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

2. 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

3. 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.

4. 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

5. 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

6. 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 : Virtual Physiological Human
EC/ICT Health Start discussing Physiome research
Molecular Biology
After summer 2005, White Paper completed in the autumn of 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

7. 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

8. 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
Monomer A
1 - 99
Flaps
Leucine - 90, 190
Glycine - 48, 148
Catalytic Aspartic Acids - 25, 125
Saquinavir
P2 Subsite
N-terminal
C-terminal

9. 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

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

12. .. 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!