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