Patrick J. Stover, PhD

1. 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

2. Common Nutrient Deficiencies: Known: Vitamin A Iron Iodine Zinc Folate Others: Vitamin B12

3. Food and Agriculture Systems • How do you balance the agenda? • Food/Ag Production? • Economics? Exports? Energy? • Food Consumption/Food Quality? • Alleviation of Hunger? • Alleviation of Malnutrition? • Health/Disease Prevention/Increased productivity? • What is Achievable? • Science/Evidence base? • Food for Health? • Food as Medicine? • "Above all, do no harm" • Economics • Cost/Benefit? Policy Practice/Training Research NUTRITION Double Burden What? And How? But Vilsack, newly installed in his regal but still-undecorated office on Independence Avenue, is out to redefine himself and his vision. In an interview this week, he called for a "new day" for the U.S. Department of Agriculture's sprawling bureaucracy, which he believes should champion not only farmers but also everyone who eats. "This is a department that intersects the lives of Americans two to three times a day. Every single American," he said. "So I absolutely see the constituency of this department as broader than those who produce our food -- it extends to those who consume it." It is a significant departure from the traditional view of the USDA, which historically has emphasized programs that support commercial farming, such as price guarantees for crops and marketing promotions for exports. NFHS-3

4. 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 medicineDate of Publication: 1998

5. 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

6. Managing/Engineering the Food System • Types of food • Manipulation of the food supply • Biofortification • Fortification • Voluntary • Mandated • Supplementation

7. 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.

8. 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

9. Dietary Components Human Genome Gene-Nutrient Interactions Nutrition and Evolution Genome Primary Sequence - mutation rate - selection Genome Programming - stem cells Gene Expression Food Intolerances Dietary Requirements Susceptibility to metabolic disease

10. Classifying Humans: Paving the way for personalized medicine & nutrition Milner JA. Nutrition in the 'omics' era. Forum Nutr. 2007;60:1-24. Review. Pharmacogenomics- Should drugs be matched to the individual? Nutritional Genomics- Should 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”?

11. Birth Defect Prevention gene-diet interactions

12. Neural Tube Closure • Requires precise coordination of: • - Cell Proliferation • - Survival • - Differentiation • - Migration • Neural Tube Defects • spina bifida • anencephaly

13. 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.

14. 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

15. 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

16. Mechanism? Folic Acid NTD Prevention 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 • Exacerbate common concerns of unintended consequences

17. 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.

18. Undernutrition and Growth in India NFHS-3 2005-2006 Stunting reflects failure to receive adequate nutrition over a long period of time and is also affected by recurrent and chronic illness. Three indices of physical growth that describe the nutritional status of children: • Height-for-age (stunting) • Weight-for-height (wasting) • Weight-for-age (underweight)

19. Fetal Origins of Adult Diseaseor “Barker” Hypothesis Fetal environmental exposures, especially nutrition, act in early life to program risk for adult health outcomes “Program” “Imprint” Risk Phenotype obesity hypertension insulin resistance Metabolic Disease CVD diabetes metabolic syndrome Early Nutrition Experiences • Stem Cells • Sense  Adapt • Irreversible programming

21. Avy/a mice Persistent Effects of B-Vitamin Nutrition • 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 what your mother ate? Nat Genet. 1999 23:314 J Nutr. 2002 132:2393S Mol Cell Biol 2003 23:5293 Envir Health Perspect. 2006 114:567

22. Genome Programming During Development-- Targeting Methylation --(Physiol. Rev. (2005) 85:571-633) Low Maternal Protein Reduced 11b-HSD2 expression (Glucocorticoid catabolism) Human GC therapy Loss of Placental GC Barrier Epigenetic Imprint Erased by Histone Deacetylase Inhibitors Increased Fetal GC 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

23. Folate Prevents Birth Defects in Early Development ? Stunting/ Nutrition in Early Development Programs Chronic Disease Folate Programs Gene Expression in Early Development

24. Unintended Consequences of Nutrient (folic acid) Supplementation Diabetologia (2008) 51:29-38

25. 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)

26. Insulin resistance 356

27. “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

28. 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 ….

29. J Nutr 139:1-7, 2009

30. 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)

31. 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)

32. 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)

33. Risk factors by treatment group

34. Risk factors (ORs) associated with metabolic syndrome * Significant

35. “There is still much to be learned about the effects of micronutrient nutrition during this critical period of the lifespan.”

36. 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

37. Harmonizing Nutrition and Food Systems Policy Practice/Training Research NUTRITION • 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

38. Water Infection Human Nutrition Adolescent Pregnancy Education Inadequate Diets Disease Food and nutrition is not the same!

39. Thank you