Transcript Yeast Systems Biology as a foundation for drug discovery

Systems Biology – challenges in
experimental and theoretical sciences
Prof. Stefan Hohmann
Department of Cell and Molecular Biology
Göteborg University, Sweden
[email protected]
CMB - Cell and Molecular Biology - Group Stefan Hohmann
Systems Biology – an approach
Understanding the higher-order properties of systems of
biomolecules (rather than individual biomolecules) by
applying to biology approaches of mathematics,
theoretical physics, computer sciences and engineering.
Using mathematical models may move biology from a
descriptive to a predictive discipline.
Predictive capabilities to treatment of diseases and
bioengineering.
CMB - Cell and Molecular Biology - Group Stefan Hohmann
Systems Biology - directions
Top-down or data-driven
Networks from large-scale data
Bottom-up or model-driven
Dynamic modelling – simulating processes over time
CMB - Cell and Molecular Biology - Group Stefan Hohmann
EC funds several projects on
dynamic modelling in FP6
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QUASI – yeast MAPK signalling
AMPKIN – AMP-activated protein kinase signalling
COSBICS – JAK-STAT and MAPK signalling
RIBOSYS – yeast RNA metabolism
YSBN – Coordinating yeast systems biology
CMB - Cell and Molecular Biology - Group Stefan Hohmann
Quantifying signal transduction
CMB - Cell and Molecular Biology - Group Stefan Hohmann
QUASI consortium
• Gothenburg (biology: S Hohmann, P Sunnerhagen;
chemistry: M Grøtli) Sweden
• Barcelona (biology: F Posas) Spain
• Vienna (biology: G Ammerer) Austria
• Zürich (biology: M Peter) Switzerland
• Berlin (theoretical physics: E Klipp) Germany
CMB - Cell and Molecular Biology - Group Stefan Hohmann
Types of measurements to
estimate parameters
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Rate of changes of phospho-MAPK
Certain other phospho-proteins
Rate of changes of mRNA levels of reporter genes
Levels and rate of change and transport of glycerol
Rate of change of certain protein-protein interactions
Hog1 MAPK nuclear shuttling
CMB - Cell and Molecular Biology - Group Stefan Hohmann
Types of perturbations to test
mathematical models
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Genetic changes in pathways
Genetic changes in responses (osmoregulation)
Specific kinase inhibitors
Changes in experimental conditions
CMB - Cell and Molecular Biology - Group Stefan Hohmann
Integration of signalling, gene expression,
metabolism, transport and biophysical changes
Figure 1
Phosphorelay module
high osmolarity
Osmotic stress
v2TCS ?
v1TCS
Sln1HisP
Sln1
Sln1AspP
ADP ATP
Sln1
v3TCS
Ypd1
Plasma
membrane
Signal
pathway
Ypd1HisP
v4TCS
Ssk1AspP
Ssk1
v5TCS
MAP
kinase Hog1
cascade
Pi
Internal
osmotic
pressure
Phospho
relay
Ssk1 system
e
i
Glucose
Ssk1
Ssk2
Pi
MAP kinase
cascade
module

v1MAP
ATP ADP
v10
synthesis
v2MAP
ATP ADP
Pbs2
v13 Fps1
ADP
Metabolism
NAD
2 ADP
2 ATP
NADH
Gpp2
Glycerol
Transcription
GPD1, GPP2,….
Translation
Fps1
Gpd1, Gpp2,….
Glycerol
v4
G3P
Glycerol
extern
Osmotic
stress
v3MAP
v5
GAP
v6
v9
4 NAD
v7 v8
3 CO2
Gpd1
v11
v12 Gpp2
G3P
NADH NAD
ATP ADP
Pyruvate
4 NADH
DHAP
synthesis
NADH
NAD
NAD
v14
NADH
Ethanol
v16
ADP
v15
ATP
ATP ADP
Pbs2P
v-2MAP
Pi
Pbs2P2
v-3MAP
Hog1P2
vtrans
Pi

v4MAP
ATP ADP
Hog1
v5MAP
Hog1P
Hog1P2
v-5MAP
Pi
CMB - Cell and Molecular Biology - Group Stefan Hohmann
nucleus
Hog1P2nuc
vts
Gene
expression
module
Hog1
vtrans1
cytosol
ATP ADP
v-4MAP
Pi
Glycerol, ex
ATP
v3
Fruc-1,6-BP
DHAP
Gene expression

ADP
Gluc-6-P
ADP ATP
Glucose
Hog1
nucleus
Ssk2P
v-1MAP
ATP
Glk1 v2
Gpd1
cytosol
Metabolism
module
Glucose
uptake
v1
External
osmotic
pressure
vtrans2
Ptp2
Hog1nuc
vdephos
mRNAnuc
vex
vpd
vtl
Proteins
mRNAcyt
vrd
Edda Klipp
Biophysical changes
i = f(Glycerol)
Waterflow over membrane = f(i, e, t)
Volume change = f(Waterflow)
(see text)
Questions addressed by QUASI
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Feedback control mechanisms
in pheromone and highosmolarity signalling MAPK
pathways
Control of cell cycle by MAPK
pathways
Control of a eukaryotic osmolyte
system
Regulation of gene expression
by Hog1 MAPK
Integration of converging
branches of signalling pathway
(HOG branches)
Pathway crosstalk
CMB - Cell and Molecular Biology - Group Stefan Hohmann
AMPKIN
Systems Biology of AMP-activated
protein kinase
AMPK is the cellular
energy regulator in
eukaryotes and a
possible target for
drugs towards
diabetes type II
CMB - Cell and Molecular Biology - Group Stefan Hohmann
AMPKIN
AMPKIN consortium
• Gothenburg (biology: S Hohmann; physics: M Goksör)
Sweden
• Lyngby (bio-engineering: J Nielsen) Denmark
• Rostock (computer science: O Wolkenhauer) Germany
• London (biology: D Carling) UK
• Arexis/Biovitrum (drug company – left project) Sweden
CMB - Cell and Molecular Biology - Group Stefan Hohmann
AMPKIN
Types of measurements to
estimate parameters
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Glycolytic flux and rates of changes of metabolite levels
Rates of changes of phospho-AMPK
Rates of changes of phosphorylated forms of certain target
proteins
Activity of target enzymes
Absolute levels and rates of changes for many pathway
components
Rates of changes of mRNA levels for reporter genes
Population proflies using reporter-XFP and FACS
Nuclear shuttling of Mig1
CMB - Cell and Molecular Biology - Group Stefan Hohmann
AMPKIN
Types of perturbations to test
mathematical models
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Genetic changes in pathways
Genetic changes in metabolism
Specific kinase inhibitors
Changes in experimental conditions
CMB - Cell and Molecular Biology - Group Stefan Hohmann
AMPKIN
Questions addressed by AMPKIN
• Comparative modelling of yeast
and mammalian pathways
• Integration of metabolism and
signalling
• Mechanisms controlling
pathway activity
• Signalling via kinases or
phosphatases
• Contributions of parallel
pathways
CMB - Cell and Molecular Biology - Group Stefan Hohmann
FP7 calls with deadline April 2007
• A system approach to eukaryotic unicellular organism
biology.
• Modelling of T-cell activation.
• Fundamental approaches to stem cell differentiation.
• Developing an integrated in vitro, in vivo and systems
biology modelling approach to understanding
apoptosis in the context of health and disease.
UNICELLSYS
• Eukaryotic unicellular organism biology – systems
biology of the control of cell growth and proliferation
• Large collaborative project 2008-2012, five years
• EC-funding 11.7 million €
• Sixteen partners and more than 30 principle
investigators
• Bringing together major capacity in data generation
and dynamic modelling
CMB - Cell and Molecular Biology - Group Stefan Hohmann
UNICELLSYS
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Organisation
Expertise
Expertise and roles in project
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UGOT
S Hohmann, T Nyström, A Blomberg, P
Sunnerhagen, M Goksör
Signal transduction, ageing, stress responses, phenomics, global gene
expression, single cell analyses
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FCC
M Jirstrand, H Schmidt
Systems theory, software implementation
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DTU
J Nielsen, C Workman
Metabolomics, genome-wide reconstruction, networks, bioinformatics
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ETHZ
U Sauer, R Aebersold, M Peter, J Stelling
Metabolomics, Proteomics, signal transduction, single cell analysis, dynamic
modelling, systems theory
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UPF
F Posas
Signal transduction, stress responses, quantitative analyses
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CRG
L Serrano
Protein design, protein complexes, modelling of transcriptional networks.
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VUA
H Westerhoff, B Bakker
Metabolomics, different modelling approaches, biological theory
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UNIMAN
S Oliver, D Kell, P Mendes
High-throughput phenotyping; physiology, quantitative transcriptomics,
proteomics, metabolomics; modelling; database design, data standards
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ABER
R King
High-throughput phenotyping; machine learning; logical modelling
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UNIMIB
L Alberghina, M Vanoni, E Martegani
Cell cycle control, signal transduction, quantitative analyses
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MPG
E Klipp, S Krobitsch
Dynamic modelling, signal transduction, transcriptomics, protein interaction
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UOXF
B Novak
Cell cycle, dynamic modelling
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MUW
K Kuchler, G Ammerer
Signal transduction, proteomics, protein interaction
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UEDIN
J Beggs, D Tollervey
RNA metabolism, ribosome biogenesis, quantitative measurements
UNICELLSYS
The overall objective of UNICELLSYS is a quantitative understanding of
fundamental characteristics of eukaryotic unicellular organism biology: how cell
growth and proliferation are controlled and coordinated by both extracellular and
intrinsic stimuli. Achieving an understanding of the principles with which systems
of bio-molecules function requires integrating quantitative experimentation with
simulations of dynamic mathematical models in a systems biology approach.
PKA, TOR, Snf1, Snf3/Rgt2
Growth
Nutrients
PHD
PKA
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Development
Stress
PKA, HOG, PKC
STE, PKC
Proliferation
CMB - Cell and Molecular Biology - Group Stefan Hohmann
STE
Hormone
Conclusions
• Quantitative understanding of cell and organism
physiology is a multidisciplinary endeavour
• Major challenges in data generation (quantitative,
molecule numbers, time resolved, single cells....)
• Major challenges for modelling (abstraction, parameter
and model identification/discrimination, model
reduction, integration of different processes, moleculemodule-cell-organ-organism, stochastic processes....)
• Challenges in defining appropriate research
infrastructures and forms of collaboration locally and
Europe-wide
CMB - Cell and Molecular Biology - Group Stefan Hohmann
Present collaborators and funding
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The QUASI EC Project (2007): F Posas, M Peter, G Ammerer, E Klipp, M Grøtli, P Sunnerhagen
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The MalariaPorin EC Project (2007): E Beitz, P Agre, S Flitsch, H Grubmüller
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The Sleeping Beauty EC Project (2008): E Lubzens, M Clark, R Reinhard, J Cerda, J Nielsen
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The Systems Biology Early Stage Training EC project (2008): R van Driel, E Klipp, R Heinrich
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The Yeast Systems Biology Network (2008) with about 20 groups in Europe (EC-funded Coordination
Action) and 40 groups world-wide
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The Sweden-Japan Vinnova project (2009): H Kitano
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The AMPKIN EC Project (2009): D Carling, J Nielsen, O Wolkenhauer, Biovitrum/Arexis AB
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The Aqua(glycero)porin RTN EC Project (2010): S Flitsch, H Grubmüller, P Deen, A Engel, S Nielsen, R
Neutze, J Cerda, Z Vajda, E Klipp
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The CELLCOMPUT NEST EC Project (2011): F Posas, R Solé, M , E Klipp, M Grøtli
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The UNICELLSYS EC Project (2012): 16 different partners
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Funding from the Swedish Research Council (2007)
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Ingvar grant from SSF (2010) to Karin Lindqvist
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Funding from the Swedish Research Council (2007) to Markus Tamás (position and project)
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Faculty platforms in Quantitative Biology and Chemical Biology (2009/11) with groups in in physics (D
Hanstorp), chemistry (M Grøtli), computational biology (M Jirstrand, O Nerman, B Wennberg), structural
biology (R Neutze) and biology (T Nyström, A Blomberg, P Sunnerhagen)
CMB - Cell and Molecular Biology - Group Stefan Hohmann
Courses and conferences
CMB - Cell and Molecular Biology - Group Stefan Hohmann