Current advances in genomic technology are opening the way for a new era in which nutrient doses for individuals will be tailored to their unique biochemical requirements. Well, according to American people, the most nutritious foods in daily cuisine play very important role for their health, similar to the role of the best gun safe for their weapons.
Just as Shakespeare’s character Othello was described as “one that loved not wisely, but too well,” America might be characterized as a nation that eats not wisely but far too well. Nearly half the people in the United States struggle with a weight problem, or at least have the feeling that they ought to worry about their weight. Such concerns are entirely justified. Between 25 and 30 percent of us are overweight, and an additional 14.5 percent of Americans are clinically obese. Moreover, unless something changes, these percentages are likely to increase, as sedentary occupations characteristic of the “new economy” steadily replace “old economy” agricultural and manufacturing jobs that required much more in the way of manual labor.
These trends in decreasing physical activity and increasing obesity have serious medical consequences. People who are overweight have two to four times the risk of chronic heart disease compared to those whose weights are at or below optimum levels. Some 15.7 million Americans have the most common (type 2) form of diabetes mellitus, which often is triggered by obesity. Treatment of this single metabolic disorder costs an estimated $98 billion. If trends in inactivity continue in our steadily aging population, the incidence of diabetes alone is projected to increase about 60 percent by 2025. Similar statistics can be offered for coronary heart disease, which is significantly affected by levels of fat consumption. Furthermore, overweight contributes markedly to the incidence and severity of joint disorders such as osteoarthritis–which tends to reduce activity levels still further, thereby contributing to a self-reinforcing problem of weight control.
Although the processes and statistics of such degenerative diseases may not be known in detail by everyone, nearly all of us are aware that when we are overweight we don’t feel at our best. Even in the absence of clinical symptoms, we are likely to have less energy and more disabilities. Even more serious are the dangers that go unfelt and unseen: elevated cholesterol levels and high blood pressure. The former contributes to buildup of plaque deposits in arteries, while the latter pumps harder against the stiffened arterial walls–an altogether risky combination that can be ignored for years but only against increasingly rising odds of heart attack, stroke, kidney damage, and more.
Conflicting diet docs
Rising levels of education have heightened general awareness of such problems, and many people seriously consider making efforts to improve both appearance and health. But even when they are motivated by serious concerns, they confront other problems, in the form of conflicting claims aboutexercise and diet programs. In the popular realm of books with diet advice, the most visible skirmishing is at the macronutrient level: fats, carbohydrates, and protein. The marketplace offers various experts giving profoundly different macronutrient intake advice.
- The resultant confusion is so serious that in February the U.S. Department of Agriculture took the unusual step of convening a panel of experts to discuss and debate three strikingly different recommendations for diets to control body weight. The extremes were clear; one (Dean Ornish) advocated meals high in carbohydrates, while another (Robert Atkins) permitted all the meat that adherents of the diet might want to consume–but little else. In addition, Barry Sears advocated a middle position, but it seemed almost equally unconvincing in the absence of independent assessment. Unsurprisingly, given such different standpoints, no consensus was reached.
Yet nutrition involves not only the big three macronutrients but also numerous micronutrients: vitamins,minerals, trace elements, and even electrolytes. As we enter the new century, science stands at the door to a major transformation in our understanding and management of both macro- and micronutrients. For the moment, however, most research is focused on the micronutrients.
- The key to these revolutionary developments is the demonstration that each of us is genetically unique–and therefore is almost certain to thrive on a diet tailored to our individual needs rather than merely getting along on some general regimen.
An individual or a statistic
At the recent scientific megaconference Experimental Biology 2000, an entire symposium was devoted to the topic of nutritional and metabolic diversity: understanding the basis of biological variance in the obesity/diabetes/cardiovascular disease connection. Within this symposium, which represented the most current thinking on the subject, the papers demonstrated clearly the sharp contrast between conventional and innovative approaches. Perhaps most striking was the lecture by R.M. Krauss of the University of California at Berkeley on diet-gene interactions as illustrated by the diversity in dietary effects on atherosclerosis susceptibility. His surprising but well-documented results showed that, counter to the general dietary recommendation that Americans should decrease the percentage of fats in their diets, a subset of the population has a genetic makeup that causes them to respond to lowered fat intake with a rise in the levels of low density lipoproteins (LDLs–carriers of cholesterol to the cells) in the blood.
Since the U.S. diet tends to produce an unhealthy excess of LDLs, this change would impair the management of cholesterol levels in certain individuals, a result opposite to that expected from a low-fatdiet. These results pointed up the high desirability of identifying relevant genotypes and prescribing diets tailored specifically to them–what might be termed “individualized” or “genomically tailored” nutrition.
At the same symposium, some papers presented more conventional approaches to diet, emphasizing the common needs of broad groups in the population based on such factors as age, gender, and activity levels. A prime example was a paper that outlines the recommended dietary allowances (RDAs) for the year 2000. Assumed here was a normal (bell- curve) distribution of nutrient needs in the population. As has been the convention for more than 50 years, nutrient levels were targeted at the broad middle range of population, then augmented with a “safety factor” that raises the recommended levels to take into account those who might have greater needs for certain nutrients: people who were very active physically, pregnant women, and nursing mothers. This strategy for prescribing dietary composition might be characterized as “statistical nutrition.”
In summary, we could say that the symposium highlighted what may be the twilight of statistical nutrition and the dawn of genomically tailored nutrition. Of course, we should acknowledge that the statistical approach to nutrition has served the U.S. population well for decades. At the same time we are called to recognize that science is beginning to offer alternatives that can serve everyone even better; that is, every one of us uniquely. One source of urgency impelling a shift to genomically tailored nutrition is the RDA convention of factoring in the augmented amounts–those “safety factors.”
Too much or not enough?
Among the many gene-based nutritional variants is hemochromatosis, an iron metabolism disorder whose symptoms include hair loss, joint pain, and persistent fatigue. Although often undiagnosed, hemochromatosis is the most common inherited illness in the United States. Because our population has diverse origins, frequencies vary widely. Among people with western European, particularly Anglo-Saxon, backgrounds, about one or two individuals per thousand have inherited the same responsible gene from both parents, that is they are homozygous for the gene. Those who have only one of the responsible genes, the heterozygous carriers, are quite common–1 in 20 to 1 in 30. Those homozygotes who suffer from hemochromatosis do not have a nutritional deficiency; rather they have too much iron in their bodies because they selectively retain this element. For such people, the RDA “safety factor” added for iron can only exacerbate their condition.
Of course, the problem of a poor fit between individual nutritional needs and standard dietary prescriptions can go in the other direction as well. For example, people with sickle cell disease require not only higher than normal doses of iron because of severe inherited anemia but also higher than normal doses of vitamin C. This is a case in which the substitution of a single nucleotide base at the DNA level creates very special nutritional requirements. An extreme example such as this can help us understand why different dietary studies might produce conflicting results.
Just recently, vitamin C–recommended in large doses by dietary gurus such as the late Linus Pauling for its antioxidant action among other properties–has been shown in one study to raise, not lower, the risk of arterial plaque formation. In the absence of a plausible mechanism of action, these results are controversial. Might differences in the composition of the subject populations be part of the explanation for differing results?
Genetic variations account for not only hemochromatosis and sickle cell anemia but a diversity of other generally rare conditions. Among these are phenylketonuria (PKU), which occurs in about 1 in 20,000 births. Affected individuals cannot digest milk or milk products because they lack the gene for making an enzyme that breaks down the common amino acid phenylalanine, which happens to be particularly concentrated in milk. Such gene-based differences in food-processing capabilities call into question the statistical nutrition assumption that a single diet could be suitable for just about everyone, because we all are relatively uniform genetically. Of course, at some informal level many people have isolated bits of information that should instead reinforce a belief in the genetic uniqueness of every person. After eating beets, for example, some people produce reddish urine while others do not. Most people can taste a family of chemical compounds, thioureas, that are widely distributed in plants of the genus Brassica, including cabbage, cauliflower, brussels sprouts, turnips, rutabagas, and other common vegetables; to others of us, such compounds are tasteless.
For decades such knowledge has remained in the realm of dietary curiosity, overshadowed by official assurances that the diversity so documented is unimportant in comparison with nutritional needs that have been officially codified in the form of RDAs. The main RDA table sets levels for protein, vitamins, minerals, trace elements, and electrolytes. As noted previously, different levels are recommended for infants and children, men and women, and females who are pregnant or lactating. Nonetheless, at the core of the RDA tables is a “reference woman” (between 23 and 50 years of age, 5 feet 5 inches tall, who maintains her weight of 128 pounds on 2,000 calories) and a “reference man” (5 feet 9 inches tall, weighing 154 pounds, maintained on 2,700 calories). Both sleep or rest for eight hours per day, sit for seven hours, stand for five, walk for two, and participate in light physical activity for the remaining two hours. These nutrient RDA values are set on the assumption that the nutritional requirements for very nearly all people (about 95 percent of the population) will be met by them.
Pro choice (in foods)
The statistical approach to nutrition embodied in the RDA is similar to the approaches embodied in recommendations for pharmaceutical drugs, exposure to radiation, and so on–that most of any population described by a more or less normal distribution will be served relatively well and few will be harmed. In one sense these assumptions have been acceptable; after all, Americans are generally well fed (and as noted at the outset, many of us are too well fed), relatively free of disease, and so on.
But then, it could be argued that in the first several decades of the century, Americans were served very well indeed by Henry Ford’s Model T: four cylinders powering four wheels, on which rested a metal box that purchasers could have in any color as long as it was black– perhaps the ultimate embodiment of a “one size fits all” philosophy. Subsequent decades have produced not only an explosion of automotive stylistic variation but real distinctions in size, fuel economy, speed, and safety. As a result of scientific and engineering advances, we have an enormous variety of choices to match lifestyles, preferences, and pocketbooks (or usually at least some reasonable compromise among those factors).
Should we settle for less choice in our foods than in the automotive realm, when our lives and health might be better served by the recognition that nutritional needs differ more widely than traditionally accepted? Persons with LDL levels in the 5 percent tail- end of a normal curve, for example, have lower than average risk for atherosclerotic heart disease but (for reasons as yet unknown) manifest higher than average levels of risk for a variety of cancers and diseases of the lungs and gastrointestinal tract.
Persons with a related syndrome, abetalipoproteinemia (ABL), exhibit extreme limitations in absorbinglipids (dietary fats) through their intestines. They also show signs of central nervous system degeneration and tend to experience retinal damage early in life. Similarly, chylomicron retention disease resembles ABL with respect to the malabsorption of dietary fat and its consequences, although the precise nature of the molecular disorder is unknown. Given these and other inherited disorders that affect lipid uptake from the digestive tract, it is not difficult to imagine the existence of still other genetic variants with less radical effects on both lipid uptake (and hence availability of the lipids as calories) and weight gain or loss.
Saved by the chip
The rapid advance of genomic science introduces the emerging possibility of identifying these variant genes for numerous metabolic differences, just as we have already identified variant genes for other physiological differences. Research scientists at the University of Cincinnati have discovered that the substitution of a single DNA base at a genetic locus involved in regulating blood pressure can be used to predict whether a given patient with congestive heart failure would respond better to the usual drugs or require alternative therapy. Researchers have identified other such single nucleotide polymorphisms correlated with biochemical uniqueness, and diagnostic chips are being produced to test for them [see “Genes on a Chip,” The World & I, September 1997, p. 189]. These chips should be commercially available within the year.
A review of the recent literature on the contribution of genes to human metabolic and nutritional differences reveals abundant and detailed evidence along the lines of the preceding examples. Diverse genetic variants influence the metabolism of amino acids and fats, a variety of vitamins and minerals, and carbohydrates such as the sugars fructose, galactose, and glucose. Comparative genomic research also reinforces the idea that genes contribute significantly to the relationship between diet and weight control. One group of investigators has reported finding five mutant genes, located on five different chromosomes, that cause obesity in mice. Regions homologous (structurally and functionally comparable) to these mutations are also located on five human chromosomes. The different chromosomal regions associated with obesity seem to be part of complex, multigene systems, a picture that fits well with what we know about the overall interplay of heredity and environment in nutrition and growth.
Given the rapidity with which gene sequencing can be carried out, it is all but certain that during the next decade, a full or partial readout of one’s genome will become as routine and essential a part of health care as a detailed family history is now. Once this step has been taken, population-based RDA values can–and should–be supplanted by individualized prescriptions for diet and physical activity.
Recognition of biochemical uniqueness should result in a unique array of solutions to one of our most common “weighty” problems.n
Robert B. Eckhardt is professor of developmental genetics and evolutionary morphology in the Department of Kinesiology at Pennsylvania State University.