1. www.sbpax.orgwww.sbpax.org SW 4 HCLS Aug 28 2012 SBPAX: Turning Bio Knowledge into Math Models, Automated Oliver Ruebenacker (PanGenX) SW 4 HCLS, Tue, Aug 28, 2012 www.sbpax.org www.sbpax.org

2. www.sbpax.org SW 4 HCLS Aug 28 2012 Biological Pathway Exchange (BioPAX, www.biopax.org) Molecular Pathways in OWL: Physical Entities (Protein, DNA, RNA, Complex, Small Molecule), Interactions (Conversion, Control, etc.), States (Phosphorylations, etc.) Cross-references to DBs (molecules, functions, publications, etc) Genes, provenance, evidence, etc. Versions: Level 3 (2010), Level 4 in progress Governance: community, elected editors Tools: PaxTools, Online Validator, Cytoscape Plugin Interoperability: Combine Core Standard

3. www.sbpax.orgwww.sbpax.org SW 4 HCLS Aug 28 2012 Qualitative Bio Knowledge on Web Pathway Commons (BioPAX Level 2): BioGRID, MSKCC Cancer Cell Map, HPRD, HumanCyc, SBCNY, IntAct, MINT, NCI/Nature PID, Reactome 1,623 pathways, 585,000 interactions, 106,000 physical entities, 564 organisms BioPAX Level 3 being tested UniProt: 531,473 SwissProt, 16,504,022 TrEMBL ChEBI: 26,091 entries NCBI Taxonomy: 814,119 taxons Foundational Model of Anatomy: 120,000+ terms

4. www.sbpax.orgwww.sbpax.org SW 4 HCLS Aug 28 2012 Systems Biology Pathway Exchange (SBPAX, www.sbpax.org) Integrated with BioPAX classes Extension to BioPAX L3 as SBPAX3 Proposal for BioPAX L4 Arranges Systems Biology terms (e.g. Systems Biology Ontology), numbers and units into hierarchies Units based on Units of Measurement Expressions (UOME)

5. www.sbpax.orgwww.sbpax.org SW 4 HCLS Aug 28 2012 Systems Biology Ontology (SBO) Project by BioModels.net, curator Nick Juty Comprehensive collection of SB-relevant terms, hierarchical Includes terms for many rate laws, parameters and quantities For rate laws, includes math expression and references to SBO terms of the parameters (e.g. term for Michaelis-Menten rate law refers to term for Michaelis constant)

6. www.sbpax.orgwww.sbpax.org SW 4 HCLS Aug 28 2012 Units of Measurement Expressions (UOME) UOME core: ontology to define units: By scaling, exponentiation, offset, product or quotient of other units By reference to controlled vocabulary (e.g. UO) UOME list: long list of predefined units (e.g. micro mole per milligram per minute) Can convert to SBML/VCell units

7. www.sbpax.orgwww.sbpax.org SW 4 HCLS Aug 28 2012 Quantitative Bio Knowledge on Web SABIO-RK: SBML export, rich on SBO; implemented BioPAX L3, SBPAX3 export; Signaling Gateway Molecule Pages: 672 curated pages (interactions), large diversity of quantitative values, BioPAX L3 and SBPAX3 export MetaCyc, EcoCyc: collecting enzymatic rate constants; SBML, BioPAX L3 export; SBPAX3 interest;

8. www.sbpax.orgwww.sbpax.org SW 4 HCLS Aug 28 2012 Virtual Cell Time-course simulations: Deterministic or stochastic Spatial or compartmental Physiological Model: Compartments (e.g. anatomical structures) Abundancies (e.g. concentrations / molecule numbers) Processes (e.g. chemical reactions) Can be converted to math model Math Model: General differential equations Openness: Open source, MIT- licensed

9. www.sbpax.orgwww.sbpax.org SW 4 HCLS Aug 28 2012 Virtual Cell Architecture Client: Java app + native libs (Win, Linux, Mac) Start from Web (JNLP) Some standalone capacity Talks to Server Server: Java, spawns solver processes, talks to database Database: Oracle (any SQL would do) Solvers: Processes run on cluster Mostly C++

10. www.sbpax.orgwww.sbpax.org SW 4 HCLS Aug 28 2012 Bob's Theory Question: How do FUD, BBL, OMG interact? Bob the Biologist has a theory Now he needs to test it (simulation!) Bob the Biologist The Question ? ? ? FUD OMG BBL FUD OMG BBL LOL FUD IMHO Bob's Theory

11. www.sbpax.orgwww.sbpax.org SW 4 HCLS Aug 28 2012 A realistic Model for Bob's Theory For realistic simulation, need some context Bob's Theory (new exciting research) The Context (stuff everyone knows already)

12. www.sbpax.orgwww.sbpax.org SW 4 HCLS Aug 28 2012 Trends Biological Details → Complete Knowledge Knowledge → Computer-processable Knowledge → Public Computers → Much faster Bio Models → Complete Biochem Details Model Building → Automatic Model Builder → Knowledgebase Frontend

13. www.sbpax.orgwww.sbpax.org SW 4 HCLS Aug 28 2012 Bio Knowledge from Web into VCell Systems Biology Linker (SyBiL) at VCell: Grab Bio Knowledge from Web to build and annotate models Qualitative: Queries Pathway Commons, UniProt, ChEBI; imports BioPAX (since years) Quantitiative: SBPAX3 from SGMP, SABIO-RK

14. www.sbpax.orgwww.sbpax.org SW 4 HCLS Aug 28 2012 Same Reality  Many Models Model = Biology + Method Biology: biological reality; qualitative + quantitative; general + specific (  BioPAX, SBPAX) Method: cropping, filtering, merging, requirements, assumptions, simplifications, omissions, artifacts (  SED-ML) Model: Math (  SBML, VCML, CellML)

15. www.sbpax.orgwww.sbpax.org SW 4 HCLS Aug 28 2012 Demo Demo of latest VCell features

16. www.sbpax.orgwww.sbpax.org SW 4 HCLS Aug 28 2012 Acknowledgements VCell: Jim Schaff, Michael Blinov, Ion Moraru, Dan Vasiliescu, Xintao Wei, Fei Gao, Anu Lakshminarayana BioPAX: Emek Demir, Gary Bader, Igor Rodchenkov, Andria Splendiani, Peter D'Eustachio, Huaiyu Mi Signaling Gateway Molecule Pages: Ashok Dinasarapu SBO: Nick Juty SABIO-RK: Wolgang Mueller, Martin Golebiewski, Ulrike Wittig, Renate Kania, Lenneke Jong, Enkhjargal Algaa "Stagnation and the search for truth are always opposites." - Nadezhda Tolokonnikova