applying the scientific method to simulation experiments

Applying  the  Scien.fic  Method  to  Simula.on  Experiments

Frank  T.  Bergmann,  PhD  California  Ins8tute  of  Technology  

University  of  Heidelberg  Bergman@caltech.edu  

Outline

Background  &  Introduc8on  

Simula8on  Experiment  Descrip8on  Markup  Language  –  SED-­‐ML  

SoMware  Support  

Conclusion  

Scien.fic  Method

Scien&fic  method  –  body  of  techniques  for  inves3ga3ng  phenomena  and  acquiring  new  knowledge,  as  well  as  for  correc&ng  and  integra&ng  previous  knowledge.  

hOp://en.wikipedia.org/wiki/Scien8fic_method  

Models

Models

Teusink  et.  al,  2003,  DOI:  10.1046/j.1432-­‐1327.2000.01527.x  

Adapted  from  Michael  Hucka    

Model

Species

Species  

Reac.ons

Species  

Reac8ons  

Species  

Rate  Laws

Reac8ons  

Systems  Biology  Markup  Language  (SBML) <?xml version="1.0" encoding="UTF-8"?> <sbml xmlns="http://www.sbml.org/sbml/level2/version4"

level="2" version="4"> <model id="BorisEJB" name="BorisEJB"> <listOfCompartments> <compartment id="compartment" size="1"/> </listOfCompartments> <listOfSpecies> <species id="MKKK" compartment="compartment"

initialConcentration="90"/> <species id="MKKK_P" compartment="compartment"

initialConcentration="10"/> [ . . . ] </listOfSpecies> <listOfParameters> <parameter id="J0_V1" value="2.5"/> <parameter id="J0_Ki" value="9"/> <parameter id="J0_n" value="1"/> <parameter id="J0_K1" value="10"/> [ . . . ] </listOfParameters> <listOfReactions> <reaction id="J0" reversible="false"> <listOfReactants> <speciesReference species="MKKK"/> </listOfReactants> <listOfProducts> <speciesReference species="MKKK_P"/> </listOfProducts> <listOfModifiers> <modifierSpeciesReference species="MAPK_PP"/> <modifierSpeciesReference species="MAPK_PP"/> </listOfModifiers> <kineticLaw> <math xmlns="http://www.w3.org/1998/Math/MathML"> <apply> [ . . . ]

SBML  SoCware  Guide

hOp://sbml.org/SBML_SoMware_Guide  

Journals

• BioMedCentral  (all  journals)  • Biophysical  Journal  • Computa8onal  and  Mathema8cal  Biology  •  FEBS  Journal  •  IET  Systems  Biology  • Molecular  Systems  Biology  • Nature  (all  NPG  journals)  • PLoS  (all  journals)  • PNAS  • Royal  Society  of  Chemistry  (all  journals)  • UCSD  Molecule  Pages  

hOp://sbml.org/Documents/Publica8ons_known_to_accept_submissions_in_SBML_format  

Models

Teusink  et.  al,  2003,  DOI:  10.1046/j.1432-­‐1327.2000.01527.x  

Simula.on  Experiments

Simula.on  Experiments

Huang  et.  al,  1996,  DOI:  10.1073/pnas.93.19.10078  

biomodels.net/biomodels

biomodels.net/biomodels

Adapted  from  Michael  Hucka    

Simula.on  Experiments

Huang  et.  al,  1996,  DOI:  10.1073/pnas.93.19.10078  

Cura8on  tab  of  BioModel  #9  

Curator's comment: (updated: 15 Jul 2013 13:25:23 BST)#Figure 2B of the reference publication has been reproduced using Copasi 4.10 (Build 55). A logarithmic parameter scan over a range of "MAPKKK activator (Ras)" values with simultaneous calculation of the steady state was performed.#

Simula.on  Experiments

Huang  et.  al,  1996,  DOI:  10.1073/pnas.93.19.10078  

Curator's comment: (updated: 15 Jul 2013 13:25:23 BST)#Figure 2B of the reference publication has been reproduced using Copasi 4.10 (Build 55). A logarithmic parameter scan over a range of "MAPKKK activator (Ras)" values with simultaneous calculation of the steady state was performed.#

Large  scale  integra.ve  models  …  

Outline

Background  &  Introduc8on  

Simula8on  Experiment  Descrip8on  Markup  Language  –  SED-­‐ML  

SoMware  Support  

Conclusion  

Simula.on  Experiment  Descrip.on  Markup  Language

SED-­‐ML:  Repeatable  simula.on  experiments

Model  

SED-­‐ML:  Repeatable  simula.on  experiments

Model  Simula8on  

SED-­‐ML:  Repeatable  simula.on  experiments

Model  Simula8on  

Task  

SED-­‐ML:  Repeatable  simula.on  experiments

Model  Simula8on  

Task  

Data  Generators  

SED-­‐ML:  Repeatable  simula.on  experiments

Data  Generators  

Task  

Reports  

Model  Simula8on  

SED-­‐ML  Level  1  Version  1

SED-­‐ML  Level  1  Version  2

Data  Generators  

Task  

Reports  

Model  Simula8on  

Parameters  

Repeated  Task  

Steady    State  

One  Step    

SED-­‐ML  L1V2

SED-­‐ML  Future

SED-­‐ML

• Coverage  • Simula8ons  (stochas8c  /  determinis8c  /  steady  state)  • Parameter  Scans  (8me  course  /  steady  state  /  n-­‐dimensional)  • Dosing  /  Pulse  experiments  

• Work  in  Progress  • Accessing  Experimental  Data,    • Op8miza8on  • Parameter  Es8ma8on  

Outline

Background  &  Introduc8on  

Simula8on  Experiment  Descrip8on  Markup  Language  –  SED-­‐ML  

SoMware  Support  

Conclusion  

SED-­‐ML  Script  Editor

hOp://libsedml.sf.net    

SED-­‐ML  Web  Tools

hOp://sysbioapps.dyndns.org/SED-­‐ML_Web_Tools    

Systems  Biology  Workbench

hOp://sbw.sf.net    

Systems  Biology  Workbench

hOp://sbw.sf.net    

Systems  Biology  Workbench

hOp://sbw.sf.net    

CellDesigner

hOp://celldesigner.org    

hOp://pysces.sf.net    

SBSI  –  SED  ED

hOp://sourceforge.net/projects/sbsi/    

COPASI

hOp://www.copasi.org/    

VCELL

hOp://www.nrcam.uchc.edu/    

JWS  Online

hOp://jjj.biochem.sun.ac.za/    

Libraries

•  libSedML:  .NET;  BSD  License    hOp://libsedml.sourceforge.net  

•  libSEDML:  C/C++  with  bindings  for  .NET,  Java,  Perl,  Python,  R,  Ruby;  BSD  License,  hOps://github.com/Bergmann/libsedml  

 •  jlibsedml:  Java;  MIT  License    hOp://sourceforge.net/projects/jlibsedml/  

•  clibsedml,:  C;  BSD  License  hOp://sourceforge.net/projects/clibsedml  

Outline

Background  &  Introduc8on  

Simula8on  Experiment  Descrip8on  Markup  Language  –  SED-­‐ML  

SoMware  Support  

Conclusion  

Conclusions

• Opportunity:  Simula8on  Experiments  as  readily  exchangeable  as  computa8onal  models  •  Independently  of  SoMware  tools  à  independent  verifica8on  of  results  •  Con8nue  in  another  tool  right,  where  you  leM  off  in  one  tool  •  Possibility  of  full  documenta8on  of  experiments  •  Reuse  the  precisely  same  experiment  for  different  models.    

•  SoMware  Support  is  growing,  readily  available  in  a  number  of  tools.  

Next  Steps  …  

•  Finalize  SED-­‐ML  Level  1  Version  2  • Prototype  on  Version  3  

•  Export  remaining  experiments  from  the  SBW  Simula8on  Tool    •  Finish  work  on  SED-­‐ML  exporters  

•  SED-­‐ML  -­‐-­‐>  Matlab  •  SED-­‐ML  -­‐-­‐>  Jarnac  

Acknowledgements

 •  SED-­‐ML  Editors:  Frank  T.  Bergmann,  Dagmar  Waltemath,  Jonathan  Cooper,  David  Nickerson,  Nicolas  Le  Novère,  Andrew  Miller,  Richard  Adams  

• BioModels  Support  Team  

•  SED-­‐ML  Community  

• Ursula  Kummer,  Michael  Hucka,  Herbert  Sauro  

More  Informa.on  

•  SED-­‐ML:  hOp://sed-­‐ml.org    hOp://8nyurl.com/sed-­‐ml-­‐l1v2-­‐rc    hOps://lists.sourceforge.net/lists/lis8nfo/sed-­‐ml-­‐discuss/      

•  SED-­‐ML  Web  Tools:    hOp://sysbioapps.dyndns.org/SED-­‐ML_Web_Tools    

•  SBML:    hOp://sbml.org/  hOp://biomodels.net/biomodels