Turning Biological Knowledge into Mathematical Models, Automatically

Oliver Ruebenacker, Michael Blinov, Ion Moraru, Jim Schaff, University of Connecticut Health Center

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

OMGBBL

OMGBBL

LOL

FUD

IMHO

Bob's Solution

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)

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

Qualitative Bio Knowledge on WebPathway Commons (BioPAX Level 2): BioGRID, MSKCC Cancer Cell Map, HPRD, HumanCyc, SBCNY, IntAct, MINT, NCI/Nature PID, Reactome1,623 pathways, 585,000 interactions, 106,000 physical entities, 564 organismsBioPAX Level 3 being testedUniProt: 531,473 SwissProt, 16,504,022 TrEMBLChEBI: 26,091 entriesNCBI Taxonomy: 814,119 taxonsFoundational Model of Anatomy: 120,000+ terms

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;

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

Quantitative Bio versus ModelingModel = Biology + Method

Biology: biological reality; qualitative + quantitative; general + specific ( => BioPAX, SBPAX)

Method: cropping, filtering, merging, requirements, assumptions, simplifications, omissions, artifacts ( => VCell)

Model: Math (=> SBML, CellML)

Systems Biology Pathway Exchange (SBPAX)

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)

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)

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

How to get the molecular weight

For most common: Hardcode weight, e.g. for ATP, Ca, GTP

Metabolites: Download from ChEBI

Proteins: Get sequence from UniProt Calculate weight from sequence Add modifications (e.g. phosphorylations)

Using the VCell Model DB

Create statistics of all public models (some filtering) Classify by compartments, species, reactions Group species by ChEBI classes and UniProt

keywords Find correlations between compartment

sizes, initial conditions, kinetic parameters To create new models, find similar existing

models, calculate numbers based on patterns/correlations.

Acknowledgements VCell: Jim Schaff, Michael Blinov, Ion Moraru, Dan

Vasiliescu, Xintao Wei, Fei Gao, Anu Lakshminarayana

BioPAX: Emek Demir, Gary Bader, 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

Virtual Cell (Model View)Virtual Cell (Pathway View)

http://sbpax.org http://vcell.org