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Platform
Modeling / BioinformaticsCoordinator: Prof. E. D. Gilles
Presentation Heidelberg, July 7th 2004
Sven Sahle, EML research gGmbH
BMBF-Funding Initiative “Systems of Life – Systems Biology”
Humboldt University, Berlin:Prof. H.-G. Holzhütter, Charité, Mathematical
Modeling
Prof. R. Heinrich, Biology, Theoretical Biophysics
Prof. T. Höfer, Institute for Theoretical Biohysics
Prof. A. Herrmann, Biology, Molecular Biophysics
Prof. H. Herzel, Institute for Theoretical Biology
Prof. J. Reich, MDC for Molecular Medicine, Bioinformatics
EML Research, Heidelberg:Dr. U. Kummer, Bioinformatics and
Computational Biochemistry
Dr. R. Wade, Molecular and Cellular Modeling
MPI DCTS, Magdeburg:Prof. E.D. Gilles, Systems Biology
Prof. S. Schuster, Univ. Jena, Bioinformatics
Platform partners
Mission:
The platform “modeling/bioinformatics” is devoted to the development of methods and tools for the efficient construction, analysis, integration and exchange of complex mathematical models in systems biology.
The platform interacts with all partners of the initiative by:
•Providing novel methods and tools for the systems-level
analysis of the hepatocyte.
•Conducting specific research projects in cooperation with
the partners to develop methods, tools and standards.
Key objectives of research and development
• Unified methodology for the kinetic modeling of complex cellular networks encompassing metabolic, signal transduction and genetic sub-structures with a focus on network representation and complexity reduction.
• Novel methods for the analysis of complex networks based on systems theory regarding structural properties, network decomposition, identification of model structures, and others.
• New and/or improved computer tools for standardized modeling and simulation, including model and data storage.
• Integration of experimentation and modeling with respect to efficient experimental design and real-time control of biological processes.
Coordination of activities
• Distribution of tasks both in development of mehods/tools and research on cellular systems
• Progress meetings of the platform partners every 6 months.
• Annual international workshop `Modeling and simulation of complex biological systems´ open to all researchers within the BMBF initiative.
• Internal web portal for modeling and bioinformatics
Kinetic modeling of complex cellular networks with special focus on hepatocytes
I. Methods and tools
• Generalized control theory of cellular networks based on the well-established concept of metabolic control theory (Heinrich/Kacser).
• Standards for the formal and graphical representation of cellular networks.
• Theoretical framework for identification and evaluation of potential interfaces between various types of cellular networks.
• Inter-active software modules for computer simulations of hepatocyte-relevant kinetic models.
II. Modeling of selected sub-networks
…
Kinetic modeling of selected sub-networks: successive development of an
integrated model
Ca-mediated cell-cell
interactionexpression control of
metastasis genes
Wnt-ß-catenine signaling pathway
ubiquitin-dependent
protein turnover
metabolism and
biogenesis of lipoproteins
intra-cellular
lipid traffic
interfaces between the various modules of the integrative cell model
identification of potential oncogenes and tumor suppressor genes in signaling pathways
prediction of systemic effects upon administration of proteasome inhibitors
identification of target enzymes for the pharmacological treatment of disorders in the lipid metabolism of the liver
integrated kinetic model applications (examples)
project „vectorial transport through virtual hepatocytes” (Heidelberg)
cooperation
network project „systems biology of primary and regenerating hepatocytes (Freiburg)
cooperation
platform cell biology „3D bioartificial human liver cell systems“ (Berlin/Jena)
cooperation
Characterization of complex signaling and regulatory processes in hepatocytes using modeling and systems theory analysis
I. Methods and tools
• Modeling concepts for regulatory networks
• Visualization of models and simulations in ProMoT
• Structural analysis of signal transduction networks
• Software sensors for process control
II. Model-based analysis of selected sub-networks
• Mitogenic and apoptotic signaling pathways
• Signal integration in proliferation control
Characterization of complex signaling and regulatory processes in hepatocytes using modeling and systems theory analysis
SYCAMORE
I. Evaluate and integrate existing methods
II. Develop new methods
• Complexity reduction of big models
• Hybrid simulation methods
• Structure based methods to compute kinetic constants
• Sensitivity analysis of higher order
• Semi-automatic generation of models from databases
III. Apply tools to selected sub-systems of the hepatocyte
Heidelberg Magdeburg Berlin All groups
Gene networks
Cell cycle regulation
Expression control of metastasis genes
Ubiquitin-dependent protein turnover
Signaling networks
Wnt/ß-catenine pathway
Ca-mediated cell-cell interactions
Mitogenic and apoptotic pathways
Ca-mediated cellular signal transduction
Metabolic networks
Metabolism and biogenesis of lipoproteins
Intracellular lipid transport
Cytochrome P450 enzyme systems
Modelingmethods
Networkanalysis
Computer-based tools
Models and experiments
Reduction of complex kinetic models
Further development of standards for model exchange (SBML)
Symbolic representation of elementary processes and networks
Identification and evaluation of interfaces between cellular networks
Generalized control theory for cellular networks
Structural analysis of regulatory networks
PROMOT/DIVAmodeling / model library, simulation,model analysis
Interactive software modules for computer simulation
SYCAMOREexpert system for mathematical modeling and experimental design
Parameter estimation from system data and protein structures
Software sensors for hepatocyte bioreactors
Model-based experimental design
Me
tho
ds
an
d t
oo
lsC
ellu
lar
sys
tem
s
COPASI a simulator for complex pathways
modelling
reporting
analysis
simulation
modelling
reporting
analysis
simulation
Traditional tools:
text editor
command line tool plotting tool (eg. gnuplot)
command line tool
COPASI will combine all this in one tool with a graphical user interface. Users of COPASI should be biochemists and biologists without expert knowledge about simulation methods.
-> promote methods of systems biology
modelling
reporting
analysis
simulation
How is the biochemical reaction network described in COPASI?
• there are some chemical species• species are involved in chemical reactions• reactions happen with a certain speed.• all this happens in a compartment (of the cell)
Compartments just have a Volume.
Species are contained in compartments. They have a concentration or particle number (which can be converted using the volume of the compartment)
modelling
reporting
analysis
simulation
Deterministic simulation
The model is converted to a set of differential equations. The simple example (A -> B, v = k*substrate/(kM+substrate)) will give:
dA/dt = -k*A(kM+A)
dB/dt = +k*A(kM+A)
These differential equations are then numerically integrated using the LSODA solver (Adams for nonstiff regions, Gear for stiff regions).
Some Details
• written in C++ using QT library• available for Linux, Unixes, MacOs X, and
Windows• will be free for academic use
COPASI is developed in cooperation with Pedro Mendes, Virginia Bioinformatics Institute, Blacksburg, USA
Conclusion:COPASI will be an easy to use tool including powerful standard methods of systems biology.
COPASI also acts as a framework for the new modelling, simulation, and analysis tools that are developed in the BCB group
SYCAMORE
SYCAMORE (Systems biology Computational Analysis and MOdelling Research Environment) is a project carried out at EML Research, Heidelberg with the following aims: • Build a suite of methods and tools to faciliate the integration of experimental and computational approaches • Support the user in the choice of appropriate computational tools to tackle a specific problem
SYCAMORE
In order to develop SYCAMORE we need to
• Evaluate and integrate existing methods and
• Develop new methods in
• Complexity reduction of big models• Hybrid simulation methods• Structure based methods to compute kinetic constants• Sensitivity analysis of higher order• Semi-automatic generation of models from databases
SYCAMORE SYCAMORE architecture: