Creating a new language to support
open innovation
Michael Hucka, Ph.D.
Department of Computing + Mathematical Sciences
Ca...
Outline
Background and introduction
The Systems Biology Markup Language (SBML)
Complementary efforts: MIRIAM and SED-ML
COM...
Outline
Background and introduction
The Systems Biology Markup Language (SBML)
Complementary efforts: MIRIAM and SED-ML
COM...
Research today: experimentation, computation, cogitation
“ The nature of systems biology”
Bruggeman & Westerhoff,
Trends Microbiol. 15 (2007).
Large-scale integrative models are growing
Many models have traditionally been published this way
Problems:
• Errors in printing
• Missing information
• Dependencies...
Experiences from BioModels Database
BioModels Database:
• Public database of published computational models in biology
• M...
Experiences from BioModels Database
BioModels Database:
• Public database of published computational models in biology
• M...
Experiences from BioModels Database
BioModels Database:
• Public database of published computational models in biology
• M...
Is it enough to make your (software X) code available?
It’s vital for good science:
• Someone with access to the same soft...
Is it enough to make your (software X) code available?
It’s vital for good science—
• Someone with access to the same soft...
Different tools different interfaces & languages
Outline
Background and introduction
The Systems Biology Markup Language (SBML)
Complementary efforts: MIRIAM and SED-ML
COM...
SBML:alinguafranca
forsoftware
Format for representing computational models of biological processes
• Data structures + usage principles + serialization ...
The raw SBML
The process is central
• Literally called a“reaction”in SBML
• Participants are pools of entities (biochemical species)
Mo...
SBML is now widely used
Dozens of journals accept models in SBML format
100’s of software tools available today
1000’s of ...
Contents of BioModels Database
Contents today:
• 142,000+ pathway models (converted from KEGG)
• 460+ hand-curated quantit...
Free software libraries – libSBML
Reads, writes, validates SBML
Can check & convert units
Written in portable C++
Runs on ...
Free software libraries – JSBML
Pure Java implementation
API is compatible with libSBML but
more Java-like
Functionality i...
Evolution of SBML continues
Today: SBML Level 3
• Level 3 Core provides framework for common models
• Level 3 packages add...
Level 3 package What it enables
Hierarchical model composition Models containing submodels ✔
Flux balance constraints Cons...
NationalInstituteofGeneralMedicalSciences(USA)
European Molecular Biology Laboratory (EMBL)
JST ERATO Kitano Symbiotic Sys...
Outline
Background and introduction
The Systems Biology Markup Language (SBML)
Complementary efforts: MIRIAM and SED-ML
COM...
Mathematical semantics
Biological semantics
Visual interpretation
Discrete stochastic entities
Continuous lumped parameter...
Modelerswanttousetheirownconventions
Modelerswanttousetheirownconventions
No standard
identifiers
Modelerswanttousetheirownconventions
Low info
content
No standard
identifiers
Raw models alone are insufficient
Need standard schemes for
machine-readable annotations
• Identify entities
• Mathematical ...
Addresses 2 general areas of annotation needs:
MIRIAM is not specific to SBML
MIRIAM(MinimumInformationRequestedIntheAnnota...
Addresses 2 general areas of annotation needs:
MIRIAM is not specific to SBML
MIRIAM(MinimumInformationRequestedIntheAnnota...
Example of a problem that can be solved with annotations
http://www.ebi.ac.uk/chebi
Low info
content
Example of a problem that can be solved with annotations
http://www.ebi.ac.uk/chebi
Low info
content
Known by different na...
MIRIAM annotations for external references
Goal: link model constituents to corresponding entities in
bioinformatics resou...
How do we create globally unique identifiers consistently?
Long story short—developed by the Le Novère group at the EBI
• R...
Another problem: software can’t read figure legends
?
BIOMD0000000319 in BioModels Database
Decroly & Goldbeter, PNAS, 1982
SED-ML = Simulation Experiment Description ML
Application-independent format
•Captures procedures, algorithms, parameter v...
Efforts like SED-ML improve reproducibility of publications
Waltemath et al.,
BMC Sys Bio 5, 2011.
Outline
Background and introduction
The Systems Biology Markup Language (SBML)
Complementary efforts: MIRIAM and SED-ML
COM...
Need interoperable formats, but developing them is not easy
Need people with diverse set of knowledge & skills
• Scientific...
Need interoperable formats, but developing them is not easy
Need people with diverse set of knowledge & skills
• Scientific...
Realizations about the state of affairs in late-2000’s
• Many standardization efforts overlapped, but lacked coordination
• ...
Standardization efforts represented in COMBINE today
BioPAX
Qualifiers
GPML
COMBINE Standards
Associated Standardization Effo...
Those are the products of successful, open collaborations!
Examples of community organization
Two main annual meetings, plus ad hoc workshops
• COMBINE meeting: status updates, pres...
What motivates people to do this?
Solving a problem for yourself/your closed group is easier and quicker
• So what are the...
COMBINE is open to all—and COMBINE needs you!
http://co.mbine.org
Current coordinators:
• Nicolas Le Novère, Mike Hucka, F...
Outline
Background and introduction
The Systems Biology Markup Language (SBML)
Complementary efforts: MIRIAM and SED-ML
COM...
Time it well
• Too early and too late are bad
Start with actual stakeholders
• Address real needs, not perceived ones
Star...
Not waiting for implementations before freezing specifications
• Sometimes finalized specification before implementations tes...
Nicolas Le Novère, Henning Hermjakob, Camille Laibe, Chen Li, Lukas Endler,
Nico Rodriguez, Marco Donizelli,Viji Chelliah,...
SBML http://sbml.org
BioModels Database http://biomodels.net/biomodels
MIRIAM http://biomodels.net/miriam
identifiers.org h...
I’d like your feedback!
You can use this anonymous form:
http://tinyurl.com/mhuckafeedback
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Creating a new language to support open innovation

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Presentation given on 19 August 2013 at a BioBriefings meeting of the BioMelbourne Network (http://www.biomelbourne.org/events/view/289) in Melbourne, Australia.

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Creating a new language to support open innovation

  1. 1. Creating a new language to support open innovation Michael Hucka, Ph.D. Department of Computing + Mathematical Sciences California Institute of Technology Pasadena, CA, USA BioBriefing – BioMelbourne Network, Australia, August 2013 Email: mhucka@caltech.edu Twitter: @mhucka
  2. 2. Outline Background and introduction The Systems Biology Markup Language (SBML) Complementary efforts: MIRIAM and SED-ML COMBINE: the Computational Modeling in Biology Network Conclusion
  3. 3. Outline Background and introduction The Systems Biology Markup Language (SBML) Complementary efforts: MIRIAM and SED-ML COMBINE: the Computational Modeling in Biology Network Conclusion
  4. 4. Research today: experimentation, computation, cogitation
  5. 5. “ The nature of systems biology” Bruggeman & Westerhoff, Trends Microbiol. 15 (2007).
  6. 6. Large-scale integrative models are growing
  7. 7. Many models have traditionally been published this way Problems: • Errors in printing • Missing information • Dependencies on implementation • Outright errors • Can be a huge effort to recreate Is it enough to communicate the model in a paper?
  8. 8. Experiences from BioModels Database BioModels Database: • Public database of published computational models in biology • Many models are curated – i.e., made to work & annotated - If not available in electronic form, they encode it from the paper Their experiences? • Vast majority of models encoded directly from the publication did not work as published - Often (not always) due to common errors – typos, omissions • Success rate improved in recent years thanks to more people providing their models in electronic formats More is needed to make computational results reproducible
  9. 9. Experiences from BioModels Database BioModels Database: • Public database of published computational models in biology • Many models are curated – i.e., made to work & annotated - If not available in electronic form, they encode it from the paper Their experiences? • Vast majority of models encoded directly from the publication did not work as published - Often (not always) due to common errors – typos, omissions • Success rate improved in recent years thanks to more people providing their models in electronic formats More is needed to make computational results reproducible http://biomodels.net/biomodels
  10. 10. Experiences from BioModels Database BioModels Database: • Public database of published computational models in biology • Many models are curated – i.e., made to work & annotated - If not available in electronic form, they encode it from the paper Their experiences? • Vast majority of models encoded directly from the publication did not work as published - Often (not always) due to common errors – typos, omissions • Success rate improved in recent years thanks to more people providing their models in electronic formats More is needed to make computational results reproducible
  11. 11. Is it enough to make your (software X) code available? It’s vital for good science: • Someone with access to the same software can try to run it, understand it, verify the computational results, build on them, etc. • Opinion: you should always do this in any case
  12. 12. Is it enough to make your (software X) code available? It’s vital for good science— • Someone with access to the same software can try to run it, understand it, build on it, etc. • Opinion: you should always do this in any case But it’s still not ideal for communication of scientific results: • What if they don’t have access to the same software? • What if they don’t want to use that software? • What if they want to use a different conceptual framework? • And how will people be able to relate the model to other work?
  13. 13. Different tools different interfaces & languages
  14. 14. Outline Background and introduction The Systems Biology Markup Language (SBML) Complementary efforts: MIRIAM and SED-ML COMBINE: the Computational Modeling in Biology Network Conclusion
  15. 15. SBML:alinguafranca forsoftware
  16. 16. Format for representing computational models of biological processes • Data structures + usage principles + serialization to XML • (Mostly) Declarative, not procedural—not a scripting language Neutral with respect to modeling framework • E.g., ODE, stochastic systems, etc. Important: software reads/writes SBML, not humans SBML = Systems Biology Markup Language
  17. 17. The raw SBML
  18. 18. The process is central • Literally called a“reaction”in SBML • Participants are pools of entities (biochemical species) Models can further include: • Compartments • Other constants & variables • Discontinuous events • Other, explicit math Core SBML concepts are fairly simple • Unit definitions • Annotations
  19. 19. SBML is now widely used Dozens of journals accept models in SBML format 100’s of software tools available today 1000’s of models available in SBML format today 0 100 200 300 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 254+ today
  20. 20. Contents of BioModels Database Contents today: • 142,000+ pathway models (converted from KEGG) • 460+ hand-curated quantitative models • 460+ non-curated quantitative models 8% 2% 3% 6% 6% 7% 8% 9% 24% 27% signal transduction metabolic process multicelullar organismal process rhythmic process cell cycle homeostatic process response to stimulus cell death localization others (e.g., developmental process) Database data from 2013
  21. 21. Free software libraries – libSBML Reads, writes, validates SBML Can check & convert units Written in portable C++ Runs on Linux, Mac, Windows APIs for C, C++, C#, Java, Octave, Perl, Python, R, Ruby, MATLAB Well documented API Open-source (LGPL) http://sbml.org/Software/libSBML
  22. 22. Free software libraries – JSBML Pure Java implementation API is compatible with libSBML but more Java-like Functionality is subset of libSBML Open source (LGPL) http://sbml.org/Software/JSBML
  23. 23. Evolution of SBML continues Today: SBML Level 3 • Level 3 Core provides framework for common models • Level 3 packages add additional constructs to the Core
  24. 24. Level 3 package What it enables Hierarchical model composition Models containing submodels ✔ Flux balance constraints Constraint-based models ✔ Qualitative models Petri net models, Boolean models ✔ Graph layout Diagrams of models ✔ Multicomponent/state species Entities w/ structure; also rule-based models draft Spatial Nonhomogeneous spatial models draft Graph rendering Diagrams of models draft Groups Arbitrary grouping of components draft Distributions Numerical values as statistical distributions in dev Arrays & sets Arrays or sets of entities in dev Dynamic structures Creation & destruction of components in dev Annotations Richer annotation syntax Status
  25. 25. NationalInstituteofGeneralMedicalSciences(USA) European Molecular Biology Laboratory (EMBL) JST ERATO Kitano Symbiotic Systems Project (Japan) (to 2003) JST ERATO-SORST Program (Japan) ELIXIR (UK) Beckman Institute, Caltech (USA) Keio University (Japan) International Joint Research Program of NEDO (Japan) Japanese Ministry of Agriculture Japanese Ministry of Educ., Culture, Sports, Science and Tech. BBSRC (UK) National Science Foundation (USA) DARPA IPTO Bio-SPICE Bio-Computation Program (USA) Air Force Office of Scientific Research (USA) STRI, University of Hertfordshire (UK) Molecular Sciences Institute (USA) SBML funding sources over the past 13+ years
  26. 26. Outline Background and introduction The Systems Biology Markup Language (SBML) Complementary efforts: MIRIAM and SED-ML COMBINE: the Computational Modeling in Biology Network Conclusion
  27. 27. Mathematical semantics Biological semantics Visual interpretation Discrete stochastic entities Continuous lumped parameter State transition Meanfieldapproximation Model type Model creation Model annotation Model analysis Numericalresults Model life-cycle Model representation level COMBINE efforts cover different facets of modeling ... ConceptduetoNicolasLeNovère
  28. 28. Modelerswanttousetheirownconventions
  29. 29. Modelerswanttousetheirownconventions No standard identifiers
  30. 30. Modelerswanttousetheirownconventions Low info content No standard identifiers
  31. 31. Raw models alone are insufficient Need standard schemes for machine-readable annotations • Identify entities • Mathematical semantics • Links to other data resources • Authorship & pub. info Modelerswanttousetheirownconventions Low info content No standard identifiers
  32. 32. Addresses 2 general areas of annotation needs: MIRIAM is not specific to SBML MIRIAM(MinimumInformationRequestedIntheAnnotationofModels) Requirements for reference correspondence Scheme for encoding annotations Annotations for attributing model creators & sources Annotations for referring to external data resources
  33. 33. Addresses 2 general areas of annotation needs: MIRIAM is not specific to SBML MIRIAM(MinimumInformationRequestedIntheAnnotationofModels) Requirements for reference correspondence Scheme for encoding annotations Annotations for attributing model creators & sources Annotations for referring to external data resources Annotations for referring to external data resources
  34. 34. Example of a problem that can be solved with annotations http://www.ebi.ac.uk/chebi Low info content
  35. 35. Example of a problem that can be solved with annotations http://www.ebi.ac.uk/chebi Low info content Known by different names –  do you want to write all of them into your model? salicylic acid
  36. 36. MIRIAM annotations for external references Goal: link model constituents to corresponding entities in bioinformatics resources (e.g., databases, controlled vocabularies) • Supports: - Precise identification of model constituents - Discovery of models that concern the same thing - Comparison of model constituents between different models MIRIAM approach avoids putting data content directly in the model • Instead, it points at external resources that contain the data
  37. 37. How do we create globally unique identifiers consistently? Long story short—developed by the Le Novère group at the EBI • Resource identifiers (URIs) combine 2 parts: • There’s a registry for namespaces: MIRIAM Registry - Allows people & software to use same namespace identifiers • There’s a URI resolution service: MIRIAM Resources & identifiers.org - Allows people & software to take a given identifier and figure out what it points to namespace entity identifier { { Identifies a dataset Identifies a datum within the dataset
  38. 38. Another problem: software can’t read figure legends ? BIOMD0000000319 in BioModels Database Decroly & Goldbeter, PNAS, 1982
  39. 39. SED-ML = Simulation Experiment Description ML Application-independent format •Captures procedures, algorithms, parameter values Can be used for •Simulation experiments encoding parametrizations & perturbations •Simulations using more than one model and/or method •Data manipulations to produce plot(s) http://sedml.org Simulation Model Task Data generators Reports
  40. 40. Efforts like SED-ML improve reproducibility of publications Waltemath et al., BMC Sys Bio 5, 2011.
  41. 41. Outline Background and introduction The Systems Biology Markup Language (SBML) Complementary efforts: MIRIAM and SED-ML COMBINE: the Computational Modeling in Biology Network Conclusion
  42. 42. Need interoperable formats, but developing them is not easy Need people with diverse set of knowledge & skills • Scientific needs • Technical implementation skills • Practical experience Need manage multiple phases of a standardization effort • Creation • Evolution • Support
  43. 43. Need interoperable formats, but developing them is not easy Need people with diverse set of knowledge & skills • Scientific needs • Technical implementation skills • Practical experience Need manage multiple phases of a standardization effort • Creation • Evolution • Support } This is just for the specification of the standards, to say nothing of the necessary software and other infrastructure!
  44. 44. Realizations about the state of affairs in late-2000’s • Many standardization efforts overlapped, but lacked coordination • Efforts were inventing their own processes from scratch • Many individual meetings meant more travel for many people • Limited and fragile funding didn’t support solid, coherent base COMBINE = Computational Modeling in Biology Network • Coordinate standards development • Develop common procedures & tools (but not impose them!) • Coordinate meetings • Provide a recognized voice Motivations for the creation of COMBINE
  45. 45. Standardization efforts represented in COMBINE today BioPAX Qualifiers GPML COMBINE Standards Associated Standardization Efforts Related Standardization Efforts
  46. 46. Those are the products of successful, open collaborations!
  47. 47. Examples of community organization Two main annual meetings, plus ad hoc workshops • COMBINE meeting: status updates, presentations, outreach - Next COMBINE: Paris, Sep 16–20, 2013 • HARMONY: Hackathon on Resources for Modeling in Biology - Software development, interoperability hacking COMBINE 2012, TorontoCOMBINE 2011, Heidelberg
  48. 48. What motivates people to do this? Solving a problem for yourself/your closed group is easier and quicker • So what are these people getting out of it? Some advantages of an open, community-oriented approach: • Finding better solutions they wouldn’t find alone - Arguments Discussions leads to realizations & better solutions • Contributions to science – publications, peer recognition • Support of a standard makes their software more desirable • Sense of community involvement Some admitted disadvantages: • Agreement takes time – progress can be very slow • Solutions may include features you didn’t plan on, or need
  49. 49. COMBINE is open to all—and COMBINE needs you! http://co.mbine.org Current coordinators: • Nicolas Le Novère, Mike Hucka, Falk Schreiber, Gary Bader
  50. 50. Outline Background and introduction The Systems Biology Markup Language (SBML) Complementary efforts: MIRIAM and SED-ML COMBINE: the Computational Modeling in Biology Network Conclusion
  51. 51. Time it well • Too early and too late are bad Start with actual stakeholders • Address real needs, not perceived ones Start with small team of dedicated developers • Can work faster, more focused; also avoids“designed-by-committee” Engage people constantly, in many ways • Electronic forums, email, electronic voting, surveys, hackathons Make the results free and open-source • Makes people comfortable knowing it will always be available Be creative about seeking funding Some things we (maybe?) got right with SBML
  52. 52. Not waiting for implementations before freezing specifications • Sometimes finalized specification before implementations tested it - Especially bad when we failed to do a good job ‣ E.g.,“forward thinking”features, or“elegant”designs Not formalizing the development process sufficiently • Especially early in the history, did not have a very open process Not resolving intellectual property issues from the beginning • Industrial users ask“who has the right to give any rights to this?” Some things we certainly got wrong
  53. 53. Nicolas Le Novère, Henning Hermjakob, Camille Laibe, Chen Li, Lukas Endler, Nico Rodriguez, Marco Donizelli,Viji Chelliah, Mélanie Courtot, Harish Dharuri Attendees at SBML 10th Anniversary Symposium, Edinburgh, 2010 John C. Doyle, Hiroaki Kitano Mike Hucka, Sarah Keating, Frank Bergmann, Lucian Smith, Andrew Finney, Herbert Sauro, Hamid Bolouri, Ben Bornstein, Bruce Shapiro, Akira Funahashi, Akiya Juraku, Ben Kovitz OriginalPI’s: SBMLTeam: SBMLEditors: BioModelsDB: Mike Hucka, Nicolas Le Novère, Sarah Keating, Frank Bergmann, Lucian Smith, Chris Myers, Stefan Hoops, Sven Sahle, James Schaff, DarrenWilkinson And a huge thanks to many others in the COMBINE community This work was made possible thanks to a great community
  54. 54. SBML http://sbml.org BioModels Database http://biomodels.net/biomodels MIRIAM http://biomodels.net/miriam identifiers.org http://identifiers.org SED-ML http://biomodels.net/sed-ml SBO http://biomodels.net/sbo SBGN http://sbgn.org COMBINE http://co.mbine.org URLs
  55. 55. I’d like your feedback! You can use this anonymous form: http://tinyurl.com/mhuckafeedback

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