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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
             (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


                                                                1
           MAX PLANCK INSTITUTE
FOR DYNAMICS OF COMPLEX TECHNICAL SYSTEMS
                MAGDEBURG



               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)

                                                        2
      BROAD SPECTRUM OF PROCESSES TO DEAL WITH:



 Provides
methods and
                     SYSTEM SCIENCES                     Integrating
                          (SYSTEM THEORY)                factor
   tools




              Chemical      Biochemical     Biological     •••
              Processes      Processes      Networks



                                                                 3
                                SYSTEMS BIOLOGY



„Systems biology is the                         Quantitative     Data-
                                                Measurement      bases
synergistic application of
                                            Hypo-          Virtual     Modeling
experiment, theory, and                                  Biological
                                            theses                     Tool
modeling towards                                          Laboratory
understanding biological                  Genetic
                                          Modi-                              Visuali-
processes as whole systems                fication                           zation
instead of isolated parts.“
       Systems Biology Group/Caltech                 Analysis       Synthesis
                                                          Modeling Concept




                                       Interdisciplinary approach towards a
                                       quantitative and predictive biology
                                                                                        4
                     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
                                                                        5
                  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
                                                              6
                 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 …
                                                                          7
                                           PROJECTS OF THE GROUP



SIGNAL TRANSDUCTION
                                                            SIGNAL TRANSDUCTION
    AND REGULATION
                                                               AND REGULATION
  IN BACTERIAL CELLS                                            IN EUKARYOTES



       Quantitative            Data-
       Measurement             bases

 Hypo-                  Virtual        Modeling
 theses                Biological      Tool
                      Laboratory                      COMPUTER AIDED MODELING
Genetic
Modi-                                                       AND ANALYSIS
fication                                   Visuali-
                                           zation       OF CELLULAR SYSTEMS
           Analysis            Synthesis

               Modeling Concept



                                                                                8
                      PROJECT:
SIGNAL TRANSDUCTION AND REGULATION IN BACTERIAL CELLS


        Mathematical Modeling of                           Redox Control in                                    Phototaxis in
     Catabolite Repression in E.coli                   Photosynthetic Bacteria                           Halobacterium Salinarum
(K. Bettenbrock, S. Fischer, A. Kremling)              (H. Grammel, S. Klamt)                                  (T. Nutsch)




                                              Uni Stuttgart (Prof. Gosh; ISR)        MPI Biochemie (Prof. Oesterhelt)
Uni Osnabrück (Prof. Lengeler)                Uni Magdeburg (Prof. Reichl)           Uni Freiburg (Dr. Marwan)




                                                           Two-component              Regulation of Stress Sigma Factor σS
                                                     Signal Transduction in E.coli               (T. Backfisch)
         Quantitative     Data-                              (A. Kremling)                                                                      In vivo model
         Measurement      bases                                                          rpoS transcription                      RpoS translation                                                                              S proteolysis



     Hypo-
                                                                                                                                                       OxyS



                                  Modeling
                                                                                                                                                                                                                                 ~P


                    Virtual
                                                                                                               Poly                                                                                                   RssB P
                                                                                                              70     mRNA
                                                                                                                                                        Hfq          S               S                                              RssB
                                                                                                                                                                                S
                                                                                                                                                                                                             RssB P



     theses        Biological     Tool
                                                                                           rpoS gene                                     DsrA
                                                                                                                                   Hu           RprA                                                      ClpX   S
                                                                                                                                                              OxyS
                                                                                                                                                                                                SClpXP      ClpP




                  Laboratory
                                                                                                                                         Hfq
                                                                                                       Crp




                                                                                                                                                                     S




                                                                                                                                                                                                                  A
                                                                                                                       P  70




                                                                                                                                                                                                                ss
    Genetic




                                                                                                                                                                                                              ,R
                                                                                                                                                                                                            sB
                                                                                                                                                                                                         Rs
    Modi-                          Visuali-                                                                                                                                          Expression of  targetgenes
                                                                                                                                                                                                    S
                                                                                                                                        Competition for polymerase




    fication                       zation
                                                                                                                                                                                                                   Poly
                                                                                                                                                                                                                   S
                                                                                                                                                              Poly


                                                                                                                                         70
                                                                                                                                                                          PS        S targetgene




           Analysis       Synthesis
                                                                                                                                                                                                                                                14

                                              Uni München (Prof. Jung)               FU Berlin (Prof. Hengge)
               Modeling Concept

                                                                                                                                                                                                            9
SUB-PROJECT: CATABOLITE REPRESSION IN E. coli




                                                10
SUB-PROJECT: REDOX CONTROL OF PHOTOSYNTHETIC BACTERIA




                        Fructose

              EMP             -6-
                       Fructose
                       phosphate                                          -
                                                                C4/C5/C6/C7
                                                      -
                                          Glyceraldehyde        Intermediates
                                          3-phosphate
                       Glyceraldehyde
                                   -                    CBB-    ATP
                       3-phosphate                      Cycle
                                                 NADH
                              NADH                ATP                 -1,5
                                                                Ribulose -
                NADH                                            bisphosphate
                     3-Phospho-
            Formiate glycerate             3-Phospho-
            Acetate         NADH           glycerate
                                                                      CO2

              TCA OA
                 -                 2-OG
              Cycle
                             SCoA
               NADH
               FADH




                                                                                11
PHOTOTAXIS IN HALOBACTERIUM SALINARUM




                                        12
           BLOCK-DIAGRAM OF PHOTOTAXIS

MOLECULAR ORIENTED:




SIGNAL ORIENTED:




                                         13
INTERACTING REGULATORY SYSTEMS




                                 14
                                           PROJECTS OF THE GROUP



SIGNAL TRANSDUCTION
                                                            SIGNAL TRANSDUCTION
    AND REGULATION
                                                               AND REGULATION
  IN BACTERIAL CELLS                                            IN EUKARYOTES



       Quantitative            Data-
       Measurement             bases

 Hypo-                  Virtual        Modeling
 theses                Biological      Tool
                      Laboratory                      COMPUTER AIDED MODELING
Genetic
Modi-                                                       AND ANALYSIS
fication                                   Visuali-
                                           zation       OF CELLULAR SYSTEMS
           Analysis            Synthesis

               Modeling Concept



                                                                                15
                             PROJECT:
         SIGNAL TRANSDUCTION AND REGULATION IN EUKARYOTES

       Mathematical Modeling of Cell             Catabolite Repression in Yeast                Quantitative      Data-
       Cycle Regulation in Eukaryotes                      (J. Stelling)                       Measurement       bases
                (J. Stelling)
                                                                                           Hypo-           Virtual       Modeling
                                                                                           theses         Biological     Tool
                                                                                                         Laboratory

                                                                                           Genetic
                                                                                           Modi-                           Visuali-
                                                                                           fication                        zation

                                                                                                 Analysis        Synthesis
                                                                                                      Modeling Concept


     Uni Stuttgart (Prof. Seufert)             Uni Halle (Prof. Breunig)



                                                                                              TCR Signaling Pathway
                                             HGF/c-Met Signaling Pathway                  (J. Saez-Rodriguez, X. Wang)
         TNF-induced Apoptosis
       (H. Conzelmann, T. Sauter)                   and H. pylori
                                                     (S. Ebert)




Uni Stuttgart (Prof. Pfizenmaier)
                                                                                  Uni Magdeburg (Prof. Schraven)
                                        Uni Magdeburg (Prof. Naumann)                                                    16
                                                                                  MIT/Merrimack (B. Schoeberl)
       SUB-PROJECT: CELL CYCLE OF S. CEREVISIAE


                          cell division
                                          M
                                           4n
                                           DNA
                                 G2                                          mass
                                              CLB1-4     CLN1-3   2n
                                                          SIC1    DNA   G1   growth
                                                CLB3-6
                   replication            2...4n
                                          DNA
                   control
                                          S
                       DNA-Replication                              START



   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
                                                                                      17
            SUB-PROJECT: CELL CYCLE OF S. CEREVISIAE

       Molecular Interactions               Undisturbed Cell Cycle

     cell growth




Complex interconnection of gene               Nocodazole arrest
expression and proteolysis of 9 cyclins
and the inhibitor Sic 1 leads to periodic
cyclin-kinase activities

                                                                     18
DECOMPOSITION OF SIGNALING NETWORKS INTO MODULES




                                              19
      BMBF: SYSTEMS BIOLOGY – SYSTEMS OF LIFE
Interaction of Signal Transduction and Cell Cycle Regulation
                         in Eukaryotes
    T-cell     Hepatocyte      Epidermal   Insulin   Tumor
    Receptor   Growth          Growth                Necrosis
               Factor          Factor                Factor




                            Cell cycle                          20
   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
                                                                                  21
                        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
                                                          22
THANK YOU!




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