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CellML & Synthetic Biology

CellML & Synthetic Biology. James Lawson Friday 16 th May 2008. Overview. Rundown on what the CellML team do here What is “synthetic biology?” What does CellML have to do with it?. ABI Team. We have grown!. (arrows show people who joined last year). 2001 - present.

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CellML & Synthetic Biology

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  1. CellML & Synthetic Biology James Lawson Friday 16th May 2008

  2. Overview • Rundown on what the CellML team do here • What is “synthetic biology?” • What does CellML have to do with it?

  3. ABI Team We have grown! (arrows show people who joined last year)

  4. 2001 - present “CellML is intended to support the definition of models of cellular and subcellular processes. CellML facilitates the re-use of models and parts of models by using a component-based architecture. Models are split into logical sub-parts called components that are connected together to form a model.” – CellML 1.0 specification

  5. What is CellML? • Language for description of mathematical models • Developed at ABI (mainly) • Open XML standard • Describes structure, mathematics, metadata • MathML for mathematics • RDF for metadata

  6. Why is there a need for CellML? • Designed for storage & exchange of models • Reference implementation of a model • Publication of model code • Model reuse ERRORS A model is created and translated into parameter sets and equations then read and interpreted and finally reimplemented

  7. Why is there a need for CellML? • If the model author published their model in CellML, this process could be avoided ERRORS A model is created and translated into parameter sets and equations then read and interpreted and finally reimplemented

  8. Scope of CellML • CellML 1.1 current version, 1.2 in pipeline • Flexible: not limited to biological systems • Philosophy: • Only describes structure and maths. All else is metadata. • Multiscalar: from biochemistry to physiology

  9. Signal transduction Electrophysiology Biomechanics CellML can describe multiscalar systems

  10. IUPS Physiome Project Nickerson et al. Computational multiscale modeling in the physiome project: modeling cardiac electromechanics., IBM J. Res. & Dev., 50(6), 617-630, 2006

  11. PCEnv • Physiome CellML Environment • Developed at ABI • Open source / free environment for editing and simulating CellML models • Uses CellML API • Built using Mozilla/XUL framework • Platform agnostic

  12. CellML Model Repository • www.cellml.org/models started life as set of test-cases for CellML • Now a repository of >330 unique CellML models based on peer reviewed publications • Approximately half curated • Models can be uploaded concurrent with publication • Locus for sharing and reuse of models

  13. Model Curation • Important element of the work done in the CellML community • Purpose is to provide validated, tested reference implementations of models • Errors produced in code > publication > reproduction process must be eliminated • Metadata and documentation • Ontological annotation • Authorship, citation and revision histories

  14. CellML in CMISS • Use CellML models to inform cell behaviour in heart (and other) models • John Davidson, Jesse Ashton, Jichao Zhao • Know more than me • Are very friendly • Are not the only people doing this

  15. CellML Community • Active international community of developers and users • Cellml.org serves as focal point • CellML specifications • CellML Model Repository • User profiles • Hosts proposals, wikis, tutorials, FAQs etc. • Meeting minutes, news, conference proceedings • Software downloads • Tracker

  16. Projects in the Pipeline • CellML 1.2 • Metadata • Working with CellML in PCEnv • The new CellML Model Repository “PMR2” • Using CellML: plans for community and curation

  17. CellML 1.2 • Latest stable version of CellML is 1.1 • Last changed in 2002, frozen in 2006 • Community canvassing process • ‘Purification’ of CellML according to philosophy

  18. CellML 1.2 • CellML too large to be implemented in entirety • => concept of secondary specifications which represent a subset of CellML • Individual tools can implement these in entirety • E.g. ‘stochastic CellML’

  19. CellML 1.2 • Reaction element removal • Ontologies and constrained vocabularies: increasing CellML’s specificity in a modular fashion – CellMLBio Ontology • New typing system • Implementation of a complex typing system • Multiple subsets: each subset introduces one core functionality • E.g. vectors, matrices, operations over these • Lambda calculus being considered

  20. CellML Metadata • Metadata specification to be frozen • Development of CellMLBio Ontology • Annotation of variables and components with biologically relevant information • Automatic generation of diagrams of CellML models • Use of graphing & simulation metadata to reproduce figures from publications

  21. PCEnv • PCEnv development strongly coupled to development of CellML API • Ability to link to and display references to web accessible databases • Further support for metadata editing and processing • Rendering of and user interaction with model diagrams • Non-linear solver

  22. CellML Model Repository – “PMR2” • Current version of CellML Model Repository does not adequately handle multi-file CellML 1.1 models • “PMR2” currently in development • Current prototype software uses distributed version control system, will allow full revision histories, treatment of CellML as code. • Will allow models in the repository to reference each other using import element

  23. PMR2 • Facilitates decomposition of models into modular components. • Models are then composed of networks of these components and descriptions of the relationships between these. • Curated, ontologically annotated components able to be searched, sorted, combined

  24. Future cellml.org community • Web-based communities are becoming commonplace • International scientific collaboration demands effective communication media • Project-centric workspaces • Meeting minutes, project descriptions, seminars / posters, software downloads

  25. Synthetic Biology

  26. Synthetic Biology • Wikipedia: “A new area of research that combines science and engineering in order to design and build ("synthesize") novel biological functions and systems” • SB1.0 held in 2004, SB4.0 in Hong Kong, October this year • Synthetic biology tipped to be key technology of early 21st century

  27. True Genetic Engineering • An engineering approach to genetic engineering! • Abstraction • Standardisation • Modularity • CAD • Refinement of natural products • Resources need to be refined before their behaviour can be reliably described in calculations • MIT has lead the charge with their “Registry of Standard Biological Parts”

  28. You might also have heard the term “Biobrick” What is a ‘Biological Part’? Definition is shaky, but: “A nucleic acid sequence that encodes a definable biological function” – Shetty et al. 2008 Specification information for a Biological Part – looks like it was written by an engineer….

  29. “International Genetically Engineered Machine” competition • Undergraduate competition started in 2004 • Central to current synthetic biology community • 2008: 53 teams registered, 31 pending registration

  30. What has this got to do with us? • I have been following synthetic biology since about mid 2005 • Mike Cooling is also very interested • We have been sneakily bouncing ideas off each other in our spare time

  31. CellML & Synthetic Biology • Synthetic biology currently DNA-centric, with much time spent cloning genes in the lab • We propose that more can be done in silico • We are interested in creating a ‘Registry of Standard Biological Models’ • We are collaborating with researchers from MIT, Imperial College and Newcastle to create a repository of modular, reusable curated models – c.f. the CellML Model Repository and write a paper about it…

  32. So Mike and I recently visited the UK

  33. And we had a great time • We visited Neil Wipat’s group at the School of Computing Science at Newcastle University • We also attended the BioSysBio 2008 conference at Imperial College, London • Focuses on systems and synthetic biology You may recognise Neil – he spent his sabbatical at the ABI over the summer. During this time Mike and I got to know him and started doing some work together.

  34. Newcastle University • Mike and I gave a tag team talk • Mike on modularity in CellML • My talk was a general ‘CellML now and in the future’ overview • Newcastle is fielding a 2008 iGEM team • Their team has a heavy focus on modeling of Standard Biological Parts • CellML is one of the chief technologies involved in their project • Mike and I are official advisors to their team

  35. Newcastle University • Bio-ontologies • Philip Lord is a bio-ontologies expert • Was very interested in the CellML-Bio Ontology • Much important feedback received regarding CellML & associated services • E.g. Java bridges to API, programmatic access to CellML repository, stochastic modeling in CellML

  36. BioSysBio2008 • Academic content of keynotes was average • Workshops and ‘quality’ of attendees 10/10 • Interesting to see what people knew / thought of CellML • Physiome Project, CellML, Peter Hunter got big mention in introductory talk of conference • Many people knew little about CellML and simply saw it as SBML’s ‘poor cousin’

  37. Standards in Synthetic Biology • Dedicated workshop at BioSysBio • Mike and Neil presented on why ‘Standard Parts’ need to be modeled and why CellML is the best technology for this • Explicit modularity very important • SBML is incumbent but lacking • Synthetic Biology ontology being developed

  38. Open Science • Open access journals – “BMC” • “Open notebook science” • Universal Scientific Brownie Points • Problem of rewarding non-publication contributions such as blog posts, reviews etc. • Movement may have ramifications for ABI • Watch this space…

  39. Synthetic Biology & CellML • Mike and I are working on a paper with Neil Wipat, Barry Canton from MIT and Vincent Rouilly from Imperial College • Aim to model ‘Standard Biological Parts’ in a manner that allows these models to be combined and simulated • Aim to provide a curated repository of these models

  40. Synthetic Biology & ABI • Synthetic biology is primarily an engineering discipline. Currently wet-lab oriented but starting to involve more in silico work • Will have vast industrial relevance within 10 years • ABI needs to consider whether it wants to get involved • iGEM team could be perfect 4th year project • Upcoming ABI wet lab capabilities could be used • Collaboration with wet-lab specialists required

  41. Acknowledgements • Peter Hunter & Poul Nielsen for allowing me to indulge my imagination • The CellML team • Mike Cooling

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