DCI for Clinical Translational Research Shantenu Jha, LSU & UC-London Peter Coveney, UC-London Slide acknowledgement Barbara Alving, NIH

Opportunities for Research and NIH Francis Collins Applying high throughput technologies Translating basic science discoveries into new and better treatments Benefiting health care reform Comparative effectiveness research Prevention and personalized medicine Health disparities research Pharmacogenomics Health research economics Focusing on global health Reinvigorating and empowering the biomedical research community 1 January 2010 Vol 327 Science, Issue 5961, Pages 36-37

The Translation Gap National Health Expenditures as a Percent of GDP Source: Butler D. Translational research: Crossing the valley of death. Nature. 2008;453:840–2.

Biomedical Technology Research Scope: from basic discovery to clinical research Scale: from molecule to organism Optics & Laser Technology Microscopy Fluorescence spectroscopy In Vivo diagnosis Imaging MRI Image-guided therapy PET CAT Ultrasound Informatics Resources Genetics Modeling of complex systems Molecular dynamics Visualization Imaging informatics Technology for Structural Biology Synchrotron x-ray technologies Electron microscopy Magnetic resonance Technology for Systems Biology Mass spectrometry Proteomics Glycomics & glycotechnology Flow cytometry 4

VPH: Ambitious Way Forward What is the Physiome? The Physiome is the quantitative and integrated description of the functional behaviour of the physiological state of an individual or species The key to successful computational physiology is the capture of structure-function relationships in a computationally efficient manner. [Crampin et al., 2003] “We need adaptable tools able to cope with multi-physics and multi-scale problems ranging from molecular to physiological levels. In-house tools must be developed, maintained and updated, or the scientists must rely on available software, adapting it to their specific needs“ Describe physiome; IUPS project = International Union of Physiological Sciences (IUPS) Physiome project began at Glasgow conference (1993), formally launched at St Petersburg Conference (1994), roadmap in 2005. The Physiome Project is a worldwide public domain effort to provide a computational framework for understanding human and other eukaryotic physiology. It aims to develop integrative models at all levels of biological organisation, from genes to the whole organism via gene regulatory networks, protein pathways, integrative cell function, and tissue and whole organ structure/function relations. Projects included the development of: ontologies to organise biological knowledge and access to databases markup languages to encode models of biological structure and function in a standard format for sharing between different application programs and for re-use as components of more comprehensive models databases of structure at the cell, tissue and organ levels software to render computational models of cell function such as ion channel electrophysiology, cell signalling and metabolic pathways, transport, motility, the cell cycle, etc. in 2 & 3D graphical form software for displaying and interacting with the organ models which will allow the user to move across all spatial scales An important goal of the project is to develop teaching applications for physiology Who are the Leading figures in IUPS projects: Peter Hunter (NZ), James Bassingthwaighte (US) “The predictive paradigm in the treatment of disease” In order to obtain patient-specific simulations, simulations must be performed on a routine basis in the clinical setting. … high performance computing required for transient CFD simulation must be accessible, possibly using Grid technology

VPH/Physiome History -- Consilience Human Genome Project 1st meeting standards working group Systems Biology ICT Bio: need for standards working group Grid Computing Finite Elements VPH NoE starts Microcomputers/home computers White paper completed FP7 call 2 Objective ICT-2007.5.3: Virtual Physiological Human EC/ICT Health Start discussing Physiome research Molecular Biology After summer 2005, White Paper completed in the autumn of 2005. This was part of a Workshop connected to the FIMH conference and was held in Barcelona. This White Paper was made at the expert workshop held on 1stJune 2005 in Barcelona. There goal of this paper to shape a clear overview of on-going relevant activities, to build a consensus on how they can be complemented by new initiatives for researchers in the EU and to identify possible mid-term and long term research challenges. This initiative is an add-on to the existing scientific areas already supported by the European Commission. Activities identified span from better use of existing data and tools to the development of new methods, libraries and tools. Some of the main aspects of the VPHare the need to further development of numerical modelling and simulation and of innovative imaging processing methods to make use of them, the multidisciplinary dimension, the infrastructure needed and finally the acceptance issue. It is important to underline t Towards Virtual Physiological Human: Multilevel Modelling And Simulation Of The Human Anatomy And Physiology At same time proposal was submitted to Call FP6 STEP – a strategy for the Europhysiome Call 6 FP6 STEP: a Strategy for The EuroPhysiome - coordinate European efforts toward the development of the Virtual Physiological Human At heart of this was the need for a EuroPhysiome Project, coined to describe the integrated European approach required to: Bring together all European physiome ‘type’ projects avoid redundancy, duplication increase coherence & momentum of European work – this is where the VPH comes in Physiome at IUPS Conference Physiome Project VPH Roadmap for (STEP) Roadmap for Physiome FP6: STEP 1993 1997 2005 2006 2007 2008 2009

VPH- I FP7 projects Industry Parallel VPH projects Other Clinics                    VPH- I FP7 projects Industry Parallel VPH projects Grid access CA CV/ Atheroschlerosis IP Liver surgery STREP Breast cancer/ diagnosis STREP Heart/ LVD surgery STREP Osteoporosis IP Oral cancer/ BM D&T STREP The Virtual Physiological Human is at the heart of the VPH projects. STREPs – Specific targeted research projects FP6 STREPs (Specific Targeted Research Projects) are either projects designed to gain knowledge or improve existing products, processes or services, or demonstration projects to prove the viability of new technologies. STREPs can also be characterized by the implementation of these two types of activity (R&D and demonstration IP s – Initiative projects CA’s – Coordination action Cancer STREP Networking NoE Heart /CV disease STREP Vascular/ AVF & haemodialysis STREP Liver cancer/RFA therapy STREP Alzheimer's/ BM & diagnosis STREP Heart /CV disease STREP Other Security and Privacy in VPH CA Clinics

Patient-specific HIV drug therapy HIV-1 Protease is a common target for HIV drug therapy Enzyme of HIV responsible for protein maturation Target for Anti-retroviral Inhibitors 9 FDA inhibitors of HIV-1 protease So what’s the problem? Emergence of drug resistant mutations in protease Render drug ineffective Drug resistant mutants have emerged for all FDA One part of “HIV Cycle” Need for speedy calculation Monomer B 101 - 199 Monomer A 1 - 99 Flaps Leucine - 90, 190 Glycine - 48, 148 Catalytic Aspartic Acids - 25, 125 Saquinavir P2 Subsite N-terminal C-terminal

VPH: LONI-TeraGrid-DEISA Project Aim: To enhance the understanding of HIV-1 enzymes using replica-based methods across federated TG-DEISA-LONI Do so using general-purpose, extensible, scalable approach Test limits of Distributed Scale-Out – both algorithmic and infrastructure limits As part of the VPH project, to ultimately help build the CI for quick, efficient (patient-specific) decision-tools using predictive MD of drugs and enzymatic targets (HIV-1 protease) Integration of SAGA into Binding Affinity Calculator (BAC) tools to facilitate distributed Scale-Out Protonation study of Ritonavir bound to HIV-1 Protease wild type Study of binding affinity between 6 HIV-1 Protease mutants and the drug Ritonavir using SAGA-BAC Tools Simulation and calculation workflow

JA.NET (UK) 40Gb network TeraGrid 40Gb backbone DEISA 10Gb network Transatlantic 10Gb link TeraGrid 40Gb backbone DEISA 10Gb network

.. And You Asked # What problem was your project designed to solve? True Grand Challenge – scientific and research infrastructure Many elements to VPH/Translational Research. Focus on lowering TTC # How did the community come together? Collectively Seduced by Money… # What were the challenges? Trade off between General purpose vs Customised solutions/approaches “Novel” Usage Modes of Research Infrastructure – viewed as disruptive # What did you learn? [Ongoing project] Difficult to interoperate across infrastructure Establish Application-level Interoperability not just Service-level Interoperabilty # What have you achieved Utilized multiple resources in a given grid infrastructure, but still struggling to do routine concurrent simulations across distinct DCI (Grid projects) # What is left to be done? Software, policies, interoperability … all in all: A lot!