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Metals, Mega-trends, and Me: Reflections on Research and the Vision for the Dalla Lana SPHHoward Hu, M.D., M.P.H., Sc.D.St Michaels HospitalUniversity of TorontoApril 3, 2013HousekeepingPotential conflicts of interest:NoneMy contact information:Howard.hu@utoronto.ca416-978-1841At 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.

Hus Odyssey & Background

Boston City Hospital: Internal Med 82-8585-06Full prof & Tenure: 2002New York/Brown/EinsteinSummers of 73,74: shipyards

2006-2012 Department Chair, U Michigan

Population research on chronic disease in kids & adultsEnvironmentNutritionGeneticsEpigenetics35% with global partners Clinical medicine

July 2012

Sri Ramachandra University4Beautiful Canada

Some not so beautiful facts

SARS Walkerton Avian influenza Obesity epidemic Aging subpopulations Alzheimers epidemic Food security Environmental degradation Circumpolar health disparities Major asbestos exporter

CrowdedDiverse

Coming Global Realities* Canadian statistics are proportionate with similar trends*AgingStratified(Social class)

UrbanizedPolluted

Hot, Thirsty & Hungry

Global climate change: the ultimate example of global health disparities & inequity?

Graham Environmental Sustainability Institute http://provost.umich.edu/gesiProduction of Greenhouse Emissions

Projected Mortality from Global Warming (water & food scarcity, disasters, shifts in infectious disease)OppressedDebt-ridden

The health providers view:The Global Burden of Disease

Within the disparities:Other disparitiesNew HIV/AIDS cases

The role of public health & medicine?Huge, for some problemsDisease prevention & treatmentBig advances in progress in the basic biology of diseaseControlling the costs of health careSignificant, for someE.g., forecasting impacts of climate change on healthDocumenting the impact of social class, income disparities, and lack of human rights on healthSmall for othersE.g., research clearly shows that education of women is the best predictor of lower population growth not the availability of contraception

Where do we put our money and resources to maximize health????prabhatWhat causes disease?Whats a sustainable health system?What do we need to know?

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

Genetics: The Human Genome Project

Completion in 2003: amazing basic science achievementBUT:Relatively few disease genes identifiedOnly modest advances in ability to either treat OR prevent chronic disease

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

Landmark study, enormous power

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

Similarly, we can estimate the environmental contribution to other CDsDepression: ~70%Parkinsons: ~90%Alzheimers (Late onset, >65 yo): ~60%Essential Hypertension: ~60%Osteoporosis: ~60%Schizophrenia: ~60%Gene-environment interactions ??The 3 most difficult challengesto molecular epi research of gene-environment interactions:ExposureExposureExposurei.e., measuring, estimating, modeling exposures to chemical toxicants and the dose-response relationshipWhat 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?

Dr. Hus Great Summer JobWhat really was most dangerous about the exposure?Who gets cancer, and who doesnt?How to tell?

2525 years of research on another global pollutant: leadPaint, pipes, leaded-gasoline, food cans, many other products

Result: we all have quite a bit of lead in our bodiesHave to go to pre-historic man to find levels near natural background

Policy: Progressive decline in allowable levels of lead in a childs bloodSuccess of sortsSoon to be lowered again to 5 g/dL?

The hidden problem:Cumulative lead exposure(as reflected by bone lead levels)

Hu et al, 1996BONE LEAD AND HYPERTENSION In community-exposed men.*

*Adjusted for age, body mass index, family history of hypertension, smoking, alcohol ingestion, dietary calcium, dietary sodium

Hu et al, 1996BONE LEAD AND MORTALITYIn community-exposed men*

Weisskopf et al, 2009*Adjusted for age, body mass index, smoking, race

*Adjusting for age, smoking

BONE LEAD AND CATARACTSIn community-exposed men*Schaumberg et al, 2004Gene-Environment Interactions: Lead, the Hemochromatosis genes C282Y/H63D, and CognitionMore intracellular iron and leadSynergistic promotion of oxidationHFE carrier adults had worse cognition given same lead burden

WildtypeHFE carriers

Wang et al, 2006New Direction: Is early life lead exposure a risk factor for Alzheimers ???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

Early Life Exposures in Mexico to Environmental Toxicants Project

Fetal exposure to moms mobilized bone lead stores independently predict poorer offspring IQ at age 2 years

Weisskopf et al., EHP 2006Lead and Magnetic Resonancy Spectroscopy (MRS) findingsbone lead ~ myoionosital/ creatine ratio in the hippocampusMarker of gliosisSeen as early change in Alzheimers (preceding neuronal loss)

Post-mortem brainsAlzheimers v ControlEpigenome discoveryTransmembrane Protein 59 identifiedresponsible for post-translational glycosylation of APPleads to retention of APP in the Golgi apparatusStudies on lead exposure in progress

Bakulski et al, in pressTake away?The impact of non-genetic risk factors on disease remains underexploredBetter tools now emergingIn particular, biomarkers & other exposure assessment tools; epigenomicsInfluences on disease must be appreciated over the life courseThe lines between public health (risk factors/prevention) & medicine (diagnosis/treatment) are blurring

MeMeMeEpigenetic ProgrammingExposomics?ExposomicsUofT effort being initiated by Greg Evans et al

The Epigenome: linking past exposures to future diseaseU of T has strengths in this area.Art PetronisEpigenetics of psychosisAM DubucEpigenetics of brain tumorsR WeksbergPlacental epigenetics

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

Examples of Major Units & Partners

Many investigators working on the Big Preventable Problems Our Schools emerging vision for the futureFive Foundational Sciences + Three Major Themes + Five Cross-cutting Drivers (5+3+5)Cross-cutting Drivers (Values and Skills)Human Rights, Equity & Social JusticeParticipation & PartnershipsSustainabilityInnovationLeadership

Foundation Sciences:EpidemiologyBiostatisticsHealth Care & Public Health PolicySocial & Behavioural SciencesOccupational & Environmental HealthThe U.S.: lots of action, but a very steep climb

Special June 2012 IssueTrue integration of primary care with public health

With the Affordable Care Act, efforts to address this in the U.S. But:low incentives for practitionerssmall primary care work force hard to growCanadaa big opportunityuniversal health care coverage, large primary care workforceMany questionsWhat 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!

At Dalla Lana:Creation of a New DivisionAimed precisely at the intersection of public health and primary care/clinical medicine

Ross UpshurSpecific goalsCreating innovative approaches to Clinical Public Health scholarshipA new journal ??Collaboratories for testing and evaluating system-wide approaches for integrationWith PHO, F&CM, selected Hospital/Health SystemsUndergraduate Health Professionals EducationOverhauling & enriching the Med Schools Determinants of Community Health (DOCH) curriculumCreating an innovative MD-MPH programGraduate Professional TrainingStrengthening the Prev Med & Public Health Residency

21st century primary care: synthesis of population & individual careIf we get this right:The DLSPH SweetspotRethinking and remaking communities & their public health/health care delivery systemsPartnership Initiatives in Shanghai, Sao Paolo, Bangladesh

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

The unfinished agendaof infectious diseasesImportant strength at UTHIV/AIDS, STDs, etc.Emerging infectionsMajor partner with the Public Health of Ontario Agency

Spatial statistics, Biostatistics,Bioinformatics---InformationEnormous amounts of information on multiple macro and micro scalesIntegration affords immense opportunities for life sciences and epidemiologyTake away: informatics holds huge promisebut is also an enormous challenge

Entrepreneurship and public health/medicine

Products for public healthVaccinesDevices, e.g., Low emissions cooking stovesLow risk field circumcision instrumentsLong-distance learningSocial entrepreneurship & public healthExample: Health Media & Risky Behaviors

The Ceiling Effect in Education & TrainingWhat knowledge must our students have?We are at the limits of what we can stuff into their brains.History: very similar to medical education in the 1980sConsider:Multi-disciplinary problem-based learning & competencies (case studies)Information sourcing, triage, organization, applicationInter-professional Teams, culture, communication

Thank youInstitution building is funbut science is also still funhoward.hu @utoronto.ca