Metals, Mega-trends, and Me: Reflections on Research and the Vision for the Dalla Lana SPH

1. Metals, Mega-trends, and Me: Reflections on Research and the Vision for the Dalla Lana SPH Howard Hu, M.D., M.P.H., Sc.D. St Michael’s Hospital University of Toronto April 3, 2013

2. Housekeeping • Potential conflicts of interest: • None • My contact information: • Howard.hu@utoronto.ca • 416-978-1841

3. At the end of this presentation participants should be able to: • Describe trends in globalization, demographics, environmental stressors, and the burden of disease. • Estimate the impact of environmental stressors on chronic disease through research on cohorts of twins. • Use the case-study of lead toxicity to demonstrate the use of novel clinical biomarker tools in measuring the impact of environmental stressors on chronic disease. • Reflect on other opportunities that have emerged for integrating public health and medical research. • Discuss new initiatives that will provide leadership in Canada on integrating public health and clinical medicine from the perspective of the Dalla Lana School of Public Health.

4. 2006-2012 Department Chair, U Michigan… Hu’s Odyssey & Background July 2012 Summers of ’73,’74: shipyards New York /Brown /Einstein • Population research on chronic disease in kids & adults • Environment • Nutrition • Genetics • Epigenetics • 35% with global partners • Clinical medicine Boston City Hospital: Internal Med ’82-’85 Sri Ramachandra University ’85-’06 Full prof & Tenure: 2002

5. Beautiful Canada

6. Some not so beautiful facts… • SARS • Walkerton • Avian influenza • Obesity epidemic • Aging subpopulations • Alzheimer’s epidemic • Food security • Environmental degradation • Circumpolar health disparities • Major asbestos exporter

7. * Coming Global Realities… Crowded Diverse * Canadian statistics are proportionate with similar trends

8. Aging Stratified (Social class…)

9. Urbanized Polluted

10. Hot, Thirsty & Hungry

11. Global climate change: the ultimate example of global health disparities & inequity? Production of Greenhouse Emissions Projected Mortality from Global Warming (water & food scarcity, disasters, shifts in infectious disease) Graham Environmental Sustainability Institute │ http://provost.umich.edu/gesi

12. Oppressed Debt-ridden

13. The health providers view:The Global Burden of Disease

14. Within the disparities:Other disparities • New HIV/AIDS cases

15. The role of public health & medicine? • Huge, for some problems • Disease prevention & treatment • Big advances in progress in the basic biology of disease • Controlling the costs of health care • Significant, for some • E.g., forecasting impacts of climate change on health • Documenting the impact of social class, income disparities, and lack of human rights on health • Small for others • E.g., research clearly shows that education of women is the best predictor of lower population growth • not the availability of contraception

16. Where do we put our money and resources to maximize health????

17. prabhat • What causes disease? • What’s a sustainable health system? • What do we need to know?

18. “Causes”: Downsteam (to be treated)v. Upstream (preventable)

19. Genetics: The Human Genome Project Completion in 2003: amazing basic science achievement BUT: Relatively few disease genes identified Only modest advances in ability to either treat OR prevent chronic disease

20. Genes v. Environment?Studies of twins Concordance of disease occurrence in monozygotic (MZ) v dizygotic (DZ) twins high in MZ/ low in DZ high heritability (genes!) medium in MZ/ medium in DZ low heritability; high influence by environmental factors shared by twins low in MZ/ low in DZ low heritability; high influence by environmental factors specific to each twin Quantitative estimates can be generated using structural equation models

21. Landmark study, enormous power

22. The unexpectedly large influence of environment on cancers: the Scandinavian Twin Study-- Lichtenstein et al., (NEJM, 2000) • Genetics only explains 27% of breast cancer • “Shared” environment only 6% • Individual environment explains 67% • Similar figures for other cancers

23. Similarly, we can estimate the environmental contribution to other CDs • Depression: ~70% • Parkinson’s: ~90% • Alzheimer’s (Late onset, >65 yo): ~60% • Essential Hypertension: ~60% • Osteoporosis: ~60% • Schizophrenia: ~60% • Gene-environment interactions ??

24. The 3 most difficult challengesto molecular epi research of gene-environment interactions: • Exposure • Exposure • Exposure • i.e., measuring, estimating, modeling exposures to chemical toxicants and the dose-response relationship • What metric of exposure is biologically most important? • Current? Cumulative? Peak? At some specific lifestage? (Timing) • What is the dose-response? • Monotonic linear? Threshold? U-shaped?

25. Dr. Hu’s Great Summer Job… • What really was most dangerous about the exposure? • Who gets cancer, and who doesn’t? • How to tell?

26. 25 years of research on another global pollutant: lead • Paint, pipes, leaded-gasoline, food cans, many other products…

27. Result: we all have quite a bit of lead in our bodies… • Have to go to pre-historic man to find levels near natural background…

28. Policy: Progressive decline in allowable levels of lead in a child’s blood… • Success of sorts… • Soon to be lowered again to 5 μg/dL?

29. The hidden problem:Cumulative lead exposure(as reflected by bone lead levels) Hu et al, 1996

30. BONE LEAD AND HYPERTENSION In community-exposed men.* Hu et al, 1996 *Adjusted for age, body mass index, family history of hypertension, smoking, alcohol ingestion, dietary calcium, dietary sodium

31. BONE LEAD AND MORTALITYIn community-exposed men* Weisskopfet al, 2009 *Adjusted for age, body mass index, smoking, race

32. BONE LEAD AND CATARACTSIn community-exposed men* Schaumberg et al, 2004 *Adjusting for age, smoking

33. Gene-Environment Interactions: Lead, the Hemochromatosis genes C282Y/H63D, and Cognition More intracellular iron and lead Synergistic promotion of oxidation HFE carrier adults had worse cognition given same lead burden Wang et al, 2006 Wildtype HFE carriers

34. New Direction: Is early life lead exposure a risk factor for Alzheimer’s ??? Landmark studies in mice & monkeys by Zawia et al. Early life (but not late life) exposure programmed animals for late life over-expression of APP, etc. Mechanism likely to be epigenetic

35. Early Life Exposures in Mexico to Environmental Toxicants Project Fetal exposure to mom’s mobilized bone lead stores independently predict poorer offspring IQ at age 2 years

36. Weisskopf et al., EHP 2006Lead and Magnetic Resonancy Spectroscopy (MRS) findings bone lead ~ myoionosital/ creatine ratio in the hippocampus Marker of gliosis Seen as early change in Alzheimers (preceding neuronal loss…)

37. Bakulskiet al, in press • Post-mortem brains • Alzheimer’s v Control • Epigenome discovery • TransmembraneProtein 59 identified • responsible for post-translational glycosylation of APP • leads to retention ofAPPin the Golgi apparatus • Studies on lead exposure in progress

38. Me Me Me Epigenetic Programming Take away? • The impact of non-genetic risk factors on disease remains underexplored • Better tools now emerging • In particular, biomarkers & other exposure assessment tools; epigenomics • Influences on disease must be appreciated over the life course • The lines between public health (risk factors/prevention) & medicine (diagnosis/treatment) are blurring…

39. Exposomics? Exposomics • UofT effort being initiated by Greg Evans et al…

40. The “Epigenome”: linking past exposures to future disease… U of T has strengths in this area. Art Petronis Epigenetics of psychosis AM Dubuc Epigenetics of brain tumors R Weksberg Placental epigenetics

41. 1925 established by the Rockefeller Foundation 1975 absorbed by UT Medicine 2004 SARS crisis 2008 re-established School 2009 endowed by Dalla Lana family 2012: >300 faculty; >$30 million research; >400 students, growing Many investigators working on the Big Preventable Problems… Examples of Major Units & Partners

42. Our School’s emerging vision for the futureFive Foundational Sciences + Three Major Themes + Five Cross-cutting Drivers (5+3+5) • Foundation Sciences: • Epidemiology • Biostatistics • Health Care & Public Health Policy • Social & Behavioural Sciences • Occupational & Environmental Health • Cross-cutting Drivers • (Values and Skills) • Human Rights, Equity & Social Justice • Participation & Partnerships • Sustainability • Innovation • Leadership

43. The U.S.: lots of action, but a very steep climb Special June 2012 Issue

44. True integration of primary care with public health • With the Affordable Care Act, efforts to address this in the U.S. • But: • low incentives for practitioners • small primary care work force – hard to grow • Canada—a big opportunity • universal health care coverage, • large primary care workforce • Many questions • What prevention activities should get more resources? What works? • What are the most desirable outcomes? How should they be measured? • What does it really mean to work in teams? How? • What are the professions and roles that make sense for the future? • Needs research & scholarship!

45. At Dalla Lana:Creation of a New Division Ross Upshur Aimed precisely at the intersection of public health and primary care/clinical medicine

46. Specific goals • Creating innovative approaches to “Clinical Public Health” scholarship • A new journal ?? • “Collaboratories” for testing and evaluating system-wide approaches for integration • With PHO, F&CM, selected Hospital/Health Systems • Undergraduate Health Professionals Education • Overhauling & enriching the Med School’s Determinants of Community Health (DOCH) curriculum • Creating an innovative MD-MPH program • Graduate Professional Training • Strengthening the Prev Med & Public Health Residency

47. 21st century primary care: synthesis of population & individual care

48. If we get this right:The DLSPH “Sweetspot” Rethinking and remaking communities & their public health/health care delivery systems Partnership Initiatives in Shanghai, Sao Paolo, Bangladesh

49. A few of the other big challenges (and opportunities) for public health & medicine

50. The unfinished agendaof infectious diseases • Important strength at UT • HIV/AIDS, STDs, etc. • Emerging infections • Major partner with the Public Health of Ontario Agency