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Personalizing foods: is genotype necessary?
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Personalizing foods: is genotype necessary? Laurent B Fay1 and J Bruce German2 The inescapable conclusion of a just a decade of nutrigenomics research must now be brought to practice. Humans differ in their responses to diet and many of these differences are being assigned to genetic polymorphisms. However, differences in the varying responses to diet between humans are not solely because of genetic variation. Lifestage, lifestyle, prior nutritional and physiological variables and even your mother’s microflora all influence the differences between humans. The question becomes: are all of these inputs to an individual’s health measurable as part of a nutritional phenotype assessment? The answer to this question is increasingly, yes. As variations in humans can be both measured and even more importantly understood, the implications of those measures to dietary guidance become actionable. More accurate assessment of the inputs to human health and the consequences of those inputs measured as accurate proteomic and metabolomic analyses would bring personalized health to practice far faster than waiting for a predictive knowledge of genetic variation. Addresses 1 Nestle´ Research Centre, PO Box 44, Vers-chez-les-Blanc, CH-1000, Lausanne 26, Switzerland 2 University of California, Department of Food Science and Technology, Davis, CA 95616, USA Corresponding author: Fay, Laurent B ([email protected]) and German, J Bruce ([email protected])
Current Opinion in Biotechnology 2008, 19:121–128 This review comes from a themed issue on Food Biotechnology Edited by Hannelore Daniel and Martin Kussmann
0958-1669/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.copbio.2008.02.010
together with optimized dietary guidelines ensured highquality nutrition. Over the past 100 years public health goals have thus been population-based agricultural production chains embedded into corresponding policies and food consumption guidelines to ensure that all of the essential nutrients are obtained by all individuals within a population. As we are discovering in the 21st century, the reality of diet and health is that all individuals within a population are not optimally healthy when consuming the same diets. Imbalances of dietary intakes of calories and the various macronutrients and micronutrients relative to different lifestyles are leading to metabolic imbalances and even diseases. Atherosclerosis, obesity, diabetes, hypertension, osteoporosis, allergy, and neurodegenerative diseases are all either increasing outright in subsets of the population or at least failing to decline in spite of massive improvements in medical care. Furthermore, variations in dietary intakes of essential nutrients among subsets of the population are still responsible for discouraging rates of birth defects, early onset age degeneration of various tissues, and diet-induced metabolic diseases during pregnancy. Finally, humans are beginning to pursue lifestyles that change their needs for specific diets. Thus, a new era of health must include a personalization of diet, yet it is not clear what scientific research is needed, what industrial processes are required, nor what economic models are capable of guiding, applying, and financing the personalization of the world’s largest human enterprise — food. This article discusses the basic determinants of human variation in dietary responses, the scientific tools needed to assess these differences in the population, and the industrial processes that must be considered to prepare the agricultural enterprise for a future in which foods are personalized for health.
The diversity of the human condition Introduction The magnificent research successes of nutrition sciences of the 20th century saw the identification of all the essential nutrients and the understanding of their biological importance in controlling metabolism and in maintaining health. Bringing this science to practice meant that in all developed societies diseases caused by nutrient-deficiencies could mostly be prevented and consumers could obtain all of the essential nutrients in needed quantities in the diverse diets that different people consume. Industrialization of food processing for improved nutrient retention, by nutrient enrichment and fortification was also a key to the public health success which www.sciencedirect.com
Humans span an astonishing range of phenotypes. Healthy human adults vary in height, weight, activity, cognition, strength, endurance, flexibility, and in their preference for foods. We are most alike at birth, but as we progress through various lifestages, we diversify into myriad lifestyles. Unfortunately, while the 20th century saw a massive scientific investment in researching the basic biological processes of humans, detailing biochemistry from genetics to physiology, the majority of that research catalogued the commonalities of these processes across all humans. Only recently have scientists begun to approach the research needed to catalog and understand the molecular basis behind the variations across humans. Current Opinion in Biotechnology 2008, 19:121–128
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Humans differ due to a wide range of basic biological variables. These variables are in some cases genetically based chromosomal differences, for example, male, female, or allelic polymorphisms in structural or regulatory regions of specific genes. In other aspects, differences are because of the age and particular lifestage of an individual (e.g. infancy, pregnancy, lactation, pre-menopause and post-menopause, and puberty). In others, variables are due to environmental influences that are either exogenous and random (e.g. exposure to sunlight, toxins, allergens, bacterial inoculum, etc.) or endogenous and volitional, for example, chosen lifestyle (e.g. exercise, athletic training, excess caloric intake and obesity, sedentary behavior, sleep cycle alteration, meal frequency, and temporal variation). Furthermore, each of these variables — if acting at a particular point in an individual’s development or lifestage — may exert effects on various epigenetic or non-genetic elements. These effects may then confer persistence of a particular phenotype through much of that individual’s subsequent life and alter that individual’s response to dietary components.
Genotype The field of Nutrigenetics is rapidly discovering in molecular (sequence) detail those genetic differences across the human population that are related to differences in needs for or responses to various nutritional variables [1,2]. An international consortium is beginning to address the wholesale annotation of the human genome according to nutritional criteria [3]. The use of SNP technologies to measure an individual’s genotype and provide nutritional recommendations based on known genetic variables is already a commercially viable practice, although the total number of gene-nutrient factors and interactions remains quite small [4]. Nonetheless, as the genes responsible for human diversity are recognized, the capabilities of genotyping to provide individuals with actionable knowledge about their unique predispositions for diet, drugs, and lifestyle will invariably increase as both a scientific and commercial reality.
Lifestage The nutritional requirements of humans vary according to many features of an individual’s stage in life. Early in life, the demands of growth and development change rapidly as do dietary needs and responses [5]. Puberty and the transition to reproductive fertility cause a significant change in hormonal status and precipitate a diverse range of physiologic and metabolic consequences, many of which alter dietary needs and responses [6]. The reproductive cycle itself, estrus, pregnancy, lactation and involution are all distinct physiological states for which varying nutritional implications are expanding beyond guidelines [7,8]. With the success of modern disease prevention and therapeutic strategies, the life expectancy of humans has increased dramatically. One result of this success has been the emergence of elderly as a sustained Current Opinion in Biotechnology 2008, 19:121–128
and distinct lifestage. With greater numbers of elderly humans, their unique physiological, metabolic, and even microbial states are being recognized, including their unique nutritional needs [9,10]. Finally, various disease, injury, or pathological states intrude upon virtually every individual at some point in their lives. As clinical nutrition gains more knowledge of the unique metabolic demands of disease states and the solutions designed to cure them, nutritional solutions are being designed to accelerate the rate of recovery and minimize the long-term consequences to individuals during these periods.
Environment The environment in which an individual lives is taken in this review to include all aspects of exogenous inputs to their phenotypes, including acute and chronic, random and volitional, and chemical and behavioral. The nature of these inputs can be described/measured by their source (e.g. geographical distribution and solar UV irradiation) or their effects (e.g. vitamin D formation) [11]. These inputs can be either random and unavoidable (urban pollution) or volitional (smoking). These inputs may also be generalized to a larger population (exposure to fluoridated drinking water) or may be unique to specific individuals (chronic consumption of sweetened beverages) [12].
Lifestyle Amidst the myriad lifestyle factors that alter nutritional status, a critical aspect affecting an individual’s environment and their nutritional phenotype is the breadth of the food marketplace. Although this affords many individuals the opportunity to choose increasingly diverse diets throughout the year, for others choice does not necessarily afford diversity [13]. One of the luxuries of modern humans is the freedom of individuals to pursue and adopt preferred lifestyles. Faced with a highly diverse food supply, individuals within societies are pursuing wide dietary intakes of nutrients, caloric content, macronutrient compositions, and chemical compositions. These are all in conspicuously diverse forms that vary in structure, complexity, and rheology across wide temporal habits (from a single large meal per day to a dozen small, snack-like eating occasions).
Environment genotype = imprinting Environment at one stage of an individual’s life can exert persistent effects on the nutritional phenotype later in life (imprinting, programming, memorization, or colonization). The explicit covalent modifications of DNA that persists through cell divisions are now recognized and are increasingly well described in the field of epigenetics [14]. Persistence is also seen in the proliferation of specific cell and tissue types during certain stages of life. The development of preferences for sensory attributes of foods — principally olfactory preferences — persist through much of an individual’s life, guiding their lifelong food choices. Finally, an environmental factor that exerts www.sciencedirect.com
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persistent effects on nutritional phenotype is the makeup and genetic diversity of the various micro-organisms living on and in each individual. Imprinting processes during fetal development have been shown to cause methylation differences across entire regions of an individual’s genome and can result from various nutrient imbalances and deficiencies including calories of the mother [15]. As technologies to measure epigenetic DNA modifications emerged, studies in animal models exposed to various nutrients, environmental, and lifestyle factors have been shown to influence DNA methylation state [16]. Such studies imply that nutritional factors are also relevant to humans and would be predicted to result in similar persistent effects through epigenetic changes in an individual’s genome. The remodeling of cells and tissues as a form of imprinting has been well documented, though not yet fully understood. Adipocyte hyperplasia early in development is proposed to be one of the factors that accounts for the high predisposition of adult obesity in children who are overweight [17]. These studies by Ailhaud’s group have documented in animals that specific dietary factors early in life — of animals at least — produce or inhibit the proliferation of adipocytes that in and of itself could account for a persistent and altered response to diets later in life. Interestingly, the dietary factors v6 and v3 polyunsaturated fatty acids are apparently effective at altering the cellular development within the range of normal human diets. Muscle mass is also responsive to the combination of conditioning and protein content of the diet [18]. The persistence of muscle mass, its influence on whole body energy metabolism, its metabolic contributions post training, and a larger store of amino acids as muscle proteins would be predicted to alter the response of an individual to various health states and diet [19]. The imprinting of sensory preference is perhaps the least understood but most influential in the conditioning of modern humans to their habitual diets. Humans apparently do not rely on nutrient cues to guide their food choices, instead, they rely on a system of acquired food preferences to influence their dietary choices. The remarkable property of olfactory preference is the process by which positive and negative preferences for particular flavors are acquired in an individual as a series of complex, contextual memories early in life [20]. This system of acquired flavor preferences underlies much of the cultural variation in foods and cuisines around the world. This also means that flavor preferences for foods with poor nutrient quality, if acquired by an individual early in life, will guide a life long habit of poor food choices, in spite of the fact that the sensations will continue to be perceived as highly positive. These olfactory-based food preference patterns can be developed very early in life, for example, the flavor preferences of www.sciencedirect.com
lambs for grazing is acquired from maternal feeding patterns established prior to weaning [21]. A final means by which early diet can program an individual’s response to diet is the capacity of early diet to influence an individual’s microbiome (the ensemble of micro-organisms cohabiting each of us). Such dietary influences can be both through direct inoculation of particular micro-organisms present in foods [22] or via the selective manipulation of subsets of micro-organisms by food components that can only be fermented/utilized by certain bacterial populations [23]. Until recently, the role of an individual’s microflora was considered to be relatively minor in terms of their overall health. Following on the stunning revelations by Gordon’s group on the influence of specific bacteria on energy metabolism and predisposition to obesity, the microflora is being increasingly viewed as a pivotal factor in human metabolism, immunity, sensation, disease resistance, inflammation, and comfort [24].
The tools to assess human phenotypic diversity Several excellent articles and chapters provide detailed information and analysis of the tools that are emerging to assess human genotypes and phenotypes [25,26]. Therefore, this article does not elaborate on these in great detail. Suffice it to say that human assessment as the background to personalizing diets is moving forward both scientifically and commercially.
Nutrigenetics and nutrigenomics The tools necessary to sequence the genetic variation in humans are coming into commercial practice. Although whole genome sequencing is possible, it is currently impractical because of cost but expected to become much cheaper in the following years. Nonetheless, the science of assigning human variation to genetic polymorphism is proceeding. As each new polymorphism is discovered that link aspects of human nutritional variation to specific genetic loci, these sites could be and probably will be easily incorporated into the technologies capable of analyzing tissue and body fluid samples from consumers. Transcriptomics, proteomics, and metabolomics applications as described in the chapter by Kussmann et al. are not yet applied in human nutritional intervention studies with well-genotyped subgroups to assess how genetic variation determines the connectivity and responses of transcripts, proteins, and metabolites. Unfortunately, there is a long way to go before our understanding of the genetic sequence basis of human variation in response to diet is in any sense either comprehensive or predictive.
Proteomics and metabolomics The tools to address the challenge of accurately assessing human diversity in the accuracy and comprehensiveness Current Opinion in Biotechnology 2008, 19:121–128
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are emerging, though not yet fully capable of delivering routine measurements of human phenotype for improving diets and public health. Proteomics will be challenging because of analytical and biological issues. The overall dynamic range of individual protein levels spans 6 orders of magnitude in a cell and even 10 orders of magnitude in specific compartments of the human body, for example, in plasma [27]. Protein structures are in principle predictable from their sequences, as Domingues et al. [28] found that 66% of the proteins having a similar fold also exhibit a similar function. However, the function of a protein depends also on its environment, a circumstance that complicates these considerations substantially — the probability of a protein function defined purely at the protein level being globally valid for a given organism or even population is very small. Thus, proteomics will be a valuable toolset for specific proteomic subsets, comprehensive proteomics of entire biofluid samples such as plasma will not be practical for routine assessment soon. Metabolomics has its own set of challenges particularly given the lack of scientific consensus as to its definition [29–33]. Although accurate measures of subsets of metabolites are practical today, there are not yet publicly accessible databases of metabolites annotated to phenotype [34]. These are absolutely necessary to a metabolomics based health assessment system.
The variables of food that relate to human diversity Diet is a much more varied set of elements than previously considered when humans were viewed as a population. Unquestionably, the discoveries of the essential nutrients led to a major public health breakthrough by ensuring that populations received all of the essential nutrients, thus preventing diseases originating from nutrient deficiencies. Despite the fact that the vast majority of the population is indeed adequately nourished it is now increasingly apparent that even from the perspective of essential nutrients, individuals within the population can be guided to improved health through more individualized recommendations. Beyond the essential nutrients is where food diversity is proving to be most important to individual health. Macronutrient contents, from simple sugars to high-quality protein, influence the health of individuals depending on their health status and phenotype. For example, foods high in simple carbohydrates and starches are damaging individuals with insulin resistance [35], yet can improve the muscle status of elite endurance athletes with high insulin sensitivity [36]. Diets high in protein are suggested to be deleterious to the metabolic programming of early infants [37], yet supportive of the health and retaining muscle in the elderly [38]. The field of nutrition has invested considerable efforts in the pursuit of simple bioactive molecules and their potential to mitigate the risk and progression of chronic and degenerative diseases. Although some important principles have emerged, it is perhaps the Current Opinion in Biotechnology 2008, 19:121–128
variation in response among individuals to those bioactive factors that is the most important lesson to take forward into the future of personal diet and health. What is discouragingly understudied is the importance of food structure to the subsequent metabolic effects of diet [39]. The effective separation of food and nutrition into two scientific fields has practically disabled this entire dimension of human variation and severely crippled the credibility of either scientific endeavor.
Personalized nutrition in action Food personalization has been practiced for centuries. Today, the scientific basis and industrialization of personalized food choices is emerging (Figure 1). Human beings have always used organoleptic food preferences as a key driver of their overall food choices. Food choices based on personal preferences are rooted in individual experience, including sensory acuity, cultural habits, and income. Moreover, the nutrition community recognized long ago that different physiological events require significant adaptations to diet. For example, pregnant women, active athletes, and elderly people have different nutrient requirements, and those needs dictate the composition of their optimal diet. The increasing awareness in the public of the potential of their diets to change acute and long-term health and performance has led them to select foods and commodities — from low-calorie foods to oats — for their cholesterol-reducing properties, or for athletes to consume high-protein products during a regimen of weight-bearing exercise. Today, the foods in the marketplace allow a substantial personalization of diets according to the knowledge of the consumer of their personal desires/needs and the marketing of various solutions (Table 1). Of course this segmentation invariably means shrinking the target consumer group. What are criteria underlying the personal choices of consumers in a seemingly unlimited world of options? Taste
The most immediate and easily accessed basis for personalization of foods is simple taste and flavor preferences. Even though personal taste preferences have been the basis for food choices for literally thousands of years, the genetic diversity of taste and olfactory sensation in humans is now recognized to be part of the diversity of food preferences [40,41,42]. In addition to genetic variation, olfactory preferences are principally a learned response to prior diet. Learned olfactory preferences to particular foods and flavors vary even within honey bees [43]. Cultural mores
There is considerable diversity of foods based on core beliefs of their suitability to a particular religious or philosophy value system. Although the origins and the perpetuation of these choices (halal or kosher foods, www.sciencedirect.com
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Figure 1
The extent to which the levels by which foods are personalizing in 2007 relative to the scientific research and technology necessary to bring them forward into the marketplace and service their consumer segments.
vegetarian diets, religious fasting, etc.) are not necessarily based on personal nutritional criteria they do produce nutritional consequences, whether desirable or not [35,44,45]. Lifestage
Considerable experience by humans over the centuries has led to personalization of foods according to the different physiological needs associated with the stages of human life (e.g. infancy, weaning, pregnancy, lactation, aging, and recuperating from illness). Innovative research is indicating that diets during many of the lifestage transitions (weaning, lactation) are important for longterm effects on health [46]. Lifestyle events
Many more immediate aspects of personalization of diets are associated with lifestyle choices and the events in such self-selected lifestyles. Although scientific evidence is rapidly building around these distinctive lifestyle choices and the physiological stresses that they produce, historical observational and anecdote are still the basis to a wide variety of assumptions for the value of specific foods. www.sciencedirect.com
Foods within this category are as disparate as beverages and products for athletes before, during, and after sports events, to products associated with increased risks of deep vein thrombosis caused by airline flights [47,48]. In these cases of lifestyle foods, the event itself is the distinguishing property for segmenting food products. Lifestyle diseases
Lifestyle diseases develop in a subset of the population and provide another opportunity for the personalization of the specific consumers who are at risk of, or actually experiencing failure of their health and the potential of specific foods to target functions that protect their health. Although modern diagnostic sciences are developing sensitive methods to distinguish those who are at greater risk, a wide variety of therapeutically oriented products are marketed to those at risk or actually diseased as a direct result of chronic lifestyle choices. Nutrientspecific products are of potential value whether targeted either to the symptoms of the problem (excess body weight, intestinal discomfort) or the lifestyle choices themselves such as smoking, sedentary lifestyle or high-fat diets [35,49]. Current Opinion in Biotechnology 2008, 19:121–128
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Table 1 Levels of personalization Personalization basis
Gain of knowledge
Marketing channel
Taste preference Cultural Mores Lifestage processes Lifestyle events
Personal experience Social experience Social history Participant experience Epidemiology Family history Nutrigenetics
Advertising Package labeling Health guidelines Event marketing
Lifestyle diseases Inherited diseases Genetic predispositions
Functional foods Clinical products Co-market genotyping
Different levels of personalization are recognized by different criteria and this knowledge has been gained both by the scientific community and the consumer by different means. The marketing channels by which products are directed to consumers based on these levels of personalization also differ.
Inherited health issues and diseases
Humans have recognized the familial basis to much of health throughout recorded history, and foods have been an integral part of their solutions. From predispositions to allergies and intolerances to inherited errors of inborn metabolism, diet is well known to contribute to these processes and to their prevention. The importance of diet to the problem of specific aspects of inborn errors of metabolism has led to the worldwide adoption of blood spot analyses at birth. It is now routine for most of the children born today to be tested for up to 10 metabolic diseases, not by genotyping them, but by accurate by measurings of normal metabolites whose inordinate abundance in blood are a diagnostic signature of the condition [50]. Phenylketonurea is well managed by metabolitebased diagnostics for the personalization of low phenylalanine foods. The dramatic risk to the health of the rarely affected individuals justifies measuring all infants at birth even though the vast majority is uninvolved [51].
to distinguish important biological differences merges with the industrial means to deliver individual solutions. This direction is not a genuine revolution in food, but rather the next step in a very long established diversification of foods that has been ongoing literally for centuries. For such personalization, genotyping technologies are not necessary. Practical solutions will benefit for the vast majority of consumers just by focusing food personalization on delivering properly validated nutritional solutions to well-established subsets of the population. Infants, active adults, athletes, pregnant and lactating women, frail elderly, and all consumers who suffer from inherited or acquired diseases, are all unique and foods that both address their nutritional issues and ensure compliance by considering personal preferences in taste, texture, and appearance. Providing nutritional foods for helping individuals recovering from disease is a clear opportunity to develop parallel approaches along with personalized medicine already being adopted by clinicians. The science of genomics has established clear proofs-of-principle that humans are importantly different with respect to optimal diets. As science builds the knowledge of how genetic variations affect predispositions to disease, and as genotyping technologies a readily accessible, consumers will gain value by being informed of their personal genetic variations and especially those genetic variations that can be successfully altered by appropriate diets. Yet, we are not different solely because of genetic variations. This highlights the necessary synergies between the genotyping approaches and the holistic investigations of the metabolism using proteomics and metabolomics. It is this combined approach that will provide accurate assessments of individual health promises to accelerate dramatically the ability of individuals to gain knowledge of their personal needs and the food marketplace to deliver genuinely revolutionary benefits to a large subset of the population, one consumer at a time.
Genetic predispositions
References and recommended reading
A final level of personalization is basing food choices solely on genetic variations. This approach refers to personalizing food from genotyping data alone in which no other discernible aspect of phenotype would provide equivalent information. Such methods for assigning diversity among individuals are now becoming possible, though for only a very small subset of genetic variations and a small number of individuals [4]. The problem for industrialization of such approaches is that one must deliver huge amounts of information, yet the recommendations for change will be limited to a small group of people sharing the same genotype and having similar dietary requirements.
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41. Knaapila A, Keskitalo K, Kallela M, Wessman M, Sammalisto S, Hiekkalinna T, Palotie A, Peltonen L, Tuorila H, Perola M: Genetic component of identification, intensity and pleasantness of odours: a Finnish family study. Eur J Hum Genet 2007, 15:596-602. 42. Wooding S, Bufe B, Grassi C, Howard MT, Stone AC, Vazquez M, Dunn DM, Meyerhof W, Weiss RB, Bamshad MJ: Independent evolution of bitter-taste sensitivity in humans and chimpanzees. Nature 2006, 440(7086):930-934. 43. Gil M, De Marco RJ: Apis mellifera bees acquire long-term olfactory memories within the colony. Biol Lett 2006, 2:98-100. 44. Rakiciog˘lu N, Samur G, Topc¸u A, Topc¸u A: The effect of Ramadan on maternal nutrition and composition of breast milk. Pediatr Int 2006, 48:278-283. 45. Koebnick C, Garcia AL, Dagnelie PC, Strassner C, Lindemans J, Katz N, Leitzmann C, Hoffmann I: Long-term consumption of a raw food diet is associated with favorable serum LDL cholesterol and triglycerides but also with elevated plasma homocysteine and low serum HDL cholesterol in humans. J Nutr 2005, 135:2372-2378. 46. Krebs NF, Westcott JE, Butler N, Robinson C, Bell M, Hambidge KM: Meat as a first complementary food for
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breastfed infants: feasibility and impact on zinc intake and status. J Pediatr Gastroenterol Nutr 2006, 42: 207-214. 47. Kuipers S, Cannegieter SC, Middeldorp S, Robyn L, Bu¨ller HR, Rosendaal FR: The absolute risk of venous thrombosis after air travel: a cohort study of 8,755 employees of international organizations. PLoS Med 2007, 4:e290. 48. Murray B: The role of salt and glucose replacement drinks in the marathon. Sports Med 2007, 37:358-360. 49. Zhang J, Munger RG, West NA, Cutler DR, Wengreen HJ, Corcoran CD: Antioxidant intake and risk of osteoporotic hip fracture in Utah: an effect modified by smoking status. Am J Epidemiol 2006, 163:9-17. 50. Wilcken B, Wiley V, Hammond J, Carpenter K: Screening newborns for inborn errors of metabolism by tandem mass spectrometry. N Engl J Med 2003, 348:2304-2312. 51. Weigel C, Rauh M, Kiener C, Rascher W, Knerr I: Effects of various dietary amino acid preparations for phenylketonuric patients on the metabolic profiles along with postprandial insulin and ghrelin responses. Ann Nutr Metab 2007, 51: 352-358.
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Personalizing foods: is genotype necessary? Laurent B Fay1 and J Bruce German2 The inescapable conclusion of a just a decade of nutrigenomics research must now be brought to practice. Humans differ in their responses to diet and many of these differences are being assigned to genetic polymorphisms. However, differences in the varying responses to diet between humans are not solely because of genetic variation. Lifestage, lifestyle, prior nutritional and physiological variables and even your mother’s microflora all influence the differences between humans. The question becomes: are all of these inputs to an individual’s health measurable as part of a nutritional phenotype assessment? The answer to this question is increasingly, yes. As variations in humans can be both measured and even more importantly understood, the implications of those measures to dietary guidance become actionable. More accurate assessment of the inputs to human health and the consequences of those inputs measured as accurate proteomic and metabolomic analyses would bring personalized health to practice far faster than waiting for a predictive knowledge of genetic variation. Addresses 1 Nestle´ Research Centre, PO Box 44, Vers-chez-les-Blanc, CH-1000, Lausanne 26, Switzerland 2 University of California, Department of Food Science and Technology, Davis, CA 95616, USA Corresponding author: Fay, Laurent B ([email protected]) and German, J Bruce ([email protected])
Current Opinion in Biotechnology 2008, 19:121–128 This review comes from a themed issue on Food Biotechnology Edited by Hannelore Daniel and Martin Kussmann
0958-1669/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.copbio.2008.02.010
together with optimized dietary guidelines ensured highquality nutrition. Over the past 100 years public health goals have thus been population-based agricultural production chains embedded into corresponding policies and food consumption guidelines to ensure that all of the essential nutrients are obtained by all individuals within a population. As we are discovering in the 21st century, the reality of diet and health is that all individuals within a population are not optimally healthy when consuming the same diets. Imbalances of dietary intakes of calories and the various macronutrients and micronutrients relative to different lifestyles are leading to metabolic imbalances and even diseases. Atherosclerosis, obesity, diabetes, hypertension, osteoporosis, allergy, and neurodegenerative diseases are all either increasing outright in subsets of the population or at least failing to decline in spite of massive improvements in medical care. Furthermore, variations in dietary intakes of essential nutrients among subsets of the population are still responsible for discouraging rates of birth defects, early onset age degeneration of various tissues, and diet-induced metabolic diseases during pregnancy. Finally, humans are beginning to pursue lifestyles that change their needs for specific diets. Thus, a new era of health must include a personalization of diet, yet it is not clear what scientific research is needed, what industrial processes are required, nor what economic models are capable of guiding, applying, and financing the personalization of the world’s largest human enterprise — food. This article discusses the basic determinants of human variation in dietary responses, the scientific tools needed to assess these differences in the population, and the industrial processes that must be considered to prepare the agricultural enterprise for a future in which foods are personalized for health.
The diversity of the human condition Introduction The magnificent research successes of nutrition sciences of the 20th century saw the identification of all the essential nutrients and the understanding of their biological importance in controlling metabolism and in maintaining health. Bringing this science to practice meant that in all developed societies diseases caused by nutrient-deficiencies could mostly be prevented and consumers could obtain all of the essential nutrients in needed quantities in the diverse diets that different people consume. Industrialization of food processing for improved nutrient retention, by nutrient enrichment and fortification was also a key to the public health success which www.sciencedirect.com
Humans span an astonishing range of phenotypes. Healthy human adults vary in height, weight, activity, cognition, strength, endurance, flexibility, and in their preference for foods. We are most alike at birth, but as we progress through various lifestages, we diversify into myriad lifestyles. Unfortunately, while the 20th century saw a massive scientific investment in researching the basic biological processes of humans, detailing biochemistry from genetics to physiology, the majority of that research catalogued the commonalities of these processes across all humans. Only recently have scientists begun to approach the research needed to catalog and understand the molecular basis behind the variations across humans. Current Opinion in Biotechnology 2008, 19:121–128
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Humans differ due to a wide range of basic biological variables. These variables are in some cases genetically based chromosomal differences, for example, male, female, or allelic polymorphisms in structural or regulatory regions of specific genes. In other aspects, differences are because of the age and particular lifestage of an individual (e.g. infancy, pregnancy, lactation, pre-menopause and post-menopause, and puberty). In others, variables are due to environmental influences that are either exogenous and random (e.g. exposure to sunlight, toxins, allergens, bacterial inoculum, etc.) or endogenous and volitional, for example, chosen lifestyle (e.g. exercise, athletic training, excess caloric intake and obesity, sedentary behavior, sleep cycle alteration, meal frequency, and temporal variation). Furthermore, each of these variables — if acting at a particular point in an individual’s development or lifestage — may exert effects on various epigenetic or non-genetic elements. These effects may then confer persistence of a particular phenotype through much of that individual’s subsequent life and alter that individual’s response to dietary components.
Genotype The field of Nutrigenetics is rapidly discovering in molecular (sequence) detail those genetic differences across the human population that are related to differences in needs for or responses to various nutritional variables [1,2]. An international consortium is beginning to address the wholesale annotation of the human genome according to nutritional criteria [3]. The use of SNP technologies to measure an individual’s genotype and provide nutritional recommendations based on known genetic variables is already a commercially viable practice, although the total number of gene-nutrient factors and interactions remains quite small [4]. Nonetheless, as the genes responsible for human diversity are recognized, the capabilities of genotyping to provide individuals with actionable knowledge about their unique predispositions for diet, drugs, and lifestyle will invariably increase as both a scientific and commercial reality.
Lifestage The nutritional requirements of humans vary according to many features of an individual’s stage in life. Early in life, the demands of growth and development change rapidly as do dietary needs and responses [5]. Puberty and the transition to reproductive fertility cause a significant change in hormonal status and precipitate a diverse range of physiologic and metabolic consequences, many of which alter dietary needs and responses [6]. The reproductive cycle itself, estrus, pregnancy, lactation and involution are all distinct physiological states for which varying nutritional implications are expanding beyond guidelines [7,8]. With the success of modern disease prevention and therapeutic strategies, the life expectancy of humans has increased dramatically. One result of this success has been the emergence of elderly as a sustained Current Opinion in Biotechnology 2008, 19:121–128
and distinct lifestage. With greater numbers of elderly humans, their unique physiological, metabolic, and even microbial states are being recognized, including their unique nutritional needs [9,10]. Finally, various disease, injury, or pathological states intrude upon virtually every individual at some point in their lives. As clinical nutrition gains more knowledge of the unique metabolic demands of disease states and the solutions designed to cure them, nutritional solutions are being designed to accelerate the rate of recovery and minimize the long-term consequences to individuals during these periods.
Environment The environment in which an individual lives is taken in this review to include all aspects of exogenous inputs to their phenotypes, including acute and chronic, random and volitional, and chemical and behavioral. The nature of these inputs can be described/measured by their source (e.g. geographical distribution and solar UV irradiation) or their effects (e.g. vitamin D formation) [11]. These inputs can be either random and unavoidable (urban pollution) or volitional (smoking). These inputs may also be generalized to a larger population (exposure to fluoridated drinking water) or may be unique to specific individuals (chronic consumption of sweetened beverages) [12].
Lifestyle Amidst the myriad lifestyle factors that alter nutritional status, a critical aspect affecting an individual’s environment and their nutritional phenotype is the breadth of the food marketplace. Although this affords many individuals the opportunity to choose increasingly diverse diets throughout the year, for others choice does not necessarily afford diversity [13]. One of the luxuries of modern humans is the freedom of individuals to pursue and adopt preferred lifestyles. Faced with a highly diverse food supply, individuals within societies are pursuing wide dietary intakes of nutrients, caloric content, macronutrient compositions, and chemical compositions. These are all in conspicuously diverse forms that vary in structure, complexity, and rheology across wide temporal habits (from a single large meal per day to a dozen small, snack-like eating occasions).
Environment genotype = imprinting Environment at one stage of an individual’s life can exert persistent effects on the nutritional phenotype later in life (imprinting, programming, memorization, or colonization). The explicit covalent modifications of DNA that persists through cell divisions are now recognized and are increasingly well described in the field of epigenetics [14]. Persistence is also seen in the proliferation of specific cell and tissue types during certain stages of life. The development of preferences for sensory attributes of foods — principally olfactory preferences — persist through much of an individual’s life, guiding their lifelong food choices. Finally, an environmental factor that exerts www.sciencedirect.com
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persistent effects on nutritional phenotype is the makeup and genetic diversity of the various micro-organisms living on and in each individual. Imprinting processes during fetal development have been shown to cause methylation differences across entire regions of an individual’s genome and can result from various nutrient imbalances and deficiencies including calories of the mother [15]. As technologies to measure epigenetic DNA modifications emerged, studies in animal models exposed to various nutrients, environmental, and lifestyle factors have been shown to influence DNA methylation state [16]. Such studies imply that nutritional factors are also relevant to humans and would be predicted to result in similar persistent effects through epigenetic changes in an individual’s genome. The remodeling of cells and tissues as a form of imprinting has been well documented, though not yet fully understood. Adipocyte hyperplasia early in development is proposed to be one of the factors that accounts for the high predisposition of adult obesity in children who are overweight [17]. These studies by Ailhaud’s group have documented in animals that specific dietary factors early in life — of animals at least — produce or inhibit the proliferation of adipocytes that in and of itself could account for a persistent and altered response to diets later in life. Interestingly, the dietary factors v6 and v3 polyunsaturated fatty acids are apparently effective at altering the cellular development within the range of normal human diets. Muscle mass is also responsive to the combination of conditioning and protein content of the diet [18]. The persistence of muscle mass, its influence on whole body energy metabolism, its metabolic contributions post training, and a larger store of amino acids as muscle proteins would be predicted to alter the response of an individual to various health states and diet [19]. The imprinting of sensory preference is perhaps the least understood but most influential in the conditioning of modern humans to their habitual diets. Humans apparently do not rely on nutrient cues to guide their food choices, instead, they rely on a system of acquired food preferences to influence their dietary choices. The remarkable property of olfactory preference is the process by which positive and negative preferences for particular flavors are acquired in an individual as a series of complex, contextual memories early in life [20]. This system of acquired flavor preferences underlies much of the cultural variation in foods and cuisines around the world. This also means that flavor preferences for foods with poor nutrient quality, if acquired by an individual early in life, will guide a life long habit of poor food choices, in spite of the fact that the sensations will continue to be perceived as highly positive. These olfactory-based food preference patterns can be developed very early in life, for example, the flavor preferences of www.sciencedirect.com
lambs for grazing is acquired from maternal feeding patterns established prior to weaning [21]. A final means by which early diet can program an individual’s response to diet is the capacity of early diet to influence an individual’s microbiome (the ensemble of micro-organisms cohabiting each of us). Such dietary influences can be both through direct inoculation of particular micro-organisms present in foods [22] or via the selective manipulation of subsets of micro-organisms by food components that can only be fermented/utilized by certain bacterial populations [23]. Until recently, the role of an individual’s microflora was considered to be relatively minor in terms of their overall health. Following on the stunning revelations by Gordon’s group on the influence of specific bacteria on energy metabolism and predisposition to obesity, the microflora is being increasingly viewed as a pivotal factor in human metabolism, immunity, sensation, disease resistance, inflammation, and comfort [24].
The tools to assess human phenotypic diversity Several excellent articles and chapters provide detailed information and analysis of the tools that are emerging to assess human genotypes and phenotypes [25,26]. Therefore, this article does not elaborate on these in great detail. Suffice it to say that human assessment as the background to personalizing diets is moving forward both scientifically and commercially.
Nutrigenetics and nutrigenomics The tools necessary to sequence the genetic variation in humans are coming into commercial practice. Although whole genome sequencing is possible, it is currently impractical because of cost but expected to become much cheaper in the following years. Nonetheless, the science of assigning human variation to genetic polymorphism is proceeding. As each new polymorphism is discovered that link aspects of human nutritional variation to specific genetic loci, these sites could be and probably will be easily incorporated into the technologies capable of analyzing tissue and body fluid samples from consumers. Transcriptomics, proteomics, and metabolomics applications as described in the chapter by Kussmann et al. are not yet applied in human nutritional intervention studies with well-genotyped subgroups to assess how genetic variation determines the connectivity and responses of transcripts, proteins, and metabolites. Unfortunately, there is a long way to go before our understanding of the genetic sequence basis of human variation in response to diet is in any sense either comprehensive or predictive.
Proteomics and metabolomics The tools to address the challenge of accurately assessing human diversity in the accuracy and comprehensiveness Current Opinion in Biotechnology 2008, 19:121–128
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are emerging, though not yet fully capable of delivering routine measurements of human phenotype for improving diets and public health. Proteomics will be challenging because of analytical and biological issues. The overall dynamic range of individual protein levels spans 6 orders of magnitude in a cell and even 10 orders of magnitude in specific compartments of the human body, for example, in plasma [27]. Protein structures are in principle predictable from their sequences, as Domingues et al. [28] found that 66% of the proteins having a similar fold also exhibit a similar function. However, the function of a protein depends also on its environment, a circumstance that complicates these considerations substantially — the probability of a protein function defined purely at the protein level being globally valid for a given organism or even population is very small. Thus, proteomics will be a valuable toolset for specific proteomic subsets, comprehensive proteomics of entire biofluid samples such as plasma will not be practical for routine assessment soon. Metabolomics has its own set of challenges particularly given the lack of scientific consensus as to its definition [29–33]. Although accurate measures of subsets of metabolites are practical today, there are not yet publicly accessible databases of metabolites annotated to phenotype [34]. These are absolutely necessary to a metabolomics based health assessment system.
The variables of food that relate to human diversity Diet is a much more varied set of elements than previously considered when humans were viewed as a population. Unquestionably, the discoveries of the essential nutrients led to a major public health breakthrough by ensuring that populations received all of the essential nutrients, thus preventing diseases originating from nutrient deficiencies. Despite the fact that the vast majority of the population is indeed adequately nourished it is now increasingly apparent that even from the perspective of essential nutrients, individuals within the population can be guided to improved health through more individualized recommendations. Beyond the essential nutrients is where food diversity is proving to be most important to individual health. Macronutrient contents, from simple sugars to high-quality protein, influence the health of individuals depending on their health status and phenotype. For example, foods high in simple carbohydrates and starches are damaging individuals with insulin resistance [35], yet can improve the muscle status of elite endurance athletes with high insulin sensitivity [36]. Diets high in protein are suggested to be deleterious to the metabolic programming of early infants [37], yet supportive of the health and retaining muscle in the elderly [38]. The field of nutrition has invested considerable efforts in the pursuit of simple bioactive molecules and their potential to mitigate the risk and progression of chronic and degenerative diseases. Although some important principles have emerged, it is perhaps the Current Opinion in Biotechnology 2008, 19:121–128
variation in response among individuals to those bioactive factors that is the most important lesson to take forward into the future of personal diet and health. What is discouragingly understudied is the importance of food structure to the subsequent metabolic effects of diet [39]. The effective separation of food and nutrition into two scientific fields has practically disabled this entire dimension of human variation and severely crippled the credibility of either scientific endeavor.
Personalized nutrition in action Food personalization has been practiced for centuries. Today, the scientific basis and industrialization of personalized food choices is emerging (Figure 1). Human beings have always used organoleptic food preferences as a key driver of their overall food choices. Food choices based on personal preferences are rooted in individual experience, including sensory acuity, cultural habits, and income. Moreover, the nutrition community recognized long ago that different physiological events require significant adaptations to diet. For example, pregnant women, active athletes, and elderly people have different nutrient requirements, and those needs dictate the composition of their optimal diet. The increasing awareness in the public of the potential of their diets to change acute and long-term health and performance has led them to select foods and commodities — from low-calorie foods to oats — for their cholesterol-reducing properties, or for athletes to consume high-protein products during a regimen of weight-bearing exercise. Today, the foods in the marketplace allow a substantial personalization of diets according to the knowledge of the consumer of their personal desires/needs and the marketing of various solutions (Table 1). Of course this segmentation invariably means shrinking the target consumer group. What are criteria underlying the personal choices of consumers in a seemingly unlimited world of options? Taste
The most immediate and easily accessed basis for personalization of foods is simple taste and flavor preferences. Even though personal taste preferences have been the basis for food choices for literally thousands of years, the genetic diversity of taste and olfactory sensation in humans is now recognized to be part of the diversity of food preferences [40,41,42]. In addition to genetic variation, olfactory preferences are principally a learned response to prior diet. Learned olfactory preferences to particular foods and flavors vary even within honey bees [43]. Cultural mores
There is considerable diversity of foods based on core beliefs of their suitability to a particular religious or philosophy value system. Although the origins and the perpetuation of these choices (halal or kosher foods, www.sciencedirect.com
Personalizing foods Fay and German 125
Figure 1
The extent to which the levels by which foods are personalizing in 2007 relative to the scientific research and technology necessary to bring them forward into the marketplace and service their consumer segments.
vegetarian diets, religious fasting, etc.) are not necessarily based on personal nutritional criteria they do produce nutritional consequences, whether desirable or not [35,44,45]. Lifestage
Considerable experience by humans over the centuries has led to personalization of foods according to the different physiological needs associated with the stages of human life (e.g. infancy, weaning, pregnancy, lactation, aging, and recuperating from illness). Innovative research is indicating that diets during many of the lifestage transitions (weaning, lactation) are important for longterm effects on health [46]. Lifestyle events
Many more immediate aspects of personalization of diets are associated with lifestyle choices and the events in such self-selected lifestyles. Although scientific evidence is rapidly building around these distinctive lifestyle choices and the physiological stresses that they produce, historical observational and anecdote are still the basis to a wide variety of assumptions for the value of specific foods. www.sciencedirect.com
Foods within this category are as disparate as beverages and products for athletes before, during, and after sports events, to products associated with increased risks of deep vein thrombosis caused by airline flights [47,48]. In these cases of lifestyle foods, the event itself is the distinguishing property for segmenting food products. Lifestyle diseases
Lifestyle diseases develop in a subset of the population and provide another opportunity for the personalization of the specific consumers who are at risk of, or actually experiencing failure of their health and the potential of specific foods to target functions that protect their health. Although modern diagnostic sciences are developing sensitive methods to distinguish those who are at greater risk, a wide variety of therapeutically oriented products are marketed to those at risk or actually diseased as a direct result of chronic lifestyle choices. Nutrientspecific products are of potential value whether targeted either to the symptoms of the problem (excess body weight, intestinal discomfort) or the lifestyle choices themselves such as smoking, sedentary lifestyle or high-fat diets [35,49]. Current Opinion in Biotechnology 2008, 19:121–128
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Table 1 Levels of personalization Personalization basis
Gain of knowledge
Marketing channel
Taste preference Cultural Mores Lifestage processes Lifestyle events
Personal experience Social experience Social history Participant experience Epidemiology Family history Nutrigenetics
Advertising Package labeling Health guidelines Event marketing
Lifestyle diseases Inherited diseases Genetic predispositions
Functional foods Clinical products Co-market genotyping
Different levels of personalization are recognized by different criteria and this knowledge has been gained both by the scientific community and the consumer by different means. The marketing channels by which products are directed to consumers based on these levels of personalization also differ.
Inherited health issues and diseases
Humans have recognized the familial basis to much of health throughout recorded history, and foods have been an integral part of their solutions. From predispositions to allergies and intolerances to inherited errors of inborn metabolism, diet is well known to contribute to these processes and to their prevention. The importance of diet to the problem of specific aspects of inborn errors of metabolism has led to the worldwide adoption of blood spot analyses at birth. It is now routine for most of the children born today to be tested for up to 10 metabolic diseases, not by genotyping them, but by accurate by measurings of normal metabolites whose inordinate abundance in blood are a diagnostic signature of the condition [50]. Phenylketonurea is well managed by metabolitebased diagnostics for the personalization of low phenylalanine foods. The dramatic risk to the health of the rarely affected individuals justifies measuring all infants at birth even though the vast majority is uninvolved [51].
to distinguish important biological differences merges with the industrial means to deliver individual solutions. This direction is not a genuine revolution in food, but rather the next step in a very long established diversification of foods that has been ongoing literally for centuries. For such personalization, genotyping technologies are not necessary. Practical solutions will benefit for the vast majority of consumers just by focusing food personalization on delivering properly validated nutritional solutions to well-established subsets of the population. Infants, active adults, athletes, pregnant and lactating women, frail elderly, and all consumers who suffer from inherited or acquired diseases, are all unique and foods that both address their nutritional issues and ensure compliance by considering personal preferences in taste, texture, and appearance. Providing nutritional foods for helping individuals recovering from disease is a clear opportunity to develop parallel approaches along with personalized medicine already being adopted by clinicians. The science of genomics has established clear proofs-of-principle that humans are importantly different with respect to optimal diets. As science builds the knowledge of how genetic variations affect predispositions to disease, and as genotyping technologies a readily accessible, consumers will gain value by being informed of their personal genetic variations and especially those genetic variations that can be successfully altered by appropriate diets. Yet, we are not different solely because of genetic variations. This highlights the necessary synergies between the genotyping approaches and the holistic investigations of the metabolism using proteomics and metabolomics. It is this combined approach that will provide accurate assessments of individual health promises to accelerate dramatically the ability of individuals to gain knowledge of their personal needs and the food marketplace to deliver genuinely revolutionary benefits to a large subset of the population, one consumer at a time.
Genetic predispositions
References and recommended reading
A final level of personalization is basing food choices solely on genetic variations. This approach refers to personalizing food from genotyping data alone in which no other discernible aspect of phenotype would provide equivalent information. Such methods for assigning diversity among individuals are now becoming possible, though for only a very small subset of genetic variations and a small number of individuals [4]. The problem for industrialization of such approaches is that one must deliver huge amounts of information, yet the recommendations for change will be limited to a small group of people sharing the same genotype and having similar dietary requirements.
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