A Systems Biology Approach to Microbiology and Cancer

Systems biology is an interdisciplinary field that focuses on elucidating complex biological processes (systems) by investigating the interactions among its components through an iterative cycle composed of data generation, data analysis and mathematical modeling. Our contributions to systems biology revolve around the following two axes:

• Data analysis: Two data analysis projects, which were initiated when I was a co-op at GlaxoSmithKline, are discussed in this thesis. First, next generation sequencing data generated for a phase I clinical trial is analyzed to determine the altered microbial community in human gut before and after antibiotic usage (Chapter 2). To our knowledge, there have not been similar comparative studies in humans on the impacts on the gut microbiome of an antibiotic when administered by different modes. Second, publicly available gene expression data is analyzed to investigate human immune response to tuberculosis (TB) infection (Chapter 3). The novel feature of this study is systematic drug repositioning for the prevention, control and treatment of TB using the Connectivity map.

• Mathematical modeling: Polynomial dynamical systems, a state- and time- discrete logical modeling framework, is used to model two biological processes. First, a denitrification pathway in Pseudomonas aeruginosa is modeled to shed light on the reason of greenhouse gas nitrous oxide accumulation (Chapter 4). It is the first mathematical model of denitrification that can predict the effect of phosphate on the denitrification performance of this bacterium. Second, an iron homeostasis pathway linked to iron utilization, oxidative stress response and oncogenic pathways is constructed to investigate how normal breast cells become cancerous (Chapter 5). To date, our intracellular model is the only expanded core iron model that can capture a breast cancer phenotype by overexpression and knockout simulations.