4
Implications for the Future

Moderated by John Milner, Chief, Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute


As a field of scientific research, nutrigenomics has tremendous potential. Science is not done in a vacuum, however, and if nutrigenomics is to reach its potential, a number of details in arenas outside of science must be addressed. These include issues involving ethics, economics, industry, and public policy.

ISSUES IN ETHICS

Presented by David Castle, Chair in Science and Society, Department of Philosophy, University of Ottawa, Ontario, Canada

Public Attitudes Toward Nutrigenomics

Acceptance of nutrigenomics by the public will depend not just on the products of scientists and industry but also on attitudes toward this field of research, said David Castle. Castle’s work focuses on how science and technology agendas are established, how the products and services that arise from innovations in technology make their way into society, and what determines the success or failure of a new technology such as nutrigenomics. One of the primary factors is how the technology is received by the public.

The general public has a number of concerns about nutrigenomics. For example, how advanced is the state of the science, and what is the evi-



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Nutrigenomics and Beyond: Informing the Future - Workshop Summary 4 Implications for the Future Moderated by John Milner, Chief, Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute As a field of scientific research, nutrigenomics has tremendous potential. Science is not done in a vacuum, however, and if nutrigenomics is to reach its potential, a number of details in arenas outside of science must be addressed. These include issues involving ethics, economics, industry, and public policy. ISSUES IN ETHICS Presented by David Castle, Chair in Science and Society, Department of Philosophy, University of Ottawa, Ontario, Canada Public Attitudes Toward Nutrigenomics Acceptance of nutrigenomics by the public will depend not just on the products of scientists and industry but also on attitudes toward this field of research, said David Castle. Castle’s work focuses on how science and technology agendas are established, how the products and services that arise from innovations in technology make their way into society, and what determines the success or failure of a new technology such as nutrigenomics. One of the primary factors is how the technology is received by the public. The general public has a number of concerns about nutrigenomics. For example, how advanced is the state of the science, and what is the evi-

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary dence that nutrigenomics can make a difference in an individual’s health? It is also important to understand the cause-and-effect relationships being studied and the balance of the benefits and the risks involved in making lifestyle and diet changes that may be advised through a nutrigenomics-derived nutritional prescription. A primary area of concern with the collection of the information to be used to generate a nutritional prescription is what happens to genetic information that is submitted to a company or a clinic for testing. It is important to consumers to know who has access to their information and whether their employers or insurers get access it. Other concerns include the use of personal information in a public database. Will it ever be completely deleted, or will it always be there for others to uncover if they really want to? Consumers are also concerned with how nutrigenomics technology will be regulated. “They want the tests regulated,” Castle said. “They want the health claims regulated.” At the same time, consumers recognize that nutrigenomics will demand a type of regulation that is different from the types of regulation for both pharmaceuticals and foods, perhaps a type of regulation that contains elements of both. “This is actually the principal challenge for regulators,” Castle said: “to understand what new innovative regulatory structures have to be developed in order to be able to handle this complex field.” The problem is that the government is used to regulating in vertically well-organized, tightly integrated fields, such as pharmaceuticals or foods, and when something like nutrigenomics that cuts across these fields comes along, there is no easy way to develop novel regulations. There are additional concerns about access and equity. Many individuals worry that nutrigenomics will turn out to be a luxury product that is available only to a few and that much of the world’s population will not benefit because of a lack of access. These issues are closely tied to that of how nutrigenomics will be delivered to the public. Castle introduced two basic delivery models: private and public. These models parallel the scientific divide between the analysis of an individual’s DNA to provide a personalized dietary prescription and the use of an understanding of the relationship between genes and nutrients to make dietary recommendations that will apply to almost everyone. There are four separate delivery models. The first one is the consumer model, in which individuals pay for and consume nutrigenomics products on their own. An individual consumer might, for example, find a nutrigenomics company on the Internet, send away for a test kit, take a cheek swab, return it to the company, and then use the test results to shape his or her eating habits. The consumer model puts nutrigenomics into the hands of the public. It is convenient, empowers the

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary consumer, and conveys a sense of control over a part of life and insight into what the future might look like, all within the privacy and comfort of one’s own home. However, since such testing is done outside of consultation with a medical doctor or other health care professional, it raises the issue of the standardization and regulation of testing procedures. The second type of model is the health care practitioner model, in which the testing and counseling are offered by genetic specialists, primary care practitioners, or nutrition specialists. The benefit of this model, according to Castle, is that the patient would be receiving information that is integrated into all of the rest of the health care that he or she is receiving. Unfortunately, there are not enough trained practitioners to provide such care. “Nutrition and genetics are still not high on the medical training curricula,” Castle noted, “so most doctors might be unable or unwilling to play such a role.” The third model offers an alternative. This is a blended model, in which a comparatively few nutrigenomics specialists would provide services to medical doctors and other health care practitioners. For example, a physician might contract with a company that generates nutrigenomics reports for the physician’s patients and that also provides the medical staff with training and guidance. These three models have one thing in common: they each provide individualized nutrigenomics services. In the consumer model, the health care practitioner model, and the blended model, the focus is on the benefits and risks to the individual. They all involve individuals taking advantage of nutrigenomics technology one person at a time. The fourth model is the public health model, in which nutrigenomics provides generalized nutrition guidance to the public. It gives up some of the power of personalized dietary advice to focus on nutritional advice that can benefit population groups. In the United States, much of the focus has been on models that deliver individualized nutrigenomics advice, but the question about which model is most appropriate for service delivery raises a number of ethical issues and raises political and societal questions about health care delivery as well. To illustrate, Castle described debate taking place in the United Kingdom, where the Department of Health recently released a report called Choosing Health: Making Healthy Choices Easier.1 The focus of the report is on the role of government provision of health information and the development of social structures that allow individuals to control their health decisions, with the hope that such an approach would lead to greater public interest in disease prevention. The concept is to put tools into the 1 Available at: http://www.dh.gov.uk/en/Policyandguidance/Organisationpolicy/Modernisation/Choosinghealth/index.htm.

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary hands of individuals and move toward a system with little direct government involvement. This approach is similar to that used in models in the United States that provide nutrigenomics technologies to individuals and allow them to make better decisions about nutrition and health. In response to Choosing Health: Making Healthy Choices Easier, the Food Ethics Council, a nongovernmental organization in the United Kingdom, released its own report. The report argues against the idea of personalization, claiming that personalization is “actually just one small cog in a broader neo-conservative agenda to save costs and reduce government involvement in people’s lives.” Rather than viewing personalization in terms of personal empowerment, the Food Ethics Council sees the issue as a way of separating individuals from their government and disengaging government from the provision of health care to its citizens. Instead of personalization, the report argues for a move in the opposite direction, toward a rights-based way of thinking about food and health, where people have a right to safe and healthy foods and, thus, government has an obligation to see that they are provided. “So what they are fundamentally disagreeing with,” Castle said, “is the portrayal of personal choice as the key issue for improved public health.” In the course of making its arguments, the Food Ethics Council offers some points that have particular relevance for the future of nutrigenomics in the United States. First, there is a natural economic barrier to taking advantage of something like nutrigenomics that will skew its group of users. “The early adopters tend to be well educated,” Castle noted. “They tend to be affluent, certainly more affluent and educated than average.” Individuals with the money, time, and education to learn about nutrigenomics will tend to be those who use it, while others will lag behind. “This is a significant problem,” Castle said. “The knowledge key that somebody uses to get into the nutrigenomics room comes with a pretty high socioeconomic barrier to it, and not just paying for the services.” Another point that the Food Ethics Council makes is that the personalization agenda can distract people from paying attention to the state’s responsibility for public health initiatives—to the extent that the state does indeed have such a responsibility. However, whether one accepts the arguments of the Food Ethics Council or not, Castle said, they offer a clear statement of the potential problems with the personalized model for delivering nutrigenomics products. The greatest power of nutrigenomics may well lie in offering specialized advice to individuals, and a focus on public health can dilute that promise. Ultimately, the objective is that, through intervention strategies like nutrigenomics, individuals will live longer, happier, healthier lives. The best way to achieve this goal is to provide tailored advice and then to document its impact on the health and well-being among individuals in the population. If health advice from

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary nutrigenomics is diluted, possibly through the public health approach, it will be difficult to document success and thus launch the science more broadly. Related to this issue is how best to communicate information about nutrigenomics so that the public can understand it and apply it. Too much information can create confusion, resulting in noncompliance with dietary guidelines. The problem, according to Castle, is that no one has done systematic public consultation and engagement work on nutrigenomics to determine the drivers for applied nutrigenomics research and to determine how individuals form perceptions and the role of the media in informing those perceptions. In closing, Castle raised the issue of whether it is possible to use both a personalized approach and a public health approach to the application of nutrigenomics. This possibility is frequently offered as a compromise to obtain the best of both approaches. The answer is not known at this time; it is an issue that must be addressed, however, if nutrigenomics is to reach its potential in improving people’s lives and health. SCIENCE JOURNALISM AND THE NUTRIGENOMICS REVOLUTION Presented by Sally Squires, Health and Nutrition Columnist, The Washington Post, and Susan Okie, Contributing Editor, New England Journal of Medicine Although basic researchers may not spend much time thinking about the best ways to communicate their findings to the public, in the case of nutrigenomics, such communication will be essential. Not only will public attitudes have great influence on funding and regulation, but ultimately, it will be members of the public who are the consumers of nutrigenomics information. One advantage that the field of nutrigenomics holds in terms of communicating results to the public is that it will not be necessary to work to get the public’s attention. “The public is absolutely hungry for this information,” Sally Squires told the workshop. “They couldn’t be hungrier.” That hunger, however, also holds a risk for the field. Since the public is so eager for results, the temptation will be to offer results—even when they are tentative—or to speculate about the future; and that is something that should be avoided. “It is going to be really, really important not to oversell this field and not to promise more than is there.” Susan Okie echoed that advice: “I think that the worst thing that this field could do right now would be to try to sell it to journalists or to the public on the basis that

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary this field is soon going to come up with personalized dietary prescriptions for everybody based on their genes,” she said. The key to communicating effectively with the public will be to explain clearly what nutrigenomics is and what it has to offer. “It needs to be a very simple message,” Squires said. “If you are looking to get your message across, I urge you to look at the way politicians get their messages across in terms of sound bites. You are going to have to have good spokespersons who can really give a clear message, and you will probably be dealing with a lot of reporters who are not necessarily educated in either science or medicine.” The task will be made much more difficult by the innate complexity of the field of nutrigenomics. Okie warned that this topic, that is, the whole idea that genes could determine an individual’s response to dietary guidelines, is complicated and highly nuanced. As an example, Okie pointed to studies that have identified differences in individual responses to dietary changes, for example, how dietary modification may reduce blood pressure in some individuals and have no effect in others. This individual variability increases the difficulty of trying to craft guidelines for the public, and it raises the question of how one creates general advice for the public that everyone can follow. Furthermore, there is no guarantee that the public will heed the advice. Referring to the two delivery models that Castle spoke about, the public health model and the individualized-advice model, Okie pointed out that it has been very difficult to get people to modify personal choices even in the face of overwhelming evidence that they can improve their chances of good health by following a particular path. “If you think about it,” she said, “a lot of people have a sort of a genetic profile—it is known as their family history.” Maybe they have family members who are obese or suffering from type II diabetes, or perhaps they have a father who had a heart attack at age 50. Is there any evidence, she asked, that having this kind of a genetic profile actually motivates people to be more faithful to following preventive dietary guidelines when they themselves do not actually have the disease? “Even with high public awareness and concern about the health risks of obesity, for example, and even with the stigma that exists now against obese people, most people are not very successful at avoiding weight gain and are very unsuccessful, for the most part, at keeping weight off, even if they manage to lose it.” It therefore seems likely that one of the most difficult parts of conveying nutrigenomics information to the public may well be to do it in a way that makes it likely that people will actually apply that information and change their behavior.

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary NEEDS AND OPPORTUNITIES IN THE BIOMEDICAL SCIENCES: INTERACTING NETWORKS Presented by Ralph Greenspan, Dorothy and Lewis B. Cullman Fellow in Experimental Neurobiology, The Neurosciences Institute, San Diego, California Ralph Greenspan explained why basic research is essential to progress in any area of science and particularly in a developing area like nutrigenomics. “The dust bin of research history is starting to fill up with models of disease which were cured in the laboratory in an animal; those cures had absolutely no effect when they were taken to clinical trials.” Such events occur because biological networks accomplish things in multiple ways. Although superficial similarities or even bona fide pathologic similarities between a disease model and a human disease may exist, the cure does not happen in the same way in the animal model and humans. For that reason, a greater level of understanding things is absolutely essential. Whether or not model animals will acquire diabetes in exactly the same way that humans do is not the point. Of importance is understanding the principles of operation to identify the similarities between mechanisms in the human context. Drosophila (the fruit fly) is often used as a model because at least 50 percent of its genes are counterparts to human genes. Furthermore, among the human genes that are known to cause or increase susceptibility to disease, fully two-thirds are represented in the Drosophila genome, even though neither genome is particularly large, about 14,000 genes for Drosophila and 20,000 to 30,000 genes for humans. Given that there are relatively few genes, the combinations of how they work is absolutely critical, including understanding the ways that different versions of different genes combine to give particular outcomes. In short, relatively subtle differences between networks can result in big differences in their behaviors, and if there is to be a good understanding of how biological actions arise from the interactions of different genes, it is essential to perform the fundamental research necessary to create a detailed picture of how biological systems work. Gene Networks As an example of the complexity of such interactions, the Greenspan laboratory studied a mutation in the gene for syntaxin 1A, which causes Drosophila to pass out quickly when it is exposed to temperatures of about 39°C, or about 102°F (normal flies without the mutation are also affected by these temperatures, and they eventually become uncoordinated and fall to the bottom of a glass tube holding them, but it takes far longer for

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary the heat to takes its toll). Sixteen other mutations that suppress this behavior were also identified, increasing the time that the flies stayed active at the high temperature. Thus, a fly with a mutation in the gene for syntaxin 1A and one of the other mutations would be less affected by the heat than a fly with the syntaxin 1A gene mutation alone. To determine how the 16 mutations interacted with each other, investigators bred flies that each had two of the mutations, although not the syntaxin 1A mutation, and then observed the flies for their ability to endure heat. Comparison of the results for the various pairings led to a mathematical prediction of what effect each of the pairings should have on a fly’s ability to withstand the heat if there were no interaction between the different pairs of genes, that is, if all the effects were additive. When the actual results were compared with the predicted results to discover which pairs of genes did have synergistic interactions, some pairs of genes had a positive interaction, that is, their combined effect on the fly’s ability to withstand heat was greater than that which would be expected if their effects were just added together, whereas other pairs had a negative interaction. Still other pairs had no synergistic interaction at all. With these findings indicating that the genes are interacting in a network, a further experiment was performed to determine how this network changes when the flies differ in genotype at one locus: the syntaxin 1A gene itself. The result is that the synergistic interactions among genes are almost entirely different, depending on the genotype at the syntaxin 1A locus. The implication of this finding is that a gene network of this kind is not stable; rather, it is dependent upon the particular variants of the genes within it. If one gene changes, the relationships between many other genes in the network will change in response—and those changes can be radical. Changes in a network have wide ramifications. In the example of syntaxin 1A, the genes isolated were not the ones that would be predicted to be intimately involved with the process of synaptic vesicles in neurons (which is where syntaxin has a role). A wide range of genes were affected, for example, genes affecting metabolism and genes affecting the cytoskeleton. In other words, it is a highly interconnected network. Gene and Metabolic Networks Gene networks also interact with metabolic networks in a number of different ways: they can alter the expression levels of genes, they can alter the protein structure (which can change the functionality of a gene), or they can alter signal transduction and metabolic pathways (Figure 4-1). The manner in which genes can affect a metabolic network can be illustrated by two types of flies, rovers and sitters. A fly larva placed on a plate with food will exhibit two types of exploring behavior: it will either

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary FIGURE 4-1 Gene network interactions with metabolic networks. move around a lot or it will mostly remain in one place. This difference is apparent throughout the life span of the fly. The difference between the two types of behavior is due to a subtle difference in the level of expression of the gene for a cyclic guanosine monophosphate-dependent protein kinase. Rovers express slightly higher levels of the enzyme than sitters, and this is enough to produce the marked behavioral difference. Because the difference is food related, the gene was expected to interact with the fly’s metabolism. Experiments to determine whether gene variants affected metabolism revealed that the gene affects many of the enzymes involved in the citric acid cycle. Testing of the flies’ responses to acetylcarnitine, a metabolite whose level is affected by the citric acid cycle, showed that one of the variants responds and the other one does not. Thus, the gene affecting food-related behavior also alters the response to an intermediate in nutrient metabolism. Figure 4-2 shows that there are a number of interacting networks through which nutrients modify gene expression, metabolism, and other physiologic events. Because small differences in a network can have large effects on

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary FIGURE 4-2 Genotype interactions with metabolic networks. behavior, individual genetic variations can cause large differences in response to environmental stimuli. The interactions between the nutrient environment and the genome are extremely important, and there are many intervening steps. Evaluation of these interactions and the intervening steps offers a dynamic approach to addressing the interactions between nutrition and the genome. NUTRIGENOMICS: INDUSTRY’S PERSPECTIVE Presented by Peter Gillies, Adjunct Professor, Department of Nutrition Science, Pennsylvania State University; Adjunct Professor, Department of Nutrition, University of Toronto; and Senior Research Fellow in Central Research and Development, E. I. du Pont de Nemours & Company The Business Challenge Peter Gillies believes that businesses interested in nutrigenomics are in a bit of a dilemma: “This is clearly an area where the consumer is ahead

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary of all of us,” he said. People are familiar with the idea of a relationship between diet and genes, they know that it may be possible to tailor diets to individuals, and they are already interested in products. “People are looking for things that we may not yet be able to deliver.” Not only does industry not have many nutrigenomics-based products to offer at this time, but most companies are still trying to determine if they really need or even want to incorporate nutrigenomics strategies into their businesses, how much they should invest in it, and what the business model should be. At present, there is still a great deal of confusion and uncertainty surrounding the field and its practical impact on human health and nutrition. Some companies have drawn an analogy between nutrigenomics and pharmacogenomics, thereby linking the science of food and pharmacology. Traditionally, the food and pharmaceutical industries have been worlds apart. The pharmaceutical industry operates in the world of unmet medical needs, rational drug design, clinical trials, and physicians who oversee and manage the interactions between drugs and patients. The food industry, by contrast, operates in the world of taste and convenience, food-related clinical trials are limited in number and scope, and products are promoted directly to consumers. The two worlds, however, have started to move a bit closer together. There are now foods for which there are valid health claims that are grounded in science and approved by the Food and Drug Administration (FDA). In this regard, the food industry has begun moving into the health arena through the manufacture of functional foods and nutraceuticals. Notably, scientists who have experience in the pharmaceutical industry have been moving into the food industry. The movement of such scientists may help bring the rigor of pharmacology into nutrition science that Gillies believes that it really needs. “These scientists bring with them a grounding in pharmacology [and] an understanding of biomarkers, and, more importantly, they bring with them their ‘-omic’ tool kits.” However, it is one thing to migrate pharmacology scientists and their technologies; it is quite another thing to migrate pharmacology-like expectations. “I think what we tend to have done is to migrate some of the business models that we associate with the pharmaceutical industry and some of the consumer expectations that go along with it, and this is when we start to get into trouble.” It is important to remember that foods are subtle bioactive entities, not potent drugs. Foods are not biologically targeted designer molecules; they are complex mixtures with pleiotropic nutritive and pharmacological activities. Collectively, the integrated effects of foods can have significant benefits based on changes in disease biomarkers, such as serum lipid levels; however, data on their direct

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary effects on underlying disease processes and associated clinical sequelae are much harder to come by. Business models in the food industry are very different from those in the pharmaceutical industry. The food industry does not have a return on investment that is equivalent to that of the pharmaceutical industry. Whereas the pharmaceutical industry can readily protect its investments with patents, the food industry is more likely to do so with trade secrets. Furthermore, although the pharmaceutical industry operates in a “risk-benefit” paradigm, there is nothing like that in the food industry; the food industry uses a “safe and beneficial” paradigm. Ultimately, the food industry will have to find its own way in the development and marketing of nutrigenomics products, and for this to happen a new paradigm is needed. The food industry can glean a number of lessons from the experience of the pharmaceutical industry. For example, the successes in pharmacogenomics were catalyzed by the availability of a major funding system. “The NIH [National Institutes of Health] allowed highly significant amounts of money to go to laboratories to enable the work to get done. The work got done. Research networks were formed.” Unfortunately, there is little evidence thus far that this will happen in nutrigenomics. “We need to provide funding for this field to move ahead.” Collaborations between industry and academia have been important to pharmacogenomics; something similar is needed for nutrigenomics. A problem that has slowed the advancement and broader adoption of pharmacogenomics has been the limited ability to generate and share data from large clinical trials. Issues such as privacy, consent, and intellectual property intervened; and the field was not able to develop the databases that it had hoped it would be able to develop. Gillies emphasized the need for publicly accessible nutrigenomic databases. As the field of nutrigenomics unfolds in the United States, one can look to Europe for some guidance. In 2004, for example, the European Commission formed the European Nutrigenomics Organization (NuGO) to foster the development of nutrigenomics in Europe (see Box 4-1). The organization’s activities include training nutrigenomic researchers, validating and standardizing technologies, and bringing researchers together from across the continent to communicate and collaborate. “I think that what we need over here in the United States is a NuGO,” Gillies said. One area in which Europe excels is forming partnerships with a purpose. A good example of that is the LIPGENE consortium, an organization that comprises 25 research centers around Europe with the purpose of understanding how diet and genetics interact in the development of chronic diseases, such as metabolic syndrome. “In the LIPGENE project,” Gillies said, “you have the agricultural industry, the dairy industry, and

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary BOX 4-1 The European Nutrigenomics Organization The European Nutrigenomics Organization (NuGO) comprises 20 partner organizations in 10 countries. NuGO was formed in 2004 and is funded by the European Commission’s Research Directorate General under the Food Quality and Safety Priority of the Sixth Framework Programme for Research and Technological Development. NuGO aims to provide a forum for research integration and to enhance future research efforts in nutrigenomics. NuGO cites on its website six specific aims: Strengthen the European scientific and technological excellence in nutrigenomics by bringing together the critical mass of resources and expertise needed to offer leadership in the rapidly developing field of nutrigenomics. Define individual response to nutrients and refine the requirements for population subgroups on the basis of genetic variations, sex, and life stages. Determine the relative health benefits and risks of food compounds for different population subgroups and improve public health. Spread excellence in nutrigenomics beyond the partnership through training, sharing of methods and facilities, dissemination, and exploitation and enter into dialogue with stakeholder groups. Support the competitive aim of the European food industry, facilitating its growth for knowledge-based healthier food production. Promote understanding in the ethical, social, legal, economic, and scientific issues of concern in nutrigenomics. SOURCE: The European Nutrigenomics Organization. Available at http://www.nugo.org/everyone/24017, accessed January 9, 2007. the food industry coming together to develop novel products that have nutritional benefits; and they are doing so in a way that engages both society and members of the business community in a structured partnership.” The goal is to modify the diet with products enriched with omega-3 fatty acids and then to evaluate their impact on metabolic syndrome. Gillies closed with comments about the future of nutrigenomics in the United States. First, he said, it is important to recognize that at the moment nutrigenomics is “a very fragile paradigm.” There are very few success stories. He suggested that they may well be coming in the future, but until then it is important to remain grounded and to not get too far out in front of the data. At the same time, it will not pay to be too timid. “Industry is in a catch-22. If we engage too early, we will most assuredly fall prey to the problems of hope and hype. If we engage too late, we will have lost the opportunity to shape our future.” Perhaps, he said, the cor-

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary rect approach is to put together some sort of national agenda in this area. Finally, one of the keys to enabling the success of nutrigenomics will be having the proper bioinformatics infrastructure in place. “These are not the types of technical platforms that we have in the food industry,” he said. “Somehow we need to make these available to the food industry in order for them to move ahead.” NEEDS AND OPPORTUNITIES IN THE FOOD AND AGRICULTURAL SCIENCES Presented by Joseph Spence, Director, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture No matter how great the potential of nutrigenomics to deepen the understanding of nutrition and to point the way to healthier eating is, that potential will not be realized without corresponding advances in other areas. One of those areas is agriculture and the food industry. Joseph Spence addressed the role that agriculture and the food industry can play in helping nutrigenomics meet its potential. Spence pointed out that that role will develop in a number of different areas; one of the most important will be modification of the nation’s food supply to reflect new understandings about nutritional requirements, something that is already being done on a limited scale. For example, the Agricultural Research Service (ARS) developed the heart-healthy NuSun sunflower as a variety high in oleic acid, a monounsaturated fatty acid. That variety now accounts for about 77 percent of the sunflowers produced for oil seeds in the United States. The NuSun sunflower was developed by traditional breeding methods, but researchers are also using genetic engineering methods to create varieties with desired characteristics. Scientists at ARS have also produced transgenic tomatoes that contain four to eight times as much lycopene, a carotenoid known for its strong antioxidant properties, as nontransgenic tomatoes. As nutrigenomics research reveals more details about the roles of various nutrients, the agriculture industry can modify food to take these findings into account for future research and development. Of particular importance will be demonstration of the clear nutritional benefits of these various nutrients for individuals, as illustrated in Figure 4-3. “We cannot fall into the trap of saying this probably will have a beneficial effect,” Spence said. “We have to clearly identify the health benefits and get people to understand that these are long-term benefits.” Another role traditionally played by the U.S. Department of Agri-

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary FIGURE 4-3 The role of value-added products, e.g., from nutrigenomics, in improved outcomes, particularly improved health, to consumers. culture has been to make recommendations for a healthy diet with such tools as the food pyramid, originally released in 1992 and modified in 2005. The original food pyramid was a population-based, one-size-fits-all model with one set of guidelines intended for everyone, but the revised version (MyPyramid) consists of a number of pyramids that are matched to individuals on the basis of age, sex, and level of physical activity. Nutrigenomics will make it possible to extend this pattern and to offer dietary guidelines that are even more closely focused on individuals. “We have different genetic backgrounds, different life styles, and so on,” Spence noted, “so it is very difficult, in the nutrigenomic age, to continue to make dietary advice that is based on population types of studies.” In the future, he suggested, dietary guidelines will take into account an individual’s genetic background and will vary the recommendations on the basis of that individual’s ancestry. Although relatively little work has been done in this area so far, it seems likely that nutrigenomics studies will eventually pinpoint ways in which nutritional advice should differ between, for example, American Indian/Alaska Natives and descendants of northern Europeans, and nutritional guidelines should be written to reflect those insights.

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary THE ECONOMIC POTENTIAL OF NUTRIGENOMICS Presented by Patricia Danzon, Celia Moh Professor, Wharton School of Management; Professor and Chair, Department of Health Care Systems; and Professor of Insurance and Risk Management, University of Pennsylvania One of the driving forces behind the development of any technology is the expectation of financial reward. A technology that is expected to pay off handsomely will tend to attract more investment and develop more quickly than one whose financial prospects are less sanguine. Patricia Danzon spoke about the potential economic impact of nutrigenomics in managing health care costs. Danzon said that because the science of nutrigenomics is still in its infancy, it would be foolhardy to try to estimate the economic impact at this point. She therefore devoted her presentation to offering ideas on the economic potential of nutrigenomics and on strategies to maximize that potential. Figure 4-4 shows that expenditures on health care in the United States have been rising rapidly. About 15 percent of the gross domestic product is spent on medical care,” she noted. “Interestingly,” she commented, “we are now almost at the point where about half of that is coming out of public funds.” In addition, the average cost of an insurance premium for the average family is about $12,000 a year. Furthermore, that 15 percent FIGURE 4-4 National health expenditures (NHEs) as a share of the gross domestic product (GDP) and private and public shares of NHE, selected years, 1965 to 2014. SOURCE: Stephen Heffler et al. U.S. Health Spending Projections for 2004-2014. Health Affairs, web exclusive, W5-74. February 23, 2005. http://content.healthaffairs.org/cgi/content/full/hlthaff.w5.74/DC1.

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary of GDP spent on medical care is just the tip of the iceberg, she said. The entire economic burden of disease and poor health, including such things as lost productivity, is far greater. Furthermore, most of the spending on health care goes toward treatment rather than prevention. Ninety-five percent of health care spending is on people who are sick, with only 5 percent spent on preventing people from getting sick, Danzon said, quoting Tommy Thompson, former secretary of the U.S. Department of Health and Human Services. If more money was spent on effective prevention, the economic benefit could be considerable. This is an area in which nutrigenomics would be expected to have a major economic effect. Danzon offered two caveats. First, it is not clear how easy it will be to get individuals to change their behavior in response to nutrigenomics-based advice. Second, the apparent potential of a field is not always met. “I am struck by the fact that for the last 5 years so little has been delivered [in the pharmaceutical industry] compared to what was promised by the more optimistic people at the time of the mapping of the human genome.” Nonetheless, nutrigenomics could yield a huge economic impact if the gains in scientific knowledge are significant. The economic benefits of nutrigenomics are likely to be long term. The effects of dietary change, however, are likely to be cumulative and affect diseases that occur later in life. Thus, a marker of the benefit of nutrigenomics may be its impact on the severity of disease or disease progression. In addition, efforts at disease prevention are the most cost-effective when they target high-risk diseases among the population subgroups most likely affected. This is because the cost of prevention is spread out among everyone who is a target of the prevention effort, whereas the savings come only when the disease that is the target of prevention is prevented in those who would have acquired the disease otherwise. Thus, disease prevention is more cost-effective when efforts to prevent diseases that are particularly costly are targeted to high-risk subpopulations. Cost-effectiveness may also improve if the cost of prevention is decreased. According to Danzon, it makes sense to think in terms of modifying diets rather than adding supplements, which can add considerably to the cost of a nutritional regimen. Unfortunately, she noted, the current system is generally set up to favor the use of supplements rather than simply encouraging the consumption of a variety of foods. Insurance companies, for example, are likely to pay for medicines or dietary supplements that are prescribed for medical reasons, but they generally do not pay for healthier foods. Similarly, if the FDA approves supplements but says nothing about foods that may have a therapeutic impact, consumers’ choices may be affected. “We are heading into an era where there are

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary going to be new types of regulations that need to be put in place and new ways of thinking about insurance coverage to make sure that we enhance this movement and don’t distort it.” Finally, Danzon pointed out that it will be important to demonstrate conclusively the effectiveness of various nutrigenomics interventions. If the nutrigenomics data signal is obscured by the general “noise” that consumers are regularly bombarded with, not enough people will pay attention. Thus, it will be important to make the signal-to-noise ratio big enough to influence consumer behavior. If that can be done and if care can be taken to target high-risk diseases and subgroups and to rethink regulatory and insurance strategies, Danzon said, “I think that nutrigenomics research has the potential to have huge economic benefits.” NUTRIGENOMICS IN ACADEMIC AND PUBLIC HEALTH: HOW CAN WE MOVE THE FIELD FORWARD? Presented by Harvey V. Fineberg, President, Institute of Medicine, the National Academies To close the workshop, Harvey Fineberg summed up the proceedings of the previous 2 days and offered two new concepts to consider as nutrigenomics moves into the future. First, Fineberg spoke of the challenge that nutrigenomics will pose to the existing public health paradigm. There are a variety of public health programs aimed at prevention, for example, programs that encourage the use of seat belts and smoking cessation and programs that issue dietary guidelines aimed at lowering the risk of cancer. For the most part, they are all applied uniformly and universally to the population. “Everyone is told, ‘Wear a seat belt.’ Everyone is told, ‘You should stop smoking, and if you don’t smoke, don’t start.’ Everyone is told what dietary guidelines are appropriate.” The seat-belt advice is unlikely to change, since it is unlikely that it would be determined that some people are at less risk of bodily injury in an accident and thus do not need to wear them. It is at least conceivable, Fineberg said, that a small percentage of the population is not put at risk by smoking and that no matter how much tobacco smoke they inhale, they would still have a very small risk of developing lung cancer, but the smoking advice would likely remain the same. Dietary advice is different, however. It is not just possible but likely that there are nutrients that affect some population groups differently than others, and public health guidelines will have to take such differences into account. That will put greater demands on the public, however. It will not simply be a matter of knowing that it is a good idea to wear seat belts whenever you go somewhere in a car. Instead, as Fineberg pointed

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Nutrigenomics and Beyond: Informing the Future - Workshop Summary out, “a public health paradigm of universal education is going to have to be adapted to the scientific reality and scientific knowledge as it develops and it unfolds.” This paradigm will demand a greater effort from both the people who develop the guidelines and those who follow them. Furthermore, like efforts in physics to develop a grand unified theory that would unite a number of areas of physics into one, biology and health also have a challenge to develop an analogous grand unification theory. That is, many different factors are known to play a role in the development of disease. These range from socioeconomic and demographic factors, behavioral choices, and environmental exposures such as nutrients or chemicals all the way to the genetic makeup of an individual and how that interacts with the specific constituents of foods. “Is it possible,” Fineberg asked, “that over time we can identify what ultimately must be the biological common pathways through which all determinants of disease or health must ultimately exercise their effect?” Such an understanding would certainly require new theoretical developments and ways of expressing and calculating biological mechanisms, but there is no reason to believe that the development of such a grand unification theory is not possible. Fineberg concluded with a question meant to be a provocation and a challenge to the audience and to those everywhere interested in nutrigenomics: “Is it not possible that nutrition science—bridging, as it does, everything from human behavior, cultural values, all the way through to nutrigenomics and metabolomics and so on—might not be the crossroads for such a grand unification theory for health and disease?”

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