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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.

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Systems biology challenges in experimental and theoretical sciences
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
Systems Biology – an approach theoretical sciences

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
Systems Biology - directions theoretical sciences

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
EC funds several projects on dynamic modelling in FP6 theoretical sciences

  • 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
Quantifying signal transduction theoretical sciences

CMB - Cell and Molecular Biology - Group Stefan Hohmann


Quasi consortium
QUASI consortium theoretical sciences

  • 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
Types of measurements to estimate parameters theoretical sciences

  • 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
Types of perturbations to test mathematical models theoretical sciences

  • 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, theoretical sciences

metabolism, transport and biophysical changes

Edda Klipp

CMB - Cell and Molecular Biology - Group Stefan Hohmann


Questions addressed by quasi
Questions addressed by QUASI theoretical sciences

  • Feedback control mechanisms in pheromone and high-osmolarity 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


Systems biology of amp activated protein kinase

AMPKIN theoretical sciences

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 consortium

AMPKIN theoretical sciences

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


Types of measurements to estimate parameters1

AMPKIN theoretical sciences

Types of measurements to estimate parameters

  • 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


Types of perturbations to test mathematical models1

AMPKIN theoretical sciences

Types of perturbations to test mathematical models

  • Genetic changes in pathways

  • Genetic changes in metabolism

  • Specific kinase inhibitors

  • Changes in experimental conditions

CMB - Cell and Molecular Biology - Group Stefan Hohmann


Questions addressed by ampkin

AMPKIN theoretical sciences

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
FP7 calls with deadline April 2007 theoretical sciences

  • 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
UNICELLSYS theoretical sciences

  • 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


Unicellsys1
UNICELLSYS theoretical sciences


Unicellsys2

PKA, TOR, Snf1, Snf3/Rgt2 theoretical sciences

Growth

Nutrients

PHD

PKA

?

Development

Stress

PKA, HOG, PKC

STE, PKC

Proliferation

Hormone

STE

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.

CMB - Cell and Molecular Biology - Group Stefan Hohmann


Conclusions
Conclusions theoretical sciences

  • 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, molecule-module-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
Present collaborators and funding theoretical sciences

The QUASI EC Project (2007): F Posas, M Peter, G Ammerer, E Klipp, M Grøtli, P Sunnerhagen

The MalariaPorin EC Project (2007): E Beitz, P Agre, S Flitsch, H Grubmüller

The Sleeping Beauty EC Project (2008): E Lubzens, M Clark, R Reinhard, J Cerda, J Nielsen

The Systems Biology Early Stage Training EC project (2008): R van Driel, E Klipp, R Heinrich

The Yeast Systems Biology Network (2008) with about 20 groups in Europe (EC-funded Coordination Action) and 40 groups world-wide

The Sweden-Japan Vinnova project (2009): H Kitano

The AMPKIN EC Project (2009): D Carling, J Nielsen, O Wolkenhauer, Biovitrum/Arexis AB

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

The CELLCOMPUT NEST EC Project (2011): F Posas, R Solé, M , E Klipp, M Grøtli

The UNICELLSYS EC Project (2012): 16 different partners

Funding from the Swedish Research Council (2007)

Ingvar grant from SSF (2010) to Karin Lindqvist

Funding from the Swedish Research Council (2007) to Markus Tamás (position and project)

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
Courses and conferences theoretical sciences

CMB - Cell and Molecular Biology - Group Stefan Hohmann


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