1. BioUML SOFTWARE FRAMEWORK FOR SYSTEMS BIOLOGY Overview  2004 - 2010 ITC Software All rights reserved.

2. Motivation Systems Biology requires an integrated software environment that spans the comprehensive range of capabilities including: access to databases with experimental data tools to formalize descriptions of biological systems’ structure and function tools to simulate and visualize biological systems

3. Results BioUML is designed as a common purpose framework for systems biology providing formalized graphic notation to describe the structure and function of biological systems, their visualization and simulation as well as access to databases with relevant experimental data.

4. Architecture Meta model Database modules Diagram viewer Diagram editor Database search engine Visual modeling and simulation tools

5. Meta model Meta model provides an abstract layer to present the structure of any biological system as a clustered graph that further can be visualized as a diagram or be stored as XML files.

6. Database module: concept We introduce the concept of a module that serves to incorporate different databases on biological pathways into the BioUML framework. If we use a metaphor, then BioUML can be imagined as an operating system (for example Windows), and modules are the concrete programs (for example MS Word).

7. Database modules We have developed modules for the following databases on biological pathways: GeneNet (IC&G, SB RAS, Russia) http://wwwmgs.bionet.nsc.ru TRANSPATH (BIOBASE GmbH, Germany) http://transpath.gbf.de KEGG pathways (Kyoto University, Japan) http://www.kegg.com

8. Diagram viewer Information from different databases on biological pathways can be mapped into objects from BioUML meta model. Thereafter the diagram viewer can visualize the structure of biological systems as diagrams.

9. Diagram viewer Main features: Seamless integration with databases on biological pathways: –clickable diagram nodes –hyperlinks support Powerful system of filters allowing user to highlight components with the specified properties. Print and print preview support. Saving diagram as GIF images. Zoom..

10. Clicking on any diagram node you can get the object description from the corresponding database. This is “Hs:IRF2” gene description from the GeneNet database.

11. Experimental data for “Antiviral response” diagram has been got from three species : - chicken (Gallus gallus) - human (Homo sapiens) - mouse (Mus musculus). Using filters user can select (highlight) only those components which are specific for the selected species, for example for Mus musculus.

12. Similarly user can select only those components whose expression was experimentally proven in the specified cell types, for example in human T-lymphocytes.

13. Diagram editor. Visual editing of diagrams. Allows associate arbitrary image with diagram node. Seamless integration with databases on biological pathways. Powerful editor for database records associated with diagram elements. Powerful search engine allowing a user to find all components interacted with selected one. Undo/redo support.

14. Components toolbar allows user to add into diagram component of specified type. By clicking on any diagram node user can edit corresponding database record using powerful component editor. Search engine allows a user to search database to find all components interacted with selected one and add them into the diagram.

15. Database search engine Database search engine allows user to find database records with the specified properties. Features: Unified interface for all database modules and database tables. User can use any component property (database field) for searching. Possibility to use regular expression (Perl5 regular expressions). Possibility to use many fields for search simultaneously. Searched results are presented in tabular forms. User can edit database records from result set.

16. First user should specify database module and database table for further searching. Here it is “GeneNet” module and “Protein” table. Specifying filter values for database fields user can select the needed records. Here we would like to select proteins: regulated by interferons (we can use regular expression /.*IFN.*/ for this purpose)

17. After pressing “Start” button we will get a table containing all database records specifying the give condition. Further you can select any record to view its description or edit it.

18. Graph search engine Graph search engine allows user to query database, find interconnected components and present result as a graph A predefined set of graph layout algorithms allows to arrange graph nodes The resulted graph can be extended and edited using BioUML editor

19. Results of search of components interconnected with “Hs:HSF-1-p” protein.

20. BioUML modeler BioUML modeler allows a user to model continuous dynamics systems that can be represented by system of ordinary differential equations (ODEs). A simulated biological system is presented as a pathway simulation diagram: –variables are associated with graph nodes –differential equations are associated with graph edges To specify the right side of a differential equation the MATLAB language is used. Additionally, some conventions are used for variable names. After such a diagram is built, the BioUML modeler allows the user to automatically generate executable models as MATLAB M-files and start a powerful MATLAB ODE suite for model simulations.

21. BioUML modeler: an example The example below demonstrates the application of BioUML modeler for simulations of a simple pharmacokinetic model. Here 100 units of some drug A were injected intravenously. This drug can be break up by some enzyme E in the liver giving the metabolite B. We suggest that drug flow from blood to liver is proportional to the drag amount in the blood. The same is true for drug flow from the liver to the blood, however, the constant is different (k_1 in the first case and k_2 in the second case). We also assume that the enzyme concentration in the liver is E0 and the dynamics of the reaction can be described using Michaelis-Menten equation.

22. 100 units of some drug A were injected intravenously. This drug is transferred from blood to liver. This drug can be broken up by some enzyme E in liver giving the metabolite B.

23. We suggest that drug flow from blood to liver is proportional to drag amount of in the blood with constant k_1. The same is true for drug flow from liver to blood, however the constant is other: k_2. Enzyme concentration in liver is E0 and unchangeable. Dynamics of break up reaction can be described using Michaelis-Menten equation.

24. Using this table user can specify initial values for all variables.

25. Similarly user can specify initial values for all constants.

26. The “Start” tab allows user to specify ODE solver and time interval.

27. When “Start” button is pressed BioUML automatically generates mathematical model and invokes MATLAB to solve this model and present results graphically.

28. BioUML modeler: generated M- files For the model simulation using MATLAB BioUML modeler generates two M-files: script file for the model simulation and graphical presentation of results. function to calculate dy/dt for the model.

29. BioUML modeler script file for model simulation and graphic result presentations %constants declaration global k_1 k_2 k_3 k_E0 k_Km v_blood v_liver k_1 = 0.1 k_2 = 0.05 k_3 = 0.01 k_E0 = 1.0 k_Km = 0.1 v_blood = 100.0 v_liver = 100.0 %Model variables and their initial values y = [] y(1) = 100.0 % y(1) - $blood.A y(2) = 0.0 % y(2) - $liver.A y(3) = 0.0 % y(3) - $liver.B y(4) = 1.0 % y(4) - $liver.E %numeric equation solving [t,y] = ode23('pharmo_simple_dy',[0 200],y) %plot the solver output plot(t, y(:,1),'-',t, y(:,2),'-',t, y(:,3),'-',t, y(:,4),'- ') title ('Solving pharmo_simple problem') ylabel ('y(t)') xlabel ('x(t)') legend('$blood.A','$liver.A','$liver.B','$liver.E');

30. BioUML modeler Function to calculate dy/dt for the model. function dy = pharmo_simple_dy(t, y) % Calculates dy/dt for 'pharmo_simple' model. %constants declaration global k_1 k_2 k_3 k_E0 k_Km v_blood v_liver % calculates dy/dt for 'pharmo_simple' model dy = [ -k_1*y(1)+k_2*y(2) -k_3*k_E0*y(2)/(k_Km+y(2)/v_liver)-k_2*y(2)+k_1*y(1) k_3*k_E0*y(2)/(k_Km+y(2)/v_liver) 0]

31. Features for BioUML 2.0 Import/export SBML models Similar to UML formalized visual language for systems biology Adding other computational models: –Discrete events –Hybrid models –FSM Providing a set of standard reactions to simplify creation of complex diagrams Graphical layout of improvements Modules for other databases on biological pathways

32. Availability First public release: July 19, 2002 BioUML 1.0 planned to be free for non profit organizations BioUML sources (meta model, database modules and some other) will be publicly available.

33. We hope you enjoyed our presentation ! ITC Software Tel.: +1 978 287 4855 info@itcsoftware.com www.itcsoftware.com We hope you enjoyed our presentation ! ITC Software Tel.: +1 978 287 4855 info@itcsoftware.com www.itcsoftware.com