The Biology of Ageing e-Science Integration and Simulation System

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The Biology of Ageing e-Science Integration and
Simulation System

• Tom Kirkwood, Darren Wilkinson,
• Richard Boys, Colin Gillespie,
• Carole Proctor, Daryl Shanley

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www.basis.ncl.ac.uk

• GRID-based research node to model/simulate
  hypotheses about mechanisms of ageing
• Accessible and interactive
• Nature Reviews Molecular Cell Biology 20034
  243 -249

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Modelling the ageing process
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Virtual Ageing Cell

• Telomere loss and oxidative stress Proctor
  Kirkwood Mech Ageing Dev 2001.
• Mitochondrial mutation Kowald Kirkwood J Theor
  Biol 2000.
• Somatic mutation Kirkwood Proctor Mech Ageing
  Dev 2003.
• Telomere capping Proctor Kirkwood Aging Cell
  2003
• Extrachromosomal DNA circles Gillespie et al J
  Theor Biol 2004
• Genetic pathways eg Sir2 gene action (in
  progress)
• Protein turnover Chaperones, ubiquitin-proteasome
  system (Proctor et al. Mech Ageing Dev 2004 and
  in progress)
• Antioxidant system Shanley et al (in progress)
• Network models
• Mitochondrial mutation, oxidative stress, protein
  turnover (Kowald Kirkwood Mutation Res 1996)
• Somatic mutation, telomere loss, mitochondrial
  mutation (oxidative stress (Sozou Kirkwood
  JTheor Biol 2001)

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A module of the virtual ageing cell the action
of chaperones and their role in ageing

• Proctor et al. 2004 Mechanisms in Ageing and
  Development

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Cellular functions of chaperones

• Folding of nascent proteins
• Assist in assembly of protein structures
• Refolding of denatured proteins
• Transport of proteins through cellular membranes
• Targeting of proteins for degradation
• Prevention of protein aggregation

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Protein model for quality control
Wickner et al. (1999) Science 286 1888-1893
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Hsp90 Model of Regulation of HSF1
Zou et al. (1998) Cell 94471-480
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Steps in building and using a model

1. Draw a diagram of the system.
2. Give values to the boxes representing the number
   of molecules and to the arrows representing the
   reaction rates.
3. Use a software tool to translate the diagram into
   computer code.
4. Use the simulator to discover the dynamic
   behaviour of the system.

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Building a model of the chaperone system

• (i) The role of chaperones in preventing protein
  aggregation

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(ii) Autoregulation of Hsp90
dimerisation
trimerisation
Hsf1
DiH
TriH
binding
Hsf1
Hsp90
Hsp90
synthesis
TriH
DNA binding
HSE
HSE
degradation
Abbreviations Hsf1 heat shock factor-1 DIH dimer
of Hsf1 TriH trimer of Hsf1 HSE heat shock element
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Model is coded in SBML

• ltsbml xmlns"http//www.sbml.org/sbml/level2"
  version"1" level"2" gt
• ltmodel id"Hsp90model1" gtltlistOfCompartmentsgtltc
  ompartment id"cell" spatialDimensions"3"
  size1 name"cell" /gtlt/listOfCompartmentsgtltlis
  tOfSpeciesgtltspecies id"NatP" compartment"cell"
  initialAmount"6000000.0" nameNatP" /gtltspecies
  idHsp90" compartment"cell" initialAmount30000
  .0" name" Hsp90 " /gt .
• lt/listOfSpeciesgtltlistOfParametersgtltparameter
  id"k1" value"7.04E-8" namek1" /gt .
• lt/listOfParametersgtltlistOfReactionsgtltreaction
  id"protein_misfolding" reversible"false"
  gtltlistOfReactantsgtltspeciesReference
  speciesNatP" gtlt/speciesReferencegtlt/listOfReact
  antsgtltlistOfProductsgtltspeciesReference
  speciesMisP" gtlt/speciesReferencegtlt/listOfProdu
  ctsgt .
• lt/reactiongt .
• lt/listOfReactionsgtlt/modelgtlt/sbmlgt

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Stochastic simulation

• Reactions are picked at random according to
  their rates.
• After each reaction, the number of each species
  is updated.

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Adding further detail to the model
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Combining models in the BASIS system

• Other components will include models of the
  mitochondria the antioxidant system damage to
  nuclear DNA telomere shortening and signalling
  pathways.
• Combining the mitochondria and chaperone model
  via ROS and ATP

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BASIS architecture
User PC
Web browser
BASIS client software
Internet (GRID)
BASIS file server
Web server
CGI scripts
e-mail notification
Web services
API
Database
Job Scheduler
Linux beowulf cluster
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BASIS architecture

• Web server is running apache
• Condor as a job scheduler
• python as an all purpose glue
• SBML is parsed and manipulated using libSBML for
  C python
• postgresql for the database
• graphviz for the visualisation of the SBML models

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BASIS model repository

• Users have a private space for their
  models/simulations
• Once a model is made public it cannot be deleted
• useful for the publication of models
• Models can be accessed through a web-service
  interface
• other tools can access the models
• Models are referenced using urns, e.g.
  urnbasis.nclmodel10

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Example web-services

• To put a model into your space
• putModel(SId, sbml)
• Using libSBML graphviz
• visualiseSBMLReaction(sbml, reaction)

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Whats new?

• More interaction with biologists
• especially PhD students
• Virtual ageing cell
• more computer resources needed Grid
• Web services
• import models from other databases

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BASIS TeamTom Kirkwood Darren Wilkinson
Richard BoysColin Gillespie Carole Proctor
Daryl ShanleyCollaborators at
NewcastleThomas von Zglinicki David
LydallGabriele SaretzkiTim Cowen (IAH/UCL)Doug
TurnbullChris MorrisJohn MathersNeil WipatNE
E-Science CentrePaul WatsonRob Smith
Acknowledgements

• Unilever
• Janette Jones
• Jonathan Powell
• Frans van der Ouderaa
• Berlin (MPI Inst. Mol. Genet.)
• Axel Kowald
• University of Bologna
• Claudio Franceschi
• Silvana Valensin
• Paolo Tieri
• INSERM Paris
• Francois Taddei
• Tufts University/USDA
• Jose Ordovas
• University of Liverpool
• Brian Merry
• University of Semmelweis
• Csaba Soti
• Ottawa Regional Cancer Centre