Policy
Practice/Training
Research
NUTRITION
Engineering Agriculture & Food Systems
to Alleviate Malnutrition and Promote
Health in Diverse Populations:
Nurture, Nature and the Hippocratic Oath
Patrick J. Stover, PhD
Common Nutrient
Deficiencies:
Known:
Vitamin A
Iron
Iodine
Zinc
Folate
Others:
Vitamin B12
FoodPolicy
and Agriculture Systems
Practice/Training
How do you balance the agenda?
Research
Food/Ag Production?
NUTRITION
-Economics? Exports? Energy?
Food Consumption/Food Quality?
Double Burden
-Alleviation of Hunger?
But Vilsack, newly installed in his regal but still-undecorated
office on Independence Avenue, is
-Alleviation of Malnutrition? What? And How?
out to redefine himself and his vision. In an interview this week, he called for a "new day" for
-Health/Disease
Prevention/Increased
productivity?
the U.S. Department
of Agriculture's sprawling
bureaucracy, which
he believes should champion
not only farmers but also everyone who eats.
What is Achievable?
"This is a department
that intersects
the lives of Americans two to three times a day. Every
-Science/Evidence
base?
single American," he said. "So I absolutely see the constituency of this department as broader
- Food for Health?
than those who produce our food -- it extends to those who consume it."
- Food as Medicine?
-"Abovefrom
all, do
harm" view of the USDA, which historically has
It is a significant departure
theno
traditional
- Economics
emphasized programs
that support commercial farming, such as price guarantees for crops and
- Cost/Benefit?
marketing promotions
for exports.
NFHS-3
Gerald Fink
Director
Whitehead Institute at the Massachusetts Institute of Technology
"I expect that in the year 2005 (when the entire human genome is scheduled to be mapped
and sequenced), on the back of our foods, there are going to be a lot of things like that, because
we are going to know a lot more about ourselves. And I think the field of nutrition, which, in my
own opinion now, has not benefited from the advances in molecular genetics, will be a
completely different field. That will be the most revolutionized field in the year 2005. And the
reason is that we will know lots more, we will actually know something about nutrition so you
won't pick up one day and say fat is good for you and the next day fat is bad for you. Because we
will know that some people it is good for and some people it is bad for.
"We will be able to know what people can metabolize and what some people can't metabolize.
….We're going to have a new definition of what it means to be healthy."
http://www.laskerfoundation.org/rprimers/hgp2.html
The Human Genome Project: Part Two: Ushering in a new era of molecular medicine
Date of Publication: 1998
Human Genome Project
(1990-2003)
http://www.ornl.gov/sci/techresources/Human_Genome/home.shtml
-Assemble & understand cellular networks
- Manipulate cellular networks for Health
- Pharmaceuticals & Nutrients
Managing/Engineering the Food
System
• Types of food
• Manipulation of the food supply
– Biofortification
– Fortification
• Voluntary
• Mandated
• Supplementation
Human Genetic Variation
Single nucleotide polymorphisms (SNPs) -
Common variations in DNA sequence
Contribute to genetic diversity
Frequency of about 1 in every 1000 bases of DNA
There are 10 M SNPs in the human genome.
SNPs contribute to complex traits that include
susceptibility to chronic diseases, metabolism and drug
efficacy.
Human Genetic Variation and Nutrition
UNESCO
Universal Declaration on The Human Genome and Human Rights
Section A, Article 3:
The human genome, which by its nature evolves, is subject to mutations. It contains
potentialities that are expressed differently according to each individual’s natural and social
environment including the individuals state of health, living conditions, nutrition and education.
UNESCO Document 27 V / 45 Adopted by the Thirty First General Assembly of UNESCO, Paris,
November 11, 1997
Gene-Nutrient Interactions
Nutrition and Evolution
Genome Primary Sequence
- mutation rate
- selection
Genome Programming
- stem cells
Gene Expression
Human
Genome
Dietary
Components
Food Intolerances
Dietary Requirements
Susceptibility to metabolic disease
Classifying Humans: Paving the way for personalized medicine & nutrition
Milner JA. Nutrition in the 'omics' era. Forum Nutr. 2007;60:1-24. Review.
PharmacogenomicsShould drugs be matched
to the individual?
Nutritional GenomicsShould diet be matched
to the individual or ethnic/genetic
subpopulation?
What impact will this have on
Public Health Nutritional Interventions?
What if only certain population subgroups benefit? Will others accrue risk?
What is the standard for “Doing no harm”?
Birth Defect Prevention
gene-diet interactions
Neural Tube Closure
Requires precise
coordination of:
- Cell Proliferation
- Survival
- Differentiation
- Migration
Neural Tube Defects
- spina bifida
- anencephaly
Neural Tube Defects (NTDs)
Result from Gene-Nutrient Interactions
• The most common congenital abnormality at birth in US
(1-2 in 1000 births)
• 2,500 affected births in the US/year
• Rate is 5-10/1000 in developing countries
• Recurrence rate is 1-5/100
• Critical period within a month of fertilization
(6 weeks after LMP)
• Economics
– Cost $250,000.00 in medical costs in the first 5 years.
Folic acid and prevention of neural
tube defects (NTD)
• Clinical Observations:
Relationship between impaired folate status and NTDs.
• Clinical Trials:
Periconceptual vitamin supplementation (including folic acid)
decreases the incidence of NTDs by 70%.
– Occurrence of NTD in Hungarian trials by Czeizel et al
– Recurrence of NTD in British MRC trial by Mills et al
Prevention of Folate-Responsive Birth Defects
In 1992 the US PHS issued a recommendation that women of
childbearing age consume 0.4 mg folic acid/day to reduce their
risk of neural tube defect affected pregnancy.
Approaches:
1. Increased intake of dietary folate
2. Targeting the at risk group for supplement use
3. Fortification of the food supply
Why is Folic Acid Fortification Controversial?
•
First fortification initiative that did not seek to remedy a nutritional deficiency, but
rather sought a medicinal purpose: remedy a “rare” disorder
•
Targets a small population subgroup (who benefits, who accrues risk?)
•
The fortificant is not a natural or functional folate (Folic Acid)
•
Mechanism of folate-NTD relationship unknown;
Mechanism of folate-cancer relationship unknown
Folic Acid
•
Mechanism?
NTD Prevention
Exacerbate common concerns of unintended consequences
Lessons Learned
• Nutrient deficiencies occur across all socioeconomic classes. Hunger
is an outcome of poverty; malnutrition is multidimensional, and
results from gaps in policy/implementation and/or gaps in
knowledge.
– B-vitamin deficiencies are common in all regions
• Vitamin B12
– Prevalence of malnutrition > poverty
• Genetic subpopulations may respond differently to nutrition
interventions.
• We need to know how nutrients function at a fundamental level to
ensure our interventions are effective and low risk.
Undernutrition and Growth in India
NFHS-3 2005-2006
Stunting reflects failure to receive adequate nutrition over a long
Three
indices
of physical
that describe
the nutritional
of children:
period
of time
and is growth
also affected
by recurrent
andstatus
chronic
illness.
• Height-for-age (stunting)
• Weight-for-height (wasting)
• Weight-for-age (underweight)
Fetal Origins of Adult Disease
or “Barker” Hypothesis
Fetal environmental exposures, especially nutrition, act in early
life to program risk for adult health outcomes
“Program”
“Imprint”
Early Nutrition
Experiences
Risk Phenotype
obesity
hypertension
insulin resistance
Stem Cells
Sense  Adapt
-Irreversible programming
Metabolic Disease
CVD
diabetes
metabolic syndrome
Persistent Effects of B-Vitamin Nutrition
Avy/a mice
-Maternal diet programs fetal stem cells that
affect on coat color
- Programming persists into adulthood
independent of diet; may be heritable
- Risk for obesity and cancer also programmed
Nat Genet. 1999 23:314
J Nutr. 2002 132:2393S
Mol Cell Biol 2003 23:5293
Envir Health Perspect. 2006 114:567
You are what you eat …. or you are
what your mother ate?
Genome Programming During Development
-- Targeting Methylation -(Physiol. Rev. (2005) 85:571-633)
Low Maternal Protein
Reduced 11b-HSD2 expression
(Glucocorticoid catabolism)
Loss of Placental GC Barrier
Human GC therapy
Increased Fetal GC
Epigenetic Imprint Erased by
Histone Deacetylase Inhibitors
GC Induced Events
- Small placenta
- CNS defects
- Attenuated HPA axis feedback sensitivity
- Altered GR promoter methylation/expression declines
- Altered dopaminergic programming
- Increased PEPCK expression
(in adulthood/2nd generation)
- inhibited insulin suppression of
gluconeogenesis
- increased insulin
- glucose intolerance
Outcomes
- Low Birth weight (IUGR)
- Elevated Plasma GC in adulthood
- Hypertension
- Hyperglycemia
- Insulin Resistance
- Hyperinsulinaemia
- Anxiety
Folate Prevents
Birth Defects
in Early
Development
Stunting/
Nutrition
in Early
Development
Programs
Chronic Disease
Folate Programs
Gene Expression
in Early
Development
Unintended Consequences of Nutrient (folic acid)
Supplementation
Diabetologia (2008) 51:29-38
Methods
• Longitudinal study population in rural India
– (poor, vegetarian, low B12, adequate folate)
• Pregnant women (n=700) from 6 villages in India
received a folate/iron supplement from 18 weeks
gestation.
• Children (n=674) at 6 years of age
• Measure of insulin resistance: Homeostatic model
assessment of insulin resistance (HOMA-R)
Insulin resistance
356
“Low maternal vitamin B12 and high folate status
may contribute to the epidemic of adiposity and
type 2 diabetes in India”
- Large impact on folic acid fortification for NTD prevention
However, the Pune study data are
observational; observational data
should not be used to make causal
inferences …..
The relationship between low vitamin
B12 and high folate lacks biological
explanation ….
J Nutr 139:1-7, 2009
Community-based randomized
control trial, rural Nepal, 1999-2001
•
•
•
•
•
Control Vitamin A (1 mg RE)
Vitamin A + FA (400µg)
Vitamin A + FA + iron (60 mg)
Vitamin A + FA + iron + zinc (30 mg)
Vitamin A + Multiple micronutrient (all of
the above + 11 additional vitamins and
minerals)
Findings from original RCT
• Supplements given early pregnancy to 3
months post partum
• Unit of randomization: sector (n=426)
• 4130 infants followed up through 6 months of
age to monitor morbidity/mortality
• Compared to control, reduced risk of LBW by
16% (FA+iron) and 14% (MM)
Follow-up assessments - 2006
•
•
•
•
Children 6 to 8 years
3,900 children surviving to 6 months
3,524 enrolled (~ 93%:93 to 95% by group)
Measurements: BP’s, anthropometry, waist,
skin-folds, triglycerides, cholesterol, glucose,
HBA1c,insulin, creatinine, microalbuminuria
• 33% - non-fasting (no insulin)
Risk factors by treatment group
Control
FA
FA/iron
FA/FE/Zinc
MM
3.80
3.86
3.91
3.91
3.86
HbA1c
5.1
5.07
5.09
5.11
5.10
Insulin
15.13
16.28
15.83
16.19
15.63
HOMA
0.43
0.47
0.45
0.47
0.45
TriGl
1.06
1.03
1.06
0.98*
1.04
Glucose
mmol/L
pmol/L
mmol/L
Risk factors (ORs) associated with
metabolic syndrome
Control
FA
FA/iron
FA/FE/Zinc
MM
High
glucose
1.0
1.07
1.14
1.17
1.12
Low HDL
1.0
0.88
0.84
1.05
1.00
High TG
1.0
0.76
1.06
0.73
0.92
High BP
1.0
0.89
0.91
0.93
1.10
High WC
1.0
0.87
0.99
0.89
0.96
Met Sx
1.0
0.63*
1.02
0.96
1.00
* Significant
“There is still much to be learned about the effects
of micronutrient nutrition during this critical period
of the lifespan.”
Policy
Practice/Training
Research
NUTRITION
Harmonizing Food and Agriculture Systems for Health
In Genetically Diverse Populations
- Dietary patterns, not nutrient intakes, are best predictors of health
- Food based approaches are always more desirable
- Care should be taken to ensure single nutrient approaches,
especially in undernourished populations, are safe
Harmonizing Nutrition and Food Systems
Policy
Practice/Training
Research
NUTRITION
Nutrition Science
Knowledge and Knowledge Gaps
- Nutrients/Diets and Health
- Nutrition Assessment/Surveillance of Populations
- Epigenetic/Genetic/Ethnic subpopulations
Nutrition Implementation
- Sustainable Ag/Food Systems
- Intervention/Delivery Systems
- Monitoring
- Social Behavioral Science
- Context Specificity
- Health/cost benefit
Enablers
Comprehensive road map for (mal)nutrition
Coordination :
Governmental agencies
Strong Universities/Strong collaborations
Public-private partnership
Global partnerships
Food and nutrition is not the same!
Water
Infection
Education
Human
Nutrition
Disease
Adolescent
Pregnancy
Inadequate
Diets
Thank you