Which are the greatest recent discoveries and the greatest future challenges in nutrition?
Discoveries
The discovery that folic acid prevents birth defects was judged to be the greatest discovery in nutrition science since 1976. It was a discovery in which neither the speakers nor the audience had been actively involved. In fact, the discovery that periconceptional supplementation with folic acid prevents most cases of spina bifida and anencephaly was not made by nutrition scientists, but by British doctors working on the prevention of birth defects (Smithells et al., 1976; MRC Vitamin Study Research Group, 1991). The story of this discovery spans 50 years (Willett, 1998). A synthesis of data from clinical observations, biochemistry, epidemiology, genetics and randomized clinical trials was required to establish that periconceptional folic acid prevents birth defects. The discovery also overturned the dogma that an apparently balanced diet provides enough of all nutrients. The subsequent addition of folic acid to staple foods in North America clearly reduced the incidence of this most common of the major congenital abnormalities (Persad et al., 2002).
The discovery ranked no. 2 was the health effects of trans fatty acids. Three of the five speakers had been involved in this discovery (Mensink and Katan, 1990;Willett et al., 1993), so there may be bias here. But the discovery of the adverse effects of trans fatty acids on blood lipoproteins and incidence of heart disease continues to affect both nutritional guidelines and food composition worldwide. Throughout the twentieth century, the partial hardening of oils with the concomitant production of trans fatty acids had been a pillar of the food industry, with huge investments in research and factories (Korver and Katan, 2006). All that is being phased out now, and the replacement of partially hydrogenated by unprocessed oils is likely to prevent many myocardial infarctions.
No. 3 was the nutritional regulation of gene transcription. Examples of this are the way dietary fatty acids regulate hepatic fatty acid synthesis and breakdown via nuclear receptors (Shulman and Mangelsdorf, 2005), but the discoveries go beyond that. Molecular biology is opening up the black box of the regulation of intermediary metabolism (Desvergne et al., 2006), and this has consequences for our understanding of vitamin, protein, lipid and carbohydrate metabolism, and of disease development.
Arguably, this discovery might have been combined with no. 6, the LDL receptor and its regulation by diet. The regulation of the activity of the LDL receptor by dietary cholesterol was elaborated by Brown and Goldstein around 1976 in a model of brilliant simplicity and predictive power (Kovanen et al., 1981). Unfortunately, we still lack a similar insightful explanation of why the structure of dietary fatty acids affects blood lipid levels. Why do saturated and trans-unsaturated fatty acids raise and cis-unsaturated fatty acids lower LDL cholesterol? Many mechanisms have been proposed, but none entirely satisfactory (Spritz et al., 1965; Spritz and Mishkel, 1969; Beynen and Katan, 1985; Fox et al., 1987; Lin et al., 2005).
Discovery nos. 4 and 5 both represent gains made in obesity research. Essential to discovery no. 4, progress in measuring energy intake, was the doubly labeled water technique for estimating energy expenditure and intake. Application of this technique to humans (Schoeller and van Santen, 1982) showed that traditional dietary history and recall methods underestimated energy intake, and that this bias increases with increasing body fatness. The paradox that the more obese a person is, the less they appeared to eat had puzzled scientists, but it took many doubly labeled water measurements plus years of heated debate before it was accepted that obese people eat more than lean people, at least in populations with limited variation in physical activity. The issue was sensitive because the results of the doubly labeled water studies seemed to put the blame on obese subjects, and in addition, they appeared to discredit the recall techniques so widely used in nutrition and dietetics.
Discovery no 5, fat tissue as an endocrine organ, was heralded by the discovery of leptin and its absence in a genetic model of rodent obesity (Zhang et al., 1994). Leptin was followed by tumor-necrosis factor-
, adiponectin, resistin and other hormones. These have drastically changed our view of adipose tissue metabolism and have given important insights into the mechanisms linking obesity with type II diabetes, atherosclerosis and other diseases (Rosen and Spiegelman, 2006; Trujillo and Scherer, 2006).
No. 7, obesity is a normal response to an abnormal environment, represents a step forward in a different area of the obesity issue, namely the role of the environment. Until recently, the search for causes of weight gain focused on genetic or metabolic abnormalities of obese people. Also, obese individuals were considered to lack the willpower to eat less or exercise more (Prentice and Jebb, 1995). But from a public health point of view, obesity can be also be viewed as a normal reaction to an abnormal environment (Egger and Swinburn, 1997) instead of a disorder. Attempts to improve individual diet and exercise habits may not be enough to curb the obesity epidemic; we may also need to create healthier school environments, transportation systems and town planning.
No. 8, alcohol causes breast cancer (Williams and Horm, 1977), and no. 9, body fatness is the second most avoidable cause of cancer (Lew and Garfinkel, 1979), together represent the major known dietary causes of cancer. Implicitly, they also illustrate the problems and frustrations of the diet and cancer field. Early in our 30-year time frame, observations on carotenes and on dietary fat seemed to offer hope of reducing the incidence of cancer through changes in nutrient intake (Petoet al., 1981), but new research has shown that the prospects for reducing cancer through a change of nutrient intake are more limited (WCRF, 2007). There remains a real possibility that we have not investigated the critical periods in life. Effects of diet during childhood and early adult life on later risk of cancer remain to be explored, as are effects of various foods and nutrients. But such research will not come easily. As it is, reductions in alcohol intake and in obesity could already have a marked impact on the incidence of cancer of the breast and other organs. Both doctors and the general public are little aware of the alcohol–cancer link.
No. 10, plant stanols/sterols and lipid metabolism, was not a discovery of the period 1976–2006 proper, as the effect of plant sterols on cholesterol was already known in the 1950s (Wilkinson et al., 1955). But it took until the 1990s before large amounts of plant stanols could be incorporated into margarine in a way that conserves or even enhances their cholesterol-lowering potency. The effect of such margarines on cholesterol equals that of the rest of the diet combined (Miettinen et al., 1995; Jenkins et al., 2003). Products with sterols and stanols became the paradigm for branded foods with health claims, and they remain one of the few 'functional foods' with proven efficacy in reducing a biomarker for a disease. But they have to compete with a class of drugs with an unbeatable record for clinical effectiveness and safety, that is, the statins. Sterols/stanols owe their market position more to the fact that they are perceived as a food than to superior efficacy in preventing heart disease. There is also some concern that absorption of sterols may promote the very disease that they aim to prevent. The prototype of such an effect of absorbed sterols on atherosclerosis is phytosterolemia or sitosterolemia (Bhattacharyya and Connor, 1974). Patients with homozygous phytosterolemia overabsorb plant sterols, and they develop massive xanthomas and atherosclerosis.
No. 11, diabetes can be prevented by diet and lifestyle, builds on another observation made before 1976, namely that obesity causes type II diabetes. But in spite of the huge impact of obesity on diabetes risk seen in observational studies, the efficacy of lifestyle changes in trials still came as a surprise. A non-randomized study of modest levels of exercise and weight reduction from Sweden found a remission rate in diabetics of over 50% (Eriksson and Lindgarde, 1991), and in a Chinese study, the number of patients progressing from impaired glucose tolerance to frank diabetes was reduced by 36% (Pan et al., 1997). The first large randomized trial was done in Finland (Tuomilehto et al., 2001), closely followed by one in the United States, (Knowler et al., 2002) and both found that fairly small changes in diet, activity and weight reduced diabetes incidence by 58%. Diet and weight loss were clearly more efficacious than the standard drug treatment, metformin. (Knowler et al., 2002) How can 20 to 30 min of moderate exercise per day plus a 3- to 6-kg weight loss reduce the incidence of type II diabetes by more than half? We do not know. But an even more urgent question is how we can change our world so that more patients receive and comply with this most powerful of diabetes treatments.
Discovery no. 12 was interaction of carbohydrate/glycemic load with insulin resistance. There is controversy over diets with a low glycemic index for the treatment of diabetes. However, the effect of glycemic index on postprandial blood glucose levels in diabetics is incontrovertible (Jenkins et al., 1983). New research is extending the concept of glycemic index beyond the treatment of diabetics to prevention of diabetes (Salmeron et al., 1997), but the data are still incomplete and therefore controversial.
Discovery no. 13 deals with the finding that something does not work: after high hopes for antioxidants, large randomized trials showed that vitamin E does not reduce cardiovascular disease, at least not in patients who have the disease or are at high risk for it. (The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group, 1994) It still remains possible that vitamin E has a role in the primary prevention of cardiovascular disease, but the issue is unlikely to be settled by clinical trial evidence.
No. 14, the effect of fish oil fatty acids to reduce mortality in coronary heart disease patients, has been a topic of interest ever since the initial observation that Eskimos (Inuit) have a high fat intake but low rates of coronary heart disease. (Bang et al., 1971) It received support from Nobel prize-winning research on fatty acids and prostaglandins, was strengthened by observational findings in Zutphen (Kromhout et al., 1985) and many subsequent epidemiological studies, and was initially upheld by clinical trials. Recent trial data have, however, been less consistent (Brouwer et al., 2006). More trials are in the pipeline.
No. 15, the multisystemic role of vitamin D, is still at an early stage. Reported effects of vitamin D on cancer, diabetes and muscle function are intriguing but not yet established beyond doubt (Garland et al., 1985; Martinez et al., 1996;Holick, 2006).
Challenges
The speakers and the audience together nominated 17 challenges. As some of these were similar, we collated them into the 14 challenges.
Three other challenges also drew over 10% of the votes.
The first of these, and no. 2 in the overall ranking, was Can diet delay cognitive decline? Its election may have been helped by the recent completion in Wageningen of the FACIT trial, which showed that folic acid reduced the decline in memory in elderly volunteers (Durga et al., 2007). Further studies in this direction are obviously worthwhile, because the effect of B-vitamins on cognitive decline is far from settled. The effect of n-3 fatty acids from fish on cognitive decline also deserves further exploration (Beydoun et al., 2007; van Gelder et al., 2007).
Challenge no. 3 was restore the balance between private and public control of nutrition research. This had nothing to do with any specific line of research, but it reflected widespread concern that nutrition research has become overly market-oriented and sensitive to commercial interests (Katan, 2007). Over the past 20 years, there has been a strong preference for market forces to take care of research priorities, but some correction may be imminent. For example, the European Research Council is beginning to award research grants based exclusively on scientific excellence; this new program no longer requires the commercial applicability that is a prerequisite for much of the other research funded by the European Union. Although collaboration with industry can yield valuable research results, as testified by the FACIT (Durga et al., 2007) and SOFA (Brouwer et al., 2006) trials, industry-sponsored research will probably not lead to the long-term scientific breakthroughs that we need.
Challenge no. 4 was the reductionistic approach versus the food pattern approach. This sounds philosophical but it is a concrete issue that has been around for many years: should we do research and give dietary recommendations in terms of molecules and their actions, or of foods and diets? The popularity of the 'Mediterranean diet' (800 PubMed hits as of 17 May 2007), shows that the holistic approach is gaining territory among scientists. But when is a diet Mediterranean? That is hard to decide without assigning a number for 'Mediterranean-ness'. On the other hand, the benefits of certain foods are hard to summarize in terms of the molecules in them: the effect of low-fat, high-carbohydrate diet (Schaefer et al., 1995) on weight loss may be due more to their taste and structure than to a particular content of any macro- or micronutrient. Similarly, there is more to corn and pellagra than the low niacin content of corn. Foods are complex and our knowledge is limited, so nutrition and health is unlikely to be reduced entirely to molecular interactions.
Another 10 challenges each gathered a few percentage of the votes. Some referred to practical problems that have been with us for a while, such asimplementing diet in clinical practice and reduction of salt in foods, some were of a more general nature, such as diet and low-grade systemic inflammation, from genetics to epigenetics and the use of substances from plants to prevent disease. Some were methodological, for example, How can we prove that lifestyle interventions work? and How can we measure energy balance in free living people?
Finally, two represent work in progress in the diet-heart field. One is the role of B-vitamins and homocysteine lowering in the prevention of cardiovascular disease.Up till now the results of clinical trials of homocysteine lowering have been disappointing, but the largest trials will only report in the next few years (B-Vitamin Treatment Trialists' Collaboration, 2006). Trials may not provide the final answer, because short-term application of high doses in patients with existing disease may not be equivalent to long-term intake of modest amounts by healthy people. But a trial of the primary prevention of heart disease with B-vitamins in healthy subjects is unlikely to happen because the size and cost would be prohibitive.
Another work in progress is the role of 
-linolenic acid in prevention of coronary heart disease mortality. This might be solved by the ongoing Alpha Omega Trial (http://clinicaltrials.gov/ct/show/NCT00139464), which is due to report in 2010. Or it might not: certainty does not come easy in nutrition research, but fortunately, 2036 is still a long way off.
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