give rise to similar behaviors. In fact, my idea is to study the metabolic response to diverse environmental conditions by predicting and analyzing changes in the internal molecular environment and in the underlying multi-omic networks. I also adapt statistical and mathematical methods (including principal component analysis and hypervolume) to evaluate short term metabolic evolution and perform comparative analysis of metabolic conditions. On the other hand, my vision is that a biomolecular system can be cast as a ?biological computer?, therefore providing insights into computational processes. I therefore study how computation can be performed in a biological system by proposing a map between a biological organism and the von Neumann architecture, where metabolism executes reactions mapped to instructions of a Turing machine. A Boolean string represents the genetic knockout strategy and also the executable program stored in the ?memory? of the organism. I use this framework to investigate scenarios of communication among cells, gene duplication, and lateral gene transfer. Remarkably, this mapping allows estimating the computational capability of an organism, taking into account also transmission events and communication outcomes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Information technology ; Computer science ; Cell biology