National Center forResearch Resources NATIONAL INSTITUTES OF HEALTH T r a n s l a t I n g r e s e a r c h f r o m b a s i c d i s c o v e r y t o i m p r o v e d p a t I e n t c a r e

Connecting the Nation's Researchers, Patients and Communities: Next Steps

Biological and Environmental Research Advisory Committee Department of EnergySeptember 1, 2009

Barbara Alving, M.D., M.A.C.P.Director

National Center for Research Resourceswww.ncrr.nih.gov

NCRR

ClinicalClinical

Community

National Center for Research ResourcesTranslating research from basic discovery to improved patient care

Improved patient

care

Pre-clinical

animal model resources

technology & informatics advances

clinical research support

research capacity

& training

community engagement

science education

NCRR

NCRR Div Clinical Research: Clinical and Translational Science Awards (will include 60 academic health centers working as a consortium and as a cooperative agreement with NIH)

To ensure new discoveries lead to To ensure new discoveries lead to improved public health, clinical science improved public health, clinical science must evolve to better:must evolve to better:

Implement biomedical discoveriesDevelop, test, and bring new prevention strategies into medical practice more rapidlyCatalyze change - lower barriers between disciplinesEncourage creative and innovative approaches.

www.CTSAWeb.org

NCRR

Five CTSA Strategic Goals

To enhance:

National Clinical Research Capability and Efficiency

Training and Career Development of Clinical and Translational Investigators

Consortium-Wide Collaborations

Health of Our Communities and the Nation

T1 Translational Research

NCRR

NCRR Division of Biomedical TechnologyTranslating discoveries into tools for biomedical research

Biomedical Technology Research Centers (BTRC) Shared Instrumentation High-End Instrumentation Investigator-Initiated Research Grants (R01, R21) Biomedical Informatics Research Network (BIRN) Small Business Opportunities (SBIR/STTR)

Technology Discovery

Advances in technology open new areas of inquiry

Biomedical discoveries create a need for new technologies

NCRR

Shared and High-End Instrumentation Program (S10): Overview

Unique and critical NIH mechanisms

Provide funding in cost-range from $100K to $2.0M• SIG Program (funding range $100k to

$500K) • HEI Program (funding range $750k to

$2.0M)

Equipment which is too costly to obtain with regular NIH research grants

Highly cost-effective mechanisms

Instruments placed in core facilities

Shared by an average of 8-10 grantees

NCRR

Collaboration between groups with different expertise and resources (technical, scientific, social and political)

Shared infrastructure to support collaboration (designed to be extensible to other biomedical communities)

Open access and dissemination of data and tools (i.e. Open Source)

Bringing transparent GRID Computing to Biomedical Research

Biomedical Informatics Research Network (BIRN)A shared biomedical IT infrastructure

NCRR

BTRCs: 52 Nationally Accessible Engines for Translational Research

IndividualInvestigators

NIH Programs

CTSAConsortium

IndividualInvestigators

NIH Programs

CTSAConsortium

Technology Discovery

• Enabling technologies

• Expertise

• Computing

Each BTRC is accessible to NIH-supported investigatorsand programs from across the nation.

BTRCs

NCRR

52 Unique Centers classified in 5 Broad Areas Scope: from basic discovery to clinical research Scale: from molecule to organism

Technology forStructural Biology

Synchrotron x-ray technologies

Electron microscopy

Magnetic resonance

Technology forSystems Biology

Mass spectrometry

Proteomics

Glycomics & glycotechnology

Flow cytometry

Optics & LaserTechnology

Microscopy

Fluorescence spectroscopy

In Vivo diagnosis

Imaging Technology

• MRI

• Image-guided therapy

• PET

• CAT

• Ultrasound

Informatics Resources

Genetics

Modeling of complex systems

Molecular dynamics

Visualization

Imaging informatics

Biomedical Technology Research Centers

NCRR

Interagency Collaboration for Development of Biomedical Technology

NCRR interacts with DOE through our Biomedical TechnologyResearch Centers (BTRC) program:

BTRC program

BTRCs located at

DOE National Laboratories

• Systems Biology BTRCs

• Structural Biology BTRCs3 jointly supported with DOE/BER

Technology forStructural Biology

Synchrotron x-ray technologies

Electron microscopy

Magnetic resonance

Technology forSystems Biology

Mass spectrometry

Proteomics

Glycomics & glycotechnology

Flow cytometry

NCRR

NCRR Leverages Resources at DOE National Laboratories to support NIH research

NCRR Division of Biomedical Technology Funds Biomedical Technology Research Centers (BTRC) to

translate advances in physical sciences into tools for biomedical research

DOE National Labs Facilitate R&D that is expensive and complex Presents opportunities for NCRR to leverage unique

expertise and infrastructure in the physical sciences

Personnel Instrumentation development Instrumentation access

NCRR Enables $200M of NIH-funded research by supporting nine BTRCs for $20M at seven National labs through

NCRR

Technology forSystems Biology

Mass spectrometry

Proteomics

Glycomics & glycotechnology

Flow cytometry

Systems Biology Biomedical Technology Research Centers at National Laboratories

National Flow Cytometry ResourceLos Alamos National Laboratory

National Resource for Biomedical Accelerator Mass Spectrometry Lawrence Livermore National Laboratory

Proteomics Research Resource for Integrative Biology Pacific Northwest National Laboratory

National Flow Cytometry ResourceLos Alamos National Laboratory

National Resource for Biomedical Accelerator Mass Spectrometry Lawrence Livermore National Laboratory

Proteomics Research Resource for Integrative Biology Pacific Northwest National Laboratory

NCRR

Development of new instrumentation and applications

–Access to unique LANL infrastructure

–Access to scientists with unique technical and mathematical capabilities

Provides access to state-of-art flow cytometry instrumentation

Provides training for the biomedical research community

New technology: flow cytometry based on sound waves

Training: “build a cytometer” course

National Flow Cytometry Resourceat Los Alamos National Laboratory (LANL)

NCRR

A simple, low cost, compact data acquisition system for compact, portable flow cytometersNational Flow Cytometry Resource, LANL

Developed a data system for use in low cost and/or portable instruments, based on a commercial electronics board.

NFCR makes these systems available to collaborators

Relatively low cost ($500) Technology licensed by

Acoustic Cytometry Systems, which has since been acquired by Invitrogen

NCRR

National Resource for Biomedical Accelerator Mass Spectrometry at Lawrence Livermore National Laboratory (LLNL)

Exquisitely sensitive technology for metabolic studies

Allows safe microdosing with toxic or experimental molecules in humans

14C-AMS has allowed critical questions to be answered in human nutrition, metabolism, pharmacology, and comparative medicine.

LLNL Center for Accelerator

Mass Spectrometry (CAMS)

is the foundation for the BioAMS BTRC•Expertise•Engineering•Infrastructure

1 Megavolt Biomedical AMS Instrument

10 Megavolt Instrument

NCRR

Highly toxic chemotherapy is often ineffective (response rate for non-small cell lung cancer <30%, bladder cancer 50%)

Identify chemoresistance by measuring chemotherapy-induced cell damage

Using ultrasensitive AMS, chemoresistance and the underlying mechanisms can be identified before patients receive toxic chemotherapy

Translating AMS: Identification of chemoresistance for personalized chemotherapyNational Resource for Biomedical Accelerator Mass Spectrometry, LLNL

Example: 14C-labeled platinum derivatives, the most commonly used chemotherapeutic drugs.

amol

14C/

mg

of D

NA

0

Time (h)0 5025

10

testicular cancer cells (sensitive to drug)

Breast and bladder cancer cells (resistant to drug)

Oxaliplatin-induced DNA adducts in cell lines

NCRR

Proteomics Research Resource Center for Integrative Biology at Pacific Northwest National Laboratory (PNNL)

Ultra-sensitive & high throughput proteomics technologies and supporting informatics capabilities

Leverages a large base of DOE instrumentation, infra-structure, and EMSL DOE User Facility investments

Growing number of clinical/translational proteomics applications (e.g. partner with UW and OHSU CTSAs)

Next Generation Proteomics Platform: Prototype LC-IMS-MS

22

27

32

37

42

1400

100

m/z

41

21

26

31

36

1400

100

m/z

0 3 6 9 12

15Time (minutes)

Inte

nsit

y

24

29

34

39

44

1400

100

m/z

IMS Drift TimeIMS Drift Time

IMS Drift TimeIMS Drift Time

IMS Drift TimeIMS Drift Time

IMS Drift TimeIMS Drift Time

NCRR

“Spatial mapping of protein abundances in the mouse brain by voxelation integrated with high-throughput liquid chromatography-mass spectrometry.” V.A. Petyuk, W.-J. Qian, M.H. Chin, H. Wang, E.A. Livesay, M.E. Monroe, J.N. Adkins, N. Jaitly, D.J. Anderson, D.G. Camp II, D.J. Smith, & R.D. Smith. Genome Research 17, 328-336 (2007).

3-D mapping of proteins in mouse brain enabled by voxelation and quantitative proteomicsProteomics Research Resource Center for Integrative Biology, PNNL

Analysis of one voxelated mouse brain at 1 mm resolution requires proteome analysis of ~700 tissue samples

Quantitation and spatial distributions obtained for >1000 distinct proteins

Collaboration with Prof. Desmond Smith; UCLACollaboration with Prof. Desmond Smith; UCLA

NCRR

Collaboration with the “Inflammation and Host Response to Injury” Glue Grant (NIGMS)

Proteomics analysis: 100 trauma subjects, over 7 time points (12 hour intervals) Monocyte and T-cell Proteins

Proteomics analysis Proteomics Research Resource Center for Integrative Biology, PNNL

Patient classification based on 24 proteins observed in T-cells

High throughput quantitative proteomics

Longitudinal analysis of T-cell and monocyte samples from severe trauma patients

Revealed 24 proteins predictive of bad outcomes (multiple organ failure)

Superior to microarray transcriptomic studies for same samples

Extending to larger patient population

Pathway analysis to establish biological context

Good outcome Bad outcome

NCRR

Technology forStructural Biology

Synchrotron x-ray technologies

Electron microscopy

Magnetic resonance

Structural Biology Biomedical Technology Research Centers at National Laboratories

BioCARS: A Synchrotron Structural Biology ResourceU of Chicago, APS, Argonne National Laboratory

Biophysics Collaborative Access Team Illinois Institute of Tech, APS, Argonne National Laboratory

Undulator Resource for Structural BiologyCornell U, APS, Argonne National Laboratory

Macromolecular Crystallography at the National Synchrotron Light Source Brookhaven National Laboratory, NSLS

Synchrotron Radiation Structural Biology ResourceStanford, SSRL, SLAC National Accelerator Laboratory

National Center for X-Ray TomographyUCSF, Lawrence Berkeley National Laboratory

BioCARS: A Synchrotron Structural Biology ResourceU of Chicago, APS, Argonne National Laboratory

Biophysics Collaborative Access Team Illinois Institute of Tech, APS, Argonne National Laboratory

Undulator Resource for Structural BiologyCornell U, APS, Argonne National Laboratory

Macromolecular Crystallography at the National Synchrotron Light Source Brookhaven National Laboratory, NSLS

Synchrotron Radiation Structural Biology ResourceStanford, SSRL, SLAC National Accelerator Laboratory

National Center for X-Ray TomographyUCSF, Lawrence Berkeley National Laboratory

NCRR

Synchrotron BTRCs Leverage DOE Facilities Develop New TechnologiesProvide Access for Structural and Cellular Biology

MT

WY

ID

WA

OR

NV

UTCA

AZ

ND

SD

NE

CO

NM

TX

OK

KS

AR

LA

MO

IA

MN

WI

IL

IN

KY

TN

MS AL GA

FL

SC

NC

VAWV

OH

MI

NY

PA

MDDE

NJ

CTRI

MA

ME

VTNH

DC

Brookhaven

U. Chicago, APS

IIT, APS

Stanford Univ

Cornell U., APS

UCSF, LBNL

Over 40% of all research done at synchrotrons is in the life sciences

Keith Hodgson

Steve Ealick

Bob Sweet

Keith Moffat

Carolyn Larabell

Tom Irving

NCRR

Stanford Synchrotron Radiation Laboratoryat SLAC National Accelerator Laboratory

Cooperatively funded by NCRR and DOE/BER Integrates 3 structural biology technology

development areas to serve the needs of the biomedical and environmental science communities

• Macromolecular crystallography

• X-ray absorption spectroscopy

• Small angle x-ray scattering

Services feature robotics and remote data collection

NCRR

• Research area of R. Kornberg; most of the synchrotron work was performed at SSRL and strongly enabled by the robotics

• Transcription is the process by which DNA is “read” and converted into a message that directs protein synthesis with extremely high fidelity

• Synchrotron-enabled studies have provided molecular-level insight into the function of this molecular machine

• This structural information now serves to guide the development of new antibiotics

DNA Transcription and Regulation

2006 Chemistry Nobel Prize - R.

Kornberg

NCRR

National Center for X-ray Tomographyat the Lawrence Berkeley National Laboratory

New technology to obtain 3D views of whole, hydrated cells in their native state at better than 50 nm resolution

Bridges the mesoscale resolution “gap”,The middle area between light (200 nm) and electron microscopy (3 Ångstroms)

Can locate position of tagged molecules with respect to unstained cell structures

Imaging RoomSoft X-rays

(517 eV)

Microscope

ParasiteNucleusHemoglobinMaurer’s cleftsDigestive vac.

Malaria-infected RBC

Malaria-infected RBC

NCRR

NCRR and BER jointly fund beamlines for Life Sciences (biomedical and biological) research at the existing National Synchrotron Light Source at Brookhaven National Laboratory

NSLS-II will replace NSLS, becoming operational in 2015

NIH will construct new beamlines for life sciences that will benefit both NIH and DOE/BER Researchers

NCRR looks forward to continued cooperative funding of the life sciences programs at NSLS-II with DOE/BER

Life Sciences Beamlines at NSLS-IIat Brookhaven National Laboratory

NSLS 1984-2012

NSLS-II, 2015-

NCRR

NCRR and DOE work cooperatively to support Life Sciences Research

DOE– National Labs facilitate R&D that is expensive and complex– unique expertise and infrastructure in the physical sciences

NCRR Division of Biomedical Technology– translates advances in physical sciences into tools for biomedical

research

DOE / NCRR Interaction– 9 BTRCs at 7 National Labs

– Collaborations with BER to advance unique technologies for biological and environmental research

– Enable $200M of NIH-funded research

NCRR

American Recovery and Reinvestment Act (ARRA) Budget Components

Financial & Employment Reporting

Extramural Scientific Research

(All ICs, OD)

ExtramuralConstruction

(NCRR)

Intramural Repair &

Improvement & Constr.

(B&F)

SIG & Other Cap

Equip (NCRR)

$8.2 B $1.0 B $0.5 B $0.3 B

ARRA appropriated $10 Billion (B) directly to NIHOther HHS (AHRQ) to also transfer

$0.4 B

Comparative Effectiveness

Research(OD)

NCRR

NCRR Funding through ARRA

$1.0 Billion for construction, repair and renovation

– RFA for Extramural Research Facilities Improvement Program (C06)

– RFA for Core Facility Renovation, Repair and Improvement (G20)

$300 Million for shared instrumentation and other capital research equipment

– RFA for Shared Instrumentation Grant (SIG)

– RFA for High End Instrumentation (HEI)

$310 Million for scientific research

– Supplements to existing resource programs in NCRR