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Departments of Nutritional Sciences and Biochemistry, University of Missouri, Columbia, MO 65211
2To whom correspondence should be addressed. E-mail: sunder{at}missouri.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONImportance of basic research...Status of human nutrient...Federal funding for nutrition...LITERATURE CITED |
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KEY WORDS: • exercise • genome array database • National Research Initiative • nutrient biomarkers • single polynuclear polymorphisms.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONImportance of basic research...Status of human nutrient...Federal funding for nutrition...LITERATURE CITED |
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). Less than a year later, the first annotations of the human genome were published (2
,3
). These most visible celebrations of the achievement of science offer new tools and new opportunities for human nutrition research in the 21st century. |
Importance of basic research for formulating nutrition recommendations |
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TOPABSTRACTINTRODUCTIONImportance of basic research...Status of human nutrient...Federal funding for nutrition...LITERATURE CITED |
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), and much of this increase occurred because of discoveries and subsequent application of knowledge in bioscience areas including nutrition. One hundred years ago, a trip to the grocery store or the farm was a perilous event. Immediate dangers of infection and disease and longer-term problems due to nutrient deficiency awaited the careless or unlucky shopper. Classic nutrition diseases, such as pellagra (or rickets or goiter), were a problem until discoveries provided the basis for widespread supplementation. By mid-century, supplementation of grain products with niacin, riboflavin and thiamin, milk with vitamin D, and salt with iodine largely eradicated these diseases in the U.S. How did we get to the point where acute nutritional deficiencies are no longer a major health issue in America? At the turn-of-the-century, numerous snake oils and other nutrient supplements were hawked by reputable and less-reputable merchants to provide protection from food-based perils. Some products, like cod liver oil, may in hindsight have had foundation while others were benign at best. So, what took these products off the late 20th century shelves?
These 20th century snake oils largely disappeared, not because each product was tested and shown to not be efficacious, but because basic nutrition research conducted at our nation’s universities identified the principles and levels of the required nutrients, vitamins and minerals necessary in our diet to prevent acute human deficiency diseases. In the face of knowledge, definitive recommendations and real benefit from the known essential vitamins and minerals, the snake oils of the 1900s largely disappeared from the marketplace.
Today, however, we’re faced with the new series of products—the vitamins, phytochemicals, functional foods, etc.—hawked from TV and the grocery shelves. These products are often marketed truthfully by well-meaning individuals and corporations, but can assume the properties of snake oils when marketed with unsupported promises that the consumer wants to hear. Some are undoubtedly good for us, others are questionable, and others are downright dangerous, such as products containing ephedra or St. John’s wort (5
,6
). Just as with the snake oils of the early 20th century, solid science will be needed to unravel the nutrition principles necessary to promote long-term health.
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Status of human nutrient recommendations today |
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TOPABSTRACTINTRODUCTIONImportance of basic research...Status of human nutrient...Federal funding for nutrition...LITERATURE CITED |
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), the crisis in evaluating diets for nutritional value was solved by agricultural researchers at land grant universities with the development of a biological method of assaying for required nutrients. This gave rise to the studies conducted in the first half of the 20th century that identified the fat soluble vitamins, the water soluble vitamins, the essential amino acids and most of the minerals that today we know are essential. Initial nutrient requirements were often based on growth or prevention of disease. Classic balance techniques were used to determine amino acid requirements; this approach works very effectively for nutrients that are highly absorbed, but the application of balance techniques to other nutrients has varying success because homeostatic mechanisms allow people to adapt to a broad range of nutrient intakes by using molecular regulation to increase absorption or decrease excretion rates. Biochemistry moved forward on this foundation in the mid-20th century and identified proteins and enzymes, dependent on sufficient minerals and vitamins in the diet, that could be used as markers for assessment of nutrient status.
Unfortunately, if one examines the 1989 recommended dietary allowances (RDAs)3
(8
), we find that only two of these requirements were based on biochemical parameters (vitamin K using prothrombin levels and selenium using glutathione peroxidase activity). Surprisingly, many of the 1989 requirements continued to be based on balance or factorial analyses in spite of research showing that status for these nutrients can be maintained at a variety of intakes by regulating absorption and/or excretion. Even in 1989, some requirements were based just on nutrient levels in typical diets or on disappearance from the national food supply.
The foundation for the new Dietary Reference Intakes (DRIs) released in 1998–2001 have only been strengthened slightly. Four of the new requirements are now based entirely or partially on a biochemical measure of analysis, and a number remain based on balance or factorial analysis (9
–11
). Not unexpectedly, none of the DRI human requirements at this time are based directly on analysis of gene expression.
This is a sad state of affairs for American nutrition and for American nutritional sciences. A compelling reason for the current paucity of good biomarkers for setting nutrient requirements is that we have lacked the necessary basic knowledge and tools to identify useful biomarkers. The human genome project and proteomics offer potential tools to identify these requirements and to base them on solid molecular science if we but empower this research with funding.
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Federal funding for nutrition research |
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TOPABSTRACTINTRODUCTIONImportance of basic research...Status of human nutrient...Federal funding for nutrition...LITERATURE CITED |
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), suggests that inadequate funding for competitive research has "limited its potential and placed the [National Research Initiative] program at risk." In addition, poor choices of priorities, in terms of where to invest this limited research support, have restricted the NRI program (12
). This is especially true for nutrition even when "Nutrition, Food Quality and Health" is one of the six divisions of the NRI.
Nutrition is an orphan priority in the federal funding picture. The National Institutes of Health (NIH), despite its name, is focused on the prevention of disease. In fact, the ongoing reorganization of NIH competitive grant review panels is slated to drop nutrition from the title of any of the 24 initial review groups (13
). NIH analysis of its research funding for biomedical research and training (Fig. 1
) calculates that <4% of total NIH funding is linked to nutrition ($695 million in FY00), in spite of recent heightened consumer awareness and interest in nutrition and health and in spite of potential cost-savings in disease prevention. This funding percentage has stayed relatively constant for the past 10 y. The National Science Foundation (NSF) provides support for the physical sciences and plant science, and few nutrition investigators receive funding from NSF. This leaves the USDA as the lead federal agency for nutrition research in regard to maintaining human health.
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). This competitive USDA funding of nutrition research (Fig. 1)
has increased only 18% in the past 5 y ($ 4.6 million in FY01), which is a rate of increase far below the increase in total NIH funding (
15% per year for the past 3 y). As shown in Fig. 1
, NRI funding for nutrition, like the NIH funding, has hovered around 4% of total NRI funding. If nutrition is an "orphan" priority in the federal research support profile, support for human exercise research seems to lack any home and, thus, should be called a "forgotten" priority in the federal research profile. In summary, nutrition and exercise are the two most cost-effective preventative treatments available to the American public, and yet these disciplines with headline public interest remain minor players in federal research funding. Additional new funds and a higher profile in the federal research picture will be needed if the human nutrition research is to take advantage of the sequencing of the human genome.
So what are opportunities today in this post–human genome-sequencing era? I have identified seven areas—four basic and three applied—where opportunity abounds if funding is made available and if the priority-setters have the courage to go for this gold.
1. Molecular biomarkers for nutrient status
The first opportunity I would like to discuss is the identification of molecular biomarkers for nutrient status. As Claude Bernard recognized 150 y ago, living organisms respond to changes in the environment by changing their metabolism. The key agents in these homeostatic processes are the sensors, like thermostats, of biological parameters such as temperature, body hydration, blood glucose or the level of a nutrient such as vitamin E or selenium or calcium or vitamin D. Today none of these sensors have been identified, but clearly they are encoded in the human genome and in the genomes of animals and other species. Aggressive nutritional scientists today need to seek these sensors and the related signaling proteins, enzymes and mRNAs. Analysis of the state of these sensors should be able to indicate the organism’s assessment of its status rather than the currently used biomarkers, which are used to make a best-guess at status.
Microarrays (14
,15
) are likely to be at the center of this research. Using array technology, scientists will be able to generate genome-wide maps of the impact of mild and severe nutrient deficiency or excess; these maps will provide signatures for simple nutrient deficiencies and may guide the discovery of genes responsible for the homeostasis of the nutrient of interest. Knockout animal models are also likely to be important in the discovery and characterization of these sensors. The result will be identification of appropriate parameters on which to base the nutrient requirements for our nation.
As in emerging applications of genomics to medicine, these studies are likely to identify individual-to-individual phenotypic variations in simple nutrient deficiency (see below). More exciting is the possibility that microarray analysis will help to identify the cause of more complex diseases. A signature feature of these complex diseases—called quantitative trait locus (QTL) disorders—will be a unique state of sets of gene families (16
). The role of nutrition in the development and therapy of these diseases can be studied by these same approaches that are now being contemplated by medical researchers (16
).
2. Single polynuclear polymorphisms
The human genome project has more for nutrition. With the annotation of the human genome, it is clear that there are a significant number of variations at single nucleotide base positions, called single polynuclear polymorphisms (SNPs), between any two copies of the human genome. These include inborn errors of metabolism resulting from insertions, deletions and changes in single basepairs in a gene, which yield changed amino acids in, or changed expression of, critical proteins. Recent mapping has found 1.42 million human SNPs with an average density of 1 SNP per 1.9 kb of DNA (17
). There was great excitement a few years ago when an SNP in the vitamin D receptor seemed to cause a difference of as much as 18 y in the spinal bone density of postmenopausal women (18
). This original report has not been fully substantiated (19
), but the premise is most tantalizing. We know that epidemiology can uncover significant health-promoting activity in a small number of individuals who are eating less salt or higher levels of plant proteins or who meet the five-a-day requirements for vegetables and fruits. SNPs must be what separates these responsive individuals from the rest of us. The application of QTL analysis using microarrays will make individual assessment of nutrient status a reality and should enable the characterization of individual variation in nutrient status and requirements. This is an opportunity like never before to characterize the cause of these individual differences and to identify when easy treatments like a diet change can make a profound difference in the health and well-being of individuals.
3. National genome array nutrition database
Federal support and organization is needed for public repositories of gene expression data that will make emerging sets of nutrition data available to all researchers. Databases reporting differences in gene expression due to different nutrient intakes will allow full analysis of the data by others without having to conduct the studies again. This will save federal resources and scientists’ time. Several efforts are currently underway to establish and unify repositories for data from gene array studies (Gene Expression Omnibus, http://www.ncbi.nlm.nih.gov/geo/ [20
]; Array Express, http://www.ebi.ac.uk/arrayexpress/ [21
]), and consortiums have proposed construction of databases for cancer and other diseases (22
). Nutrition needs to be added to these efforts now. Importantly, this will make this nutrition-related data available to researchers in other disciplines who lack the ability to conduct nutrition experiments but whose research evolves with a relationship to nutrition.
4. Nutrition research at all phylogenetic levels
Just because we now have an annotated human genome, nutrition research should not focus just on human nutrition. We need to continue to sustain nutrition research at all phylogenetic levels. To help us fully annotate and understand the human nutrient genome, we will need to know about the nutrient requirements and the underlying molecular mechanisms of these model organisms, including the homoeostatic sensors that these organisms employ. For example, the presence of nickel-containing enzymes in bacteria may provide the guide to find nickel-containing enzymes in humans. In turn, this may reveal new molecular bases for unexplained disease. Additionally, nutrient requirements for pathogenic bacteria or viruses (see below) may be important in devising nutritional regimens in the treatment of disease.
5. Diet and human health
The role of diet in promoting human health is an important area for study in the post–human genome-sequencing era, and yet our current recommendations to the public are often in disarray due to conflicting results and multiple groups making recommendations. The new guidelines for treating people with heart disease illustrate these mixed messages. While the previous 1993 National Cholesterol Education Program report (23
) recommended delaying drug therapy in most young adult men and premenopausal women, the new 2001 report (24
) now eliminates the recommendation for a delay and instead recommends a more aggressive strategy that could increase the number of Americans using cholesterol-lowering drugs to 33 million, which is triple the current figure. Buried in the coverage is that many individuals can reduce their blood cholesterol by 10–20% via dietary intervention. Similar shifts in dietary recommendations, for instance recommended consumption of eggs or total dietary fat, continue to confuse the public (e.g., Time, 7/19/99, "Eat Your Heart Out") (25
). Clearly, better understanding of the underlying genetics should allow targeting of drug therapy toward just those who will benefit from treatment rather than up to a third of all adult Americans.
Failure of simple characterization of a lifestyle based on one nutrient clearly demonstrates that there is more to nutrition than the dietary content of known essential nutrients. For example, a Finnish study made it clear that the supplementation of ß-carotene alone had a negative impact on the recurrence of lung cancer in smokers (26
). Important societal concerns, such as early puberty in our young and atypical cancers, suggest that nutrition is more than the 45+ identified essential nutrients. An understanding of the role of phytonutrients in promoting human health should be a clear goal of human nutrition research in the post–genome-sequencing era. Similarly, the nutrition of genetically modified foods has a clear and important place in 21st century research. These studies, too, will need to be conducted in the context of the human genome and SNPs if they are to provide clear answers and recommendations.
As priorities for research on phytonutrients and genetically modified foods are established, complementation with other federal research programs will need to be considered, as illustrated by the annual budget of NIH’s newly created National Center for Complementary and Alternative Medicine (NCCAM). The NCCAM FY01 budget of $89 million was 84% of the total NRI FY01 budget and 19-fold the NRI funding for human nutrient requirements.
6. Nutrition and pathogenesis of human disease
Lethal diseases like AIDS are not new. For instance, a diagnosis of pernicious anemia once had the same sound and ring as AIDS today; if you were diagnosed with pernicious anemia before 1948, you typically had 2–5 y to live. There simply was nothing that anyone could do for you until nutrition researchers discovered that this disease was due to vitamin B-12 deficiency and that vitamin B-12 injection could reverse the disease. The influenza epidemic of 1918 came and went without much real scientific intervention, but the danger of a return is compelling. This past May, public health officials in Hong Kong killed 1.2 million birds to prevent a bird flu outbreak similar to the outbreak in 1997 that killed six people, because these outbreaks have the potential to become a lethal worldwide flu (27
).
This area of diet and disease research is not the same as discussed under diet and human health research. Instead, exciting new data suggest that the nutrient status of an organism can have profound impact not only on the overall health and immunology of the host individual, but also on the pathogenesis of the infecting organism. Dr. Melinda Beck in North Carolina is demonstrating that an avirulent coxsackie virus can mutate and become virulent in certain strains of mice fed diets lacking selenium or vitamin E (28
). What if nutrient imbalance participates in the generation of new stains of flu, such as the avian flu eradicated in Hong Kong? More recently Dr. Beck has expanded her studies to show that mutation of the influenza virus in a mouse model, too, is accelerated if the mice are selenium deficient. These studies thus suggest that poor animal nutrition, such as in Southeast Asia or Central Africa, may promote the mutations that give rise to the virulent flu viruses or perhaps Ebola-like viruses. Research funding for the study of the impact of diet on the pathogenesis of disease has the potential to vastly improve public health.
7. Exercise and health
Exercise remains a key aspect of a healthy lifestyle. Recommendations on neither diet change alone nor exercise alone seem to be effective in curbing the progression of obesity in America. A combined prescription of diet and exercise, however, may hold the key. Similarly, the primary prevention therapy for chronic heart disease (described in third report of the National Cholesterol Education Program (24
) (discussed above) includes reducing intake of saturated fat and cholesterol, increasing physical activity and practicing weight control. Clearly we need increased knowledge about all aspects of exercise and health promotion. Yet, without targeted federal funding and without a home agency, recommendations about exercise will be at the level of nutrition recommendations at the turn of the 20th century.
In summary, the science of nutrition made a profound impact on the health of Americans in the 20th century. Basic research identified the principles of human nutrition, and acute nutrition diseases have largely disappeared in America due to good nutrition, public health and advances in medicine. But today, our focus has shifted to promoting health throughout the life cycle, not just to preventing acute disease. Basic knowledge in nutrition again can help to move recommendations for long-term health onto solid footing. The USDA needs sufficient funding, organization and priority-setting to accomplish its role as the lead federal agency for maintaining human health through nutrition.
The sequencing and annotation of the human genome, accompanied by proteomics and metabolomics, can provide the tools that aggressive nutrition research will need if we are to inexpensively promote the health, longevity and well-being of America’s citizens. These opportunities in the post–genome-sequencing era include identification of the molecular biomarkers, the nutrient thermostats, which can be used to establish nutrient requirements not only under easy conditions but also in the pregnant, in the aged and in the diabetic subject. These discoveries will also have important impact on animal nutrition, in the cost of diet formulation and in protection of the environment from nutrients not needed. Characterization of SNPs in the human genome will make individual assessment of nutrient status a reality and should enable characterization of individual variations in nutrient status and requirements. The potential application of array technology to human nutrition research is exciting; federal leadership and funding for array databases that include nutrition information are needed. Nutrition research should continue to study all phylogenetic levels to take advantage of these model systems to help unravel the intricacies of human nutrition. On the applied side, application of post–genome-sequencing knowledge and tools to the study of diet and health nutrition may generate recommendations that will stand the test of time; this includes recognized nutrients, phytonutrients and other health-promoting substances in foods and analysis of the nutritional and health impact of genetically modified foods. A priority should be made to study the role of nutrition in the pathogenesis of disease, with a focus on the nutrient requirements of the pathogen as well as the host. Lastly, a funding home for nutrition and exercise research needs to be developed in this increasingly inactive, overweight and obese America. The USDA must lead and support these efforts.
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FOOTNOTES |
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3 Abbreviations used: DRI, Dietary Reference Intake; NCCAM, National Center for Complementary and Alternative Medicine; NIH, National Institutes of Health; NRC, National Research Council; NRI, National Research Initiative; NSF, National Science Foundation; QTL, quantitative trait locus; RDA, recommended dietary allowance; SNP, single polynuclear polymorphism.
Manuscript received August 3, 2001. Revision accepted September 11, 2001.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONImportance of basic research...Status of human nutrient...Federal funding for nutrition...LITERATURE CITED |
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1. Genetic Code of Human Life is Cracked by Scientists. New York Times. New York, NY .
2.
Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J., Sutton, G. G., Smith, H. O., Yandell, M., Evans, C. A. & Holt, R. A., et al (2001) The sequence of the human genome. Science 291:1304-1351.
3. International Human Genome Sequencing Consortium (2001) Initial sequencing and analysis of the human genome. Nature 409:813-958.[Medline]
4. May, R. M. (2001) Science and society. Science 292:1021-1021.[Medline]
5. Spake, A. (12 February 2001) Natural hazards. U.S. News and World Report :42-49.
6. Kockler, D. R., McCarthy, M. W. & Lawson, C. L. (2001) Seizure activity and unresponsiveness after hydroxycut ingestion. Pharmacotherapy 21:647-651.[Medline]
7. Kuhn, T. S. (1962) The Structure of Scientific Revolutions 1962 University of Chicago Press Chicago, IL. .
8. National Research Council (1989) Recommended Dietary Allowances 1989 National Academy Press Washington, DC. .
9. Food and Nutrition Board (2001) Dietary Reference Intakes for Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc 2001 National Academy Press Washington, D. C. .
10. Food and Nutrition Board (1999) Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride 1999 National Academy Press Washington, D. C. .
11. Food and Nutrition Board (2000) Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium and Carotenoids 2000 National Academy Press Washington, D.C. .
12. National Research Council (2000) National Research Initiative 2000 National Academy Press Washington, DC. .
13. Phase 1 Report Panel on Scientific Boundaries for Review (2000) Recommendations for Change at the NIH’s Center for Scientific Review 2000 NIH Available at http//www.csr.nih.gov/EVENTS/summary012000.htm. Accessed 3 August 2001..
14. Petrik, J. (2001) Microarray technology: the future of blood testing?. Vox Sang 80:1-11.[Medline]
15. Knight, J. (2001) When the chips are down. Nature 410:860-861.[Medline]
16.
Peltonen, L. & McKusick, V. A. (2001) Dissecting human disease in the postgenomic era. Science 291:1224-1229.
17. Sachidanandam, R., Weissman, D., Schmidt, S. C., Kakol, J. M., Stein, L. D., Marth, G., Sherry, S., Mullikin, J. C., Mortimore, B. J. & Willey, D. L., et al (2001) A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409:928-933.[Medline]
18. Morrison, N. A., Qi, J. C., Tokita, A., Kelly, P. J., Crofts, L., Nguyen, T. V., Sambrook, P. N. & Eisman, J. A. (1994) Prediction of bone density from vitamin D receptor alleles. Nature (London) 367:284-287.[Medline]
19. Morrison, N. A., Qi, J. C., Tokita, A., Kelly, P. J., Crofts, L., Nguyen, T. V., Sambrook, P. N. & Eisman, J. A. (1997) Prediction of bone density from vitamin D receptor alleles-corrections. Nature (London) 387:106.
20. National Center for Biotechnology Information Gene Expression Omnibus Available at: http://www.ncbi.nlm.nih.gov/geo/. Accessed 3 August 2001.
21. European Bioinformatics Institute Array Express Available at: http://www.ebi.ac.uk/arrayexpress/. Accessed 3 August 2001.
22. Free and public expression. Nature 410:851.
23. National Cholesterol Education Program & National Institutes of Health (1993) Detection, evaluation, and treatment of high blood cholesterol in adults (ATPII). NIH Pub 93-3096:1-14.
24. National Cholesterol Education Program & National Institutes of Health (2001) Detection, evaluation, and treatment of high blood cholesterol in adults (ATPIII). NIH Pub 01-3670:1-28.
25. Lemonick, M. D. () (19 July 2000) Eat your heart out. Time :40-54.
26.
Albanes, D., Heinonen, O. P., Taylor, P. R., Virtamo, J., Edwards, B. K., Rautalahti, M., Hartman, A. M., Palmgren, J., Freedman, L. S. & Haapakoski, J., et al (1996) Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. J. Natl. Cancer Inst. 88:1560-1570.
27. Associated Press () (20 May 2001) Bird flu forces poultry slaughter. Columbia Daily Tribune. Columbia, MO .
28.
Beck, M. A. (2000) Nutritionally induced oxidative stress: effect on viral disease. Am. J. Clin. Nutr. 71:1676S-1681S.
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) for FY94–01, and funding for nutrition research and training by the NIH, expressed in dollars (
, right axis) and as a percentage of the total NIH budget (
) for FY94–99. In FY99, NRI human nutrition funding was $4.52 million of $119.3 million in the total NRI budget, and nutrition-linked funding was $695 million of $17,800 million in the total NIH budget.