1 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 (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

2 MAX PLANCK INSTITUTE FOR DYNAMICS OF COMPLEX TECHNICAL SYSTEMS MAGDEBURG  Founded in 1996 as 1 st 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)

3 BROAD SPECTRUM OF PROCESSES TO DEAL WITH: SYSTEM SCIENCES (SYSTEM THEORY) Provides methods and tools ChemicalProcessesBiochemicalProcessesBiologicalNetworks Integrating factor

4 SYSTEMS BIOLOGY Data- bases Visuali- zation Hypo- theses Genetic Modi- fication Analysis Modeling Concept Synthesis Modeling Tool Quantitative Measurement Virtual Biological Laboratory Interdisciplinary approach towards a quantitative and predictive biology „ 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

5 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

6 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

7 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 …

8 PROJECTS OF THE GROUP Data- bases Visuali- zation Hypo- theses Genetic Modi- fication Analysis Modeling Concept Synthesis Modeling Tool Quantitative Measurement Virtual Biological Laboratory SIGNAL TRANSDUCTION AND REGULATION IN BACTERIAL CELLS SIGNAL TRANSDUCTION AND REGULATION IN BACTERIAL CELLS SIGNAL TRANSDUCTION AND REGULATION IN EUKARYOTES SIGNAL TRANSDUCTION AND REGULATION IN EUKARYOTES COMPUTER AIDED MODELING AND ANALYSIS OF CELLULAR SYSTEMS COMPUTER AIDED MODELING AND ANALYSIS OF CELLULAR SYSTEMS

9 PROJECT: SIGNAL TRANSDUCTION AND REGULATION IN BACTERIAL CELLS Data- bases Visuali- zation Hypo- theses Genetic Modi- fication Analysis Modeling Concept Synthesis Modeling Tool Quantitative Measurement Virtual Biological Laboratory Uni Stuttgart (Prof. Gosh; ISR) Uni Magdeburg (Prof. Reichl) Redox Control in Photosynthetic Bacteria (H. Grammel, S. Klamt) Two-component Signal Transduction in E.coli (A. Kremling) Uni München (Prof. Jung) Mathematical Modeling of Catabolite Repression in E.coli (K. Bettenbrock, S. Fischer, A. Kremling) Uni Osnabrück (Prof. Lengeler) Phototaxis in Halobacterium Salinarum (T. Nutsch) MPI Biochemie (Prof. Oesterhelt) Uni Freiburg (Dr. Marwan) Regulation of Stress Sigma Factor σ S (T. Backfisch) FU Berlin (Prof. Hengge)

10 SUB-PROJECT: CATABOLITE REPRESSION IN E. coli

11 SUB-PROJECT: REDOX CONTROL OF PHOTOSYNTHETIC BACTERIA

12 PHOTOTAXIS IN HALOBACTERIUM SALINARUM

13 MOLECULAR ORIENTED: SIGNAL ORIENTED: BLOCK-DIAGRAM OF PHOTOTAXIS

14 INTERACTING REGULATORY SYSTEMS

15 PROJECTS OF THE GROUP Data- bases Visuali- zation Hypo- theses Genetic Modi- fication Analysis Modeling Concept Synthesis Modeling Tool Quantitative Measurement Virtual Biological Laboratory SIGNAL TRANSDUCTION AND REGULATION IN BACTERIAL CELLS SIGNAL TRANSDUCTION AND REGULATION IN BACTERIAL CELLS SIGNAL TRANSDUCTION AND REGULATION IN EUKARYOTES SIGNAL TRANSDUCTION AND REGULATION IN EUKARYOTES COMPUTER AIDED MODELING AND ANALYSIS OF CELLULAR SYSTEMS COMPUTER AIDED MODELING AND ANALYSIS OF CELLULAR SYSTEMS

16 PROJECT: SIGNAL TRANSDUCTION AND REGULATION IN EUKARYOTES Mathematical Modeling of Cell Cycle Regulation in Eukaryotes (J. Stelling) Uni Stuttgart (Prof. Seufert) Data- bases Visuali- zation Hypo- theses Genetic Modi- fication Analysis Modeling Concept Synthesis Modeling Tool Quantitative Measurement Virtual Biological Laboratory TNF-induced Apoptosis (H. Conzelmann, T. Sauter) Uni Stuttgart (Prof. Pfizenmaier) Catabolite Repression in Yeast (J. Stelling) Uni Halle (Prof. Breunig) HGF/c-Met Signaling Pathway and H. pylori (S. Ebert) Uni Magdeburg (Prof. Naumann) Uni Magdeburg (Prof. Schraven) MIT/Merrimack (B. Schoeberl) TCR Signaling Pathway (J. Saez-Rodriguez, X. Wang)

17 SUB-PROJECT: CELL CYCLE OF S. CEREVISIAE M G2G2 S G1G1 2n DNA 4n DNA 2...4n DNA CLN1-3 SIC1 CLB1-4 CLB3-6 cell division mass growth DNA-Replication replication control START  The cell cycle of the yeast consists of discrete phases (G 1, S, G 2, 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

18 SUB-PROJECT: CELL CYCLE OF S. CEREVISIAE cell growth Complex interconnection of gene expression and proteolysis of 9 cyclins and the inhibitor Sic 1 leads to periodic cyclin-kinase activities Molecular Interactions Nocodazole arrest Undisturbed Cell Cycle

19 DECOMPOSITION OF SIGNALING NETWORKS INTO MODULES

20 BMBF: SYSTEMS BIOLOGY – SYSTEMS OF LIFE Interaction of Signal Transduction and Cell Cycle Regulation in Eukaryotes Epidermal Growth Factor Hepatocyte Growth Factor Insulin Tumor Necrosis Factor T-cell Receptor Cell cycle

21  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

22 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

23 THANK YOU!