1

WELCOME TO THEMAX PLANCK INSTITUTE

FOR 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

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MAX PLANCK INSTITUTEFOR 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)

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BROAD SPECTRUM OF PROCESSES TO DEAL WITH:

SYSTEM SCIENCES(SYSTEM THEORY)

Provides methods and

tools

ChemicalChemicalProcessesProcesses

Biochemical Biochemical ProcessesProcesses

Biological Biological Networks Networks

Integrating factor

• • •

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SYSTEMS BIOLOGY

Data-bases

Visuali-zation

Hypo-theses

GeneticModi-fication

Analysis

Modeling Concept

Synthesis

ModelingTool

QuantitativeMeasurement

VirtualBiologicalLaborator

y

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

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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

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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

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COMPLEXITY AND ROBUSTNESS

Complex Technical ProcessesPowerful concepts to cope with increasing complexity Modularity techniques Hierarchical structuring Redundancy and diversityBiological SystemsSimilar 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 unitsObjectives of these concepts in both fields Robustness of functionality Reduction of fragilitiesMethods and tools developed in engineering, also appropriate for biological systemsControl Theory, Nonlinear Dynamics, System Theory …

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PROJECTS OF THE GROUP

Data-bases

Visuali-zation

Hypo-theses

GeneticModi-fication

Analysis

Modeling Concept

Synthesis

ModelingTool

QuantitativeMeasurement

VirtualBiological

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

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PROJECT: SIGNAL TRANSDUCTION AND REGULATION IN BACTERIAL CELLS

Data-bases

Visuali-zation

Hypo-theses

GeneticModi-fication

Analysis

Modeling Concept

Synthesis

ModelingTool

QuantitativeMeasurement

VirtualBiological

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 inHalobacterium Salinarum

(T. Nutsch)

MPI Biochemie (Prof. Oesterhelt)Uni Freiburg (Dr. Marwan)

Regulation of Stress Sigma Factor σS

(T. Backfisch)

FU Berlin (Prof. Hengge)14

In vivo model

RssB P

70

S

S

rpoS gene

S targetgene

OxyS

Crp

RssB

ClpP

~P

S

Poly

Poly

PRssB

Hfq

rpoS transcription

Expression of S targetgenes

RpoS translation S proteolysis

mRNA

P 70

S

DsrAHu RprA

OxyS

Hfq SS

70

Poly

Competition for polymerase

PS

RssB, R

ssA

SClpXP

ClpX

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SUB-PROJECT: CATABOLITE REPRESSION IN E. coli

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SUB-PROJECT: REDOX CONTROL OF PHOTOSYNTHETIC BACTERIA

Fructose-6-phosphate

Glyceraldehyde-3-phosphate

3-Phospho-glycerate

NADHFADH

2-OG

SCoA

OATCA-Cycle

ATP

ATPNADH

CO2

C4/C5/C6/C7-Intermediates

Ribulose-1,5-bisphosphate

3-Phospho-glycerate

Glyceraldehyde-3-phosphate CBB-

Cycle

EMP

Fructose

FormiateAcetate

NADH

NADH

NADH

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PHOTOTAXIS IN HALOBACTERIUM SALINARUM

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MOLECULAR ORIENTED:

SIGNAL ORIENTED:

BLOCK-DIAGRAM OF PHOTOTAXIS

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INTERACTING REGULATORY SYSTEMS

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PROJECTS OF THE GROUP

Data-bases

Visuali-zation

Hypo-theses

GeneticModi-fication

Analysis

Modeling Concept

Synthesis

ModelingTool

QuantitativeMeasurement

VirtualBiological

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

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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

GeneticModi-fication

Analysis

Modeling Concept

Synthesis

ModelingTool

QuantitativeMeasurement

VirtualBiological

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)

IP3IP3

IL2-GenIL2IL2--GenGen

DAGDAG

PKCPKC

MAP-Kinase

Raf

Tyrosine phosphorylationP

Enzymatic cleavageNFBNF-AT

RasRas

IB/NFB

AP-1

GEM

PLC1PLC1

SOS

SOS

SOS

Grb2Grb2

SLPSLP--7676

LAT

raftraftLckLck

TCR/CD3/ ßß

AgAg

Ca++-KomplexZAP70ZAP70ZAP70

PP

P

P

(a)

(g)

(d)

(e)

P

ItkItk

GadsGads

PIP2PIPPIP22

(h)

(j)

(k)

(l)

(m)

(n)

(o)

(p)

(q)

(r)

(s)

(f)

?

Calcineurin

CSA

(i)

Ca++Ca++

(b, b´)

P

P

(c)

TCR Signaling Pathway(J. Saez-Rodriguez, X. Wang)

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SUB-PROJECT: CELL CYCLE OF S. CEREVISIAE

M

G2

S

G12nDNA

4nDNA

2...4nDNA

CLN1-3SIC1

CLB1-4

CLB3-6

cell division

massgrowth

DNA-Replication

replicationcontrol

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

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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

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DECOMPOSITION OF SIGNALING NETWORKS INTO MODULES

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BMBF: SYSTEMS BIOLOGY – SYSTEMS OF LIFEInteraction of Signal Transduction and Cell Cycle Regulation

in Eukaryotes

Epidermal Growth Factor

Hepatocyte Growth Factor

Insulin TumorNecrosisFactor

T-cellReceptor

Cell cycle

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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

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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

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THANK YOU!