BioUML ( Software framework for systems biology Overview Biosoft.Ru, Novosibirsk, Russia. Laboratory of Bioinformatics, Digital Design Technologies Institute, SB RAS. Copyright © 2002 Biosof.Ru. All rights reserved. Click or press any key to continue….

Motivation Systems biology requires integrated software environment that spans the comprehensive range of capabilities including: access to databases with experimental data tools for formalized description of biological systems structure and functioning tools for visualization and simulation of biological systems Click or press any key to continue….

Results BioUML is designed as common purpose framework for systems biology providing formalized graphic notation structure and functioning of biological systems, their visualization and simulation as well as access to databases with relevant experimental data. Click or press any key to continue….

Architecture Meta model Database modules Diagram viewer Diagram editor Database search engine Visual modeling and simulation tools Click or press any key to continue….

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

Database module: concept We introduce a concept of module that serve for incorporation of different databases on biological pathways into BioUML framework. If we use a metaphor, then BioUML can be imagined as operating system (for example Windows), and modules are concrete programs (for example MS Word). Click or press any key to continue….

Database modules Click or press any key to continue…. We have developed modules for following databases on biological pathways: GeneNet (IC&G, SB RAS, Russia) TRANSPATH (BIOBASE GmbH, Germany) KEGG pathways (Kyoto University, Japan)

Diagram viewer Information from different databases on biological pathways can be mapped into objects from BioUML meta model. After that diagram viewer can visualize structure of biological systems as diagrams. Click or press any key to continue….

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.. Click or press any key to continue….

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. Click or press any key to continue….

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. Click or press any key to continue….

Similar user can select only those components whose expression was experimentally proven in the specified cell types, for example in human T-lymphocytes. Click or press any key to continue….

Diagram editor. Click or press any key to continue…. 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.

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. Click or press any key to continue….

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. Click or press any key to continue….

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) Click or press any key to continue….

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. Click or press any key to continue….

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 Click or press any key to continue….

Results of search of components interconnected with “Hs:HSF-1-p” protein. Click or press any key to continue….

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 pathway simulation diagram:  variables are associated with graph nodes  differential equations are associated with graph edges To specify right side of differential equation MATLAB language is used. Additionally some conventions are used for variable names. When such diagram is build, BioUML modeler allows user to automatically generate executable models as MATLAB M-files and start powerful MATLAB ODE suite for model simulations.

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

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. Click or press any key to continue….

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. Click or press any key to continue….

Using this table user can specify initial values for all variables. Click or press any key to continue….

Similarly user can specify initial values for all constants. Click or press any key to continue….

The “Start” tab allows user to specify ODE solver and time interval. Click or press any key to continue….

When “Start” button is pressed BioUML automatically generates mathematical model and invokes MATLAB to solve this model and present results graphically. Click or press any key to continue….

BioUML modeler: generated M-files For the model simulation using MATLAB BioUML modeler generates two M-files: script file for model simulation and graphic result presentations. function to calculate dy/dt for the model. Click or press any key to continue….

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 = v_liver = %Model variables and their initial values y = [] y(1) = % 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'); Click or press any key to continue….

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] Click or press any key to continue….

Features for BioUML 2.0 Import/export SBML models Formalize similar with UML 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 Graph layout improvements Modules for other databases on biological pathways Click or press any key to continue….

Availability First public release will appear July 15, 2002 BioUML 1.0 planned to be free for non profit organizations BioUML sources (meta model, database modules and some other) will be publically available. Contacts: Click or press any key to continue….