CAN WE DEVELOP A COHERENT STRATEGIC FRAMEWORK FOR BIOMEDICAL RESEARCH?

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

Orders of magnitude more effective Expensive in financial and disability costs Understanding preclinical molecular events and ability to detect patients at risk Did not understand the molecular and cellular events that lead to disease Intervene before symptoms appear and preserve normal function for as long as possible Treat disease when symptoms appear and normal function is lost 21 st Century20 th Century Need to Transform Medical Research in the 21st Century

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

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.

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

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

Complexity of Biological Networks

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

Biological Data of the Future CurrentFuture DestructiveNon-Destructive QualitativeQuantitative Uni-DimensionalMulti-Dimensional Low Temporal Resolution High Temporal Resolution Non-localizedSpatially resolved Low data densityHigh data density Variable standardsCommon standards Non-CumulativeCumulative

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

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

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

Solving the “Puzzle” of Complex Diseases and Conditions

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

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

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

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 Vision affected by AMD Normal vision

Predict which patients need chemotherapy 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 Test tumor samples for mutations in these genes New Discoveries Make it Possible to “Personalize” Cancer Treatment Identified 16 informative genes

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

Systems biology Animal models Target ID & Validation Fundamental R & D Strong Bioethics and Privacy regulations Harmonization Harmonization of policies and regulations Training Pharmacogenetics Networks NECTAR Biomarkers Target identification and validation Predictive toxicology Iterative chemistry New Pathways to Discovery SCIENTIFIC FOCUS AREAS Research Teams of the Future Translational Centers Public Trust PracticePhases I-IIIPreclinical Screening/ Optimization BasicTranslationalClinical

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

“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

NIH Transforming medicine through discovery