Systems Biology – challenges in experimental and theoretical sciences Prof. Stefan Hohmann Department of Cell and Molecular Biology Göteborg University, Sweden CMB - Cell and Molecular Biology - Group Stefan Hohmann

Systems Biology – an approach Understanding the higher-order properties of systems of biomolecules (rather than individual biomolecules) by applying to biology approaches of mathematics, theoretical physics, computer sciences and engineering. Using mathematical models may move biology from a descriptive to a predictive discipline. Predictive capabilities to treatment of diseases and bioengineering. CMB - Cell and Molecular Biology - Group Stefan Hohmann

Systems Biology - directions Top-down or data-driven Networks from large-scale data Bottom-up or model-driven Dynamic modelling – simulating processes over time CMB - Cell and Molecular Biology - Group Stefan Hohmann

EC funds several projects on dynamic modelling in FP6 QUASI – yeast MAPK signalling AMPKIN – AMP-activated protein kinase signalling COSBICS – JAK-STAT and MAPK signalling RIBOSYS – yeast RNA metabolism YSBN – Coordinating yeast systems biology CMB - Cell and Molecular Biology - Group Stefan Hohmann

Quantifying signal transduction CMB - Cell and Molecular Biology - Group Stefan Hohmann

QUASI consortium Gothenburg (biology: S Hohmann, P Sunnerhagen; chemistry: M Grøtli) Sweden Barcelona (biology: F Posas) Spain Vienna (biology: G Ammerer) Austria Zürich (biology: M Peter) Switzerland Berlin (theoretical physics: E Klipp) Germany CMB - Cell and Molecular Biology - Group Stefan Hohmann

Types of measurements to estimate parameters Rate of changes of phospho-MAPK Certain other phospho-proteins Rate of changes of mRNA levels of reporter genes Levels and rate of change and transport of glycerol Rate of change of certain protein-protein interactions Hog1 MAPK nuclear shuttling CMB - Cell and Molecular Biology - Group Stefan Hohmann

Types of perturbations to test mathematical models Genetic changes in pathways Genetic changes in responses (osmoregulation) Specific kinase inhibitors Changes in experimental conditions CMB - Cell and Molecular Biology - Group Stefan Hohmann

Integration of signalling, gene expression, metabolism, transport and biophysical changes CMB - Cell and Molecular Biology - Group Stefan Hohmann Edda Klipp

Questions addressed by QUASI Feedback control mechanisms in pheromone and high- osmolarity signalling MAPK pathways Control of cell cycle by MAPK pathways Control of a eukaryotic osmolyte system Regulation of gene expression by Hog1 MAPK Integration of converging branches of signalling pathway (HOG branches) Pathway crosstalk CMB - Cell and Molecular Biology - Group Stefan Hohmann

Systems Biology of AMP-activated protein kinase AMPKIN AMPK is the cellular energy regulator in eukaryotes and a possible target for drugs towards diabetes type II CMB - Cell and Molecular Biology - Group Stefan Hohmann

AMPKIN consortium Gothenburg (biology: S Hohmann; physics: M Goksör) Sweden Lyngby (bio-engineering: J Nielsen) Denmark Rostock (computer science: O Wolkenhauer) Germany London (biology: D Carling) UK Arexis/Biovitrum (drug company – left project) Sweden AMPKIN CMB - Cell and Molecular Biology - Group Stefan Hohmann

Glycolytic flux and rates of changes of metabolite levels Rates of changes of phospho-AMPK Rates of changes of phosphorylated forms of certain target proteins Activity of target enzymes Absolute levels and rates of changes for many pathway components Rates of changes of mRNA levels for reporter genes Population proflies using reporter-XFP and FACS Nuclear shuttling of Mig1 Types of measurements to estimate parameters AMPKIN CMB - Cell and Molecular Biology - Group Stefan Hohmann

Types of perturbations to test mathematical models Genetic changes in pathways Genetic changes in metabolism Specific kinase inhibitors Changes in experimental conditions AMPKIN CMB - Cell and Molecular Biology - Group Stefan Hohmann

Questions addressed by AMPKIN Comparative modelling of yeast and mammalian pathways Integration of metabolism and signalling Mechanisms controlling pathway activity Signalling via kinases or phosphatases Contributions of parallel pathways AMPKIN CMB - Cell and Molecular Biology - Group Stefan Hohmann

FP7 calls with deadline April 2007 A system approach to eukaryotic unicellular organism biology. Modelling of T-cell activation. Fundamental approaches to stem cell differentiation. Developing an integrated in vitro, in vivo and systems biology modelling approach to understanding apoptosis in the context of health and disease.

UNICELLSYS Eukaryotic unicellular organism biology – systems biology of the control of cell growth and proliferation Large collaborative project , five years EC-funding 11.7 million € Sixteen partners and more than 30 principle investigators Bringing together major capacity in data generation and dynamic modelling CMB - Cell and Molecular Biology - Group Stefan Hohmann

UNICELLSYS

The overall objective of UNICELLSYS is a quantitative understanding of fundamental characteristics of eukaryotic unicellular organism biology: how cell growth and proliferation are controlled and coordinated by both extracellular and intrinsic stimuli. Achieving an understanding of the principles with which systems of bio-molecules function requires integrating quantitative experimentation with simulations of dynamic mathematical models in a systems biology approach. Growth Development Proliferation Nutrients Stress Hormone PKA, TOR, Snf1, Snf3/Rgt2 PHD PKA PKA, HOG, PKC ? STE STE, PKC CMB - Cell and Molecular Biology - Group Stefan Hohmann

Conclusions Quantitative understanding of cell and organism physiology is a multidisciplinary endeavour Major challenges in data generation (quantitative, molecule numbers, time resolved, single cells....) Major challenges for modelling (abstraction, parameter and model identification/discrimination, model reduction, integration of different processes, molecule- module-cell-organ-organism, stochastic processes....) Challenges in defining appropriate research infrastructures and forms of collaboration locally and Europe-wide CMB - Cell and Molecular Biology - Group Stefan Hohmann

Present collaborators and funding The QUASI EC Project (2007): F Posas, M Peter, G Ammerer, E Klipp, M Grøtli, P Sunnerhagen The MalariaPorin EC Project (2007): E Beitz, P Agre, S Flitsch, H Grubmüller The Sleeping Beauty EC Project (2008): E Lubzens, M Clark, R Reinhard, J Cerda, J Nielsen The Systems Biology Early Stage Training EC project (2008): R van Driel, E Klipp, R Heinrich The Yeast Systems Biology Network (2008) with about 20 groups in Europe (EC-funded Coordination Action) and 40 groups world-wide The Sweden-Japan Vinnova project (2009): H Kitano The AMPKIN EC Project (2009): D Carling, J Nielsen, O Wolkenhauer, Biovitrum/Arexis AB The Aqua(glycero)porin RTN EC Project (2010): S Flitsch, H Grubmüller, P Deen, A Engel, S Nielsen, R Neutze, J Cerda, Z Vajda, E Klipp The CELLCOMPUT NEST EC Project (2011): F Posas, R Solé, M, E Klipp, M Grøtli The UNICELLSYS EC Project (2012): 16 different partners Funding from the Swedish Research Council (2007) Ingvar grant from SSF (2010) to Karin Lindqvist Funding from the Swedish Research Council (2007) to Markus Tamás (position and project) Faculty platforms in Quantitative Biology and Chemical Biology (2009/11) with groups in in physics (D Hanstorp), chemistry (M Grøtli), computational biology (M Jirstrand, O Nerman, B Wennberg), structural biology (R Neutze) and biology (T Nyström, A Blomberg, P Sunnerhagen) CMB - Cell and Molecular Biology - Group Stefan Hohmann

Courses and conferences CMB - Cell and Molecular Biology - Group Stefan Hohmann