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WELCOME TO THE MAX PLANCK INSTITUTE FOR DYNAMICS OF COMPLEX TECHNICAL SYSTEMS MAGDEBURG. Program 14:30 p.m. Welcome to the institute and introduction of the Systems Biology Group (Ernst Dieter Gilles, Jörg Stelling) 15:00 p.m. Introduction of the group and purpose of study
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WELCOME TO THEMAX PLANCK INSTITUTEFOR DYNAMICS OF COMPLEX TECHNICAL SYSTEMSMAGDEBURG Program 14:30 p.m. Welcome to the institute and introduction of the Systems Biology Group (Ernst Dieter Gilles, Jörg Stelling) 15:00 p.m. Introduction of the group and purpose of study (Marvin Cassmann) 15:30 p.m. Refreshment and start of poster session 16:30 p.m. Viewing of the biological laboratories 17:30 p.m. End
MAX PLANCK INSTITUTEFOR DYNAMICS OF COMPLEX TECHNICAL SYSTEMSMAGDEBURG • Founded in 1996 as 1st Max Planck Institute of Engineering • Start of research activities in 1998 • 4 departments: • Process Engineering (Sundmacher) • Bioprocess Engineering (Reichl) • Physical and Chemical Fundamentals (Seidel-Morgenstern) • System Theory (Gilles)
BROAD SPECTRUM OF PROCESSES TO DEAL WITH: Provides methods and tools SYSTEM SCIENCES (SYSTEM THEORY) Integrating factor Chemical Processes Biochemical Processes Biological Networks •••
SYSTEMS BIOLOGY Biology Information Sciences Quantitative Measurement Data- bases Hypo- theses Modeling Tool Virtual Biological Laboratory Genetic Modi- fication Visuali- zation Analysis Synthesis Modeling Concept Systems Sciences „Systems biology is the synergistic application of experiment, theory, and modeling towards understanding biological processes as whole systems instead of isolated parts.“ Systems Biology Group/Caltech Interdisciplinary approach towards a quantitative and predictivebiology
RESEARCH GROUP: SYSTEMS BIOLOGY • Research activities started in 1998 • 17 employees working in our group • Continuous extension of research activities on metabolic regulation and signal transduction • Interdisciplinary composition of research group • Close cooperation with a network of external biology groups • Fermentation laboratory to perform experiments for model validation and hypotheses testing • Quantitative determination of cellular components • Construction of isogenic mutant strains of E. coli and other microorganisms
OBJECTIVES OF RESEARCH • Improved understanding of cellular systems • New solutions for biotechnological and medical problems (drug target identification) APPROACH • Detailed mathematical modeling • Close interconnection between theory and experiment • Model validation • Model-based design of experiments • Formulation and testing of hypotheses • System-theoretical analysis of dynamics and structural properties • Decomposition into functional units of limited autonomy • Model reduction
COMPLEXITY AND ROBUSTNESS Complex Technical Processes Powerful concepts to cope with increasing complexity • Modularity techniques • Hierarchical structuring • Redundancy and diversity Biological Systems Similar features of structuring • Natural modularity decomposition into functional units of limited autonomy • Hierarchical structuring of regulation • Redundancy and diversity of pathways, sensors and other key units Objectives of these concepts in both fields • Robustness of functionality • Reduction of fragilities Methods and tools developed in engineering, also appropriate for biological systems Control Theory, Nonlinear Dynamics, System Theory …
PROJECTS OF THE GROUP Biology Information Sciences Data- bases Quantitative Measurement Modeling Tool Hypo- theses Virtual Biological Laboratory Genetic Modi- fication Visuali- zation Analysis Synthesis Systems Sciences Modeling Concept SIGNAL TRANSDUCTION AND REGULATION IN BACTERIAL CELLS SIGNAL TRANSDUCTION AND REGULATION IN EUKARYOTES COMPUTER AIDED MODELING AND ANALYSIS OF CELLULAR SYSTEMS
PROJECT: SIGNAL TRANSDUCTION AND REGULATION IN BACTERIAL CELLS Redox Control in Photosynthetic Bacteria (H. Grammel, S. Klamt) Mathematical Modeling of Catabolite Repression in E.coli (K. Bettenbrock, S. Fischer, A. Kremling) Phototaxis in Halobacterium Salinarum (T. Nutsch) Uni Stuttgart (Prof. Gosh; ISR) Uni Magdeburg (Prof. Reichl) MPI Biochemie (Prof. Oesterhelt) Uni Freiburg (Dr. Marwan) Uni Osnabrück (Prof. Lengeler) Biology Information Sciences Regulation of Stress Sigma Factor σS (T. Backfisch) Two-component Signal Transduction in E.coli (A. Kremling) Quantitative Measurement Data- bases Hypo- theses Modeling Tool Virtual Biological Laboratory Genetic Modi- fication Visuali- zation Analysis Synthesis FU Berlin (Prof. Hengge) Uni München (Prof. Jung) Systems Sciences Modeling Concept
SUB-PROJECT:REDOX CONTROL OF PHOTOSYNTHETIC BACTERIA Fructose Fructose - 6 - EMP phosphate C4/C5/C6/C7 - Glyceraldehyde - Intermediates 3 - phosphate CBB - ATP Glyceraldehyde - Cycle 3 - phosphate Ribulose - 1,5 - NADH NADH bisphosphate 3 - Phospho - glycerate Formiate 3 - Phospho - Acetate glycerate NADH CO 2 2 - OG TCA - OA Cycle SCoA NADH FADH NADH ATP
BLOCK-DIAGRAM OF PHOTOTAXIS MOLECULAR ORIENTED: SIGNAL ORIENTED:
PROJECTS OF THE GROUP Biology Information Sciences Data- bases Quantitative Measurement Modeling Tool Hypo- theses Virtual Biological Laboratory Genetic Modi- fication Visuali- zation Analysis Synthesis Systems Sciences Modeling Concept SIGNAL TRANSDUCTION AND REGULATION IN BACTERIAL CELLS SIGNAL TRANSDUCTION AND REGULATION IN EUKARYOTES COMPUTER AIDED MODELING AND ANALYSIS OF CELLULAR SYSTEMS
PROJECT:SIGNAL TRANSDUCTION AND REGULATION IN EUKARYOTES Mathematical Modeling of Cell Cycle Regulation in Eukaryotes (J. Stelling) Catabolite Repression in Yeast (J. Stelling) Biology Information Sciences Quantitative Measurement Data- bases Modeling Tool Hypo- theses Virtual Biological Laboratory Uni Halle (Prof. Breunig) Uni Stuttgart (Prof. Seufert) Genetic Modi- fication Visuali- zation TCR Signaling Pathway (J. Saez-Rodriguez, X. Wang) HGF/c-Met Signaling Pathway and H. pylori (S. Ebert) Analysis Synthesis TNF-induced Apoptosis (H. Conzelmann, T. Sauter) Modeling Concept Systems Sciences Uni Stuttgart (Prof. Pfizenmaier) Uni Magdeburg (Prof. Schraven) MIT/Merrimack (B. Schoeberl) Uni Magdeburg (Prof. Naumann)
SUB-PROJECT: CELL CYCLE OF S. CEREVISIAE cell division M 4n DNA mass growth G2 CLN1-3 SIC1 2n DNA CLB1-4 G1 CLB3-6 replication control 2...4n DNA S START DNA-Replication • The cell cycle of the yeast consists of discrete phases (G1, S, G2, M) • The transition from one phase to the next strictly depends on a successful termination of all functions of the preceding phase and is always irreversible • The cell cycle can be interpreted as a sequential controller on the highest level of regulation
SUB-PROJECT:CELL CYCLE OF S. CEREVISIAE Molecular Interactions Undisturbed Cell Cycle cell growth Complex interconnection of gene expression and proteolysis of 9 cyclins and the inhibitor Sic 1 leads to periodic cyclin-kinase activities Nocodazole arrest
BMBF: SYSTEMS BIOLOGY – SYSTEMS OF LIFE Interaction of Signal Transduction and Cell Cycle Regulation in Eukaryotes T-cell Receptor Hepatocyte Growth Factor Epidermal Growth Factor Tumor Necrosis Factor Insulin Cell cycle
Cooperation with experimental groups • Uni Magdeburg: • Immunology (Prof. Schraven): TCR • Experimental Internal Medicine (Prof. Naumann): c-Met (HGFR) and H. pylori • Uni Leipzig: • Cell Techniques and Applied Stem Cell Biology (Prof. Bader): EGF, HGF, Insulin and TNF in hepatocytes • Uni Stuttgart: • Cell Biology and Immunology (Prof. Pfizenmaier): TNF • Methods • Phosphorylation Assays (Western Blots), Microscopical Methods, ELISA, microarrays, FACS • Cellular systems • cell lines: HeLa (EGF, TNF), MDCK (HGF), HepG2 • primary cells: mouse-Tcells (TCR), mouse/pig/man-hepatocytes The projects are supported by the German Research Foundation (DFG), German Ministery for Education and Research (BMBF) and State of Saxony-Anhalt
FUTURE OBJECTIVES • Decomposition of signaling network into modules • Criteria and system theoretical methods to demarcate modules in complex signaling networks • Analysis of signal transfer of modules • Building-up of a construction-kit containing a complete set of elementary and disjunctive modules of signal transfer • Analysis of crosstalk phenomena among signaling systems (EGF, HGF, TNF, Insulin, ...) • Analysis of differentiation processes • Interaction between signaling processes and cell cycle control