Discovery-Based Nutritional Systems Biology: Developing N-of-1 Nutrigenomic Research

Abstract

Biological and biomedical research, like many established human activities, is based on conventions and practices that become standardized over time. Many of these conventions are decades old and do not account for the great advances in knowledge resulting from modern research. Some of the main practices of biomedical research are discussed herein, in an attempt to initiate a dialogue in the nutrition community about new concepts for personalized nutrition and health. The Design of ExperimentsThe design of biomedical research experiments rests on standards developed almost 100 years ago. The methodology was codifi ed in RA Fisher's The Design of Experiments [12] a 1935 treatise that described the key elements of good research protocols. These benchmarks are a valued requisite for determining the quality of experimental results and Fisher's experimental design is now considered the gold standard for human Abstract: The progress in and success of biomedical research over the past century was built on the foundation outlined in R.A. Fisher's The Design of Experiments (1935), which described the theory and methodological approach to designing research studies. A key tenet of Fisher's treatise, widely adopted by the research community, is randomization, the process of assigning individuals to random groups or treatments. Comparing outcomes or responses between these groups yields "risk factors" called population attributable risks (PAR), which are statistical estimates of the percentage reduction in disease if the risk were avoided or in the case of genetic associations, if the gene variant were not present in the population . High throughput metabolomics, proteomic and genomic technologies provide 21 st century data that humans cannot be randomized into groups: individuals are genetically and biochemically distinct. Gene -environment interactions caused by unique dietary and lifestyle factors contribute to heterogeneity in physiologies observed in human studies. The risk factors determined for populations (i.e., PAR) cannot be applied to the individual. Developing individual risk or benefi t factors in light of the genetic diversity of human populations, the complexity of foods, culture and lifestyle, and the variety of metabolic processes that lead to health or disease are signifi cant challenges for personalizing dietary advice for healthy or medical treatments for individuals with chronic disease. Table I), when applied to the appropriate scientifi c question, produce reliable evidence for improving public and personal health. More humans survive childbirth, infancy, childhood, and through advanced age than any time in our species history [44].One of the key tenets of designing experiments is the requirement for randomization of subjects or other outbred animals to case and control groups. Randomization distributes unknown or unmeasurable characteristics between groups in an attempt to isolate and identify measurable variables that differ between or distinguish those groups. While this step was necessary in the ...

The genomics of micronutrient requirements

“…The bioavailability and bioactivity of micronutrients and bioactives differ widely according to chemical structure. Intake from dietary supplements and foods differ in content, matrices, and dose Gaine et al (2013) The micronutrient and bioactive content of plant foods is influenced by numerous plant-related factors (e.g., sun, ripeness, storage, preparation, processing), making accurate assessment of their intake difficult Gaine et al (2013) Errors in intake measurement: accuracy of food composition databases and reliability of FFQs, and intake amounts do not always equate to bioavailable doses Gaine et al (2013) The health benefits of micronutrients and bioactives in the current literature are often based on surrogate biomarkers of effect rather than actual health outcomes (endpoints), such as disease incidence or mortality Gaine et al (2013) Classical case/control designs of human clinical/nutritional intervention studies should be complemented by crossover, longitudinal studies, in which every subject is its own case and control Kaput and Morine (2012) Homeostasis varies among individuals. Challenging homeostasis may identify individual health trajectories van Ommen et al (2009) The funding required in undertaking a formal federal review of micronutrient and bioactive intake has not been viewed as a priority Gaine et al (2013) …”

“…The first is the insistence on randomization for clinical studies, and the second is the reductionist's approach used to study complex systems. While randomization was essential for pregenomic era research (Fisher 1971), the ability to characterize individuals at the genetic, proteomic, and metabolomic level demonstrated that this statistical approach-also by definition-masks inter-individual variation in response not only to nutrients but also to drugs (Guyatt et al 1990;Lillie et al 2012;Kaput and Morine 2012). Similarly, the one-gene-one-polypeptide concept best exemplified by Beadle and Tatum's 1941 analysis of auxotrophy in Neurospora sp.…”

“…Indeed, the impact of subclinical undernourishment and the micronutrient needs of populations in different environments and with diverse cultural, genetic, and agricultural histories are still unknown (Kaput and Morine 2012;Kussmann and Kaput 2014). While policymakers rely almost exclusively on population averages for micronutrient recommendations, the quantitative aspects of human nutrient requirements on the utilization, function, and metabolism of micronutrients at the cellular, organ, and whole biology system level (Young and Scrimshaw 1979) in individuals must be determined.…”

“…This more comprehensive strategy requires extensive molecular phenotyping of humans, which includes analysis of environmental, genomic, microbiological, and epidemiological factors (Kaput et al 2005;Kaput and Morine 2012;Kussmann et al 2013;Kaput et al 2014). Measuring all of an individual's complexity in diverse environments can of course not be done, but refined phenotyping at molecular level will greatly help explain the mechanisms involved in determining micronutrient requirements.…”

“…Research is ''personalized'' since one individual is assessed and informed even in the community setting. Translation of knowledge is more immediate than population-based methods and is targeted to the community and individual (McCabe-Sellers et al 2008;Kaput and Morine 2012;Monteiro et al 2014). …”