PPT

1. Jeremy M. Berg
National Institute of General Medical Sciences
April 30, 2004
NIGMS and the NIH
Roadmap for Medical
Research

2. 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

3. U.S. Health Expenditures
(Percentage of GDP)
18
16
14
12
10
1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011
Year
Percent
Actual
Projected

4. 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

5. 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?

6. 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.

7. NIH Roadmap for Medical Research
New Pathways
to Discovery
Re-engineering the
Clinical Research Enterprise
Research Teams
of the Future
NIH

8. 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

9. Multi- and Interdisciplinary Research will be
Required to Solve the “Puzzle” of Complex
Diseases and Conditions
Genes
Behavior
Diet/Nutrition
Infectious agents
Environment
Society
???

10. Bench Bedside Practice
Building Blocks
Pathways
Molecular Libraries
Bioinformatics and
Computational
Biology
Structural Biology
Nanomedicine
Translational
Research
Initiatives
Clinical
Research
Informatics
Integrated Research
Networks
Clinical outcomes
Training
National Clinical Research
Associates
Interdisciplinary Research
Pioneer Award
Nanomedicine
Public Private
Partnerships
NIH Roadmap Strategy

11. Re-engineering the
Clinical Research
Enterprise
Public-Private
Partnerships
High-risk
Research
Interdisciplinary
Research Nanomedicine
Bioinformatics and
Computational Biology
Structural
Biology
Building Blocks,
Biological Pathways
and Networks
Molecular
Libraries
and Imaging
Implementation
Groups
New Pathways
to Discovery
Research Teams
Clinical
Enterprise

12. 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

13. Roadmap Funding
dollars in millions
New Pathways
to Discovery
Re-engineering the Clinical
Research Enterprise
Research Teams
of the Future
NIH
$64.1
$26.6 $37.6
FY 2004 Funding = $128.3 (dollars in millions)

14. Roadmap Funding
dollars 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%

15.  Molecular Library and Imaging
Francis Collins, NHGRI
Tom Insel, NIMH
Rod Pettigrew, NIBIB
 Building Blocks and Pathways
Francis Collins,NHGRI
Richard Hodes, NIA
T-K Li, NIAAA
Allen Spiegel, NIDDK
 Structural Biology
Jeremy Berg, NIGMS
Paul Sieving, NEI
 Bioinformatics and Computational Biology
Jeremy Berg, NIGMS
Don Lindberg, NLM
 Nanomedicine
Jeffery Schloss, NHGRI
Paul Sieving, NEI
NEW PATHWAYS TO DISCOVERY
Working Group and Co-Chairs

16. New Pathways to Discovery
 Molecular Libraries and Imaging
 Building Blocks, Biological Pathways and Networks
 Structural Biology
 Bioinformatics and Computational Biology
 Nanomedicine

17. Three recent developments make
small molecule/chemical genomics
initiatives feasible
Human
Genome
Project
Availability of
targets
Robotic
Technology
Availability of
screening
Public sector screening
and chemistry initiative
Modern
Synthetic
Chemistry
Availability of
compounds
Compound
Collections

18. 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

19. 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

20. 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

21. New Pathways to Discovery
 Molecular Libraries and Imaging
 Building Blocks, Biological Pathways and Networks
 Structural Biology
 Bioinformatics and Computational Biology
 Nanomedicine

22. Structural Biology
 Initiative: Centers for Innovation in
Membrane Protein Production
 Applications due March 11, 2004
 $5M FY2004 Roadmap funding (~2 Centers,
P50 Mechanism)

23. 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

24.  









  










0
2
4
6
8
10
12
14
16
1960 1970 1980 1990 2000
number
of
structures
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

25. 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

26. Protein Structure
Initiative

27. 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

28. p
PSI Pilot Research Centers
UK
UK, Japan,
Israel

29. 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

30. PSI Policies
 Deposition and release of coordinates in PDB
upon completion
 Public listing of targets and progress
 Results on PSI webpage and all center websites
 Technical workshops: protein production and
crystallization; data management; target
selection; comparative modeling; structural
determination
 Repository for materials -- clones, reagents,
samples
 Databases: PDB, TargetDB, PepcDB
 Administrative supplements to R01s for
functional studies of PSI structures

31. 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

32. 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)

33. Andrzej Joachimiak, P50 GM062414

34. PROTEIN PRODUCTION
4th Generation System
In use since Dec, 2000
PROTEIN PURIFICATION
3rd Generation System
In use since March, 2002
CRYSTALLIZATION
2nd Generation System
In use since Feb., 2001
NANOVOLUME
CRYSTALLIZATION
Established, May 1998
IMAGING
1st Generation Hardware
6th Generation Software
Technology Status – Gene to Structure
HT Data Collection
1st Generation System
3rd Generation Software
Ian A. Wilson, Scripps Research Institute, P50 GM062411

35. 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 ER75
Z-domain
IR24 Gaetano T. Montelione, P50 GM062413

36. MJ0882
Sequence inference: No molecular or cellular function
Structural inference: Methyl transferase
Biochemical 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

37. PSI Pilot Phase -- Lessons Learned
1. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. http://www.nigms.nih.gov/psi.html/

44. New Pathways to Discovery
 Molecular Libraries and Imaging
 Building Blocks, Biological Pathways and Networks
 Structural Biology
 Bioinformatics and Computational Biology
 Nanomedicine

45. Bioinformatics and Computational
Biology
 Initiative: National Centers for Biomedical
Computing
 Applications received January 23, 2004
 $12M FY2004 Roadmap funding (~4
Centers, U54 Mechanism)

46. 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

47. RESEARCH TEAMS OF THE FUTURE
Working Groups and Co-Chairs
 Interdisciplinary Research
Patricia Grady, NINR
Ken Olden, NIEHS
Larry Tabak, NIDCR
 High-risk Research
Ellie Ehrenfeld, NIAID
Stephen Straus, NCCAM
 Public-Private Partnerships
Andy von Eschenbach, NCI
Richard Hodes, NIA

48. Multi- and Interdisciplinary Research
A
B
common problem
Work on
A
B
C
A
B
Multidisciplinary
Interdisciplinary
Interaction
forges new discipline

49. 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

50. 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

51. RE-ENGINEERING THE CLINICAL
RESEARCH ENTERPRISE
Working Groups and Co-Chairs
Co-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, NHLBI
Stephen Katz, NIAMS
 Enhance Clinical Research Workforce Training
Duane Alexander, NICHD
Rob Star, NIDDK
 Enabling Technologies for Improved Assessment of Clinical Outcomes
Deborah Ader, NIAMS
Larry Fine, OBSSR
Stephen Katz, NIAMS
 Regional Translational Research Centers
Stephen E. Straus, NCCAM
Steve Zalcman, NIMH
 Translational Research Service Cores
Josephine Briggs, NIDDK
Stephen E. Straus, NCCAM

52. 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

53. The NIH Roadmap:
A Work in Progress

54. www.nihroadmap.nih.gov