Edinburgh Pathway Edinburgh Pathway EditorEditor

a flexible tool for biological model creationa flexible tool for biological model creation

Anatoly SorokinAnatoly Sorokin

Edinburgh Centre for System Edinburgh Centre for System biology biology

12/01/2006 A. Sorokin

System biology System biology modelling gapmodelling gap

““Biologist can be divided into two Biologist can be divided into two classes: experimentalists who classes: experimentalists who observed things that cannot be observed things that cannot be explained, and theoreticians who explained, and theoreticians who explain things that cannot be explain things that cannot be observed.”observed.”

Katzir-KatchalskyKatzir-Katchalsky

12/01/2006 A. Sorokin

KnowledgeIntegration &

Databases

Network Reconstruction Network Reconstruction and Modelingand Modeling

Experimental Quantitative Data

Experimental Data

Expert Knowledge Literature

Pathway DatabasesQuestions:

Modes of actionIntervention sites

Hypothesis testing

Modelling ResultsValidate hypotheses

Hypothesis generationFind modes of action, intervention

sites, bindings, targets, etc.

Interesting modellingobservations: ‘gems

ATP ATP

ATPndkndk

dCDP dUDP

dUTP

UMPUDPCDP

T4 nrdABT4 nrdC

T5dut

T4 tdthyA

dCTP

ATP

ADPADP

ATPndk ndk

NH 3

dcd

PPi

H 2O

pyrHcmk

ATP ATP

ADP

PBS2dTMPase

dCMPSP8 deaminase

T4 dCTPase

ppk ppk

ppk ppk

dUDPase

rpsA

Electronic Networks

ModellingSimulation

12/01/2006 A. Sorokin

KnowledgeIntegration &

Databases

Network Reconstruction Network Reconstruction and Modelingand Modeling

Experimental Quantitative Data

Experimental Data

Expert Knowledge

Literature

Pathway Databases

Questions:

Modes of actionIntervention sites

Hypothesis testing

Modelling ResultsValidate hypotheses

Hypothesis generationFind modes of action, intervention

sites, bindings, targets, etc.

Interesting modellingobservations: ‘gems

ATP ATP

ATPndkndk

dCDP dUDP

dUTP

UMPUDPCDP

T4 nrdABT4 nrdC

T5dut

T4 tdthyA

dCTP

ATP

ADPADP

ATPndk ndk

NH 3

dcd

PPi

H 2O

pyrHcmk

ATP ATP

ADP

PBS2dTMPase

dCMPSP8 deaminase

T4 dCTPase

ppk ppk

ppk ppk

dUDPase

rpsA

Electronic Networks

Simulation

Modelling

12/01/2006 A. Sorokin

Two types of modelTwo types of model

Biological modelBiological model Keep expert Keep expert

knowledgeknowledge Proved by Proved by

experimentexperiment Variable level of Variable level of

detailsdetails Variable level of Variable level of

certaintycertainty

Numerical modelNumerical model Based on biological Based on biological

modelmodel Contains detailed Contains detailed

description of the description of the processprocess

Ready for Ready for simulationsimulation

Contains arbitrary Contains arbitrary assumptionsassumptions

12/01/2006 A. Sorokin

Biological modelsBiological models

12/01/2006 A. Sorokin

Mathematical modelsMathematical models

PDN = (SN,TN,ST-Edge,TS-Edge) where PDN = (SN,TN,ST-Edge,TS-Edge) where SN = ( SN = ( snsn 1 1 , , snsn2 2 ..., ..., snsni i ), ),

TN=( TN=( tntn 1 1 , , tntn2 2 ,..., ,..., tntnj j ), ),

ST-Edge = SN ST-Edge = SN ××N, N,

TS-Edge = TN TS-Edge = TN ××SN, SN,

and and snsn i =(sn j , i =(sn j , snsnk ,..., k ,..., snsnn : n : cmcmi ). i ).

12/01/2006 A. Sorokin

12/01/2006 A. Sorokin

Link model types Link model types togethertogether

Experimentalist orientedExperimentalist oriented Support biological modelsSupport biological models Support “Round trip” development Support “Round trip” development

Biologicalmodel

Numerical model

Purification, reduction,assumptions, parameters

Observation, Questions,Predictions

12/01/2006 A. Sorokin

System biology System biology modelling gapmodelling gap

Models are distributed in large Models are distributed in large number of papersnumber of papers

Models are published in informal Models are published in informal stylestyle

Difficult to trace all detailsDifficult to trace all details

12/01/2006 A. Sorokin

Systems Biology Markup Language (SBML)

XML-based language to share model XML-based language to share model informationinformation

Model of biological processModel of biological process Simulation orientedSimulation oriented Expect detailed description of the Expect detailed description of the

processprocess No structure to store annotation No structure to store annotation

datadata

12/01/2006 A. Sorokin

System Biology Graphical System Biology Graphical notation (SBGN) notation (SBGN)

Standard Graphical notationStandard Graphical notation RequirementsRequirements

(1) Expressiveness: The notation system should be able to describe every possible relationship among genes and proteins, as well as biological processes.

(2) Semantically unambiguous: Notation should be unambiguous.

(3) Visually unambiguous: Each symbol should be clearly identified and cannot be mistaken with other symbols. This feature should be maintained with low-resolution displays, as well as black/white printings.

(4) Extension Capability: The notation system shall be flexible enough to add new symbols and relationship in a consistent manner. This may include the use of color-coding to enhance expressiveness and readability, but information shall not be lost even with black and white displays.

12/01/2006 A. Sorokin

RequirementsRequirements Validation of networks vs. controlled vocabularies Validation of networks vs. controlled vocabularies

of Small Molecules, Genes, Proteins, and of Small Molecules, Genes, Proteins, and transcripts to control confusion of multiple transcripts to control confusion of multiple names across research areas.names across research areas.

Networks should allow adding of Networks should allow adding of Literature objects (Medline etc…)Literature objects (Medline etc…) Kinetic information to reactionsKinetic information to reactions Export in wide variety of formatsExport in wide variety of formats Any desired data related to model creationAny desired data related to model creation

Build in links to, and load Build in links to, and load publicly available data sources…publicly available data sources…

12/01/2006 A. Sorokin

Edinburgh Pathway Edinburgh Pathway EditorEditor

12/01/2006 A. Sorokin

Basic featuresBasic features Small number of basic objects to represent Small number of basic objects to represent

main concepts of the biological networkmain concepts of the biological network Metadata-oriented designMetadata-oriented design Flexible visual presentationFlexible visual presentation Hierarchical data storageHierarchical data storage Customisable direct link to external Customisable direct link to external

databasesdatabases Eclipse-based open plug-in designEclipse-based open plug-in design XML-based internal presentationXML-based internal presentation Export to SBML Export to SBML

12/01/2006 A. Sorokin

Main objectsMain objects

ShapeShape PortPort ProcessProcess LinkLink LabelLabel

12/01/2006 A. Sorokin

ShapeShape

ShapeShape represents the biological represents the biological object or subsystem, treated as "a object or subsystem, treated as "a black box" .black box" .

12/01/2006 A. Sorokin

PortPort

The port is used to designate the The port is used to designate the state of the object, in which it could state of the object, in which it could interact with other objects. The port interact with other objects. The port is the interface between the objects.is the interface between the objects.

12/01/2006 A. Sorokin

ProcessProcess

ProcessProcess visualises sequence of visualises sequence of eventsevents,, e.g. a biochemical reaction e.g. a biochemical reaction or protein interaction. or protein interaction. Chemical reactions, Chemical reactions, protein binding protein binding gene activationgene activation

12/01/2006 A. Sorokin

LinkLink

LinkLink is used to represent any pair- is used to represent any pair-wise relation between objects wise relation between objects including "identity" or "act on" including "identity" or "act on" relations. relations.

12/01/2006 A. Sorokin

LabelLabel

LabelLabel is a visual object to represent is a visual object to represent textual information and to allow textual information and to allow incorporate incorporate links to other maps and links to other maps and resources. resources.

12/01/2006 A. Sorokin

ContextContext

Description of metadata related to Description of metadata related to the mapthe map User-defined object typesUser-defined object types Domain-specific object propertiesDomain-specific object properties Default valuesDefault values

12/01/2006 A. Sorokin

Types of properiesTypes of properies

Simple dataSimple data TextText CollectionsCollections Visual dataVisual data

12/01/2006 A. Sorokin

Simple dataSimple data

Simple string of Simple string of characters:characters:EC: 6.4.1.2EC: 6.4.1.2

PubMed: 7567999PubMed: 7567999

Useful forUseful for ID in external ID in external

database (PubMed, database (PubMed, GenBank etc.)GenBank etc.)

AbbrevitionsAbbrevitions Simple descriptionsSimple descriptions Numerical values Numerical values

(constants, (constants, parameters etc.)parameters etc.)

12/01/2006 A. Sorokin

TextText Rich text with Rich text with

formatting, greek formatting, greek letters, fonts, colours, letters, fonts, colours, hyperlinks etc.hyperlinks etc.

Useful for:Useful for: Name of Name of

compounds, compounds, proteins etc.proteins etc.

Human readable Human readable descriptionsdescriptions

References to References to Internet resourcesInternet resources

12/01/2006 A. Sorokin

Collections (Text & Collections (Text & Simple data)Simple data)

List of data of the List of data of the same typesame type

List of references List of references (to PubMed)(to PubMed)

List of synonyms List of synonyms or aliasesor aliases

12/01/2006 A. Sorokin

HyperlinksHyperlinks

Link the map Link the map object with object with Internet or another Internet or another mapmap

Hierarchical Hierarchical organisation of organisation of informationinformation

SubmodelsSubmodels References to References to

external resourcesexternal resources

12/01/2006 A. Sorokin

Hover textHover text

Shows text when Shows text when mouse move on the mouse move on the objectobject

Useful forUseful for Detailed human Detailed human

readable readable description of description of objectobject

Summarized view Summarized view of object propertiesof object properties

12/01/2006 A. Sorokin

Help textHelp text

Open new pop-Open new pop-up by pressing up by pressing F2 buttonF2 button

Useful for:Useful for: Extended Extended

description of description of object with object with hyperlinks etchyperlinks etc

12/01/2006 A. Sorokin

Reference to value of the Reference to value of the propertyproperty

There is simple There is simple language to language to reference values of reference values of properties of this properties of this object or related object or related objects objects

Useful for Useful for Default values of Default values of

Help and Hover Help and Hover texttext

Default value of the Default value of the LabelLabel

12/01/2006 A. Sorokin

Visual properties: colourVisual properties: colour

12/01/2006 A. Sorokin

Visual properties: imageVisual properties: image

12/01/2006 A. Sorokin

Inheritance, default Inheritance, default value value

12/01/2006 A. Sorokin

Visual representationVisual representation

12/01/2006 A. Sorokin

Visual representationVisual representation

12/01/2006 A. Sorokin

Visual representationVisual representation

12/01/2006 A. Sorokin

Visual representationVisual representation

12/01/2006 A. Sorokin

Visual representationVisual representation

12/01/2006 A. Sorokin

Development teamDevelopment team

Igor Goryanin, The University of Igor Goryanin, The University of Edinburgh Edinburgh

Kirill Paliy, EMP Project Inc.Kirill Paliy, EMP Project Inc. Alex Selkov, EMP Project Inc.Alex Selkov, EMP Project Inc. Oleg Demin, Moscow State Oleg Demin, Moscow State

UniversityUniversity

www.bioinformatics.ed.ac.uk/epe/www.bioinformatics.ed.ac.uk/epe/

12/01/2006 A. Sorokin

Network Reconstruction Network Reconstruction and Modelingand Modeling

Experimental Quantitative Data

Experimental Data

NetworkReconstruction

ModellingSimulation

Expert Knowledge

Questions:Hypothesis testingModes of actionIntervention sites

Interesting modellingobservations: ‘gems”

KnowledgeIntegration &

Databases

Modelling ResultsValidate hypotheses

Hypothesis generationFind modes of action, intervention

sites, bindings, targets, etc.

Literature

Electronic Networks

ATP ATP

ATPndkndk

dCDP dUDP

dUTP

UMPUDPCDP

T4 nrdABT4 nrdC

T5dut

T4 tdthyA

dCTP

ATP

ADPADP

ATPndk ndk

NH 3

dcd

PPi

H 2O

pyrHcmk

ATP ATP

ADP

PBS2dTMPase

dCMPSP8 deaminase

T4 dCTPase

ppk ppk

ppk ppk

dUDPase

rpsA

Planning experiments

Pathway Databases

12/01/2006 A. Sorokin

Network Reconstruction Network Reconstruction and Modelingand Modeling

Experimental Quantitative Data

Experimental Data

BiologicalModel

ModellingSimulation

Expert Knowledge

Questions:Hypothesis testingModes of actionIntervention sites

Interesting modellingobservations: ‘gems”

KnowledgeIntegration &

Databases

Modelling ResultsValidate hypotheses

Hypothesis generationFind modes of action, intervention

sites, bindings, targets, etc.

Literature

Electronic Networks

ATP ATP

ATPndkndk

dCDP dUDP

dUTP

UMPUDPCDP

T4 nrdABT4 nrdC

T5dut

T4 tdthyA

dCTP

ATP

ADPADP

ATPndk ndk

NH 3

dcd

PPi

H 2O

pyrHcmk

ATP ATP

ADP

PBS2dTMPase

dCMPSP8 deaminase

T4 dCTPase

ppk ppk

ppk ppk

dUDPase

rpsA

Planning experiments

Pathway Databases

Literature