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 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) Year Percent Actual Projected

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 Pathways to Discovery Re-engineering the Clinical Research Enterprise Research Teams of 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 Genes Behavior Diet/Nutrition Infectious agents Environment Society ???

BenchBedsidePractice 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

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

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 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)

Roadmap Funding dollars in millions FY04FY05FY06FY07FY08FY09Total Pathways to Discovery Research Teams Clinical Research Total ,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 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

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

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

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  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

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) 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 Initiative

Protein Structure Initiative (PSI) PSI Pilot phase Nine research centers funded  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 upon completion Deposition and release of coordinates in PDB upon completion Public listing of targets and progress Public listing of targets and progress Results on PSI webpage and all center websites Results on PSI webpage and all center websites Technical workshops: protein production and crystallization; data management; target selection; comparative modeling; structural determination Technical workshops: protein production and crystallization; data management; target selection; comparative modeling; structural determination Repository for materials -- clones, reagents, samples PDB, TargetDB, PepcDB Databases: PDB, 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 PRODUCTION 4 th Generation System In use since Dec, 2000 PROTEIN PURIFICATION 3 rd Generation System In use since March, 2002 CRYSTALLIZATION 2 nd 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

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

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

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

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

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

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

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 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

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 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

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