Systems of Life - Systems Biology

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Systems of Life - Systems Biology

• Network Activities on Systems Biology
• Hepato Sys
• International Initiatives

Presentation by Gisela Miczka1, Roland Eils2 and
Siegfried Neumann3 1Projektträger Jülich,
Jülich, Germany ? 2German Cancer Research Center,
Heidelberg, Germany ? 3MERCK KGaA, Chemical
Section RD, Darmstadt, Germany NiSIS Symposium,
Portugal, October 2005
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Outline

• Hepato Sys The German Initiative on Systems
  Biology of Human Hepatocytes
• The Design of the Programme
• Goals, Structure and Projects
• Coordination and Project Management, Websites
• B. International Initiatives in System Biology
• Systems Biology for Drug Research
• International Crosslinks
• Commercial Suppliers

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2001 How to establish a BMBF funded national
research network on Systems Biology

• Start of the design-process
• Discussion forum with a multidisciplinary team of
  9 leading scientists to develop a funding
  strategy. The key criteria are
• medium to long term research programme
• synergy with existing BMBF funded research
  programmes in Genomics and Proteomics
• considers the international status of the art
• reckognizes international standards and
  contributes to them

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The Design-Process
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Goal of the Systems Biology Initiative on
Hepatocytes (HepatoSys)
The long-term goal of this systems biology
approach is to understand the dynamic processes
in a human cell and to build up mechanism-based
mathematical models of these processes in order
to predict the behaviour of the system under
defined conditions.
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Challenges

• high complexity of mammalian cells
• human diffentiated cells are not easy to handle
  and not easy to cultivate while keeping
  differentiation and metabolic properties simular
  to in vivo living cells
• the mathematical tools for modelling of cellular
  dynamics and
• systems analysis basically are not developed for
  complex systems

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The Approach

• Set up an interdisciplinary competence network
  linking bioscience with computer science,
  mathematics and engineering sciences
• Start with studies on defined biological
  functions
• Establish standardized cells, methods, and tools

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Why Hepatocytes?

• Attractivity
• central functions in metabolism (for lipids,
  carbohydrates, amino acids )
• central role in the uptake and conversion of
  drugs (transport, metabolic conversions,
  detoxification ...)
• regeneration ability
• i. e. high impact on problems in pharmacology and
  pathophysiology

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Structure of the National Competence
Network HepatoSys
Steering Committee
Collaborative Network Regeneration
Collaborative Network Detox/Dediff.
Coordinating Committee
Project Management
Platform Cell biology
Platform Modeling
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Members of the Steering Committee
Prof. Dr. Dieter Oesterhelt, MPI for Biochemistry
Munich (chairman) Dr. Roland Eils, DKFZ
Heidelberg Prof. Dr. Joseph Heijnen, Technical
University of Delft, NL Prof. Dr. Karl Kuchler,
Institute for Medical Biochemistry, University of
Wien, AU Prof. Dr. Siegfried Neumann, Merck
KGaA Darmstadt, Senior Consultant RD Prof. Dr.
Hans V. Westerhoff, Molecular Cell Physiology
Mathematical Biochemistry, BioCentrum Amsterdam,
NL
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Facts on the Starting Phase

• call for project proposals December 2001
• number of proposals 40
• start of the research work January 2004
• under this programme
• first funding period 15 Mio. /3 years
• collaborative projects 2
• platform projects
• cell biology 3
• modeling 3
• number of partners 25

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The Project Committee on HepatoSys

• Dr. Jens Timmer, University Freiburg (chairman)
• Prof. Dr. Ing. Matthias Reuss, University
  Stuttgart
• Prof. Dr.-Ing. Ernst-Dieter Gilles, MPI for
  Komplex Technical Systems, Magdeburg
• Prof. Dr. Augustinus Bader, Biomedizinisch-
• Biotechnologisches Zentrum, Leipzig

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Main Objectives of HepatoSys
Network on detoxification and dedifferentiation
in hepatocytes (Speaker Prof. Reuss, Univ.
Stuttgart-Hohenheim) Network on regeneration of
hepatocytes (Speaker Dr. Jens Timmer, Univ.
Freiburg) Platform Cell biology Development of
new cells, of optimized culture conditions, of
high throughput technology and supply of cells
for the projects in the national network
(Speaker Prof. Bader, Univ. Leipzig) Platform
Modeling Development of bioinformatics and
mathematical tools for data management, data
handling etc. and service for the projects of the
national network(Speaker Prof. Gilles, MPI
Magdeburg)
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The Network on Detoxification / Dedifferentiation

• Detoxification
• Cytochrome P 450 isoforms
• Molecular dynamics
• Kinetic experiments
• Polymorphisms
• Dedifferentiation
• Change of metabolic pathways during
  dedifferentiation

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The Network on Regeneration

• Background
• Liver regeneration is a highly regulated process
• Goal
• Understanding the pathways involved
• Method
• Data-based mathematical models
• Long term goal
• Support development of liver cell lines

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The Cell Biology Platform

• Distributing Standardized Cell Material
• Primary hepatocytes (man, mouse, rat)
• Isolation protocol, culturing, starving
  stimulation
• following SOPs
• Developing Human Cell Lines Based on
• Conditionally immortalized cells
• Somatic stem cells
• Bioreactors with controlled microenvironment

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The Modeling Platform

• Work out concepts on central data management
• Develops algorithms and software for modeling
• Supply project partners of the biology networks
  with project-specific tools in systems theory
• Develop integrated systems biology research on
  their own concepts

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Geographic Distribution of the Projects
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Coordination of the Competence Network Systems
Biologe

• Secretarial office for the BMBF Funding
  Initiative Systems
• for Life Systems Biology at University of
  Freiburg (Dr. Timmers office)
• Flyer, Brochures, Articles, Poster ...
• Webpages, Internet Representation ...
• Public Relation with Journalists and Media
• Conference Visits and Reports
• Scientific Coordination of Interdisciplinary
  Research
• Groups

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Project Management for the Competence Network
Systems Biology

• Workshop Partnering, Kick-Off Workshops,
  Annual Status
• Workshops (last one on April 28 to 29, 2005,
  next in November 2005)
• Conference Organization by DECHEMA e.V.
  Conference Office for the 5th
• International Conference on Systems Biology,
  October 9 13,
• 2004 in Heidelberg
• Coordination of due diligance, contracting and
  implemen-
• tation for a Central Data Management for the
  funding Initiative
• Systems Biology
• Organizing the Scientific Report Systems for
  PTJ, BMBF, and
• Steering Committee

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Websites

• Federal Ministry of Education and Research
• www.bmbf.de
• PTJ the Project Management Organisation Jülich
• www.fz-juelich.de/ptj/
• Competence Network Systems Biology
• www.systembiologie.de
• The Database for Systems Biology Researchers
• http//www.bcc.univie.ac.at/cgi-bin/molg/sysbiol
  /SysBiol.pl

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Systems Biology The Concepts

• Systems biology integrates the molecular parts
  list into quantitative models of biological
  functions
• Kitano, H. Science 295, 1662 (2002)
• To understand biology at the system level, we
  must examine the structure and dynamics of
  cellular and organismal function, rather than the
  characteristics of isolated parts of a cell or
  organism.

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Descriptional and analytical levels in Systems
Biology
Transcriptomics
Genome
Gene Regulation
Expression
Proteins
Metabolism
Whole Organism
TissuesandCells
Proteomics
Metabolomics
PhenotypeandPotential for Diseases
Physiomics
cit from Nicolson (2002), modified
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It is all dynamics in biological systems

• Measurements by the -omics technologies do not
  necessarily reflect real-world or endpoint
  observations

Real world
'omics world
InputsSignalsstressors etc
Note time differentials in all
interaction stages
Gene expression
Time
cell
Time
Time
Protein profile
Time
Time
Metabolic profile
OutputsBiological endpointspathologydegenerati
onregeneration
Nicolson, J.K. at al. Nature Reviews Drug
Discovery 1, 153 (2002)
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Current topics in systems biology

• Problems encountered when we try to understand
  life
• processes by simulation and modeling
• Complexity
• n Dimensionality
• Holistic versus reductionistic working modes
• Change, dynamics
• Pleiotropy and redundancy in biology
• Deterministic versus stochastic mathematics
• Bioinformatics ? System Engineering
• Need to end in understanding physiology and
  disease processes

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Complexity and emergent properties in biology

1. Complex inputs that stimulate multiple pathways
2. Integrated networks respond to the inputs by
   multiple outputs
3. Interactions between multiple cell types in multi
   cellular organisms (like man)
4. Multiple contexts and environments for each cell
   type or combination of cell types

To understand the effects of a target or a drug,
data must be derived from cell responses in
multiple environment. Butcher et al. Nature
Biotechnol. 22, 1253 (2004)
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Deliverables and limitations of approaches by
integrative biology to drug research and
development
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Examples of computational models relevant to
human disease biology
(cit. Butcher, E. C. et al., Nature Biotechnol.
22, 1253 (2004), modified)
Approach System Comments
Disease physiology Heart Diabetes Asthma Quantitative models of the heart from genes to physiology Approaches for modeling diabetes Math. models of chronic asthma for prediction of therapy response
Integrative cell models Cancer Cardio-myocytes Network models containing 1000 genes/proteins, 3000 components predicted effect of specific gene knock downs,Cancer pharmacogenetics-polymorphisms, pathways and beyond Linking modules (int. Metabolism, electrophysiology and mechanics) for computational modul of cardiomyocytes
Pathway models Multiple EGFR/MAPK NF-KB Wnt Pathway Emergent properties of signaling in network models Computational models of EGFR signaling and network model Signal processing of NF-KB signaling pathway Experimental and theoretical analysis of the Wnt Pathway, roles of APC and axin.
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Data-based mathematical modelling of the
JAK2-STAT5 Pathway (Klingmueller, pers.
commun,.)
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JAK2-STAT5 PathwayPredicting Steps Most
Sensitive for Perturbation (Klingmueller,
pers. commun.)
Mathematical prediction Dynamical parameters of
nuclear import (k3), export (k4) and delay (t)
most sensitive to perturbation
Experimental verification of mathematical
prediction
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Systems Biology Selected commercial players
Company Core Technologies Approach Deliverables
Accelrys Software Tools Software for process simulation Simulation of biological and chemical process
BayerTechnologyServices Software toolsPK-MAP PK-SIM Prediction, interpretation and extrapolation of pharmacokinetics / pharmacodynamics High quality estimates of ADME and PK
BG Medicine Bioselective Targets Biosystems Markers Application of SB for target discovery, biomarkers and predictive toxicology Targets, biomarker identification Predictive toxicology
Entelos Math. models (diff. equations) for simulation and analysis Dynamic models for disease processes on molecular, cellular and physiological levels (Physio Labs) Target ID, Evaln. Leads,Biomarkers,Clinical trial design
Gene GO META core analysis Network analysis of HAT expression data Gene profile analysis in breast cancer
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Systems Biology Selected commercial players ctd.
Company Core Technologies Approach Deliverables
Iconix HTP molecular biologyData-mining Integration of chemistry and genomics to profile drug candidates to predict toxicity Predictive toxicology
Ingenuity OntologyPathway databaseComputing on DB Identification of altered pathways from diff. expression date Target ID based on pathway analysis
Icoria Inc. (former Paradigm Genetics) Biochemical Profiling Platform Metabolic Profiling Biomarkers for DD and diagnosis
Physiomics plc In silico simulations Computer models for human diseasesPathway simulation, multiple cell systems In silico tests for interpretation of PK and PD
Surromed HTP molecular biology Data-mining Profile immune cell populations, proteins and small molecules for biomarkers. Fingerprint pathways involved in disease and therapeutic response Biomarker IDClinical trial design
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Systems Biology at Work in Drug Discovery of Big
Companies
Drug Company Research Activity Specialist Partner
Eli Lily / Lilly Systems Biology in Singapore Explore network pathways, use dynamic models to simulate cellular responses to drugs, 140 Mio. over 5 years commitment
Novartis Focus on pathway studies Cellzome AG
Novo Nordisk AS SB approach to the combinatorial nature of signal transduction
Johnson Johnson's Pharmaceutical RD Using PhysioLabs mathematical models for analysis of dynamic relationships within human biological networks (Diabetes II, hematology , clin. development, phase IV clinical trials) Entelos
Organon Using PhysioLabs on Rheumatoid Arthritis drug targets Entelos
Astra Zeneca SB in predictive toxicology Beyond Genomics
Glaxo Smith Kline SB in metabolic disease pathways, drug mechanism of action, identify new biomarkers Beyond Genomics
Lit. zit. Littlehales, C. Bio News Dec.
20047January 2005, p. 9, modified
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The Multiple Input of Systems Biology into
Molecular Medicine
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Research centers on systems biology in the USA (1)
Institute for Systems Biology Integration of the
different levels of biological information,(Hood
et al. Seattle) modeling of integral
systems - microorganism models and
yeast - immune system, cancer, hematopoeitic
development The Molecular Science
Institute Development of prediction
biology (Brenner, Brent Berkeley) - genomic,
evolutionary studies on E. coli - protein/protein
interactions - computational biology,
instrumentation Dept. on Bioengineering
Systematic analysis of genetic
circuits (Palsson, UCSD) - coordinated activities
of multiple gene products in metabolism and
cell motility - in silico metabolic routing in
E. coli Caltech Modeling of nonlinear systems in
E. coli (Simon, Doyle, Kitano, et
al.) - Simulation systems for gene regulation and
metabolism - Modeling and simulation of the cell
cycle Biomolecular Systems Initiative
(BSI) Studies on cellular networks (within cells
and between cells) at Pacific Northwest Natl.
Laboratory - in microbiological systems by
(Wiley et al.) - quantitative and integrative
cell biology
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Research centers on systems biology in the USA (2)
Alliance for Cellular Analysis of G protein
coupled or related signal Signaling
(AfCS) transduction in mammalian cells (Gilman,
Univ. Texas - identification of all involved
proteins South Western) - analysis of kinetics of
information fluxes - modeling cellular
signaling MIT Computational and Systems
Quantitative biology of cellular functions by
Biology Initiative (CSBI) experimentation,
modeling and simulation in mammalian (Sorger,
Tidor, Lauffenburger) cells and
tissues - regulation of proliferation, adhesion,
migration and transport Education in
SB Systems Biology Department Bioinformatics,
structural genomics, Quantitative
Structure Harvard Medical School Activity
Relationships in multicomponent
complexes (Kirschner, Mitchison,
Harvard) - Synthetic biological
systems - Molecular understanding of
physiological centre Education in
SB Princeton Integrative Genomics
Interdisciplinary research programmes on
quantitative biology(Botstein et al.),
University of Education in SBMichigan Life
Sciences Institute(Saltiel et al.), Stanford
UniversityBiosciences Initiative (Bio-X, Scott
et al.),Dukes Institute for Genome Sciences
andPolicy (Willard et al.)
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Recent Highlights in SB International Crosslinking

• EU-Initiatives EU SYSBIO, SYMBIONIC
  EUREKA InSysBio Project SYSMO (AU, DE, NL,
  GB, NO, SP)
• WTEC/USA http//wtec.org/sysbio Reports on
  US, EU and Japan activities
• WTEC/USA Workshop on setting up a repository
  for systems biology software, February 17-18,
  2005, Washington, USA
• 5. International Conference on Systems
  BiologyOctober 9-13, 2004, Heidelberg, Germany
• 6. International Conference on Systems
  BiologyOctober 2005, Cambridge, USA, Org Marc
  Kirschner, Harvardhttp//www.ICSB2005.org
• Start of PanAsian electronic International
  Molecular Biology Laboratory (e IMBL)Seoul, July
  12-13, 2005

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On SYSMO
This is a website of SYSMO SYSMO is a
transnational funding program for the Systems
Biology of MicroOrganisms, of The German BMBF,
the Dutch NWO-ALW, and the Austrian bmbmk.
Additional countries have been invited to join
soon.     At present SYSMO is already active in
supporting the training of scientists and
students in Systems Biology. Its first activity
is the strong support(in terms of travel
fellowships) of the FEBS advanced course (see
below).   A second, much larger activity is a
transnational research program for Systems
Biology of Microorganisms. Countries are now
asked to express their interest in participating
in and supporting this program.
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See also First FEBS Advanced Course on Systems
Biology From Molecules Modeling To Cells March
12- 18, 2005, Gosau, Austria, EU   Organized
by Roland Eils (Heidelberg), Karl Kuchler
(Vienna), Anneke Koster (Amsterdam), and Hans V.
Westerhoff (Amsterdam) Program and all
information Flyer (pdf) Registration
Pre-registration
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Systems Biology How to implement into
pharmaceutical research and development?
(1)

• Interdisciplinary approach needed, develop common
  conceptual understanding of biologists,
  mathematicians and bioinformatics experts
• Define cellular models and experiments with
  reproducable properties - sampling - culture
  conditions - validated analytical
  technologies - exp. schedules
• Iterative approaches needed between model
  builders and biological experimentators
• Provide sufficient IT hardware resources and
  software tools

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Systems Biology How to implement into
pharmaceutical research and development?
(2)

• Drug researchers should join accademic
  initiatives for strategic cooperative projects
• Drug RD should form precompetitive RD platforms
  for developing SB tools and informatics
  standards - Speak a common research language -
  Share IT resources - Train researchers on an
  integrative approach
• Drug RD should contribute views on strategic
  research priorities to academic research
  directors and share strategic concepts with
  national and cross-border research planning
  panels on precompetitive level
• The potential of systems biology for drug
  discovery and development needs a major success
  story in industry (Ideker, 2004)