| Description |
Life is a dynamic and cooperative system. Like a multidimensional network, this system includes many types of relations between many types of entities. A single human cell comprises tens of thousands of types of large, polymeric molecules such as genes, transcripts, proteins, sugars, and lipids; and there are also many more types of small, molecular metabolites. Each of these biochemical entities has speci c properties and functions in life. Healthy homeostasis demands extensive interaction and continuous change to balance internal hereditary and regulatory factors against external, environmental challenges. This complexity is the only route to survival, growth, and reproduction. Ironically, life's cooperative, adaptive system complicates medicine. Human diseases such as obesity, diabetes, cardiovascular disease, neurodegeneration, and cancer occur when the biological system is unable to maintain homeostasis. Medicine attempts to restore this balance, but there are multiple challenges to this e ort. First, e ectively all diseases are complex, as perturbations pervade the biological system and combine either compensatorily or cooperatively. Second, germ-line evolution creates hereditary heterogeneity across a population, and somatic mutations and other adaptations are progressive even within individuals. Consequently, each individual is fundamentally unique even in health, and disease itself is progressive. Essentially, the aim of personal, precision medicine is to hit a target that for each patient is both unique and constantly changing. There is an urgent need to understand the complex relations within the biological system and how this system evolves both at the level of the population's heterogeneity and each disease's progression. Metabolism is an integral part of life's complex system and is of interest to understand human health and disease. This collection of chemical reactions on metabolites supplies the energetic and biosynthetic needs of cells, tissues, and organisms. This dissertation describes studies to explore metabolism from both reductionist and systemic perspectives. Reductionist experiments o er intricate detail on mechanisms of metabolic regulation and their putative disruption in human disease. Systemic analyses describe the extent of connectivity and cooperativity in metabolism. Together these approaches are essential for the reliable design of experiments and the accurate interpretation of their measurements, especially from modern omics technologies that measure biological entities at nearly comprehensive scales. iv |
