Jeremy M. Berg
National 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 organ...
U.S. Health Expenditures
(Percentage of GDP)
18
16
14
12
10
1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 20...
Imperatives for NIH
 Accelerate pace of discoveries in life
sciences
 Translate research more rapidly from
laboratories ...
How was the Roadmap developed?
 Extensive consultations with stakeholders,
scientists, health care providers
 What are t...
What is the NIH Roadmap?
 A framework of priorities the NIH as a
whole must address in order to optimize its
entire resea...
NIH Roadmap for Medical Research
New Pathways
to Discovery
Re-engineering the
Clinical Research Enterprise
Research Teams
...
The Biological Data of the Future
 Destructive
 Qualitative
 Uni-dimensional
 Low temporal resolution
 Low data densi...
Multi- and Interdisciplinary Research will be
Required to Solve the “Puzzle” of Complex
Diseases and Conditions
Genes
Beha...
Bench Bedside Practice
Building Blocks
Pathways
Molecular Libraries
Bioinformatics and
Computational
Biology
Structural Bi...
Re-engineering the
Clinical Research
Enterprise
Public-Private
Partnerships
High-risk
Research
Interdisciplinary
Research ...
Key elements of Roadmap funding and
management
 All Institutes:
 Participate with their scientific community in defining...
Roadmap Funding
dollars in millions
New Pathways
to Discovery
Re-engineering the Clinical
Research Enterprise
Research Tea...
Roadmap Funding
dollars in millions
FY04 FY05 FY06 FY07 FY08 FY09 Total
Pathways to
Discovery
64 137 169 182 209 188 948
R...
 Molecular Library and Imaging
Francis Collins, NHGRI
Tom Insel, NIMH
Rod Pettigrew, NIBIB
 Building Blocks and Pathways...
New Pathways to Discovery 
 Molecular Libraries and Imaging
 Building Blocks, Biological Pathways and Networks
 Structu...
Three recent developments make
small molecule/chemical genomics
initiatives feasible
Human
Genome
Project
Availability of
...
Molecular Libraries:
Putting Chemistry to Work for
Medicine
 Six national screening centers for small
molecules
 Public ...
Collaborative Pipeline of a
NIH Chemical Genomics Center
Investigator
Customized
Assay
Screen
Probe picking, confirmation,...
Molecular Imaging Roadmap
Components
 Development of high resolution probes for cellular
imaging
 RFA issued in 2004
 h...
New Pathways to Discovery 
 Molecular Libraries and Imaging
 Building Blocks, Biological Pathways and Networks
 Structu...
Structural Biology
 Initiative: Centers for Innovation in
Membrane Protein Production
 Applications due March 11, 2004
...
Centers for Innovation in Membrane
Protein Production
 Many physiologically and pharmaceutically
important proteins are m...
0
2
4
6
8
10
12
14
16
1960 1970 1980 1990 2000
numberofstructures
year
water-soluble proteins
membrane proteins
progress i...
Structural Biology Roadmap Plans
 Wide range of structural biology programs
throughout NIH (intramural and extramural)
 ...
Protein StructureProtein Structure
InitiativeInitiative
Protein Structure Initiative (PSI)
PSI Pilot phase
 Nine research centers funded 2000-2001
 Pilots to examine the best s...
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 thei...
PSI Policies
 Deposition and release of coordinates in PDBDeposition and release of coordinates in PDB
uponupon completio...
PSI technology and methodology
 Robotic systems for cloning, expression, purification,
characterization, crystallization,...
Research Centers
 Structures determined: 403 in first three
years (doubling each year)
 Unique structures: 70% for PSI (...
Andrzej Joachimiak, P50 GM062414
PROTEIN PRODUCTION
4th
Generation System
In use since Dec, 2000
PROTEIN PURIFICATION
3rd
Generation System
In use since Ma...
WR41
Structures analyzed with
automated NMR analysis
software developed by NESG
C-TmZip
ER14
MMP-1
IL13
FGF-2
WR90
WR64
LC...
MJ0882
Sequence inference: No molecular or cellular function
Structural inference: Methyl transferase
Biochemical assay: M...
PSI Pilot Phase -- Lessons Learned
1. Structural genomics pipelines can be constructed
and scaled-up
2. High throughput op...
PSI-2 Large-scale Centers Goals
 Increase the number of sequence families that
have at least one experimental structure
...
PSI-2 Production Phase (2005)
 Interacting network with three or four components
 Large-scale centers
 Specialized cent...
PSI-2 Large-scale Centers
 High throughput structure output
 Continued technology and methodology
development
 High thr...
PSI-2 Specialized Centers
 Methodology and technology development for
challenging proteins
 Membrane proteins
 Higher e...
PSI-2 Disease-targeted Structural
Genomics Centers (pending)
 Protein structures from pathogens and from
tissues and orga...
http://www.nigms.nih.gov/psi.html/
New Pathways to Discovery 
 Molecular Libraries and Imaging
 Building Blocks, Biological Pathways and Networks
 Structu...
Bioinformatics and Computational
Biology
 Initiative: National Centers for Biomedical
Computing
 Applications received J...
National Centers for Biomedical
Computing Partnerships of:
 Computer scientists
 Biomedical computational scientists
 ...
RESEARCH TEAMS OF THE FUTURE
Working Groups and Co-Chairs
 Interdisciplinary Research
Patricia Grady, NINR
Ken Olden, NIE...
Multi- and Interdisciplinary Research
A
B
common problem
Work on
A
B
C
A
B
Multidisciplinary
Interdisciplinary
Interaction...
Challenges to Interdisciplinary Research
 The current system of academic advancement favors
the independent investigator
...
NIH Director’s Pioneer Award
• New program to support individuals with untested,
potentially groundbreaking ideas!
• Encou...
RE-ENGINEERING THE CLINICAL
RESEARCH ENTERPRISE
Working Groups and Co-ChairsCo-Chairs
Stephen Katz, NIAMS
Stephen E. Strau...
Clinical Research:
Navigating the Roadway
 Clinical research impeded by
multiple and variable
requirements to address
fun...
The NIH Roadmap:
A Work in Progress
www.nihroadmap.nih.gov
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Major Trends in Biomedical Research

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  • <number>
  • <number>
    This slide summarized the protein structures have analyzed
    By the software AutoStructure. Most are NESG protein
    Targets, but also included among these are nonNESG proteins
    Which have been used for developing or validating the software.
  • Major Trends in Biomedical Research

    1. 1. Jeremy M. Berg National Institute of General Medical Sciences April 30, 2004 NIGMS and the NIH Roadmap for Medical Research
    2. 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. 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. 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. 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. 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. 7. NIH Roadmap for Medical Research New Pathways to Discovery Re-engineering the Clinical Research Enterprise Research Teams of the Future NIH
    8. 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. 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. 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. 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 ImplementationImplementation GroupsGroups New Pathways to DiscoveryResearch Teams Clinical Enterprise
    12. 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. 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. 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. 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. 16. New Pathways to Discovery   Molecular Libraries and Imaging  Building Blocks, Biological Pathways and Networks  Structural Biology  Bioinformatics and Computational Biology  Nanomedicine
    17. 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. 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. 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. 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. 21. New Pathways to Discovery   Molecular Libraries and Imaging  Building Blocks, Biological Pathways and Networks  Structural Biology  Bioinformatics and Computational Biology  Nanomedicine
    22. 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. 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. 24. 0 2 4 6 8 10 12 14 16 1960 1970 1980 1990 2000 numberofstructures 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. 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. 26. Protein StructureProtein Structure InitiativeInitiative
    27. 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. 28. p PSI Pilot Research Centers UK UK, Japan, Israel
    29. 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. 30. PSI Policies  Deposition and release of coordinates in PDBDeposition and release of coordinates in PDB uponupon 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 andTechnical workshops: protein production and crystallization; data management; targetcrystallization; data management; target selection; comparative modeling; structuralselection; comparative modeling; structural determinationdetermination  Repository for materials -- clones, reagents, samples  Databases: PDB, TargetDB, PepcDBPDB, TargetDB, PepcDB  Administrative supplements to R01s for functional studies of PSI structures
    31. 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. 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. 33. Andrzej Joachimiak, P50 GM062414
    34. 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. 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. 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: Nucleotidehousekeeping 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. 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. 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. 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. 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. 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. 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. 43. http://www.nigms.nih.gov/psi.html/
    44. 44. New Pathways to Discovery   Molecular Libraries and Imaging  Building Blocks, Biological Pathways and Networks  Structural Biology  Bioinformatics and Computational Biology  Nanomedicine
    45. 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. 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. 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. 48. Multi- and Interdisciplinary Research A B common problem Work on A B C A B Multidisciplinary Interdisciplinary Interaction forges new discipline
    49. 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. 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. 51. RE-ENGINEERING THE CLINICAL RESEARCH ENTERPRISE Working 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, 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. 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. 53. The NIH Roadmap: A Work in Progress
    54. 54. www.nihroadmap.nih.gov

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