Patrick Stover - Britannia

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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

Vitamin A

Vitamin B12
                  Food and Agriculture Systems

              How do you balance the agenda?
              Food/Ag Production?
                   -Economics? Exports? Energy?
              Food Consumption/Food Quality?
                    -Alleviation of Hunger?             Double Burden
                                                                office on Independence Avenue, is
But Vilsack, newly installed in his regal but still-undecorated And How?
                    -Alleviation of Malnutrition? What?
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?
                      -"Above all, the traditional
It is a significant departure from do no harm" view of the USDA, which historically has
                 - Economics
emphasized programs that support commercial farming, such as price guarantees for crops and
                      - Cost/Benefit?
marketing promotions for exports.
               Gerald Fink
               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."

 The Human Genome Project: Part Two: Ushering in a new era of molecular medicine
 Date of Publication: 1998
      Human Genome Project (1990-2003)

  -Assemble & understand cellular networks

  - Manipulate cellular networks for Health
       - Pharmaceuticals & Nutrients
Managing/Engineering the Food
• 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
         Human Genetic Variation and Nutrition

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                    Dietary
                             Genome                 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.

Should drugs be matched
to the individual?

Nutritional Genomics-
Should diet be matched
to the individual or ethnic/genetic

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.

      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

   – B-vitamin deficiencies are common in all regions
       • Vitamin B12
   – Prevalence of malnutrition > poverty

• Genetic subpopulations may respond differently to nutrition

• 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 growth that describe the nutritional status of children:
period of time and is also affected by recurrent and 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

                               Risk Phenotype        Metabolic Disease
Early Nutrition                obesity               CVD
 Experiences                   hypertension          diabetes
                               insulin resistance    metabolic syndrome

                                 Stem Cells
                              Sense  Adapt
                         -Irreversible programming
    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

                                          You are what you eat …. or you are
Nat Genet. 1999 23:314                    what your mother ate?
J Nutr. 2002 132:2393S
Mol Cell Biol 2003 23:5293
Envir Health Perspect. 2006 114:567
                  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

                                                                                        Epigenetic Imprint Erased by
                               Increased Fetal GC                                       Histone Deacetylase Inhibitors

                                              GC Induced Events
                              - Small placenta
                              - CNS defects
                              - Attenuated HPA axis feedback sensitivity              - Low Birth weight (IUGR)
                              - Altered GR promoter methylation/expression declines
                              - Altered dopaminergic programming
                                                                                      - Elevated Plasma GC in adulthood
                              - Increased PEPCK expression                            - Hypertension
                                  (in adulthood/2nd generation)
                                    - inhibited insulin suppression of
                                                                                      - Hyperglycemia
                                          gluconeogenesis                             - Insulin Resistance
                                    - increased insulin
                                    - glucose intolerance
                                                                                      - Hyperinsulinaemia
                                                                                      - Anxiety
Folate Prevents
 Birth Defects
    in Early

   Nutrition      Folate Programs
    in Early      Gene Expression
 Development          in Early
   Programs        Development
Chronic Disease
Unintended Consequences of Nutrient (folic acid)

     Diabetologia (2008) 51:29-38

• 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
• Children (n=674) at 6 years of age
• Measure of insulin resistance: Homeostatic model
  assessment of insulin resistance (HOMA-R)
Insulin resistance

   “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
      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

Glucose     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
               Risk factors (ORs) associated with
                      metabolic syndrome
             Control      FA      FA/iron   FA/FE/Zinc   MM
High                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.”



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



Nutrition Science                                       Nutrition Implementation
Knowledge and Knowledge Gaps
- Nutrients/Diets and Health                             - Sustainable Ag/Food Systems
- Nutrition Assessment/Surveillance of Populations       - Intervention/Delivery Systems
- Epigenetic/Genetic/Ethnic subpopulations                         - Monitoring
                                                         - Social Behavioral Science
                                                                   - Context Specificity
Enablers                                                 - Health/cost benefit
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!

         Infection           Water

                  Human         Adolescent
 Education                      Pregnancy

             Disease       Diets
Thank you

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