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Standards for Synthetic Biology - Data Science Research Center

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					Developing Standards:                     www.sys-bio.org
                                          www.sbml.org
Case Studies                              www.sbolstandards.org
                                          blog.analogmachine.org




       Herbert M Sauro
         Dept. of Bioengineering
  University of Washington, Seattle, WA
       hsauro@u.washinton.edu
                                                             1
          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

                                                                            2
At least two ways to start a standard:

1. Top-down: institutionalized stick and carrot

2. Grass Roots




                                                  3
            Two Examples

SBML: Systems Biology Markup Language

SBOL: Synthetic Biology Open Language




                                        4
Simulation of Computational Models




             Simulation              5
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
                                    There may be multiple paths or multiple effects
 Cell death and/or proliferation?
                                                                                 6
      How it started:
  SCAMP and Gepasi: 80/90s




             X
SCAMP

                             7
     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



                                          8
             SBML
SBML: Systems biology Markup Language

     Used to represent homogenous
multi-compartmental Biochemical Systems




                                          9
        SBML in a Nutshell
“Systems Biology Markup Language”
• 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

                                               10
            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

                                                    11
SBML – Systems Biology Markup Language




                                         12
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.




                                                    13
             There many modeling
         software tools that use SBML




www.sbml.org                            14
SBML                                    SBML
Ecosystem
                                     Unambiguous
                                        Model              Diagrams
                                      Exchange


                     Databases


                                                       Simulator
                                                    Comparison and
                    Semantic
  Journals                                            Compliance
                   Annotations

SEDML: Simulation Experiment Description Language
                                                                     15
SBGN : Systems Biology Graphical Notation
    Model repositories            Nicolas Le Novere


 BioModels.net

 As of Sep 2011:

 366 curated
 models

 398 uncurated
 models.




http://www.ebi.ac.uk/biomodels/                       16
   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.
                                                               17
            Semantic Annotations
1. SBO: Systems Biology Ontology (Quantitative terms)

2. MIASE: The Minimum Information About a
   Simulation Experiment

3. TEDDY: The Terminology for the Description of
   Dynamics

4. KiSAO: Simulation Algorithm Ontology

5. Missing: An audit trail of a modeling process.
   Missing
                                                        18
       SBO: Systems Biology Ontology

1.   [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

2.   [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-Selskabet i Christiana 1864, 35) states that…..." [] is a: SBO:0000001 ! rate
     law.

Terms can be queried programmatically via a web service


                                                                                         19
 Systems Biology Ontology in SBML
<reaction sboTerm="SBO:0000062">
                                                                     continuous framework
  <listOfReactants>
   <speciesReference species="S" sboTerm="SBO:0000015" />
 </listOfReactants>
                                                                     substrate
 <listOfProducts>
   <speciesReference species="P" sboTerm="SBO:0000011" />            product
 </listOfProducts>
 <listOfModifiers>
   <speciesReference species="E" sboTerm="SBO:0000014" />            enzyme
 </listOfModifiers>
 <kineticLaw sboTerm="SBO:0000031">
   <listOfParameters>                                                Briggs-Haldane equation
     <parameter id="Km" sboTerm="SBO:0000027" />
      <parameter id="kp" sboTerm="SBO:0000025" />
    </listOfParameters>
                                                                     Michaelis constant
    <math xmlns="http://www.w3.org/1998/Math/MathML">
     <apply> <divide/> <apply>
                        <times />   <ci>E</ci>                       catalytic rate constant
                                    <ci>kp</ci>
                                    <ci>S</ci>
                        </apply>
                        <apply>
                        <plus />    <ci>Km</ci>
                                    <ci>S</ci>
</apply> </apply> </math> </kineticLaw> </reaction>
                                                                                          20
                                                            European Bioinformatics Institute
Application: Simulator Compliance
        SBML Compliance




                                21
The Results




              22
Other Proposed Standards


Standardizing the diagrammatic notation
http://www.sbgn.org/Main_Page




                                          23
What we all learned




                      24
                    Fact:

Developing a standard has both technical
as well sociological challenges.

The sociological challenges may be greater, :(




                                            25
                Rule #1:

There must be a problem (i.e an actual
need) that a particular community wants
to solve.

• Clear scope
• Covers what is needed
• Doesn’t force you to deal with things
  that are not needed
                                          26
                 Rule #2:

Building a community from day one is
of the utmost importance.

•   Build Trust
•   Build Consensus
•   Build Enthusiasm
•   Build Ownership

                                       27
                 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


                                           28
                 Rule #4:

The process is long and drawn out, far beyond
the normal patience of review panels and
funding agencies.




                                          29
                       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 !                30
  Centralized development of supporting
            software libraries:

1) 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).


                                                   31
                 Current work of my group:
Biology          Model Reproducibility
          Data


 Simulation
    Tool         SBML

                 SEDML

                 Data       SEDML: What you did
                            with the model
                                             32
Synthetic Biology




                    33
Synthetic biology



   “The design and construction of new
   biological entities such as enzymes,
   genetic circuits, cells, and organs or the
   redesign of existing biological systems.”

   Drew Endy (Stanford)


                                                34
           The Immediate Need
Take any current publication on a synthetic
circuit and try to reproduce it, let me know how
you get on.




                                               35
The long term vision: Design, Build, Test
GFP (RFU)




            time

                   Testing/   Specification
                   Analysis




                   Build            Design




                                              36
 Synthetic Biology Open Language
 (SBOL) – SBOL Semantic
               Fabricate
                                                          SBOL

Synthetic                                                                          visual
Biologist A   DNA
              Components
                                                            B0015
              Engineer
                                             1-80           81-88         89-129
                            DNA
                                                                                         Sequence
                           Comp-
                                                                                        Annotation
                           onent

Synthetic                                   B0010        BioBrick Scar     B0012

Biologist B
                                          Terminator     BioBrick Scar   Terminator
                New
                device                                 semantic

                               describe and send
                                                                                                 37
                    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.




                                                                  38
              Overall Aim of the
            Standardization Effort

To support the synthetic biology workflow:

1.   Laboratory parts management
2.   Simulation/Analysis
3.   Design
4.   Codon optimization
5.   Assembly
6.   Repositories - preferably distributed


                                             39
             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.

                                                40
                           Synthetic Biology

                 Synthetic Biology is Engineering,
                       i.e it is not biology*




        Design                     Build                      Test


* Beware of sending synthetic biology grant proposals to a biology panel   41
                           Synthetic Biology

                 Synthetic Biology is Engineering,
                       i.e it is not biology*

                                                 Verification


        Design                     Build                      Test

                                                  Debugging

* Beware of sending synthetic biology grant proposals to a biology panel   42
                           Synthetic Biology

                 Synthetic Biology is Engineering,
                       i.e it is not biology*

                                                 Verification


        Design                     Build                      Test

                                                  Debugging

* Beware of sending synthetic biology grant proposals to a biology panel   43
 A Real Network (E. coli)



                                                                                        Host Context


                                   Design/Construction




                   Increased Repression                                  Experimental Data
                      Simulation
                                                                                        Increased
                                                                                        Repression


                                                                                                                      44
Entus et al, Systems and Synthetic Biology, 2007.   http://www.agricorner.com/e-coli-outbreak-german-farm-in-uelzen-likely-source/
Synthetic Networks
Concentration Detector

Generic Design:




If we control the level of feed-forward
Inhibition we can tune the circuit:




                                          45
Synthetic Networks
Concentration Detector

Generic Design:




Input: IPTG

Output: GFP




                         46
CAD Software- Engineering Cycle

                   Simulation



          Design



                                Fabrication




                   Testing




                                              47
Computational tools and information
resources support each step
                               iBioSim        Laboratory Information
           TinkerCell CAD


                                                                    GDice
                Clotho
                                 Analysis   Specification




                                                                BIOFAB
                                Build              Design




ApE Sequence Editor         GenoCAD
                                                            Public Data


                                                                            48
Registry of Standard Biological Parts (BioBricks)




                                                      http://parts.mit.edu

ØProvides free access to an open commons of basic biological functions that can be
 used to program synthetic biological systems

ØAnybody may contribute, draw upon, or improve the parts maintained within the
 Registry.

                                                    Endy D, 2005. Nature 438: 449-453
                                                                                    49
SBOL is extensible, allows us to form
community subgroups
                  type
    SS002                    Sample
        cell
                  strai                              Computational                         Experimental
    UW002                   MG1655         Cell
                  n                                     Models                             Measurements
        dna      type         subClassOf
  pUW4510               Plasmid      DNA

Physical and Host Context
                                                                         B0015




                                                                                                                Sequence Annotation
                                                        annotatio             annotatio         annotatio
                                                        n                     n                 n
                                                     1-80                81-88             89-129
                                                                                                         type
            Visualization                               featur               featur             featur
                                                        e                    e                  e
                                                    B0010             BioBrick Scar         B0012

                                                        type                  type              type
                                                  Terminator          BioBrick Scar       Terminator

               Assembly                                 subClassO             subClassO         subClassO

               Methods
                                                        f                     f
                                                                    Sequence Feature         Core SBOL
                                                                                               f


                                                                                                                     50
TinkerCell: Project to explore the potential of
computer aided design in synthetic biology

First prototype
called Athena
developed
by Bergmann
and Chandran




                                                  51
                Layered
          Architecture: Based
              on C++/Qt
Octave,




                                52
Each component in the TinkerCell diagram is
    associated with one or more tables




                                              53
A TinkerCell model can be composed
           of sub-models




                                     54
A TinkerCell model can be composed
           of sub-models


    ?          ?



?          ?       ?



                             ?




                                     55
                       Availability
www.tinkercell.com (Windows, Mac and Linux, released under BSD)
Contact author for details (dchandran1@gmail.com)




                                                            56
Challenges in building SBOL
• Gaining consensus in a growing community
    – Identifying and engaging stakeholders

• Fast pace of in the field
    – Terminology evolution
        • “BioBricks”  “Parts”  “DNA components”
    – Stability of use cases
        • “Standard” and “Research needs” seem contradictory
    – Software for synthetic biology is new

• Scarcity of data sources
    – Quality “knowledge” about elements
    – Heterogeneity of existing annotations

• Funding

                                                               57
Who is the we?                      http://www.sbolstandard.org/
University of Washington              BIOFAB
Deepak Chandran                       Cesar Rodriguez
John Gennari                          Akshay Maheshwari (now
Michal Galdzicki                      UCSD)
Herbert Sauro                         Drew Endy (Stanford)
                                      Joint BioEnergy Institute
University of California,             Timothy Ham
Berkeley
J. Christopher Anderson               University of Utah
                                      Barry Moore
Boston University                     Nicholas Roehner            iBioSim
Douglas Densmore                      Chris J. Myers
Virginia Bioinformatics Institute     Imperial College of London
Laura Adam                            Guy-Bart Stan
Matthew Lux
Mandy Wilson                          Newcastle University (UK)
Jean Peccoud                          Aniel

University of Toronto                 Recent Commercial
Raik Gruenberg                        Interest
                                      BBN, DNA 2.0, Agilent             58
    Acknowledgements:
        The People and the Support
Hamid Bolouri        Frank Bergmann
Andrew Finney        Deepak Chandran
Mike Hucka           Vijay Chickarmane
Herbert Sauro        Michal Galdzicki
                     Lucian Smith
Funding in chronological order(2000 -> 2011):




                                                ……   59
                               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 - $39.95
•   Author: H M Sauro


                                                                  60

				
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