GRAND CHALLENGES AND GREAT OPPORTUNITIES FOR THE PUBLIC HEALTH SCIENCES and SCHOOLS OF PUBLIC HEALTH

1. GRAND CHALLENGES AND GREAT OPPORTUNITIES FOR THE PUBLIC HEALTH SCIENCES and SCHOOLS OF PUBLIC HEALTH University of Pittsburgh GSPH Retreat, 15 March, 2004 Gilbert S. Omenn, MD, PhD University of Michigan

2. GRAND CHALLENGES Public Health Genetics Environmental Health Risk Assessment & Risk Management Affordable Quality Health Care in the U.S., and globally Engage the full range of the public health disciplines in academe and in practice

3. GRAND CHALLENGE #1: Apply all of the public health sciences to the interpretation of variation in the genome in full behavioral and environmental context

4. Our Genetic Future “Mapping the human genetic terrain may rank with the great expeditions of Lewis and Clark, Sir Edmund Hillary, and the Apollo Program.” --Francis Collins, Director National Human Genome Research Institute, 1999 Next: -- Understand the dynamic proteomic compartments -- Elucidate genetic, environmental, and behavioral interactions

5. APRIL 14, 2003:THE 50th ANNIVERSARY OF THEPUBLICATION OF THE WATSON-CRICK ARTICLE ON THE DOUBLE-HELIX STRUCTURE OF DNA

6. IT’S A NEW WORLD New Biology---New Technology Genome Expression Microarrays Comparative Genomics Proteomics Bioinformatics & Computational Biology • Evidence-Based Medicine: • “What were you doing up to now?!” • Predictive, personalized, preventive • healthcare and community health services

7. DEFINITIONS • Genetics is the scientific study of genes and their roles in health and disease, physiology, and the evolution of human development. • Genomics is the study of the sequence and functioning of the human genome---all the genetic material, the complete inheritance of a particular individual. Genomics is a modern subset of the broader field of genetics, made feasible by remarkable advances in molecular biology, biotechnology, and computational sciences.

8. Proteins are the action molecules of the cell and the leading candidates for biomarkers—in tissues and in the blood. • The Genome is a blueprint, a parts list, of genes coding for proteins. • Proteomics is the global analysis of proteins in cells or body fluids. • Techniques for global analysis of proteins are advancing rapidly, especially for discovery of biomarkers for diagnosis, treatment, and prevention.

9. Protein DNA

10. PROTEOME: GENE PRODUCTS • Highly dynamic compartment: ideal for biomarkers • Regulated at the transcriptional and post- transcriptional levels, compartmentalized in cells • Numerous post-translational modifications: glycoproteins, phosphoproteins… • Protein subsets: secreted proteins, membrane proteins, antigenic proteins, auto-antibodies

11. COMING TECHNOLOGY • Nanotechnology for sensors • Microfluidics for miniaturization and automation--DNA sequencing, protein analyses --Leroy Hood: “In 10 years, we will be able to sequence an individual’s genome for less than $1000 in a fraction of a day.” • Microarrays for proteins (e.g., tumor antigens and autoantibodies) • Nanocantilevers for detecting protein-protein interactions, down to a single cell

12. PUBLIC HEALTH AND GENETICS • Epi and Biostat: Bring together the digital code of inherited information with “environmental cues” from nutrition, metabolism, lifestyle behaviors, pharmaceuticals/nutraceuticals, and chemical, physical, and infectious exposures • The result is “systems biology” at many levels from proteins to eco-systems…and health status for individuals and communities • Recognize gene/drug interactions: efficacy and adverse effects (pharmacogenetics)

13. PUBLIC HEALTH GENETICS (2) • Infectious diseases: host-pathogen interactions/clues for epidemiology and drug and vaccine development • Nutrition: hyperlipidemias, high BP, high homocysteine, iron (hemochromatosis)… • Unhealthful behaviors: smoking, alcohol, inactivity • Chronic diseases: --predisposing genes (variants, SNPs) --genetic toxicology from exposures

14. PUBLIC HEALTH GENETICS (3) • Eco-genetics: environmental & occupational exposures and variation in susceptibility --OSH Act: set standards to protect the most susceptible worker over a lifetime at max exposure --Clean Air Act: set criteria air pollution standards to protect “most susceptible subgroup” • Training and continuing education in every public health discipline: preventive medicine, health services research, epidemiology, biostatistics, EOH, health behavior and health education, pathobiology (role for Supercourse)

15. “Harnessing Genetics to Prevent Disease & Improve Health: A State Policy Guide” Partnership for Prevention Washington DC, 2003 www.prevent.org

16. AIMS of the PfP REPORT Help state policymakers to: • Protect consumers • Monitor the implications of genetics for health, social, and environmental goals • Assure genetic advances will be tapped not only to treat medical conditions, but also to prevent disease and improve health before people become ill.

17. KEY FINDINGS • The greatest opportunity of the genomic era: personalized medicine and pharmacogenetics to prevent or better manage chronic diseases. Products and services will include vaccines, diagnostic tests, drug therapies, and drug monitoring protocols. • Genetics programs should be integrated into existing health, social, and environmental policies, rather than establishing stand-alone genetics/genomics programs

18. THE CASE FOR INTEGRATION • All health conditions have a genetic basis. • Most common diseases result from gene-environment interactions, so genetic advances are likely to extend and expand, not supplant, current practices in medicine, public health, environmental protection • Some genetic variations are associated with greater health risks than others; covering this wide range with one-size-fits- all policies is inappropriate.

19. PfP CITED MICHIGAN “At a time when many state policies were based on exceptionalism, the Michigan Governor’s Commission on Genetic Policy and Progress adopted an integration perspective and recommended that genetic issues be dealt with in the context of overall medical care values and principles”. (p.11, PFP Report)

20. HEALTH POLICIES RECOMMENDED BY PfP • Increase consumer knowledge of genetics • Strengthen public health infrastructure to accommodate genetics developments • Add genetic competencies to licensing requirements for all health professionals • Increase supply of qualified genetic counselors • Invest in genetics research agenda

21. Additional Sources of Information • CDC Office of Genomics and Disease Prevention • Assn of State and Territorial Health Officers (ASTHO): Genomics Impact Newsletter, monthly. • National Conference of State Legislatures: Genetic Technologies Project; www.ncsl.org

22. GRAND CHALLENGE #2: Discover, quantify, and reduce environmental risks to health of individuals and populations

25. “ I know no safe depository of the ultimate powers of society but the people themselves; if we think them not enlightened enough to exercise their control with a wholesome discretion, the remedy is not to take it away from them, but to inform their discretion.” - Thomas Jefferson

26. Presidential/Congressional Commission on Risk Assessment and Risk Management Risk assessment science & models Risk-management framework Communicating uncertainty Peer review Inter- and intra-agency consistency “Bright lines” Sensitive subpopulations Ecologic risk assessment Comparative risk assessment Economic analysis Judicial review

27. Objectives of Risk Assessment 1. Balance risks and benefits Drugs Pesticides 2. Set target levels of risk Food contaminants Water pollutants 3. Set priorities for program activities Regulatory agencies Manufacturers Environmental/consumer organizations 4. Estimate residual risks and extent of risk reduction after steps are taken to reduce risks

28. Major Hazardous Chemical Laws in the U.S. EPA: Air Pollutants Clean Air Act 1970, 1977, 1990 Water Pollutants Fed WP Control Act 1972, 1977 Safe Drinking Water Safe DW Act 1974, 1996 Pesticides FIFRA 1972 Food Quality & Protection FQPA, 1996 Ocean Dumping Marine Protection Act, 1995 Toxic Chemicals TSCA 1976 Hazardous Wastes RCRA 1976 Hazardous Waste Cleanup CERCLA (Superfund) 1980, 1986 FDA: Foods, Drugs, Cosmetics FDC Acts, 1906, 1938, 1962, 1977, 1997 CEQ: Envtl Impacts NEPA, 1972 OSHA: Workplace OSH Act, 1970 CPSC: Dangerous Consumer Products CPS Act, 1972 DOT: Transport of Haz Materials THM Act, 1975-79, 1984, 1990

29. Framework for Regulatory Decision-Making Epidemiology Hazard IdentificationLifetime rodent bioassays Short-term, in vitro/in vivo tests Structure / activity Potency (dose/response) Risk Characterization Exposure analysis Variation in susceptibility Information Risk Reduction Substitution Regulation / Prohibition

30. Cancers Mutations Birth defects Reproductive toxicity Immunological toxicity Biological End-Points  Neurobehavioral toxicity  Organ-specific effects  Endocrine modulation / disruption  Ecosystem effects

31. Context • Multiple sources of same agent • Multiple media/pathways of exposure • Multiple risks/effects of same agent • Multiple agents causing same effects • Public health: status / trends • Ecological health • Social, cultural, environmental justice considerations

32. Move beyond one chemical, one environmental medium (air, water, soil, food), one health effect (cancer, birth defect…) at a time in risk assessment and risk management: requires comprehensive public health view Change the Context

33. Data Gaps: “Toxic Ignorance” • Only 7% of high production volume (HPV) chemicals had full set of studies for 6 basic endpoints, while 43% of HPV chemicals have no publicly available studies for any of 6 basic toxicity endpoints (EPA, 1998) • Environmental Defense Fund report “Toxic Ignorance” and OECD (SIDS) stimulated new commitments to test

34. Eco-Genetics • The interaction of environmental exposures and genetic variation • Range of susceptibility for specific exposures • Application of gene and protein expression methods to detect and clarify “molecular signatures” as biomarkers of exposure, early adverse effect, and susceptibility

35. Reducing risk by orders of magnitude is not equivalent to linear reductions Risk Commission, Final Report, 1997