YeastX - Towards an Understanding of Nutrient Signaling and Metabolic Operation
Essentially all biological processes are orchestrated through precise and dynamic regulation of cell behavior that is initiated by the cell’s ability to “read” environmental conditions and signals, to “translate” them into intracellular commands, and to “react” with appropriate responses. As linear as it may seem, it is a truly interconnected and dynamic control system because the functional responses feed back, for example through metabolite-protein interactions. One of the most fundamental of such control systems is nutrient sensing, which establishes an intricate balance between processes that modulate gene expression and in vivo activity of about 1000 proteins within the ubiquitous metabolic network. Although supposedly well “understood”, many basic questions remain unanswered, even in model organisms.
The complexity in cellular signaling and control originates from the large number of molecules and multiple types and strengths of interactions between them and the feed back signals from the biological processes controlled by them. The molecular approach has been very successful in providing us with a qualitative and schematic understanding of many involved processes. It fails, however, to cope with this complexity because intuitive generation of hypotheses and design of conclusive experiments becomes increasingly difficult with system complexity.
While systems biology aims to address this fundamental dilemma of modern biology, it is currently limited by at least two factors. Firstly, the available experimental methods provide data that are limited by their completeness, their quantitative accuracy, and restricted diversity. Secondly, the available computational methods are not tailored towards the requirements of systems biology, such that, in most cases, the naïve notion of constructing a single predictive model is of only limited success. Nutrient signaling and its transcriptional and metabolic response in the eukaryotic model yeast S. cerevisiae is probably the most obvious test-bed for ideas and theories, because experimental verification is feasible, even at genome-scale.
YeastX will set us on a path towards comprehensive mathematical models and understanding of C and N signaling, regulation and metabolism, thereby developing fundamental experimental and computational methods for systems biology in general. As a paradigm, we will tightly integrate experimental and modeling efforts to guide and minimize time-consuming and expensive experiments. YeastX brings together leading Swiss groups from theory and biology, and is partly motivated by encouraging results from several SystemsX pilot projects. By combining the unique experimental capacity at the Institute of Molecular Systems Biology with the mathematical and computational expertise in Zurich and the yeast signal transduction expertise at ETH and in Basel, we propose to extend the scope of the previous analyses to dynamic modeling of metabolism and the regulation and information networks that control it. The iterative process of experiment and theory is quickest in yeast, and the emerging understanding, developed methods and approaches are likely to have a high impact beyond the chosen system, in particular because the underlying molecular processes are highly similar at the cellular level and the fundamental control problems are ubiquitous for most cellular information processing.
