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Dec 14, 2012 (4 years and 7 months ago)

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Emerging Standards in

Synthetic Biology

Herbert M
Sauro

Michal
Galdzicki

and Deepak
Chandran

University of Washington, Seattle

1

SBML in a Nutshell

Bottom
-
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

2

www.sbml.org

Funding

SBML
Ecosystem

SBML

Databases

Unambiguous
Model
Exchange

Semantic
Annotations

Simulator
Comparison and
Compliance

Journals

Diagrams

SEDML: Simulation Experiment Description Language

SBGN : Systems Biology Graphical Notation

3

What is Synthetic Biology

Synthetic Biology is the “design and construction

of novel artificial biological pathways, organisms

or devices, or the redesign of existing natural

biological systems.” (Royal Society)

4

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
of

Transcriptional Regulators Nature
.
2000; 403: 335
-
8
.

5

Synthetic Biology Workflow

“Creating cells that
are able to excrete
insulin at a
specified rate
during their
optimal growth.”

6

Overall Aim of the Standardization Effort

To support the synthetic biology workflow:


1.
Laboratory parts management

2.
Simulation/Analysis

3.
Design

4.
Assembly

5.
Repositories
-

preferably distributed


7

The Immediate Need

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

8

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.


9

Synthetic Biology Open Language:
SBOL

http://www.sbolstandard.org/

1.
SBOL Semantic
*

2.
SBOL Visual
*

3.
SBOL Script


First meeting in 2008,

Seattle, funded

by Microsoft

10

Synthetic Biology Data Exchange Group

Synthetic Biology Open Language (SBOL)

11

SBOL
-
visual

SBOL
-
semantic

iBioSim

http://www.sbolstandard.org/

UK, Imperial College

EU 7th
Framework

Programme

SBOL Visual (
SBOLv
)

Developed at the Berkeley

BIOFAB (
Endy

and
Arkin
)





Current about 40 symbols



Used to visually annotate

‘features’ on a DNA


Three symbol groups at present:


1. Central Dogma

2. Genetic Engineering

3. Devices

12

SBOL Visual (Implemented in Spectacles and
TinkerCell
)

13

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

14

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

ce
lls (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 backb
one

pSB1A2.
The pSB1A2 vector backbone complies with the Assembly Standard (light blue) BBF RFC 10. The B0015 sequence annotations (gre
en)

specify three features
(orange), the
BioBrick

Scar, and the parts (blue and orange indicating multiple inheritance), B0010 and B0012, which serve as transcriptional termin
at
ion
signals.
b.

Data type
Properties

used to hold information for each SBOL class follow the colon.



Sequence Annotation

Vector Backbone

Sample

Cell

Physical DNA

Assembly
Standard

pSB1A2

BBF RFC 10

SS002

pUW4510

MG1655

type

type

type

type

type

cell

dna

insert

vector

format

UW002

strain

Sequence Feature

B0015

type

annotation

1
-
80

feature

Terminator

81
-
88

BioBrick

Scar

feature

BioBrick

Scar

89
-
129

feature

Terminator

annotation

annotation

type

type

subClassOf

subClassOf

subClassOf

subClassOf

B0010

B0012

Part

type

Plasmid

subClassOf

type

15

Parts Registry at MIT

Database of parts,

basically a wiki, object

model not documented

and was generally not

available to the

public until this year.

16

SBOLr

is a web front for a knowledge
base of standard biological parts


17

http://sbolr.bhi.washington.edu/

JBEIr

Software by Timothy Ham &
Zinovii

Dmytriv

Software support:
libSBOL


18

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.

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), Java

Advanced s
imulation 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++/Qt

Extensible
visual design tool with support for
modules,
eg

simulation, annotation. Deepak
Chandran



19

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

20

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

First prototype

called Athena

Developed by

Bergmann and

Chandran

funded

by Microsoft

21

Layered Architecture:
Based on C++/Qt

Octave,

22

All Parts can be Semantically Annotated. This allow
plug
-
ins to interpret a given design
.

Enzyme

Transcription
Factor

Enzyme catalysis

Binding

Translation

Reporter

Elongation

Coding

Promoter

Terminator

Transcription

mRNA

Currently there is no

formal ontology for

synthetic biology but one

will need to be developed.

23

A
TinkerCell

model can be
composed


of
sub
-
models

24

A
TinkerCell

model can be composed


of sub
-
models


?

?

?

?

?

?

25

Users
can add new
plugins using C++, C
,
Octave,
or Python languages

26

Availability

www.tinkercell.com

(Windows, Mac and Linux, released under BSD)

Contact author for details (dchandran1@gmail.com)

27

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

Antimony

SBML and
CellML

support

28

Demo
:
Repressilator

29

Acknowledgements:
Collaborators and Funding

UW

Deepak
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




Funding

National Library of Medicine (
Galdziki
)

Other funding from NIH (
JSim
/SBW) , NIH (SBW) and NSF (
FIBR,Tinkercell
),
Microsoft Strategic Research,
BioFAB

(NSF), JBEI (DOE)

30

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

31

32

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.

33

The SBOL semantic structure

34

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

Part

type

B0015

type = instance
-
of

Each component in the
TinkerCell

diagram
is
associated with one or more tables

35