Network-centric analysis of cellular metabolism
Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
Thursday 13 June 2019 (12h15 - 13h00) - Génopode - Auditoire A
Abstract of the talk :
Metabolism plays a pivotal role in all cellular processes by providing building blocks and energy for biosynthesis and participating in decision-making. In many biomedical areas such as oncology, toxicology, immunology, stem cell research, etc., metabolism is regarded as a key driver and a differentiating factor to be exploited in diagnostics and selective therapy. Historically, the discovery of aberrant metabolism has been mainly accomplished at the genetic level, e.g. by identifying peculiar enzyme mutations in primary material, by finding upregulation of atypical (embryonic) isoforms at expression level, or screening for sensitivity to RNAi in cell lines or mice. Albeit highly valuable, these approaches suffer from intrinsic limitations in scope and sensitivity. Our lab approaches metabolism bottom-up, which means from a functional perspective. Experimentally, we rely heavily on metabolomics and the analysis of metabolic fluxes by stable isotopic tracers. Both metabolite and fluxes provide an integrated view of the metabolic network in action, which emerges from the interplay of cellular components. Over the past 10 years, our lab has pioneered multiple methods for high-throughput analysis by mass spectrometry. It has become technically straightforward to profile large cohorts with > 10’000s of samples. Consequently, the research focus shifted from data generation to data integration.
The grand challenge is to infer mechanistic insights from static and dynamic data. For this purpose, it is essential to integrate prior knowledge on the metabolic network such as topology, stoichiometry, thermodynamics, and kinetics. However, there is a general lack of suitable methods and, hence, ample room for the development of novel approaches. I will describe some of our efforts that range from graphical to kinetic models.