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Emerging Standards in Synthetic Biology
Herbert M SauroMichal Galdzicki and Deepak ChandranUniversity of Washington, Seattle
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SBML in a NutshellBottom-Up Effort
• A machine-readable format 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
www.sbml.orgFunding
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SBML Ecosystem SBML
Databases
Unambiguous Model
Exchange
Semantic Annotations
Simulator Comparison and
ComplianceJournals
Diagrams
SEDML: Simulation Experiment Description LanguageSBGN : Systems Biology Graphical Notation
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What is Synthetic Biology
Synthetic Biology is the “design and construction of novel artificial biological pathways, organismsor devices, or the redesign of existing natural biological systems.” (Royal Society)
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10 years of Synthetic Biology
Gardner TS, et al. Construction of a genetic toggle switch in Escherichia coli. Nature 2000; 403: 339-342.
Elowitz and Leibler; A Synthetic Oscillatory Network ofTranscriptional Regulators Nature. 2000; 403: 335-8.
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Synthetic Biology Workflow
“Creating cells that are able to excrete insulin at a specified rate during their optimal growth.”
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Overall Aim of the Standardization Effort
To support the synthetic biology workflow:
1. Laboratory parts management2. Simulation/Analysis3. Design4. Assembly5. Repositories - preferably distributed
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The Immediate NeedTake any current publication on a synthetic circuit and try to reproduce it, let me know how you get on.
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Long-term Aim of the Standardization Effort
Specifically:
• To allow researches to electronically exchange designs with round-tripping.
• To sent designs to bio-fabrication centers for assembly.
• To allow storage of designs in repositories and for publication purposes.
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Synthetic Biology Open Language: SBOL
http://www.sbolstandard.org/
1.SBOL Semantic*2.SBOL Visual*3.SBOL Script
First meeting in 2008, Seattle, fundedby Microsoft
Synthetic Biology Data Exchange GroupSynthetic Biology Open Language (SBOL)
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SBOL-visualSBOL-semantic
iBioSim
http://www.sbolstandard.org/
UK, Imperial College
EU 7th Framework Programme
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SBOL Visual (SBOLv)
Developed at the BerkeleyBIOFAB (Endy and Arkin) • Current about 40 symbols• Used to visually annotate‘features’ on a DNA
Three symbol groups at present:
1. Central Dogma2. Genetic Engineering3. Devices
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SBOL Visual (Implemented in Spectacles and TinkerCell)
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SBOL: Reuse of biological parts
semantic
Sequence Annotation
1-80
Terminator
81-88
BioBrick Scar
BioBrick Scar
89-129
Terminator
B0010 B0012
Part
B0015
Create a common language for engineers to describe and send parts
Synthetic Biologist A
Synthetic Biologist B
Fabricate
Synthetic Biology Open Language (SBOL)
visual
DNA Components
Engineer
New genetic device
Michal Galdzicki describe and send
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Figure 1. Diagram of the SBOL Semantic structure, illustrated with a set of information about a synthetic biology construct. a. A simplified Class (black rectangles) hierarchy (black open faced arrows) describes types (colored open faced arrows )of Individual data elements (yellow rounded rectangles) and the composition relationships between them (closed faced arrows). The example can be read as: Sample (pink) SS002 contains UW002 cells (dark green) of the MG1655 E. coli strain, which contain a plasmid (purple) pUW4510, which is composed of an parts (dark blue) an insert B0015 and vector backbone pSB1A2. The pSB1A2 vector backbone complies with the Assembly Standard (light blue) BBF RFC 10. The B0015 sequence annotations (green) specify three features (orange), the BioBrick Scar, and the parts (blue and orange indicating multiple inheritance), B0010 and B0012, which serve as transcriptional termination signals. b. Data type Properties used to hold information for each SBOL class follow the colon.
Sequ
ence
Ann
otati
on
Vect
or B
ackb
one
Sample
CellPh
ysic
al D
NA
Assembly Standard
pSB1A2
BBF RFC 10
SS002
pUW4510
MG1655type type
typetype
type
cell
dna
insertvector
format
UW002strain
Sequence Feature
B0015
type
annotation
1-80
feature
Terminator
81-88
BioBrick Scarfeature
BioBrick Scar
89-129
feature
Terminator
annotation annotation
type type
subClassOf subClassOfsubClassOf
subC
lass
Of
B0010 B0012
Part
type
Plas
mid
subC
lass
Of
type
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Parts Registry at MIT
Database of parts, basically a wiki, objectmodel not documentedand was generally not available to the public until this year.
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SBOLr is a web front for a knowledge base of standard biological parts
http://sbolr.bhi.washington.edu/
JBEIr Software by Timothy Ham & Zinovii Dmytriv
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Software support: libSBOL
Michal Galdzicki
CAD Tool
TinkerCell
Sequence Editor
Parts KB
libSBOL
SBOL-semantic
Repository
Allow for ease of access to information by software tools, using Semantic Web standards.
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List of Software in the Working Group• Clotho (BU,Berkeley), Java
Connects users to repositories of biological parts. Plugin tools then define the various functions that can be performed, mainly related to lab and parts managements. Douglas Densmore
• GenoCAD (VT)Web based tool for the design of biological devices using an attribute grammar which defines the legal composition of parts. Jean Peccoud
• iBioSim (Utah), JavaAdvanced simulation and analysis tool for synthetic and systems biology. Chris Myers
• JBEI Repository (Java), DOE support infrastructure Timothy Ham & Zinovii Dmytriv
• SBOLr (Currently Python but moving to Java)Test parts repository, ~5000 parts Michal Galdzicki
• TinkerCell (UW), C++/QtExtensible visual design tool with support for modules, eg simulation, annotation. Deepak Chandran
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Current Status of Standard• First official release will be at Synthetic Biology 5.0 at
Stanford, June, 2011
• libSBOL 1.0 available at: http://github.com
• Import/Export: GenBank, RDF, JSON
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TinkerCell: Project to explore the potential of computer aided design in synthetic biology
First prototype called Athena Developed by Bergmann and Chandran fundedby Microsoft
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Layered Architecture: Based on C++/Qt
Octave,
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All Parts can be Semantically Annotated. This allow plug-ins to interpret a given design.
Enzyme
Transcription Factor
Enzyme catalysis
BindingTranslation
Reporter
Elongation
CodingPromoter Terminator
Transcription
mRNA
Currently there is noformal ontology forsynthetic biology but onewill need to be developed.
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A TinkerCell model can be composed of sub-models
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A TinkerCell model can be composed of sub-models
?
?
?
? ?
?
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Users can add new plugins using C++, C, Octave, or Python languages
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Availabilitywww.tinkercell.com (Windows, Mac and Linux, released under BSD)Contact author for details ([email protected])
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SciPy• optimization• matrix operations• statistics• numerical methods• frequency analysis
NetworkX (lanl.gov)• graph analysis• graph layout
• structural analysis• sensitivity analysis• bifurcation analysis• parameter scan• simulation
lp_solve• flux balance analysis
Many C and Python packages are included with TinkerCell
Sundials• Time-course simulation• Steady state plot
Custom programs• Gillespie algorithm• Hill equation derivation• 2^N automatic binding events• Loops in Jacobian
AntimonySBML and CellML support
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Acknowledgements: Collaborators and Funding
UWDeepak Chandran, Michal Galdziki, Sean Sleight, Bryan Bartley, Alex Neilson
BioFAB (Berkeley, Stanford)Cesar Rodriguez, Drew Endy , Chris Anderson
Virginia Tech JBEI (DOE) Jean Peccoud Timothy Ham & Zinovii Dmytriv
Boston University CRG, Spain Douglas Densmore Raik Grunberg
FundingNational Library of Medicine (Galdziki)Other funding from NIH (JSim/SBW) , NIH (SBW) and NSF (FIBR,Tinkercell), Microsoft Strategic Research, BioFAB (NSF), JBEI (DOE)
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Textbook:Enzyme Kinetics for Systems Biology
• Available as e-book or paperback on www.analogmachine.org & • 318 pages, 94 illustrations and 75 exercises• E-book - $9.95• Paperback - $29.95
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Sequence Refinement
Examples include avoiding specific restriction sites or optimizing the codon usage. The sequence might also be optimized to avoid repeated regions that may be prone to recombination or secondary structures.
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The SBOL semantic structure
Sequence Annotation
type
type
annotation
1-80
feature
Terminator
81-88
BioBrick Scar
feature
BioBrick Scar
89-129
feature
Terminator
annotation annotation
type type
B0010 B0012
Parttype
B0015
type = instance-of
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Each component in the TinkerCell diagram is associated with one or more tables