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Developing Standards: Case Studies

www.sys-bio.org www.sbml.org www.sbolstandards.org blog.analogmachine.org. Developing Standards: Case Studies. Herbert M Sauro. Dept. of Bioengineering University of Washington, Seattle, WA hsauro@u.washinton.edu. Importance of Standards. Imagine a world where:

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Developing Standards: Case Studies

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  1. www.sys-bio.org www.sbml.org www.sbolstandards.org blog.analogmachine.org Developing Standards:Case Studies Herbert M Sauro Dept. of Bioengineering University of Washington, Seattle, WA hsauro@u.washinton.edu

  2. Importance of Standards Imagine a world where: Each company made its own incompatible nut, bold and screw? Every town had its own way to measure time. Every internet provider used different protocols for the ‘TCP/IP’ stack, email, web etc. and so on Standards are vital for the normal functioning of society

  3. At least two ways to start a standard: 1. Top-down: institutionalized stick and carrot 2. Grass Roots

  4. Two Examples SBML: Systems Biology Markup Language SBOL: Synthetic Biology Open Language

  5. Simulation of Computational Models Simulation

  6. Why? Study Perturbations Apoptosis Change the activity of a Protein, e.g. P53 by adding an inhibitor http://www.sapphirebioscience.com What effect does this have on Cell death and/or proliferation? There may be multiple paths or multiple effects

  7. How it started:SCAMP and Gepasi: 80/90s X SCAMP

  8. Exchange of Computational Models In 1999/2000 a project was started at Caltech with initial funding from Japan to devise an interchange language: SBML: Systems Biology Markup Language

  9. SBML SBML: Systems biology Markup Language Used to represent homogenous multi-compartmental Biochemical Systems

  10. SBML in a Nutshell“Systems Biology Markup Language” • A machine-readableformat for representing computational models in systems biology • Domain: systems of biochemical reactions • Specified using XML • Components in SBML reflect the natural conceptual constructs of the domain • Now over 200 tools use SBML

  11. SBML in a Nutshell“Systems Biology Markup Language” • Simple Compartments (well stirred reactor) • Internal/External Species • Reaction Schemes • Global Parameters • Arbitrary Rate Laws • DAEs (ODE + Algebraic functions, Constraints) • Physical Units/Model Notes • Annotation – extension capability • Events

  12. SBML – Systems Biology Markup Language

  13. Model Exchange Standards: SBML, CellML SBML is primarily a way to describe the biology of cellular networks from which the mathematical models can be automatically derived. CellML is a math based description from which the underling biological can be inferred.

  14. There many modeling software tools that use SBML www.sbml.org

  15. SBML SBML Ecosystem Unambiguous Model Exchange Diagrams Databases Simulator Comparison and Compliance Semantic Annotations Journals SEDML: Simulation Experiment Description Language SBGN : Systems Biology Graphical Notation

  16. Model repositories Nicolas Le Novere BioModels.net As of Sep 2011: 366 curated models 398 uncurated models. http://www.ebi.ac.uk/biomodels/

  17. MIRIAM: Minimum Information Requested in the Annotation of biochemical Models MIRIAM is not a file format but a minimum specification on how a model should be made available to the community: Reference correspondence – encoding a model in a recognized public standardized machine-readable format. Attribution annotation - A model has to provide the citation of the reference description, lists its creators, and be attached to some terms of distribution. External resource annotation - each component of a model must be annotated to allow its unambiguous identification.

  18. Semantic Annotations • SBO:Systems Biology Ontology (Quantitative terms) • 2. MIASE: The Minimum Information About a • Simulation Experiment • 3. TEDDY: The Terminology for the Description of • Dynamics • KiSAO: Simulation Algorithm Ontology • Missing: An audit trail of a modeling process.

  19. SBO: Systems Biology Ontology [Term] id: SBO:0000002 name: quantitative parameter def: "A number representing a quantity that defines certain characteristics of systems or functions. A parameter may be part of a calculation, but its value is not determined by the form of the equation itself, and may be arbitrarily assigned." [] relationship: part of SBO:0000000 ! Systems Biology Ontology [Term] id: SBO:0000012 name: mass action kinetics def: "The Law of Mass Action, first expressed by Waage and Guldberg in 1864 (Waage, P., Guldberg, C. M. Forhandlinger: Videnskabs-Selskabeti Christiana 1864, 35) states that…..." [] is a: SBO:0000001 ! rate law. Terms can be queried programmatically via a web service

  20. Systems Biology Ontology in SBML continuous framework <reaction sboTerm="SBO:0000062"> <listOfReactants> <speciesReference species="S" sboTerm="SBO:0000015" /> </listOfReactants> <listOfProducts> <speciesReference species="P" sboTerm="SBO:0000011" /> </listOfProducts> <listOfModifiers> <speciesReference species="E" sboTerm="SBO:0000014" /> </listOfModifiers> <kineticLaw sboTerm="SBO:0000031"> <listOfParameters> <parameter id="Km" sboTerm="SBO:0000027" /> <parameter id="kp" sboTerm="SBO:0000025" /> </listOfParameters> <math xmlns="http://www.w3.org/1998/Math/MathML"> <apply> <divide/> <apply> <times /> <ci>E</ci> <ci>kp</ci> <ci>S</ci> </apply> <apply> <plus /> <ci>Km</ci> <ci>S</ci> </apply> </apply> </math> </kineticLaw> </reaction> substrate product enzyme Briggs-Haldane equation Michaelis constant catalytic rate constant European Bioinformatics Institute

  21. Application: Simulator ComplianceSBML Compliance

  22. The Results

  23. Other Proposed Standards Standardizing the diagrammatic notation http://www.sbgn.org/Main_Page

  24. What we all learned

  25. Fact: Developing a standard has both technical as well sociological challenges. The sociological challenges may be greater, :(

  26. Rule #1: • There must be a problem (i.e an actual • need) that a particular communitywants • to solve. • Clear scope • Covers what is needed • Doesn’t force you to deal with things • that are not needed

  27. Rule #2: • Building a community from day one is • of the utmost importance. • Build Trust • Build Consensus • Build Enthusiasm • Build Ownership

  28. Rule #3: • For a standard to succeed, the central players • must provide tools and documentation to help • the community use the standard. • Easy to implement • Low ‘buy in’ cost

  29. Rule #4: The process is long and drawn out, far beyond the normal patience of review panels and funding agencies.

  30. Summary Initial cost for the SBML development: Initial version was funded by JST (roughly 250K direct per year for three years). Could probably get by with 150K direct. This funds a core team which is involved in: 1. Documentation 2. Organizing two workshops per year 3. Developing the initial source libraries 4. Develop a governance model 5. Follow discussions on mailing lists/workshops to address the needs of the community 6. Maintain civility during discussions !

  31. Centralized development of supporting software libraries: Prevented the standard from diverging 2) As extensions or modifications were agreed to by the community it was relatively easy for platform developers to incorporate the changes into their software. 3) Software developed in C/C++ to make the library cross-language (Java came later).

  32. Current work of my group: Model Reproducibility Biology Data Simulation Tool SBML SEDML Data SEDML: What you did with the model

  33. Synthetic Biology

  34. Synthetic biology “The design and construction of new biological entities such as enzymes, geneticcircuits, cells, and organsor the redesign of existing biological systems.” Drew Endy (Stanford)

  35. The Immediate Need Take any current publication on a synthetic circuit and try to reproduce it, let me know how you get on.

  36. The long term vision: Design, Build, Test GFP (RFU) time Testing/ Analysis Specification Design Build

  37. Synthetic Biology Open Language (SBOL) – SBOL Semantic Fabricate SBOL visual Synthetic Biologist A DNA Components B0015 Engineer Synthetic Biologist B 81-88 89-129 1-80 DNA Comp-onent Sequence Annotation BioBrick Scar B0012 B0010 New device semantic Terminator BioBrick Scar Terminator describe and send

  38. Some History The synthetic biology standardization effort was started with a grant from Microsoft in 2008 (100K). The first meeting was held in Seattle. The first draft proposal was called PoBoL but has since been renamed to SBOL – Systems Biology Open Language Since then we have (somehow) managed to organize two meetings a year since 2008, next one in Jan 2012 in Seattle.

  39. Overall Aim of the Standardization Effort To support the synthetic biology workflow: • Laboratory parts management • Simulation/Analysis • Design • Codon optimization • Assembly • Repositories - preferably distributed

  40. Overall Aim of the Standardization Effort Specifically: • To allow researches to electronically exchange designs with round-tripping. • To send designs to bio-fabrication centers for assembly. • To allow storage of designs in repositories and for publication purposes.

  41. Synthetic Biology Synthetic Biology is Engineering, i.e it is not biology* * Beware of sending synthetic biology grant proposals to a biology panel

  42. Synthetic Biology • Verification Synthetic Biology is Engineering, i.e it is not biology* Debugging * Beware of sending synthetic biology grant proposals to a biology panel

  43. Synthetic Biology • Verification Synthetic Biology is Engineering, i.e it is not biology* Debugging * Beware of sending synthetic biology grant proposals to a biology panel

  44. A Real Network (E. coli) Host Context Design/Construction Experimental Data Increased Repression Simulation Increased Repression Entus et al, Systems and Synthetic Biology, 2007. http://www.agricorner.com/e-coli-outbreak-german-farm-in-uelzen-likely-source/

  45. Synthetic Networks Concentration Detector Generic Design: If we control the level of feed-forward Inhibition we can tune the circuit:

  46. Synthetic Networks Concentration Detector Generic Design: Input: IPTG Output: GFP

  47. CAD Software- Engineering Cycle Simulation Design Fabrication Testing

  48. Computational tools and information resources support each step iBioSim Clotho TinkerCell CAD Public Data Analysis Specification ApE Sequence Editor BIOFAB Laboratory Information GDice GenoCAD Design Build

  49. Registry of Standard Biological Parts (BioBricks) http://parts.mit.edu • Provides free access to an open commons of basic biological functions that can be • used to program synthetic biological systems • Anybody may contribute, draw upon, or improve the parts maintained within the Registry. Endy D, 2005. Nature 438: 449-453

  50. SBOL is extensible, allows us to form community subgroups type SS002 Sample cell Experimental Measurements Computational Models strain Cell MG1655 UW002 dna subClassOf type DNA Plasmid pUW4510 B0015 Physical and Host Context annotation annotation annotation 81-88 89-129 1-80 type Sequence Annotation Visualization feature feature feature B0012 B0010 BioBrick Scar type type type Terminator BioBrick Scar Terminator Assembly Methods Core SBOL subClassOf subClassOf subClassOf Sequence Feature

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