NIGMS and the NIH Roadmap for Medical Research

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

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 Actual Projected 16 Percent 14 12 10 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 Year

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 NIH

8. 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 The Biological Data of the Future

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

11. Clinical Enterprise New Pathways to Discovery Research Teams

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

14. Roadmap Fundingdollars in millions ~0.9% 0.34% 0.63% To be competed for in a common pool of initiatives by all researchers from every discipline

15. NEW PATHWAYS TO DISCOVERY Working Group and Co-Chairs • 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

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

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

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. Probe List Assay Investigator Customized Assay Limited MedChem Compound Repository Cheminformatics, PubChem (NCBI) Collaborative Pipeline of a NIH Chemical Genomics Center Peer review Screen Probe picking, confirmation, secondary screens

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. B.W. Matthews Ann. Rev. Phys. Chem.27, 493 (1976) http://www.mpibp-frankfurt.pg.de/ michel/public/memprotstruct.html progress in membrane protein structure determinations parallels that of water-soluble proteins with a ~25 year offset 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. PSI Pilot Research Centers p 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. Ian A. Wilson, Scripps Research Institute, P50 GM062411 Technology Status – Gene to Structure CRYSTALLIZATION 2nd Generation System In use since Feb., 2001 PROTEIN PRODUCTION 4th Generation System In use since Dec, 2000 PROTEIN PURIFICATION 3rd Generation System In use since March, 2002 HT Data Collection 1st Generation System 3rd Generation Software IMAGING 1st Generation Hardware 6th Generation Software NANOVOLUME CRYSTALLIZATION Established, May 1998

35. Gaetano T. Montelione, P50 GM062413 IR24 FGF-2 JR19 OP3 LC8 WR33 Z-domain WR41 MMP-1 ZR18 ER115 N-TmZip WR64 ZR31 C-TmZip WR90 ER14 Structures analyzed with automated NMR analysis software developed by NESG IL13 ER75

36. Sung-Hou Kim, P50 GM062412 Samples of Structure-based discovery of function (BSGC) MJ0882 TM841 Sequence inference: No molecular or cellular function Structural inference: Fatty acid binding protein Sequence inference: No molecular or cellular function Structural inference: Methyl transferase Biochemical assay: Methyl transferease MJ0577 Sequence inference: No molecular or cellular function Structural inference: ATPase or Molecular switch Biochemical assay: Molecular switch Sequence inference: No molecular or cellular function Weak Ham1 homology Structural inference: Nucleotide binding protein (weak) Biochem. and complementation assay: Nucleotide housekeeping

37. PSI Pilot Phase -- Lessons Learned • Structural genomics pipelines can be constructed and scaled-up • High throughput operation works for many proteins • Genomic approach works for structures • Bottlenecks remain for some proteins • A coordinated, 5-year target selection policy must be developed • 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. 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 RESEARCH TEAMS OF THE FUTUREWorking Groups and Co-Chairs

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

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