1. Honours Thesis – “Metabolic Pathways” “Metabolic Pathways“ Tim Conrad conrad@csse.monash.edu.au B.Comp.Sci. Honours Thesis – Final Presentation 10/2004 Supervisor: Dr. Maria Garcia de la Banda (Optimization and Constraint Solving Research Group)

2. Honours Thesis – “Metabolic Pathways” Introduction Background Source: http://www.roche-applied-science.com  Metabolism: Chemical reactions in organisms while they feed, grow and reproduce

3. Honours Thesis – “Metabolic Pathways” Introduction Background Source: http://www.roche-applied-science.com  Metabolic Pathway: Conceptual part performing a certain functional task  Highly meshed  Complicated  Interested in:  Dynamics  Properties  Connections  Linked diseases

4. Honours Thesis – “Metabolic Pathways” Introduction Observations  Researching metabolic pathways is important  Lots of ideas and approches from many research disciplines  Lots of different practical “tools” and applications out of the ideas  Huge impact e.g. on drug design process  Much money involved

5. Honours Thesis – “Metabolic Pathways” Introduction Problems  Too many points of view from too many different disciplines  Most tools “unusable” in different disciplines and even in different work-groups  Very little team-work or collaboration

6. Honours Thesis – “Metabolic Pathways” Introduction Aims  Build platform which:  Integrates existing tools with different functionality  Provides one user-friendly interface to all tools  Allows to exchange core tools  Improves key aspects  Adds new functionality  Started off with just a vage idea

7. Honours Thesis – “Metabolic Pathways” Solution Overview Checking Simulating Modeling VisualizingAnalzying

8. Honours Thesis – “Metabolic Pathways” Solution Modeling  Biology  Computer-model … MAPKpMAPKPH'[t] == a8 * MAPKp[t] * MAPKPH[t] - d8 * MAPKpMAPKPH[t] - k8 * MAPKpMAPKPH[t] …  SBML (substances, reactions (ODEs))  Developed by Finney et al. (2000)  Quasi-standard  Many SBML models available in databases

9. Honours Thesis – “Metabolic Pathways” Solution Overview SBML … MAPKpMAPKPH'[t] == a8 * MAPKp[t] * MAPKPH[t] - d8 * MAPKpMAPKPH[t] - k8 * MAPKpMAPKPH[t] … Modeling Checking Simulating VisualizingAnalzying Checking

10. Honours Thesis – “Metabolic Pathways” Solution Checking  (Qualitative) Validation of the model  E.g.: Is every substance being produced ?  Testing hypothesis  E.g.: Are there cycles in the pathway ?  Checking engine (NuSMV) uses own syntax  Using approach by Chabrier et al. (2002)  Model needs to be translated from SBML  Model to be queried by using CTL  Ai(!(E(!(MEKp) U MAPKpp)))

11. Honours Thesis – “Metabolic Pathways” Solution Checking – Frontend to NuSMV

12. Honours Thesis – “Metabolic Pathways” Solution Overview Checking NuSMV SBML … MAPKpMAPKPH'[t] == a8 * MAPKp[t] * MAPKPH[t] - d8 * MAPKpMAPKPH[t] - k8 * MAPKpMAPKPH[t] … Modeling Simulating VisualizingAnalzying

13. Honours Thesis – “Metabolic Pathways” Solution Simulating  Quantitative analysis of substance concentration (based on ODEs)  Using Jarnac as simulation engine  Developed by Sauro et al. (2000) … MAPKpMAPKPH'[t] == a8 * MAPKp[t] * MAPKPH[t] - d8 * MAPKpMAPKPH[t] - k8 * MAPKpMAPKPH[t] …

14. Honours Thesis – “Metabolic Pathways” Solution Simulating

15. Solution Step 1: Overview Checking NuSMV Simulating Jarnac SBML … MAPKpMAPKPH'[t] == a8 * MAPKp[t] * MAPKPH[t] - d8 * MAPKpMAPKPH[t] - k8 * MAPKpMAPKPH[t] … Modeling VisualizingAnalzyingVisualizing

16. Honours Thesis – “Metabolic Pathways” Solution Visualization  Important for gaining structural insights  Many approaches available  Mainly showing isolated parts / pathways  Only using two dimensions  Most fail for “big networks” (|V| > 200)  Contribution: Implementation and integration of various well known layout algorithms - for different sizes and structures

17. Honours Thesis – “Metabolic Pathways” Solution Compared to: CellDesigner / JDesigner

18. Honours Thesis – “Metabolic Pathways” Solution Small – Medium: 2D Spring Embedder

19. Honours Thesis – “Metabolic Pathways” Solution Small – Medium: 2D Spring Embedder

20. Honours Thesis – “Metabolic Pathways” Solution Medium – Large: HDE with Octree

21. Honours Thesis – “Metabolic Pathways” Solution Medium – Large: HDE with Octree

22. Honours Thesis – “Metabolic Pathways” Solution Medium – Large: HDE with Octree

23. Honours Thesis – “Metabolic Pathways” Solution Very Large: HDE

24. Honours Thesis – “Metabolic Pathways” Solution Very Large: HDE in Hyperbolic Space

25. Honours Thesis – “Metabolic Pathways” Solution Very Large: HDE in Hyperbolic Space

26. Honours Thesis – “Metabolic Pathways” Solution Step 1: Overview Checking NuSMV Simulating Jarnac SBML … MAPKpMAPKPH'[t] == a8 * MAPKp[t] * MAPKPH[t] - d8 * MAPKpMAPKPH[t] - k8 * MAPKpMAPKPH[t] … Modeling Analzying Visualizing

27. Honours Thesis – “Metabolic Pathways” Solution Analyzing the Simulation Results  Searching for:  Sub-networks  Alternative routes  Contribution:  Mapping simulation results to our graphical network representation

28. Honours Thesis – “Metabolic Pathways” Solution Analyzing through mapping

29. Honours Thesis – “Metabolic Pathways” Solution Analyzing through mapping  Modifying and Comparing

30. Honours Thesis – “Metabolic Pathways” Solution Analyzing the Simulation Results  Searching for:  Similar dynamics of the substances involved  Contribution:  Method to detect possible co-regulated substances

31. Honours Thesis – “Metabolic Pathways” Solution Analyzes – Fluvial Topologies  Aim: Find co-regulated substances  1) New representation / encoding

32. Honours Thesis – “Metabolic Pathways” Solution Analyzes – Fluvial Topologies Used method: Memetic Algorithm (GA)  2) Reordering of the rows w.r.t. similarity

33. Honours Thesis – “Metabolic Pathways” Solution Analyzes – Fluvial Topologies  3) Calculating a continuous representation (explicit function) 2-D Fourier Row:

34. Honours Thesis – “Metabolic Pathways” Solution Analyzes – Fluvial Topologies  Impose same order to modified network

35. Honours Thesis – “Metabolic Pathways” Conclusion & Outlook  Developed platform which integrates modeling, checking, simulation and analyzing of metabolic networks  Improved / added key aspects  Visualization  Analysis  Currently applying the methods to two “real” pathways and analyse them with biologists Thanks for listening !

36. Honours Thesis – “Metabolic Pathways” Checking NuSMV Simulating Jarnac SBML … MAPKpMAPKPH'[t] == a8 * MAPKp[t] * MAPKPH[t] - d8 * MAPKpMAPKPH[t] - k8 * MAPKpMAPKPH[t] … Modeling Visualizing Analzying Named Pipes SBW libSBML Internal WxWidgets, VTK, OpenGL

37. Honours Thesis – “Metabolic Pathways” PlatformBioCHAMNuSMV SBML  BioCHAM formatBioCHAM  NuSMV format Model: Query: Query to model checker Query result