Edinburgh Pathway Editor a flexible tool for biological model creation Anatoly Sorokin Edinburgh Centre for System biology

12/01/2006 A. Sorokin System biology modelling gap “Biologist can be divided into two classes: experimentalists who observed things that cannot be explained, and theoreticians who explain things that cannot be observed.” Katzir-Katchalsky

12/01/2006 A. Sorokin Knowledge Integration & Databases Network Reconstruction and Modeling Experimental Quantitative Data Experimental Data Expert Knowledge Literature Pathway Databases Questions: Modes of action Intervention sites Hypothesis testing Modelling Results Validate hypotheses Hypothesis generation Find modes of action, intervention sites, bindings, targets, etc. Interesting modelling observations:‘gems ATP ndk dCDPdUDP dUTP UMPUDPCDP T4nrd AB T4 nrd C T5 dut T4 td thyA dCTP ATP ADP ATP ndk NH 3 dcd PPi H 2 O pyrH cmk ATP ADP PBS2 dTMPase dCMP SP8 deaminase T4 dCTPase ppk dUDPase rps A Electronic Networks Modelling Simulation

12/01/2006 A. Sorokin Knowledge Integration & Databases Network Reconstruction and Modeling Experimental Quantitative Data Experimental Data Expert Knowledge Literature Pathway Databases Questions: Modes of action Intervention sites Hypothesis testing Modelling Results Validate hypotheses Hypothesis generation Find modes of action, intervention sites, bindings, targets, etc. Interesting modelling observations:‘gems ATP ndk dCDPdUDP dUTP UMPUDPCDP T4nrd AB T4 nrd C T5 dut T4 td thyA dCTP ATP ADP ATP ndk NH 3 dcd PPi H 2 O pyrH cmk ATP ADP PBS2 dTMPase dCMP SP8 deaminase T4 dCTPase ppk dUDPase rps A Electronic Networks Simulation Modelling

12/01/2006 A. Sorokin Two types of model Biological model Biological model Keep expert knowledge Keep expert knowledge Proved by experiment Proved by experiment Variable level of details Variable level of details Variable level of certainty Variable level of certainty Numerical model Based on biological model Contains detailed description of the process Ready for simulation Contains arbitrary assumptions

12/01/2006 A. Sorokin Biological models

12/01/2006 A. Sorokin Mathematical models PDN = (SN,TN,ST-Edge,TS-Edge) where SN = ( sn 1, sn2..., sni ), TN=( tn 1, tn2,..., tnj ), ST-Edge = SN ×N, TS-Edge = TN ×SN, and sn i =(sn j, snk,..., snn : cmi ).

12/01/2006 A. Sorokin

12/01/2006 A. Sorokin Link model types together Experimentalist oriented Experimentalist oriented Support biological models Support biological models Support “Round trip” development Support “Round trip” development Biological model Numerical model Purification, reduction, assumptions, parameters Observation, Questions, Predictions

12/01/2006 A. Sorokin System biology modelling gap Models are distributed in large number of papers Models are distributed in large number of papers Models are published in informal style Models are published in informal style Difficult to trace all details Difficult to trace all details

12/01/2006 A. Sorokin Systems Biology Markup Language (SBML) XML-based language to share model information XML-based language to share model information Model of biological process Model of biological process Simulation oriented Simulation oriented Expect detailed description of the process Expect detailed description of the process No structure to store annotation data No structure to store annotation data

12/01/2006 A. Sorokin System Biology Graphical notation (SBGN) Standard Graphical notation Standard Graphical notation Requirements Requirements (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 Requirements Validation of networks vs. controlled vocabularies Validation of networks vs. controlled vocabularies of Small Molecules, Genes, Proteins, and transcripts to control confusion of multiple names across research areas. of Small Molecules, Genes, Proteins, and transcripts to control confusion of multiple 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 reactions Kinetic information to reactions Export in wide variety of formats Export in wide variety of formats Any desired data related to model creation Any 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 Editor

12/01/2006 A. Sorokin Basic features Small number of basic objects to represent main concepts of the biological network Small number of basic objects to represent main concepts of the biological network Metadata-oriented design Metadata-oriented design Flexible visual presentation Flexible visual presentation Hierarchical data storage Hierarchical data storage Customisable direct link to external databases Customisable direct link to external databases Eclipse-based open plug-in design Eclipse-based open plug-in design XML-based internal presentation XML-based internal presentation Export to SBML Export to SBML

12/01/2006 A. Sorokin Main objects Shape Shape Port Port Process Process Link Link Label Label

12/01/2006 A. Sorokin Shape Shape represents the biological object or subsystem, treated as "a black box". Shape represents the biological object or subsystem, treated as "a black box".

12/01/2006 A. Sorokin Port The port is used to designate the state of the object, in which it could interact with other objects. The port is the interface between the objects. The port is used to designate the state of the object, in which it could interact with other objects. The port is the interface between the objects.

12/01/2006 A. Sorokin Process Process visualises sequence of events, e.g. a biochemical reaction or protein interaction. Process visualises sequence of events, e.g. a biochemical reaction or protein interaction. Chemical reactions, Chemical reactions, protein binding protein binding gene activation gene activation

12/01/2006 A. Sorokin Link Link is used to represent any pair-wise relation between objects including "identity" or "act on" relations. Link is used to represent any pair-wise relation between objects including "identity" or "act on" relations.

12/01/2006 A. Sorokin Label Label is a visual object to represent textual information and to allow incorporate links to other maps and resources. Label is a visual object to represent textual information and to allow incorporate links to other maps and resources.

12/01/2006 A. Sorokin Context Description of metadata related to the map Description of metadata related to the map User-defined object types User-defined object types Domain-specific object properties Domain-specific object properties Default values Default values

12/01/2006 A. Sorokin Types of properies Simple data Simple data Text Text Collections Collections Visual data Visual data

12/01/2006 A. Sorokin Simple data Simple string of characters: Simple string of characters: EC: PubMed: Useful for ID in external database (PubMed, GenBank etc.) Abbrevitions Simple descriptions Numerical values (constants, parameters etc.)

12/01/2006 A. Sorokin Text Rich text with formatting, greek letters, fonts, colours, hyperlinks etc. Rich text with formatting, greek letters, fonts, colours, hyperlinks etc. Useful for: Name of compounds, proteins etc. Human readable descriptions References to Internet resources

12/01/2006 A. Sorokin Collections (Text & Simple data) List of data of the same type List of data of the same type List of references (to PubMed) List of synonyms or aliases

12/01/2006 A. Sorokin Hyperlinks Link the map object with Internet or another map Link the map object with Internet or another map Hierarchical organisation of information Submodels References to external resources

12/01/2006 A. Sorokin Hover text Shows text when mouse move on the object Shows text when mouse move on the object Useful for Detailed human readable description of object Summarized view of object properties

12/01/2006 A. Sorokin Help text Open new pop-up by pressing F2 button Open new pop-up by pressing F2 button Useful for: Useful for: Extended description of object with hyperlinks etc Extended description of object with hyperlinks etc

12/01/2006 A. Sorokin Reference to value of the property There is simple language to reference values of properties of this object or related objects There is simple language to reference values of properties of this object or related objects Useful for Default values of Help and Hover text Default value of the Label

12/01/2006 A. Sorokin Visual properties: colour

12/01/2006 A. Sorokin Visual properties: image

12/01/2006 A. Sorokin Inheritance, default value

12/01/2006 A. Sorokin Visual representation

12/01/2006 A. Sorokin Visual representation

12/01/2006 A. Sorokin Visual representation

12/01/2006 A. Sorokin Visual representation

12/01/2006 A. Sorokin Visual representation

12/01/2006 A. Sorokin Development team Igor Goryanin, The University of Edinburgh Igor Goryanin, The University of 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 University Oleg Demin, Moscow State Universitywww.bioinformatics.ed.ac.uk/epe/

12/01/2006 A. Sorokin Network Reconstruction and Modeling Experimental Quantitative Data Experimental Data Network Reconstruction Modelling Simulation Expert Knowledge Questions: Hypothesis testing Modes of action Intervention sites Interesting modelling observations:‘gems” Knowledge Integration & Databases Modelling Results Validate hypotheses Hypothesis generation Find modes of action, intervention sites, bindings, targets, etc. Literature Electronic Networks ATP ndk dCDPdUDP dUTP UMPUDPCDP T4nrd AB T4 nrd C T5 dut T4 td thyA dCTP ATP ADP ATP ndk NH 3 dcd PPi H 2 O pyrH cmk ATP ADP PBS2 dTMPase dCMP SP8 deaminase T4 dCTPase ppk dUDPase rps A Planning experiments Pathway Databases

12/01/2006 A. Sorokin Network Reconstruction and Modeling Experimental Quantitative Data Experimental Data Biological Model Modelling Simulation Expert Knowledge Questions: Hypothesis testing Modes of action Intervention sites Interesting modelling observations:‘gems” Knowledge Integration & Databases Modelling Results Validate hypotheses Hypothesis generation Find modes of action, intervention sites, bindings, targets, etc. Literature Electronic Networks ATP ndk dCDPdUDP dUTP UMPUDPCDP T4nrd AB T4 nrd C T5 dut T4 td thyA dCTP ATP ADP ATP ndk NH 3 dcd PPi H 2 O pyrH cmk ATP ADP PBS2 dTMPase dCMP SP8 deaminase T4 dCTPase ppk dUDPase rps A Planning experiments Pathway Databases Literature