CAN WE DEVELOP A COHERENT STRATEGIC FRAMEWORK FOR BIOMEDICAL RESEARCH?

1. CAN WE DEVELOP A COHERENT STRATEGIC FRAMEWORK FOR BIOMEDICAL RESEARCH?

2. GLOBAL Public Health Challenges Acute to Chronic Conditions Aging Population Health Disparities Emerging and Re-emerging infectious Diseases Emerging Non communicable diseases

3. Need to Transform Medical Research in the 21stCentury 20th Century 21st Century Treat disease when symptoms appear and normal function is lost Intervene before symptoms appear and preserve normal function for as long as possible Did not understand the molecular and cellular events that lead to disease Understanding preclinical molecular events and ability to detect patients at risk Expensive in financial and disability costs Orders of magnitude more effective

4. Fundamental Roadblocks in Research and Development Basic Research Biology Chemistry Development Ind.Discov. Target ID Target Valid. Screening Optimization Pre-clinical Clinical Examples of key roadblocks Insufficient read-out on safety and toxicology Lack of standardization and efficiency of clinical trials Validation of complex diseases Some opportunities for improvement Biomarkers, Animal models, Systems biology, Chemical genomics Biomarkers, Animal models, Data sharing Biomarkers, Clinical training, Regulatory harmonization, Informatics

5. What is the NIH Roadmap for Medical Research? • A framework of scientific priorities that 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 research into health, mechanisms of disease, and related behaviors.

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

7. Complexity of Biological Networks • Multiple levels of cross-talk between molecular pathways • Many molecular targets part of intricate signaling networks • Novel experimental and theoretical concepts needed

8. Complexity of Biological Networks

9. “All molecules are created equal, but some are more equal than others.” Animal Pharm* *Adapted from George Orwell’s Animal Farm

10. Biological Data of the Future

11. c GFP expression Combining Functional Imaging with GFP Linked Gene Expression 230 ml/gm 6.2 ml/gm.min c c 0 0 Permeability Vascular volume MatLyLu tumor (430 mm3), capillary marked by c Pre-ICMIC Program at JHU-RADIOLOGY NCI P20 CA86346

12. MOLECULAR NANOMACHINES Architecture of an 11,000 kDa Pyruvate Dehydrogenase Complex 475 Å J. Milne and S. Subramaniam, National Cancer Institute, NIH

13. High Field MRI of White Matter Tract Development in Mouse Embryos st ic White matter reconstruction studies of a mouse brain at embryonic day 16 (ex vivo)

14. Solving the “Puzzle” of Complex Diseases and Conditions

16. Obesity: A Worldwide Issue Cancer Athero- scleroris Hyper- tension Gall- bladder Disease Obesity Health Risks Kidney Failure Heart Failure Stroke Diabetes

17. New Discoveries in Obesity Research Using RNA Interference (RNAi) Thin Worm Source: Ashrafi et. al., Nature, Vol. 421, pp. 268-272. 305 genes 112 genes Obese Worm Normal Worm

18. Human Genome Project and HapMap Are Complete: Where Do We Go From Here? • Plummeting cost of DNA sequencing • New discoveries accelerating revolution of the practice of medicine • Genes, Environment, and Health Initiative • Identify roots of 10 most common diseases • Devise new ways of monitoring personal environmental exposures

19. Advances in Age-related Macular Degeneration (AMD) • AMD is the leading cause of blindness in people over age 60 • Variations in certain genes involved in inflammation can predict the risk of developing AMD • 56 % of the unaffected individuals had a variant that conferred protection to AMD • 74 % of those with AMD had no protective variants Normal vision Vision affected by AMD

20. New Discoveries Make it Possible to “Personalize” Cancer Treatment Impact: • 100,000 women each year can make a more informed choice • 70,000 women do not have to undergo chemotherapy • Reduces routine cost of treating these patients • For each patient year of life gained, we save ~$8,000 Identified 16 informative genes Test tumor samples for mutations in these genes Predict which patients need chemotherapy

21. Pharmaco-Genomics: Managing Human Variability • Pharmaco-Genetics Research Network (PGRN) • National collaboration of scientists studying the effect of genes on people's responses to a wide variety of medicines • Pharmaco-Genetics & Pharmaco-Genomics Knowedge Database (PharmGKB) • Integrated knowledge base for pharmacogenetics linking phenotypes and genotypes http://www.nigms.nih.gov/Initiatives

22. Basic Translational Clinical SCIENTIFIC FOCUS AREAS R & D Fundamental Target ID & Validation Screening/Optimization Preclinical Phases I-III Practice New Pathways to Discovery Systems biology Iterative chemistry Translational Centers Predictive toxicology Animal models Target identification and validation Biomarkers Networks NECTAR Pharmacogenetics Training ResearchTeams of the Future Harmonization of policies and regulations Harmonization Public Trust Strong Bioethics and Privacy regulations

23. The Future Paradigm: Transform Medicine from Curative to Preemptive Predictive Personalized Preemptive NIH research initiatives and programs are aiming to transform the practice of medicine as we know it.

24. “Meeting World Health Problems: The Need for Sound Program Planning” With the true spirit of cooperation, with the basic understanding of needs, and with the efforts of enlightened groups everywhere, we can push forward to new frontiers of world health and well-being. Dr. Joseph W. Mountin (1952) Founder of CDC

25. Transforming medicine through discovery NIH