Transcript harnessing genetics to prevent disease & improve health

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
GRAND CHALLENGES
1. Public Health Genetics
2. Environmental Health Risk
Assessment & Risk Management
3. Affordable Quality Health Care in the
U.S., and globally
Engage the full range of the public health
disciplines in academe and in practice
GRAND CHALLENGE #1:
Apply all of the public health
sciences to the interpretation
of variation in the genome in
full behavioral and
environmental context
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
APRIL 14, 2003:
THE 50th ANNIVERSARY OF THE
PUBLICATION OF THE
WATSON-CRICK ARTICLE ON
THE DOUBLE-HELIX
STRUCTURE OF DNA
IT’S A NEW WORLD
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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
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.
• 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.
Protein
DNA
PROTEOME: GENE PRODUCTS
 Highly dynamic compartment: ideal for
biomarkers
 Regulated at the transcriptional and posttranscriptional levels, compartmentalized in cells
 Numerous post-translational modifications:
glycoproteins, phosphoproteins…
 Protein subsets: secreted proteins, membrane
proteins, antigenic proteins, auto-antibodies
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
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)
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
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)
“Harnessing Genetics to
Prevent Disease & Improve
Health: A State Policy Guide”
Partnership for Prevention
Washington DC, 2003
www.prevent.org
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.
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 standalone genetics/genomics programs
THE CASE FOR INTEGRATION
• All health conditions have a genetic basis.
• Most common diseases result from geneenvironment 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-fitsall policies is inappropriate.
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)
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
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
GRAND CHALLENGE #2:
Discover, quantify, and
reduce environmental risks
to health of individuals and
populations
“ 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
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
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
Major Hazardous Chemical Laws in the U.S.
EPA: Air Pollutants
Water Pollutants
Safe Drinking Water
Pesticides
Food Quality & Protection
Ocean Dumping
Toxic Chemicals
Hazardous Wastes
Hazardous Waste Cleanup
FDA:
Foods, Drugs, Cosmetics
Clean Air Act 1970, 1977, 1990
Fed WP Control Act 1972, 1977
Safe DW Act 1974, 1996
FIFRA 1972
FQPA, 1996
Marine Protection Act, 1995
TSCA 1976
RCRA 1976
CERCLA (Superfund) 1980, 1986
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
Framework for Regulatory
Decision-Making
Hazard Identification
Epidemiology
Lifetime rodent bioassays
Short-term, in vitro/in vivo
tests
Structure / activity
Risk Characterization
Potency (dose/response)
Exposure analysis
Variation in susceptibility
Risk Reduction
Information
Substitution
Regulation / Prohibition
Biological End-Points
 Cancers
 Mutations
 Birth defects
 Reproductive
toxicity
 Immunological
toxicity
 Neurobehavioral toxicity
 Organ-specific effects
 Endocrine modulation /
disruption
 Ecosystem effects
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
Change the Context
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
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
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
Reducing risk by orders of magnitude
is not equivalent to linear reductions
1000
800
600
Level of risk
400
200
0
1 x 10-3
1 x 10-4
1 x 10-5
1 x 10-6
Risk Commission, Final Report, 1997