BioUML SBML

BioUML extensible workbench for systems biologyDesired SBML extensions: 

BioUML extensible workbench for systems biology Desired SBML extensions Fedor Kolpakov Institute of Systems Biology (spin-off of DevelopmentOnTheEdge.com) Laboratory of Bioinformatics, Design Technological Institute of Digital Techniques Novosibirsk, Russia

Main BioUML concepts and ideas: 

Main BioUML concepts and ideas

Slide4: 

Corresponding mathematical model: Example: system from two chemical reactions A B - k1[A] k1[A] R1 C - k2[B] K2[B] R2 100 0 0 k1 - reaction rate for R1 k2 – reaction rate for R2

Slide5: 

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

Slide6: 

Suggested approach can be applied for modeling biological systems using: Systems of ordinary differential equations Systems of algebra-differential equations State and transition diagrams Hybrid models Boolean and logical networks Petri nets Markov chains Stochastic models Cellular automates 1D PDE models (blood flow) … Current limitations Spatial models PDE …

Reconstruction and formal description of biological systems using different diagram types: 

Reconstruction and formal description of biological systems using different diagram types 1. Semantic network 2. Pathway diagram (semantic network + gene network or metabolic pathway) 3. Metabolic pathway 3. Gene network 4. Pathway simulation (mathematical model) Formality, details Semi structured data Structured data (reactions and its components) Kinetic data (kinetic laws, constants, initial values

Stimulus activating NF-kappaB(semantic network, ontology): 

Stimulus activating NF-kappaB (semantic network, ontology)

Slide10: 

Function of human DNA methyltransferases (pathway diagram)

Slide11: 

The biosynthesis of catecholamines (metabolic pathway)

Slide12: 

Cell cycle model of mammalian G1/S transition control with E2F feedback loops (pathway simulation diagram)

Results of SBML semantic tests: 

Results of SBML semantic tests

Slide16: 

Results for Java simulation engine, SBML level 2semantic tests

Slide19: 

BioUML modules BioUML standard module Databases Biopath/BMOND (http://biopath.biouml.org) GeneNet (http://wwwmgs.bionet.nsc.ru) KEGG/Ligand (http://www.kegg.com) TRANSPATH (http://www.biobase.de) Formats SBML – Systems Biology Markup Language, level 1, 2 (http:// www.sbml.org) CellML – Cell Markup Language (http://www.cellml.org) BioPax – Biological Pathways Exchange (http://www.biopax.org) GXL - Graph eXchange Language (http://www.gupro.de/GXL) GinML – extension of GXL for description regulatory networks (http://gin.univ-mrs.fr/GINsim) BioNetGen - mathematical models of biological systems from user-specified rules for biomolecular interactions (http://cellsignaling.lanl.gov/bionetgen)

Slide20: 

KEGG pathway

Slide21: 

CellML model

Slide22: 

SBML model

Motivation: 

Motivation For our routine work we need to extend SBML format to support: Broader range of biological models, including physiological models Models composition Multi-scale composite models (for example, model of bacterial chemotaxis) Tight integration with experimental data: model variation – to reproduce experimental condition we need to modify model structure (for example for mutations), remove or add new events or reactions (for example to simulate experimental conditions) parameters set, fitted (optimized) parameters experimental data and observation – we need some format to store these data Storage of simulation results

Required SBML extensions: 

Required SBML extensions Experiment Experiment condition Model variation Parameter set Observed values Simulated values Optimized parameter set Model composition Multi-scale model composition Graphic notation Layout information

Required SBML extensions: 

Required SBML extensions Experiment Experiment condition Model variation Parameter set Observed values Simulated values Optimized parameter set Model composition Multi-scale model composition Graphic notation Layout information

Suggestion: agent based approach for multi-scale model composition: 

Suggestion: agent based approach for multi-scale model composition Agent-based computational approaches have a natural modular architecture, which reflects the modular organization of biological systems. Bacterial chemotaxis model was simulated by Thierry Emonet and other using agent based approach. Now we try to apply agent based approach for simulation arterial hypertension.

Slide28: 

Agents are “problem solving entities with well-defined boundaries and interfaces”. Agents have goals and can determine if their situation becomes better or worse relative to the fulfillment of these goals. Agents act on locally available information; global or system-wide information is not accessible. The main difference between agents and objects is that agents are autonomous: they have the ability to control their internal state and behavior without the direction of a central authority (Wooldridge 1997). Autonomy decentralizes decision making and therefore greatly simplifies the implementation of the over whole system’s control. Because each agent decides by itself when to act and what action to perform, there is no need for a complex centralized decision making entity. Agents follow protocols to interact with their environment and to interact with each other. Because of their autonomy, agents are free to make run-time decisions about the scope (with whom to interact) and nature of the interactions. Flexibility in the timing, scope and nature of the interactions is one of the advantages of agent-based.

Simulation of arterial hypertension: 

Simulation of arterial hypertension Haemodynamic block – graph (vessels as edges, 1D PDE for blood flow in each vessel). Kidney block - molecular pathways of kidney processes involved in regulation of arterial blood pressure and water salt balance. Endocrine regulation block – pathways effects of hypothalamus, adrenal gland, and atrium hormones on cardio-vascular system. Nerve activity block - simulating action of sympathetic and parasympathetic nerve systems affecting renal processes, blood vessel tone, etc.

SuggestionBioUML team can implement drafts of SBML specifications as BioUML plug-ins to test suggested approaches from practical view point during routine work.: 

Suggestion BioUML team can implement drafts of SBML specifications as BioUML plug-ins to test suggested approaches from practical view point during routine work.

Acknowledgements: 

Acknowledgements Part of this work was partially supported by following grants: Volkswagen-Stiftung (I/75941), INTAS Nr. 03-51-5218 RFBR Nr. 04-04-49826-а Siberian Branch of Russian Academy of Sciences (interdisciplinary projects № 46). Author is grateful to for useful comments, discussions and technical support Alexander Kel Sergey Zhatchenko Software developers Annotators Mikhail Puzanov Alexandr Koshukov Ruslan Sharipov Vasiliy Hudyakov Vlad Zhvaleev Elena Cheremushkina Oleg Onegov Igor Tyazhev Ekaterina Kalashnikova Artem Shaidukov

Refined definition of graphic notation: 

Refined definition of graphic notation Object types (for example, protein, gene, reaction) Object properties (for example, phosphorilated) User defined object properties - layout information (for example, size, color, location) Rules for objects and their properties visualization Rules for semantic control of diagram integrity Selection, highlighting, filtering

Formal definition of graphic notation as XML document and integration with SBML format: 

Formal definition of graphic notation as XML document and integration with SBML format

Slide35: 

SBML … Diagram Model API BioPAX Layout information Graphic notation Layout API Notation API Rendering engine Rules processor JavaScript interpreter/compiler Initial data JavaScript API for data access Rendering API JavaScript API for creating primitives similar with SBML layout extension Basic software architecture for rendering of biological models according to specified graphic notation and layout information

Process Diagrams as a test case: 

Process Diagrams as a test case We plan to test our approach on Process Diagrams. This work will include: Formal definition of graphic notation as XML document. Integration with SBML format. Developing of plug-in for BioUML workbench that will implement suggested architecture BioUML meta-model will be used as Model API and Layout API; BioUML DiagramType will be used as Graphic notation API; BioUML graphics library will be used as Rendering API; BioUML DiagramViewBuilder will be used as prototype for Rendering Engine.