Understanding 'global' systems biology: Metabonomics and the continuum of metabolism

To apply genomic knowledge effectively in drug discovery, mechanistic connectivities between genetic variation and disease processes need to be established via systems biology approaches. Humans have hundreds of functionally specialized cell types that interact differentially with environmental factors to influence disease development and to modulate the effects of drugs. Metabonomics can provide a means of modelling these interactions, but the relationships between 'endogenous' metabolic processes (coded in the genome and intrinsic to cellular function) and 'xenobiotic' (foreign compound) metabolism are poorly understood, especially with respect to environmental factors. We present an overview of 'global' mammalian metabolic conversions that should be accounted for in human systems biology models and propose a new probabilistic approach to help understand gene-disease relationships and vexed issues of idiosyncratic drug toxicity.