1. In Silico Laboratories: The Virtual Parasite Project - An Overview SURA Grid Computing in the Life Sciences - 2006 Tarynn M. Witten, Ph.D., FGSA, FCSBC Director, Research and Development Center for the Study of Biological Complexity Visual Parasite Project Virginia Commonwealth University Richmond, VA twitten@vcu.edu

2. OVERVIEW The Team The Team Computational Biology – A Larger View Computational Biology – A Larger View In Silico Laboratories In Silico Laboratories Introduction to the VPP Introduction to the VPP – Goals Basic Parasite Information Basic Parasite Information – Pathology, life cycle, and form The VPP Program The VPP Program – Architecture, model, equations, benchmarks – Visualization Patent Application Patent Application Where to From Here Where to From Here

3. The VPP Team

4. Computational Biology Handling the “omic” hierarchy – It’s not just genes any more – ETA Systems Computational Medicine and BioSciences Group Simulations of biomedical elements – Computational Chemistry – Computational Biomechanics – Computational “Fill in your favorite noun” Frankenstein in the machine The “in silico laboratory”

5. In Silico Laboratories Not a simulation of an organism but Not a simulation of an organism but an extensible, portable, “in silico,” multi-scale, high performance computational and mathematical laboratory for research into the dynamics of host-parasite interactions an extensible, portable, “in silico,” multi-scale, high performance computational and mathematical laboratory for research into the dynamics of host-parasite interactions To test this environment by examining the host- parasite dynamics of the Trypanosoma cruzi, the causative agent in Chagas Disease To test this environment by examining the host- parasite dynamics of the Trypanosoma cruzi, the causative agent in Chagas Disease

6. BASIC T. CRUZI INFORMATION

7. Epidemiology – 1 Chagas disease is the 3 rd most common parasitic disease after malaria and schistosomiasis Estimates are that over 2 billion people worldwide are affected by these 3 parasitic diseasesEstimates are that over 2 billion people worldwide are affected by these 3 parasitic diseases Mortality estimates in Africa for schistosomiasis are 200,000/year and most are childrenMortality estimates in Africa for schistosomiasis are 200,000/year and most are children 12 species of Trypanasoma cruzi are known to occur in the US12 species of Trypanasoma cruzi are known to occur in the US Trypanosoma cruzi is the causal agent in Chagas diseaseTrypanosoma cruzi is the causal agent in Chagas disease

8. Epidemiology – 2 Recent estimates suggest that more than 17 million people throughout Latin America are currently infected with T. cruzi – currently present in 18 countries 4.8-5.4 million individuals currently exhibiting clinical symptoms4.8-5.4 million individuals currently exhibiting clinical symptoms Annual incidence 700,000 – 800,000 new casesAnnual incidence 700,000 – 800,000 new cases 45,000 deaths due to the cardiac form of the disease45,000 deaths due to the cardiac form of the disease There is no cure and therapeutic agents are highly toxicThere is no cure and therapeutic agents are highly toxic There is no treatment for chronic ChagasThere is no treatment for chronic Chagas Chagas disease is fatalChagas disease is fatal The life cycle of the parasite is complexThe life cycle of the parasite is complex

9. T. Cruzi Lifecycle

10. Pathology in Chagas Disease Transmitted through the feces of biting insectsTransmitted through the feces of biting insects Insects defecate while taking blood mealInsects defecate while taking blood meal Infected individual scratches feces into wound starting infectionInfected individual scratches feces into wound starting infection Myocarditis and cardiomyopathyMyocarditis and cardiomyopathy Alimentary tract dysfunction manifested by megaesophagus and megacolonAlimentary tract dysfunction manifested by megaesophagus and megacolon Acute stage occurs 1-2 weeks after exposureAcute stage occurs 1-2 weeks after exposure

11. BASIC PROGRAM INFORMATION

12. VPP Program Architecture Program is written in public domain languages and uses public domain software (C++, C, Fortran) Program is written in public domain languages and uses public domain software (C++, C, Fortran) Currently VPP code exceeds 20,000 lines Currently VPP code exceeds 20,000 lines Modular development of the VPP environment enables users to supply relevant lab modules for their particular research needs Modular development of the VPP environment enables users to supply relevant lab modules for their particular research needs – Standard worlds are provided (flask, test tube, etc.) – Standard parasite forms are provided (spherical, elliptical, helicoid, amoeboid, flagellar) – Standard fluids are provided (water, plasma/blood) Parasite we chose to model in the environment was the T. cruzi parasite Parasite we chose to model in the environment was the T. cruzi parasite Simulation code runs in a parallel processor (MPI) environment – Sun Grizzly (32 dual processor node cluster) Simulation code runs in a parallel processor (MPI) environment – Sun Grizzly (32 dual processor node cluster) Visualization interface allows user to visualize actual data in a “video/interactive” format – Sun V880 with in house developed interface Visualization interface allows user to visualize actual data in a “video/interactive” format – Sun V880 with in house developed interface

13. Initial Approach To T. cruzi Modeling Macro-scale biophysics at a population level Macro-scale biophysics at a population level Inclusion of host cells with cell cycle model Inclusion of host cells with cell cycle model Single parasite model (sphere with tail) Single parasite model (sphere with tail)

15. Basic Newtonian Model Four basic forces Four basic forces –Gravitational –Buoyant –Swimming –Drag

16. The Uncoupled Equations

19. VPP Visualization

25. The New Patent Application

26. Charge Gradient Patent Results from the construction of the simulation lead to a patent application utilizing charge- gradients as a means of inhibiting and/or stopping T. cruzi invasion Results from the construction of the simulation lead to a patent application utilizing charge- gradients as a means of inhibiting and/or stopping T. cruzi invasion Patent application on 4 June 2004 has been awarded provisional patent to VPP team Patent application on 4 June 2004 has been awarded provisional patent to VPP team Literature research indicates that the methodology may be applicable to a class of organisms including malaria. Literature research indicates that the methodology may be applicable to a class of organisms including malaria.

27. Patent Methodologies Argument is based upon charge-charge interaction between parasite and Argument is based upon charge-charge interaction between parasite and –Charged nano-beads experiment was completed by an NSF BBSI student –In addition, other approaches such as synthesis of peptide or RNA aptamers positively charged and used to test invasion inhibition efficacy

28. WHERE TO FROM HERE?

29. Where To From Here – 1 ? Include more biologically accurate mammalian host cell model Include more biologically accurate mammalian host cell model Develop more biologically accurate model of parasite Develop more biologically accurate model of parasite Expand module for environmental definitions Expand module for environmental definitions Include van der Waals force calculations Include van der Waals force calculations

30. Where To From Here – 2 ? Continue algorithm optimization and development Continue algorithm optimization and development – Generalized to n-processor distributed grid environments Continue GUI interface development Continue GUI interface development – Extension to 3D visualization (cave) – VRML interface

31. Where To From Here – 3 ? Invasion module Invasion module – Host-parasite proximity factors Inclusion of recognition factors, reorientation factors, attachment factors Inclusion of recognition factors, reorientation factors, attachment factors – Binding factors – Transformation for invasion Signal transduction pathways Signal transduction pathways Membrane factors Membrane factors Attachment factors Attachment factors – Physical Invasion

32. Molecular Scale Models Once parasites are in the proximity of the host cell, modeling must account for the various phases of invasion Once parasites are in the proximity of the host cell, modeling must account for the various phases of invasion

33. Where To From Here – 4 ? Extension to whole human model Extension to whole human model – Inclusion of tissue alteration factors – Pharmaco-dynamic intervention factors – Re-infection factors

34. Take Home Message Computational Biology is not just about “omics” Computational Biology is not just about “omics” Ultra-large scale environments are actively involved in addressing complex biomedical problems at super-genomic levels Ultra-large scale environments are actively involved in addressing complex biomedical problems at super-genomic levels These environments have similar problems with respect to programming, visualization, user interface design, data storage and access as the “omic” environments have These environments have similar problems with respect to programming, visualization, user interface design, data storage and access as the “omic” environments have In silico laboratories are the next extension of HPC to biomedical research and education In silico laboratories are the next extension of HPC to biomedical research and education Such laboratories can lead to insights into biomedical dynamics that were not here-to-fore envisioned Such laboratories can lead to insights into biomedical dynamics that were not here-to-fore envisioned

35. Thank You For Coming

36. Simulation Benchmark Timing -1

37. Simulation Benchmark Timing – 2