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Jeremy M. BergNational Institute of General Medical Sciences
April 30, 2004
NIGMS and the NIH Roadmap for Medical Research
Challenges for NIH
Revolutionary and rapid changes in science Increasing breadth of mission and growth Complex organization with many units
(27 institutes and centers, multiple program offices, e.g., OWHR, OAR, ORD, ...)
Structured by disease, organ, life stage, disciplines Rapid convergence of science
U.S. Health Expenditures(Percentage of GDP)
18
16
14
12
101985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011
Year
Per
cen
t
ActualProjected
Imperatives for NIH
Accelerate pace of discoveries in life sciences
Translate research more rapidly from laboratories to patients and back
Explore novel approaches orders of magnitude more effective than current
Develop new strategies: NIH Roadmap
How was the Roadmap developed? Extensive consultations with stakeholders,
scientists, health care providers What are today’s scientific challenges? What are the roadblocks to progress? What do we need to do to overcome
roadblocks?
What is the NIH Roadmap? A framework of priorities the NIH as a
whole must address in order to optimize its entire research portfolio.
A vision for a more efficient, innovative and productive system of biomedical and behavioral research.
A set of initiatives that are central to extending the quality of healthy life for people in this country and around the world.
NIH Roadmap for Medical Research
New Pathwaysto Discovery
Re-engineering theClinical Research Enterprise
Research Teamsof the Future
NIH
The Biological Data of the Future Destructive Qualitative Uni-dimensional Low temporal resolution Low data density Variable standards Non cumulative
Non-destructive Quantitative Multi-dimensional and
spatially resolved High Temporal
resolution High data density Stricter standards Cumulative
Multi- and Interdisciplinary Research will be Required to Solve the “Puzzle” of Complex Diseases and Conditions
GenesBehaviorDiet/NutritionInfectious agentsEnvironment Society???
Bench Bedside Practice
Building Blocks PathwaysMolecular LibrariesBioinformatics and Computational BiologyStructural BiologyNanomedicine
TranslationalResearchInitiatives
Clinical ResearchInformatics
Integrated ResearchNetworksClinical outcomes
TrainingNational Clinical Research Associates
Interdisciplinary ResearchPioneer Award Nanomedicine
Public PrivatePartnerships
NIH Roadmap Strategy
Re-engineering the Clinical Research
Enterprise
Public-PrivatePartnerships
High-riskResearch
Interdisciplinary Research Nanomedicine
Bioinformatics and Computational Biology
StructuralBiology
Building Blocks, Biological Pathways
and Networks
Molecular Libraries
and Imaging
ImplementationImplementationGroupsGroups
New Pathways to DiscoveryResearch Teams
ClinicalEnterprise
Key elements of Roadmap funding and management All Institutes:
Participate with their scientific community in defining all components of the Roadmap
Contribute equally and proportionately Participate directly in decision making and have a direct liaison to the Roadmap
All Roadmap initiatives are offered for competition to researchers from all fields
All research communities can compete for all initiatives The peer-review process will ensure appropriate expertise
Roadmap Funding dollars in millions
New Pathwaysto Discovery
Re-engineering the Clinical Research Enterprise
Research Teamsof the Future
NIH
$64.1
$26.6 $37.6
FY 2004 Funding = $128.3 (dollars in millions)
Roadmap Fundingdollars in millions
FY04 FY05 FY06 FY07 FY08 FY09 Total
Pathways to
Discovery
64 137 169 182 209 188 948
Research
Teams
27 39 44 92 96 93 390
Clinical
Research
38 61 120 174 214 227 833
Total 128 237 332 448 520 507 2,172
To be competed for in a common pool of initiatives by all researchers from every discipline
0.34% 0.63% ~0.9%
Molecular Library and Imaging Francis Collins, NHGRI Tom Insel, NIMH Rod Pettigrew, NIBIB
Building Blocks and PathwaysFrancis Collins,NHGRI Richard Hodes, NIAT-K Li, NIAAAAllen Spiegel, NIDDK
Structural Biology Jeremy Berg, NIGMS Paul Sieving, NEI
Bioinformatics and Computational BiologyJeremy Berg, NIGMS Don Lindberg, NLM
Nanomedicine Jeffery Schloss, NHGRI Paul Sieving, NEI
NEW PATHWAYS TO DISCOVERYWorking Group and Co-Chairs
New Pathways to Discovery
Molecular Libraries and Imaging
Building Blocks, Biological Pathways and Networks
Structural Biology
Bioinformatics and Computational Biology
Nanomedicine
Three recent developments makesmall molecule/chemical genomics
initiatives feasible
HumanGenomeProject
Availability of targets
Robotic Technology
Availability of screening
Public sector screening and chemistry initiative
Modern Synthetic Chemistry
Availability of compounds
CompoundCollections
Molecular Libraries:Putting Chemistry to Work for
Medicine Six national screening centers for small
molecules Public database for “chemical genomics” Technology advances in combinatorial
chemistry, robotics, virtual screening
Collaborative Pipeline of a NIH Chemical Genomics Center
Investigator
Customized Assay
Screen
Probe picking, confirmation, secondary
screens
Probe List
Limited MedChem
Compound Repository
Cheminformatics, PubChem
(NCBI)
Assay
Peer review
Molecular Imaging Roadmap Components
Development of high resolution probes for cellular imaging RFA issued in 2004 http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-
04-001.html Development of an imaging probe database
In process, with links to PubChem Core synthesis facility to produce imaging probes
Efforts to establish an intramural facility are underway
New Pathways to Discovery
Molecular Libraries and Imaging
Building Blocks, Biological Pathways and Networks
Structural Biology
Bioinformatics and Computational Biology
Nanomedicine
Structural Biology
Initiative: Centers for Innovation in Membrane Protein Production
Applications due March 11, 2004 $5M FY2004 Roadmap funding (~2 Centers,
P50 Mechanism)
Centers for Innovation in Membrane Protein Production
Many physiologically and pharmaceutically important proteins are membrane proteins
Few membrane proteins structures known All eukaryotic membrane protein structures
determined to date have been from proteins derived from naturally rich sources
Detergents and other agents required for solubilization and crystallization
Development of methods for the production of structurally and functionally intact membrane proteins for subsequent structural studies
0
2
4
6
8
10
12
14
16
1960 1970 1980 1990 2000
nu
mb
er
of s
tru
ctu
res
year
water-soluble proteins
membrane proteins
progress in membrane protein structure determinations parallels that of water-soluble proteins with a ~25 year offset
B.W. Matthews Ann. Rev. Phys. Chem. 27, 493 (1976)
http://www.mpibp-frankfurt.pg.de/michel/public/memprotstruct.html
Courtesy of Doug Rees, Caltech
Structural Biology Roadmap Plans
Wide range of structural biology programs throughout NIH (intramural and extramural)
Synchrotron sources supported by DOE, NIH (NCRR, NCI, NIGMS), and others
NMR instrumentation supported (NCRR, NIGMS) Protein Structure Initiative-Network of Centers
devoted to structural genomics Roadmap initiatives will be used to provide
integration of these programs
Protein Structure Protein Structure
InitiativeInitiative
Protein Structure Initiative (PSI) PSI Pilot phase Nine research centers funded 2000-2001
Pilots to examine the best strategies Methodology and technology development Construction of structural genomics pipeline
and automation of all steps Increases in efficiency and success rates and
lower costs Production of unique protein structures
p
PSI Pilot Research Centers
UK
UK, Japan,Israel
PSI Goals To make the three-dimensional atomic level structures of
most proteins easily available from knowledge of their corresponding DNA sequences
Information on function Value of comparisons of protein structures Key biochemical and biophysical problems
Protein folding, prediction, folds, evolution Other benefits to biologists
Methodology and technology developments Structural biology facilities Availability of reagents and materials Experimental outcome data on protein production and
crystallization
PSI Policies Deposition and release of coordinates in PDB Deposition and release of coordinates in PDB
upon upon completioncompletion Public listing of targets and progressPublic listing of targets and progress Results on PSI webpage and all center websitesResults on PSI webpage and all center websites Technical workshops: protein production and Technical workshops: protein production and
crystallization; data management; target crystallization; data management; target selection; comparative modeling; structural selection; comparative modeling; structural determination determination
Repository for materials -- clones, reagents, samples
Databases: PDB, TargetDB, PepcDBPDB, TargetDB, PepcDB Administrative supplements to R01s for
functional studies of PSI structures
PSI technology and methodology Robotic systems for cloning, expression, purification,
characterization, crystallization, data collection, sample changers
Automated structure determination LIMS Developments: Solubility engineering, capillary
crystallization, auto-inducing media, cell-free protein production, domain parsing, protein-pair discovery, expression vectors, disorder predictions and methods, direct crystallography
Research Centers
Structures determined: 403 in first three years (doubling each year)
Unique structures: 70% for PSI (10% for PDB)
New folds: 12% for PSI (3% for PDB) Average costs per structure –
decreasing significantly (<$240K)
Andrzej Joachimiak, P50 GM062414
PROTEIN PRODUCTION4th Generation SystemIn use since Dec, 2000
PROTEIN PURIFICATION3rd Generation System
In use since March, 2002
CRYSTALLIZATION2nd Generation SystemIn use since Feb., 2001
NANOVOLUMECRYSTALLIZATIONEstablished, May 1998
IMAGING1st Generation Hardware6th Generation Software
Technology Status – Gene to Structure
HT Data Collection1st Generation System
3rd Generation Software
Ian A. Wilson, Scripps Research Institute, P50 GM062411
WR41
Structures analyzed with automated NMR analysis
software developed by NESG
C-TmZip
ER14
MMP-1
IL13
FGF-2
WR90
WR64
LC8
ER115
N-TmZip
JR19
ZR18
OP3
WR33
ZR31 ER75Z-domain
IR24 Gaetano T. Montelione, P50 GM062413
MJ0882
Sequence inference: No molecular or cellular functionStructural inference: Methyl transferaseBiochemical assay: Methyl transferease
TM841
Sequence inference: No molecular or cellular function
Structural inference: Fatty acid binding protein
Sequence inference: No molecular or cellular function Weak Ham1 homology
Structural inference: Nucleotide binding protein (weak)Biochem. and complementation assay: Nucleotide housekeeping
Samples of Structure-based discovery of function (BSGC)
MJ0577
Sequence inference: No molecular or cellular function
Structural inference: ATPase or Molecular switch
Biochemical assay: Molecular switch
Sung-Hou Kim, P50 GM062412
PSI Pilot Phase -- Lessons Learned1. Structural genomics pipelines can be constructed
and scaled-up
2. High throughput operation works for many proteins
3. Genomic approach works for structures
4. Bottlenecks remain for some proteins
5. A coordinated, 5-year target selection policy must be developed
6. Homology modeling methods need improvement
PSI-2 Large-scale Centers Goals Increase the number of sequence families that
have at least one experimental structure Increase the number of sequenced genes for
which homology models can be built Increase the biomedical significance of the
structures Requires 4-6,000 unique experimental structures
PSI-2 Production Phase (2005) Interacting network with three or four components Large-scale centers Specialized centers for technology development
for challenging proteins Disease-targeted structural genomics centers
(pending) Knowledge Base (future)
Cooperative agreements Affiliated with the NIH Structural Biology Roadmap
PSI-2 Large-scale Centers
High throughput structure output Continued technology and methodology
development High throughput operation of all pipeline
tasks Provisions for sharing facilities with the
scientific community GM-05-001
PSI-2 Specialized Centers Methodology and technology development for
challenging proteins Membrane proteins Higher eukaryote proteins, especially human Small protein complexes Other major bottlenecks to high throughput
Major impact and applicability to PSI goals Leading toward high throughput operation GM-05-002
PSI-2 Disease-targeted Structural Genomics Centers (pending) Protein structures from pathogens and from
tissues and organ systems related to disease Member of the PSI network Under consideration by the NIH Structural
Biology Roadmap
http://www.nigms.nih.gov/psi.html/
New Pathways to Discovery
Molecular Libraries and Imaging
Building Blocks, Biological Pathways and Networks
Structural Biology
Bioinformatics and Computational Biology
Nanomedicine
Bioinformatics and Computational Biology
Initiative: National Centers for Biomedical Computing
Applications received January 23, 2004 $12M FY2004 Roadmap funding (~4
Centers, U54 Mechanism)
National Centers for Biomedical Computing
Partnerships of: Computer scientists Biomedical computational scientists Experimental and clinical biomedical and behavioral
researchers Focused on software rather than hardware Each National Center to have Driving Biological
Projects Open source requirement Programs in preparation for partnerships between
individual investigators and National Centers
RESEARCH TEAMS OF THE FUTUREWorking Groups and Co-Chairs
Interdisciplinary ResearchPatricia Grady, NINR Ken Olden, NIEHSLarry Tabak, NIDCR
High-risk Research
Ellie Ehrenfeld, NIAID
Stephen Straus, NCCAM
Public-Private PartnershipsAndy von Eschenbach, NCI Richard Hodes, NIA
Multi- and Interdisciplinary Research
A
B common problem
Work on
A
B
C
A
B
Multidisciplinary
Interdisciplinary Interaction
forges new discipline
Challenges to Interdisciplinary Research
The current system of academic advancement favors the independent investigator
Most institutions house scientists in discrete departments
Interdisciplinary science requires interdisciplinary peer-review
Project management and oversight is currently performed by discrete ICs
Interdisciplinary research teams take time to assemble and require unique resources
NIH Director’s Pioneer Award
• New program to support individuals with untested, potentially groundbreaking ideas!
• Encourages innovation, risk-taking
• Totally new application and peer review process
• Expected to be highly competitive
• Expanded eligibility – (not only traditional biomedical investigators)
• Provides $500,000/year for 5 years
RE-ENGINEERING THE CLINICAL RESEARCH ENTERPRISEWorking Groups and Co-ChairsCo-Chairs
Stephen Katz, NIAMS Stephen E. Straus, NCCAM
Subgroups Harmonization of Clinical Research Regulatory Processes
Amy Patterson, OSP Integration of Clinical Research Networks, including NECTAR
Larry Friedman, NHLBIStephen Katz, NIAMS
Enhance Clinical Research Workforce Training Duane Alexander, NICHD Rob Star, NIDDK
Enabling Technologies for Improved Assessment of Clinical Outcomes Deborah Ader, NIAMSLarry Fine, OBSSRStephen Katz, NIAMS
Regional Translational Research Centers Stephen E. Straus, NCCAMSteve Zalcman, NIMH
Translational Research Service Cores Josephine Briggs, NIDDK Stephen E. Straus, NCCAM
Clinical Research: Navigating the Roadway
Clinical research impeded by multiple and variable requirements to address fundamentally the same oversight concerns
Variability among and within agencies Creates uncertainty
about how to comply
Hampers efficiency and effectiveness
The NIH Roadmap:A Work in Progress
www.nihroadmap.nih.gov
Recommended