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4 Challenges Faced and Met in Research on Food and Health A panel of five university researchers reported on a wide variety of research programs related to food and health, ranging from promising experiments to proven treatments and from foods with healing properties to those carrying pathogens. Panel members also addressed related issues, such as the importance of collaboration and funding structures in advancing their research and what they consider the most effective approaches for combating diet-related health problems. Some panelists shared personal perspectives on developing research programs that broke interdisciplinary barriers. RESEARCH ENDEAVORS INVOLVING FOOD Researchers described how some foods are being tested for their potential to treat disease and others are being modified or fortified to enhance health. Mushrooms, essential oils, and other foods are being used in studies to treat cancer and other chronic diseases, they said. Corn has been modified to increase its protein content, and eggs and milk have been fortified with omega-3 fatty . acre .s. 35

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36 EXPLORING A VISION Food as a Curative Harry Preuss, Professor of Physiology, Medicine, and Pathology at Georgetown University Medical Center, began his career in internal medicine as a nephrologist. Initially, he worked on sugar-induced hypertension. When he found that chromium, as a nutritional supplement, circumvented that mechanism, he became committed to exploring the food and health connection, especially in preventive medicine and aging. Preuss pointed out that nutrition and health issues were often considered in the realm of"alternative medicine," a label that he questioned, saying, "Something works or it doesn't." He expressed concern that consumer information on healthy diets presented mixed and sometimes incorrect messages, and he felt that emphasis on counting calories and exercise would be beneficial. Preuss described his current research on the impact of foods such as mushrooms, bitter melon, and essential oils, and nutritional supplements on immune function, cancer, diabetes, and hypertension. He termed the findings "possibilities," saying that more research is needed to prove definitively their effectiveness. He noted that interest in the therapeutic effect of mushrooms in treating cancer and immunologic disorders is growing. As an example, Preuss offered preliminary results from one Asian study on the effect of maitake mushrooms on rats with cancerous tumors, which suggested potential shrinkage of the tumors, although he noted that the study was not a double-blind placebo- controlled study, so the result would be of limited value. He added that an extract of maitake and maitake powder have also been suggested by some to diminish the side effects of chemotherapy, but "whether this turns out to be something wonderful, we will have to see." Preliminary results of tests with grislin (a fraction of maitake), bitter melon, and a combination of the two to treat insulin resistance and hypertension associated with diabetes were positive, Preuss said. He had found that the most sensitive index of insulin resistance is a rise in blood pressure, and with treatment, blood pressure went down in every case. Cinnamon, fiber, and chromium compounds also can be effective in increasing insulin sensitivity, he noted. Preuss said he has found that some essential oils are effective as bactericides and fungicides. Two oils used in laboratory tests monolaurin derived from coconut oil and the essential oil of oregano killed Staphylococcus, Helicobacter pylori, and even anthrax. He suggested that oregano might also be effective in killing Car~dida albicar~s and Escherichia colt. "There are things that can be done with the foods that have little risk and can be helpful with chronic disorders," he concluded.

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CHALLENGES FACED AND MET Food Allered to Increase Nuiritive Value 37 Brian Larkins, Professor of Plant Sciences and Molecular and Cellular Biology at the University of Arizona, described recent efforts to enhance the protein quality of maize. He also discussed current laboratory work aimed at understanding the molecular processes underlying the changes. Some 9 to 10 billion bushels of corn are produced in the United States each year, but this widely consumed cereal has relatively poor protein quality, he said. Corn is especially low in lysine, an essential amino acid for humans and some animals. Over the last few decades, researchers have been successful in altering the protein composition of corn and increasing its lysine content. Early attempts at protein enhancement resulted in corn with a soft, starchy texture that made it susceptible to insects and produced "lousy tortillas," Larkins noted. However, plant breeders, working with modifier genes, have created a mutant protein- enhanced corn called Quality Protein Maize (QPM) that is very similar to normal corn (see Box 4-1 for a more detailed perspective). Larkins and his colleagues are studying the molecular processes and mechanisms behind the success of QPM, trying to understand how the modifiers work, how the mutation changes the lysine content, and the function of a process called endoreduplication, which amplifies the number of gene copies when the kernel is developing. They have determined that development of QPM is closely related to the structure of starch, he said. Larkins' laboratory goes beyond traditional cereal chemistry by looking at the development of corn kernels, especially the synthesis of starch and storage proteins. It has determined that part of the cytoskeleton network that surrounds the endoplasmic reticulum can serve as an indicator of the lysine content, and allows it to be used in selecting for increased protein quality. Larkins has also linked the physical structure of starch grains in the endosperm to how high- quality protein genotypes are developed. Bruce Watkins, Director of the Center for Enhancing Foods to Protect Health and Professor at Purdue University, and Adjunct Professor of Anatomy at the Indiana School of Medicine, described various ways in which foods are being altered to enhance their nutritional content and quality. He also described current research in the use of nutraceuticals and phytochemicals to prevent or correct medical conditions, such as osteoporosis and obesity.

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38 EXPLORING A VISION Box 4-1. Quality Protein Maize (QPM).32 In 1963, three scientists at Purdue University discovered opaque-2 maize, a mutant maize that was nearly twice as nutritious as normal maize and which contained proteins. The discovery of the opaque-2 gene led many scientists to believe that the protein deficiency that afflicts millions of people who depend on maize as a stable food supply could be improved by adding the opaque-2 gene to the world maize crop. However, the opaque-2 gene gives the kernel a soft, starchy texture that caused the maize to be more susceptible to insects and to break easily, and it could not be used to produce the same quality of food as normal maize. A team of maize scientists at the International Maize and Wheat Improvement Center (CIMMT) in Mexico were able to develop what is now called Quality Protein Maize (QPM), which has a greatly enhanced nutritive value, high yields, normal moisture content, and good endosperm hardiness. In 2000, Surinder K. Vasal, a maize breeder, and Evangelina Vilegas, a cereal chemist, shared the World Food Prize for their efforts in developing QPM in the 1970s and 1980s. Since 1996, CIMMT and other organizations have been able to strengthen QPM breeding and promotion programs and have targeted developing countries that use maize as a food staple. Norman E. Borlaug, Nobel Peace laureate and president of the Sasakawa Africa Association, has strongly endorsed QPM research and use through Sasakawa Global 2000, a program that has successfully promoted QPM in Ghana and several other African nations.33 The Center for Enhancing Foods to Protect Health is a faculty-led organization with a focus on advancing knowledge about food and how it affects health. It has four research aims: discovery and methods development for health protectants, such as phytochemicals and nutraceuticals; testing and validation of health benefits, using primarily cell-culture and animal models; precommercialization of functional food components introduced into traditional food products; and molecular biology and food functional genomics. The center is a collaborative effort involving faculty in the Schools of Agriculture, Consumer and Family Sciences, and Veterinary Medicine at Purdue University, and the School of Medicine, at Indiana University-Purdue University Indianapolis (IUPUI), as well as scientists at other institutions. For example, food scientists at the center are studying the feasibility of adding functional food ingredients to bread formulation while making sure that it is visually appealing 32International Maize Testing Unit: QPM Background. 2003. Available online at http://148.223.253.105/qpmbackground.htm [October 2003]. 33For more information, see the National Research Council report, Quality Protein Maize. 1988. Washington, D.C.: National Academy Press.

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CHALLENGES FACED AND MET 39 and maintains the usual qualities of white bread. The center, in cooperation with other institutions and industry, has produced eggs fortified with omega-3 fatty acids and conjugated linoleic acids, Watkins said. Researchers at the Center are also exploring how diet can correct atrophy in muscle and bone tissue that results from disuse, fractures, and space travel, and how nutraceuticals and phytochemicals affect the differentiation of osteogenic stem cells. The center has an educational component, with a special focus on middle school through college, covering the origin of foods, how foods are processed, food chemistry, and how nutrition affects health. Adult-education efforts include the Phytochemical Learning Resource, which is available on the Internet and on CD, to help nutrition educators and dieticians. Watkins' research career exemplifies the kind of integration that is being promoted for food and health research. He began his research career in animal production and animal nutrition, investigating the role of probiotic bacteria in gnotobiotic chicks to reduce enteric pathogens. He then moved on to biotin metabolism and sudden death syndrome, characterization of abnormal bone growth in nutrient deficiency, food lipids and the chemistry of functional food ingredients, molecular and physiologic actions of phytochemicals on cell function and bone biology, and nonembryonic stem-cell research in bone health. Food as Potential Pathogen Two panel members discussed the other side of food and nutrition: its potential to harm rather than nourish or heal. Linda Saif, a Professor at the Ohio Agricultural Research and Development Center of the Ohio State University, discussed her research on enteric calciviruses that affect animals and humans, including the Norwalk virus that has caused outbreaks of stomach illnesses on cruise ships and in other settings. Susan Sumner, head of the Department of Food Science and Technology at Virginia Polytechnic Institute and State University, addressed the impact of globalization of the food supply, the use of food as medicine, and the potential of food as an agent of bioterrorism. Saif reported that foodborne infections in the United States cause about 76 million illnesses each year, account for about 325,000 hospitalizations and 5,000 deaths each yearn, and have an estimated annual cost of $23 billion.35 34 Mead, P.S., Slutsker, L., Dietz, V., McCaig, L.F., Bresee, J.S., Shapiro, C., Griffin, P.M., and R.V. Tauxe. 1999. Food-related illness and death in the United States. Emerging Infectious Diseases. 5:607-625. 35 Hedberg, C. 1994. Changing epidemiology of food-borne disease: A Minnesota perspective. Clinical Infectious Diseases. 18:671-682.

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40 EXPLORING A VISION Noroviruses (caliciviruses) cause an estimated 67 per cent of the known cases if foodborne illness. Outbreaks associated with those viruses have occurred on cruise and military ships and in other institutionalized settings, such as schools and nursing homes. About 40 percent of the outbreaks are thought to be the result of foodborne infections, but the infections can also be waterborne. Saif and her colleagues have tried to address some of the impediments to working with noroviruses. They adapted a porcine enteric calicivirus to grow in cell culture by using novel methods and they are now using it as a model to try to grow human enteric caliciviruses (noroviruses and sapoviruses). The researchers also used primers originally developed to detect human caliciviruses to detect animal caliciviruses; with sequence analysis, they discovered that the two groups of viruses are genetically similar. Recently they developed an infectious clone of a porcine enteric calicivirus that they hope to use in studying the molecular basis of the virus's virulence and cell adaptation. Current research at the university focuses on determining how the viruses cause diarrhea in host species and how the infections can be prevented by using pigs and craves as animal models for sapoviruses and noroviruses similar to those that infect humans. Researchers, including those in Saif's laboratory, are using bioengineering to develop noninfectious calicivirus-like particles for use in vaccines and are trying to determine the origin of strains of the virus that affect humans particularly to see whether they are zoonotic. Enteric caliciviruses and coronaviruses are among a large number of emerging pathogens that are believed to be zoonotic. Saif singled out the SARS coronavirus as one example of the harm that such pathogens can cause. As a food microbiologist, Sumner identified food safety, food bioterrorism, a global food supply, and the use of foods as medicine as issues of importance. She discussed several unanswered questions that should be investigated further, regarding the risk that the United States faces from a food-related bioterrorist attack: How great is the risk? What types of foods are the most likely targets? What segments of the population are at greatest risk? Sumner was also concerned about the preparedness of the food producers and processors to deal with the intentional introduction of pathogens and toxins that would normally not be found in foods and that cannot be controlled with the usual food-safety practices. Consumers expect food to be processed the same, to have the same high nutritional quality, and to be equally fresh and safe, regardless of where it is produced, Sumner explained. However, globalization raises serious concerns about food safety, she continued, citing as one example fears about mad cow disease associated with beef products from the United Kingdom and, more recently, Canada. New food-processing techniques are being developed and

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CHALLENGES FACED AND MET 41 used, but how they affect the safety and nutritive value of foods has yet to be determined, she said. Questions remain about the tradeoffs between fresh and processed foods which is better from a nutrition standpoint versus a safety standpoint, and what are the best ways to strike a balance between fresh and processed foods. As with the baby-food and pet-food industries, food products are going to be targeted for development for specific health-related features, both in terms of food safety and of chronic disease. Collaboration Several panel members stressed the importance of collaboration across disciplines, agencies, and institutions to foster better research and education in food and health. They also stressed that funding agencies should establish or increase funds aimed specifically at cross-sectional research and that institutions should change their reward structures to support collaboration. Using calicivirus research as a model, Saif identified four essential components for integrated research programs: funding, collaboration, infrastructure, and graduate students and postdoctoral fellows. Establishing a broad funding foundation by breaking out veterinary, food-safety, and human-health components of her research program has allowed her to obtain funding from USDA, EPA, and NIH. Saif added that timely availability of visas for top international students and postdoctoral fellows is also essential: severe visa restrictions may jeopardize our globally competitive scientific research programs and may limit participation by international scientists in U.S. scientific meetings, thereby weakening both U.S. and global scientific research. Saif stressed the importance of collaboration among veterinary, agricultural, and biomedical scientists in studying foodborne pathogens and other disease agents suspected of originating in animals. This reminded listeners that, of 156 emerging diseases, almost three-fourths are zoonotic,36 and more information is needed about them in the natural hosts. For example, biomedical researchers only recently recognized that coronaviruses, which cause colds and other respiratory illnesses in humans and were responsible for the recent outbreak of SARS, have caused respiratory and enteric diseases in animals for many years, she said. Closer ties between animal and medical scientists could facilitate research into how those diseases are spread, but more support is needed to encourage such collaboration. She suggested that although USDA and NIH grants support basic research, sometimes bridging or targeted competitive 36Levy, Stuart B. 1996. Microbial threats and the Global Society. Emerging Infectious Diseases. 2(1): 62-63. Available on-line at ~df [January 2004].

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42 EXPLORING A VISION grants, especially in comparative medicine, are needed to develop specific diagnostics and vaccines for emerging animal diseases and animal reservoirs of human diseases and or to assess and control food-borne pathogens. Both the administrative and investigative components of research infrastructure are being taxed as many universities are changing from state-supported to state- assisted, Saif said. Grants-management offices and long-term technical support from universities are important for developing successful integrative research programs, as are facilities to study infectious animal, plant, and human pathogens, including bioterrorism agents. Without highly qualified national and international graduate students and postdoctoral fellows to carry out and carry on research, these programs would not succeed, Saif added. Nancy Lewis, Associate Professor of Nutritional Sciences and Dietetics and Chair of the Interdepartmental Nutrition Graduate Program at the University of Nebraska, described her career as a microexample of integration in this case, of nutritional biochemistry with nutrition behavior. The Interdepartmental Nutrition Program is the University of Nebraska's primary doctorate program in human nutrition, includes faculty in food science and technology, in animal science, and in the Department of Nutritional Science and Dietetics. To incorporate health behavior, a faculty member of the Psychology Department who is interested in health behavior change has recently been recruited, Lewis reported. With the added expertise, the program is better able to serve the needs of students interested in nutrition behavior. A continuing challenge for the program is meeting the graduate education and research needs of practicing dieticians, who provide the university with invaluable connections to the health-care environment. As practitioners working full-time in nutrition therapy, they are interested in enhancing their clinical skills, their understanding of science, and their level of practice. One creative solution has been to develop courses for distance delivery, so that students do not have to be on campus to meet all their educational needs. That solution will not, however, solve problems of residency requirements or of availability of research facilities. The agriculture and food and health connection can be strengthened by working with clinicians, determining and meeting their needs, Lewis said. As several panel members pointed out, collaboration is often closely aligned with funding, making it very difficult for one to occur without the other. Lewis also discussed the multistate research committee on omega-3 fatty acids called NC-1167 (Committee on N-3 Polyunsaturated Fatty Acids and Human Health and Disease) as an example of improving interdisciplinary research. Initially, the committee members had a nutritional-biochemistry perspective. By recruiting additional committee members who shared her interest in nutrition

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CHALLENGES FACED AND MET 43 behavior, she was able to incorporate this perspective into the committee's discussions and research planning. It has been successful in working with the Nebraska Heart Institute on behavioral interventions, and Lewis suggested that grant proposals requiring such integration as she has experienced, including biochemical, behavioral, and outreach or continuing-education components, would be very valuable. Larkins addressed factors that he believed contributed to his success in obtaining support. His research has been supported by several federal agencies, including the USDA's National Research Initiative (NRI), the Department of Energy's Energy Biosciences Program, and NSF, as well by industry sponsors. He concluded that his work had appeal to both the public and private sectors because some aspects have practical applications and others involve fundamental molecular genetics, molecular biology, and cell biology. His multidisciplinary approach was also attractive to students from a variety of backgrounds. He qualified his success by adding that if he had tried to support his research on the basis of nutrition, he probably would not have gotten any funding, and his diverse funding sources demonstrated that food and health research is not the primary interest or responsibility of any one agency. Larkins pointed out that the structure of research funding presented challenges to traditional food and health research: the average funding from USDA's NRI is about $60,000 per year for two years. That requires that the grant-renewal process begin in the second year of the initial grant. He contrasted that with NIH's average level of research funding: $250,000 per year for four years, not including indirect costs. He noted that agencies are more willing to fund research on organisms that can be raised in laboratories or growth chambers, such as yeast or Arabidopsis, which is relatively inexpensive and more easily justified, and less likely to fund research on crop plants, such as corn, wheat, or soybeans, which is more labor-intensive. He also noted that there has been a substantial reduction in institutional support, especially in Colleges of Agriculture, for research infrastructure. SOLUTIONS TO FOOD-RELATED HEALTH PROBLEMS Responding to a question about which technologic solutions or approaches are likely to have the most immediate effect on food-related health issues, Watkins zoned in on approaches that increase dietary intake of good fats and reduce harmful fats; this is an opportunity for developing new and better food-delivery systems. He mentioned that omega-3 fatty acids are a crucial nutrient for avoiding deficiencies and optimizing health. NIH studies indicate that omega-3 fatty acids can have dramatic effects on health, possibly even on psychiatric

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44 EXPLORING A VISION disorders, he said. However, most consumers are not getting the recommended amounts of omega-3 fatty acids in their diets, because they do not eat sufficient quantities of fish and edible oils high in this nutrient, Watkins cautioned. This underlines the importance of making the nutrient available in a broader array of foods, he said, noting that just last year FDA approved the use of DHA, an omega-3 fatty acid, in infant formulas. Technologies that reduce harmful fats in the diet are also crucial for better health, he added. They include changing how vegetable oils are processed, modifying plants that produce edible oils, and reducing the content of animal products. Looking to the future, Watkins envisioned a directed approach to food development: products would be targeted to a person's age, gender, and genetic makeup. He highlighted the opportunities presented by the Human Genome Project: new food products could be developed that lower risk of chronic disease through an understanding of how those components in foods modulate genes and protein expression. Other opportunities are the development of food components that work with drugs as drug synergists to address issues of cardiovascular disease or decreasing inflammatory response; bioactive ingredients, nutraceuticals and phytochemicals; and proteins, such as antibodies that are produced from plants. As the food supply evolves, Watkins predicted lower health-care costs, better nutrition, new medical and functional foods, delayed onset of disease, and improved quality of life. Sumner took a broad view of the role of food in health, with the convergence of such issues as food science, nutrition, food safety, diet, chronic disease, and medicine. She envisioned an integrated, multilevel approach, targeting specific populations. Sumner applauded the rich tradition of collaboration between agriculture and life sciences, but she pushed for increased collaboration with medical and veterinary colleagues. Sumner cited the example of the Virginia Tech food and health initiative, involving the Department of Food Science and Technology, the Department of Human Nutrition, Foods and Exercise, and the Center for Food and Nutrition Policy. She challenged scientists to consider how a specific research objective can fit into a bigger picture that may open up new opportunities and questions in food and health. She also called for better communication with consumers and regulators, who may be looking for a quick solution to a health problem that has taken years to develop.