https://doi.org/10.17608/k6.auckland.10080263 CellML, PMR, OpenCOR, CRBM, … David Nickerson Auckland Bioengineering Institute University of Auckland New Zealand
CellML signalling modules for the cardiac myocyte ms seconds hours days Time scale β -adrenergic α -adrenergic Ion channels, EC-coupl.g Insulin, ANP Inputs NO Peptide GFs Cytokines Cardiac myocyte transporters & mechs NE, Iso Muscarincic, ACh BNP IGF, GH β 1 β 2 α 1 I Na Na + cytokine I Na,b gp130 Na + G s G i G q pGC RTK RTK receptor p Membrane G α G βγ 3Na + G α G α G βγ PIP 3 NCX PIP 2 Ca 2+ p I κ B PLC β Jac PI3K I Ca,b AC Ca 2+ p p I Ca,T DAG + IP 3 Ca 2+ Ca 2+ ATP cAMP p p PKB Ca 2+ NF κ B STAT I Ca,L RyR2 p eNOS RAS I Cl Serca2 p Cytosol Cl - FOXO PLB Ca 2+ iNOS nNOS Ca 2+ mTOR GSK3 K + I K1 p p Ca 2+ PKC K + I Kr NO NO MAPK K + I Ks PKC δ PKC α PKA CaMK CaN CaMK PKD K + I Kto PKC ε PKC β TnI TnC p sGC sGC K + I Kp p p p 3K + ERK JNK p38K Inactive NKA MHC cGMP 2Na + Class II H + HDACs NHE p Na + NFAT cGK I cGK II NBC HCO 3 - p p OH - p p p p CHE p p p p * histone Cl - Nucleus MEF2C TFs TFs TFs TFs AE GATA4 HCO 3 - DNA c-myc, c-fos, c-jun, ras, hsp-70 V Outputs Physiological hypertrophy Hypertrophic cardiac myopathy Apoptosis Ca 2+ t T Concentric hypertrophy Eccentric hypertrophy
https://cellml.org/
https://doi.org/10.17608/k6.auckland.10080263 • XML format for encoding mathematical models • Reproducibility – Unambiguous description of the mathematical model • Reusability – Modular, composable • Comprehensible – Metadata to describe the biological semantics • Tool support – CellML API library and service – Most tools don’t support model composition 4
https://doi.org/10.17608/k6.auckland.10080263 2 .0 • Reactions are gone! • Only CellML allowed in the XML document – No metadata, annotations, cmeta: id – No extension elements • XML syntax simplifications – Grouping replaced with only encapsulation – No more map_components • Improved reusability – Connections no longer have direction – Single interface attribute controlling scope: public, private, public_and_private, none 5
https://doi.org/10.17608/k6.auckland.10080263 2 .0 • Units clarifications – No need to specify base_units explicitly – Units with offsets removed – “celsius” removed from built-in units – Component-scope unit definitions removed • Reset rules – Arbitrary rules to “reset” variables • New and compulsory MathML subset – No more “recommended” subset to support – Well defined, no confusion 6
https://doi.org/10.17608/k6.auckland.10080263 lib • New C+ + library to meet the needs of users • Supporting CellML 2.0 and beyond • Much more streamlined and maintainable • Better suited for testing out new features and extensions to the specification – Allowing rapid prototyping – Exploring alternatives – Testing model exchange and reproducibility 7
https://doi.org/10.17608/k6.auckland.10080263 The Physiom e Model Repository – PMR https:/ / m odels.physiom eproject.org/ • Over 800 publicly available workspaces – Version control repositories (git) – Historically mostly CellML models from the literature – Gradually getting more non-CellML data contributed (SED-ML, FE models, code) • Many more exposures – “releases” of workspaces – A specific version processed for display and interaction 8
https://doi.org/10.17608/k6.auckland.10080263 9 https: / / models.physiomeproject.org/ e/ 71
https://doi.org/10.17608/k6.auckland.10080263 10
https://doi.org/10.17608/k6.auckland.10080263 The Physiom e Model Repository – PMR • Consistent browser and tool integration – Content type negotiation – Same URL – REST • RDF triplestore – Indexing versioned annotations – Supporting (semantic) querying • Tools for model composition, parameter estimation, etc. 11
https://doi.org/10.17608/k6.auckland.10080263 A m odelling environm ent for reproducible science https:/ / opencor.w s 12
https://doi.org/10.17608/k6.auckland.10080263 13
https://doi.org/10.17608/k6.auckland.10080263 14
https://doi.org/10.17608/k6.auckland.10080263 15
https://doi.org/10.17608/k6.auckland.10080263 16
https://doi.org/10.17608/k6.auckland.10080263 Hands on tutorial • Using OpenCOR to explore modularity and reuse with CellML models (including SED-ML) • Making use of PMR as a version controlled workspace to archive and share your work FAIRly • Python-enabled OpenCOR • Starting to explore what is possible with machine learning using TensorFlow, CellML, OpenCOR, and Python. Alan Garny Gonzalo Maso Talou 17
https://doi.org/10.17608/k6.auckland.10080263 https://reproduciblebiomodels.org/ 18
Center Team Herbert Sauro Jonathan Karr John Gennari Ion Moraru U Washington Mount Sinai U Washington UConn Health Director TR&D 1 TR&D 2 TR&D 3 David Nickerson ABI Curation Service Support by NIBIB and NIGMS: 19
Goals Long-term • Enable more comprehensive and more predictive models that advance precision medicine and synthetic biology Short-term • Make modeling more reproducible, comprehensible, reusable, composable, collaborative, and scalable • Develop technological solutions to the barriers to modeling • Integrate the technology into user-friendly solutions • Push researchers to use these tools • Partner with journals 20
TR&Ds 21
Training and dissemination 22
Curation service 23
Acknow ledgem ents • Gonzalo Maso Talou Aotearoa • Tommy Yu Foundation • Alan Garny • Peter Hunter • ABI Physiome Group https://doi.org/10.17608/k6.auckland.10080263
ModelXchange 26
SED-ML Motivation Biological publication repository Simulation tool ? models Simulation result 27
Exam ple First attempt to run the model, measuring the spiking rate v over time load SBML into the simulation tool COPASI use parametrisation as given in the SBML file define output variables ( v ) run the time course 1 ms (standard) 100ms 1000ms 28
Exam ple Second attempt to run the model, adjusting simulation step size and duration Fig.: COPASI simulation, duration: 140ms, step size: 0.14 29
Exam ple Third attempt to run the model, updating initial model parameters Fig.: COPASI, adjusted parameter values (a=0.02, b=0.2 c=-55, d=4 ) 30
https://sed-ml.org/ 31
http://co.mbine.org
Standards for Knowledge Standards for Visual Standards for Models Representation Representation and their Analyses Core BioPAX Standards Controlled Associated Projects Infrastructure Vocabularies Standards BioModels.net qualifiers Used by core standards
Coordination board Publications ● ● Coordinating new efforts, Forums/mailing lists ● ● meetings, etc. FAIR and FAIRsharing ● COMBINE Archive ○ Harmonizing annotation ○ Uncertainty? ○
https://doi.org/10.1109/WSC.2017.8247840
http://co.mbine.org/comm
10th COMBINE Anniversary ● July 15-19 in Heidelberg ● Registration now open! ● Abstract submission deadline extended to June 15! ● http://co.mbine.org/events/COMBINE_2019 ●
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