BioUML – extensible workbench for systems biology biouml

1. BioUML – extensible workbench for systems biologyhttp://www.biouml.org Biosoft.Ru/DevelopmentOnTheEdge.com Laboratory of Bioinformatics, Design Technological Institute of Digital Techniques Novosibirsk, Russia.

2. Schedule

3. http://www.biouml.org

4. The challenge "We now have unprecedented ability to collect data about nature but there is now a crisis developing in biology, in that completely unstructured information does not enhance understanding. We need a framework to put all of this knowledge and data into — that is going to be the problem in biology. We've reached the stage where we can't talk to each other — we've all become highly specialized. We need a framework, a framework where people can come back to us and say, 'Yes, I understand.' Driving toward that framework is really the big challenge.“ Sydney Brenner Sydney Brenner, 2002 Nobel Prize winner

6. Main BioUML concepts and ideas Visual modeling Plug-in based architecture (Eclipse platform runtime from IBM). Meta model – problem domain neutral level of abstraction that describes system as compartmentalized graph. It is also common contract for all parties (software developers, problem domains specialists, annotators, mathematicians). Diagram type concept – formally defines graphical notation and provides its incorporation into BioUML workbench. Module concept - allows developer to incorporate databases on biological pathways into BioUML framework taking into account database peculiarities.

7. Visual Modeling The problem of modeling and simulating of complex systems can be significantly simplified for customers by using computer systems providing visual modeling. These visual depictions offer alternative syntax to completely and formally specify models. A number of visual syntaxes were developed and implemented in computer systems for electrical engineering and computer science. The most known graphical language for computer science is UML – Unified Modeling Language.

8. The OMG specification states: "The Unified Modeling Language (UML) is a graphical language for visualizing,specifying, constructing, and documenting the artifacts of a software-intensive system.The UML offers a standard way to write a system's blueprints, including conceptualthings such as business processes and system functions as well as concrete things suchas programming language statements, database schemas, and reusable softwarecomponents."

9. UML diagrams • use case diagram • class diagram • behavior diagrams: • statechart diagram • activity diagram • interaction diagrams: • sequence diagram • collaboration diagram • implementation diagrams: • component diagram • deployment diagram

10. UML use case diagram

11. UML class diagram

12. UML state chart diagram

13. UML activity diagram

14. UML sequence diagram

15. UML collaboration diagram

16. If we will consider UML architecture from developer view point then we will note: • UML was really designed for modeling software systems and are hardly suitable for other problem domains. • UML has complicated structure that is quite hard for implementation. OMG specification is more the 700 pages. • UML was not designed for visual modeling and simulation of dynamics of complex systems. That is why we need new language for modeling biological systems and we called this language BioUML.

17. Graphical notations for biological pathways

18. Some graphical notations for biological pathways • Kohn K.W. (1999). Molecular Interaction Map of the Mammalian Cell Cycle Control and DNA Repair Systems.Mol. Biol.Cell. 10, 2703-2734. • Kitano H. (2003). A graphical notation for biochemical networks. BIOSILICO Vol. 1. No. 5. • R. Maimon and S. Browning (2001). Diagrammatic Notation and Computational Grammar for Gene Networks.Proceedings of the International Conference on Systems Biology. 2001. • Cook D.L. et al. (2001). A basis for a visual language for describing, archiving and analyzing functional models of complex biological systems. Genome Biol. 2. RESEARCH 0012. • Database specific notations: • KEGG/Metabolic pathways; GeneNet system; TRANSPATH • …

19. Kohn K.W. (1999). Molecular Interaction Map of the Mammalian Cell Cycle Control and DNA Repair Systems.Mol. Biol.Cell. 10, 2703-2734.

21. Representation of multimolecular complexes: stimulatory and inhibitory complexes of E2F1, DP1, and pRb. (a) E2F1:DP1 dimer; (b) E2F1:DP1:pRb trimer; (c) E2F1:DP1 bound to promoter element E2 (transcriptional activation shown); (d) E2F1:DP1:pRb bound to E2 (transcriptional inhibition shown). Note that the promoter element can be occupied either by E2F1:DP1 or by E2F1:DP1:pRb (alternative binding represented by interaction lines joined at an acute angle).

23. Kitano H. (2003). A graphical notation for biochemical networks. BIOSILICO Vol. 1. No. 5.

26. R. Maimon and S. Browning. Diagrammatic Notation and Computational Grammar for Gene Networks.Proceedings of the International Conference on Systems Biology. 2001.

28. Formal description and modeling of biological systems require coordinated efforts of different group of researchers: • programmers - they should provide computer tools for this task. • problem domain experts - they should specify what and how should be described. • experimenters and annotators - they should describe corresponding data following to these rules. • mathematicians - they should provide methods for models analysis and simulations. BioUML architecture separates these tasks so they can be effectively solved by corresponding group of researchers and provides simple contract how these groups and corresponding software parts should communicate.

29. p53, The gatekeeper of death:

30. Cook D.L. et al. (2001). A basis for a visual language for describing, archiving and analyzing functional models of complex biological systems. Genome Biol. 2. RESEARCH 0012.

33. KEGG - metabolic pathways

34. KEGG - signaling pathways

35. GeneNet system A chemical formalism was employed as a basis for describing the events occurring in biological pathways 2 types of relationships between entities: reaction - the interaction between the entities that leads to the appearance of new entity regulatory event - the effect of an entity on a certain reaction

36. GeneNet – antiviral responce

37. TRANSPATH database

38. TRANSPATH – p53 pathway

39. BioUML architecture

40. Plug-in based architecture A plug-in is the smallest unit of BioUML workbench function that can be developed and delivered separately into BioUML workbench. A plug-in is described in an XML manifest file, called plugin.xml. The parsed contents of plug-in manifest files are made available programmatically through a plug-in registry API provided by Eclipse runtime. - extension points are well-defined function points in the system where other plug-ins can contribute functionality. - extension is a specific contribution to an extension point. Plug-ins can define their own extension points, so that other plug-ins can integrate tightly with them. • Plug-in • plugin.xml • Java jar files • Plug-in • plugin.xml • Java jar files • Plug-in • plugin.xml • etc. Eclipse platform runtime

44. Plugin.xml example (1) <?xml version="1.0" encoding="UTF-8"?> <plugin id="ru.biosoft.plugins.javascript“ version="0.7.4"> <requires> <import plugin="org.apache.log4j"/> <import plugin="ru.biosoft.access"/> <import plugin="ru.biosoft.workbench"/> <import plugin="biouml.workbench"/> </requires> <runtime> <library name="jsplugin.jar“/> </runtime> <extension-point name="function" id="function"/> <extension-point name="function" id="hostObject"/>

45. Plugin.xml example (2) <extension-point name="function" id="function"/> <extension-point name="function" id="hostObject"/> <extension id="help" point="ru.biosoft.plugins.javascript.function"> <function name="help" class="ru.biosoft.plugins.javascript.Global" method="help" varargs="true"> <doc description="%help.descr"> <argument name="obj" type="Object" obligatory="true“ description="%help.arg_1"/> <example code="%help.ex_1c" description="%help.ex_1d"/> <example code="%help.ex_2c" description="%help.ex_2d"/> <example code="%help.ex_3c" description="%help.ex_3d"/> </doc> </function> </extension>

46. Plugin.properties example help.descr = Returns description for the specified JavaScript function \ or host object.\nThis description should be loaded using \ 'biouml.pligins.javascript.function' or \\n'biouml.pligins.javascript.hostObject' extension point. help.arg_1 = JavaScript object of function name. help.ex_1c = help() help.ex_1d = will print description of 'help' function itself. help.ex_2c = help(print) help.ex_2d = will print description of 'print' function. help.ex_3c = help(sbw) help.ex_3d = will print description of sbw host object.

47. BioUML meta model The core of BioUML workbench is meta model. Unlike UML meta mode BioUML meta model is problem domain neutral and provides an abstract layer for comprehensive formal description of wide range of biological and other complex systems. Content of databases on biological pathways or SBML models are expressed in terms of meta model and then can be used by other workbench plug-ins.

48. Пример двух последовательных химических реакций eq1 eq3 eq2 eq4 A B C R1 R2 100 0 0 Соответствующая ему математическая модель

49. Example of formalized description of system from two chemical reactions - k1[A] - k2[B] k1[A] K2[B] A B C R1 R2 100 0 0 Description of system ID R1 ID B ID R2 ID C ID A A - >B CC .. B - >C CC .. CC .. components in the ... ... ... ... ... database // // // // // System structure is R1 R2 described as a graph C A B Mathematical model 0 - k2[B] K2[B] k1[A] 100 - k1[A] 0 of the system

50. Main BioUML meta-model classes to describe system structure as compartmentalized graph