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A systems biology approach to nutrition
research - Nutrigenomics
Elizabeth Srokowski

Abstract— The application of systems biology to nutritional
science is revolutionizing the approach and significance of
investigating the relationship between diet, health, and gene
expression. The concept of examining gene expression profiles has
provided researchers with the preliminary information necessary
to develop suitable biomarkers for metabolic diseases and to
identify potential gene targets that are influenced by nutrition.
Furthermore, because of the holistic perspective encompassing
systems biology, nutrigenomics is providing a powerful tool to
unravel the complex mechanisms involved in successful metabolic
regulation. Although, nutrigenomics is still in its beginning stages
of development, it is essential that at this stage, a critical analysis
of the implications of this technology be assessed thoroughly.
Index Terms—functional genomics, metabolic regulation,
nutritional genomics, nutrition
I. INTRODUCTION
T
he reality of the common phrase - ‘we are what we eat’, is
holding more significance as scientists slowly reveal the
relationship between diet, disease, and genes. Our dietary
intake contains thousands of biologically active substances,
many of which provide substantial health benefits. For
instance, food-derived compounds such as sulphoraphane,
curcumin, lycopene, and tea polyphenols, have been identified
as promising chemo-preventive agents [1]. Nevertheless, the
full extent of biologically active substances in our diets is
unknown.
In the past, epidemiological studies have demonstrated the
connection between dietary habits and degenerative diseases
such as cardiovascular diseases, cancer, and other chronic
diseases. However, the specific cause-effect relationship
between the amount and type of nutrient and the health or
disease phenotype has always puzzled researchers minds and
have only in part been understood [2] - [4]. This is primarily
due to the complexity of the mechanisms involved as well as
the lack of appropriate research tools needed to elucidate the
complex relationships [3].
Despite modern medicine successfully treating many
diseases, such as diseases caused by the presence of pathogens,
toxins or dysregulated cells, other health issues such as
atherosclerosis, obesity, hypertension, type 2 diabetes, and
various inflammatory diseases are caused by chronic
imbalances of normal metabolic pathways that are in part
related to diet [5]. These metabolic diseases are distinct in
their properties, and thus require distinctly different
approaches for detection, prevention and cure. Furthermore,
although the occurrence of various diseases is routinely
identified using pre-determined biomarkers, diseases caused
by long-term metabolic imbalances do not necessarily produce
biomarkers until the disease is well established. As such, novel
preventive measures are required that firstly detect the
metabolic imbalance itself, and secondly attempt to restore the
system to its optimal metabolic balance [1], [3], [5].
Consequently, in order to effectively treat the broad breadth of
diseases in existence, routine metabolic assessments need to be
incorporated into modern medical strategies. Hence, the task at
hand is no simple undertaking and presents one of the greatest
challenges for nutritional science.
A. Nutrition and diet
Nutrition plays a vital role in modulating many biochemical
pathways responsible for maintaining a normal metabolic
balance in our system. Metabolic balance is achieved by the
existence of essential and non-essential1 nutrients at their
appropriate limits as well as the correct relative proportion of
essential and non-essential nutrients in the diet [5]. A general
goal of nutritional science is to understand how multiple
nutrients interact with one another at various stages during
their utilization, as well as the various roles these dietary
inputs take on, and the consequences they have on cell and
organ function [6]. The functions and actions of nutrients are
abundant. For instance, nutrients can catalyze reactions and
serve as cofactors; serve as substrates for macromolecules that
are involved in an array of other functions; can act like a
network of computers – executing a sequence of instructions;
can alter the molecular structure, thus inhibiting or amplifying
pathways [6]. Although the aforementioned nutrient roles have
been identified, the molecular mechanism involved to achieve
nutrient homeostasis at the cellular level is not fully
understand, and thus present a whole new realm of possible
functions for nutrients.
The development of chronic metabolic diseases have long
been attributed to a wide range of environmental factors, such
as exposure to toxins, smoking and substance abuse, socioeconomic status and diet [4]. To date, there is an
overwhelming amount of evidence identifying diet as one of
the key environmental factors responsible for the development
of metabolic diseases [1]-[5]. This can possibly be attributed
to the fact that diet is a constant environmental factor in which
our genes are exposed to throughout our lifetime, thus
affecting our biological system implicitly [2]. Nutrients, or
dietary chemicals, influence physiological processes by
altering the expression of a subset of genes in the genome.
1 Essentials nutrients are obtained from the six classes of nutrients (fat,
carbohydrates, proteins, minerals, vitamins, and water), whereas non-essential
nutrients are produced within the body and are not obtained from food
digested (e.g. cholesterol) [7].
2
This alteration can occur in a number of ways, for example
dietary chemicals may: 1) act as ligands for transcription factor
receptors; 2) be metabolized by primary or secondary
metabolic pathways that ultimately alter the concentrations of
the substrates or intermediates in the process; and 3) serve as
signaling molecules [4].
Figure 1 shows a schematic
representation of the effect dietary chemicals (nutrients) have
on gene expression. They can affect gene expression directly
(A), or indirectly (B and C) [4].
Fig 1. Schematic representation of the affect nutrients have on gene
expression – directly (A) or indirectly (B and C) [4].
II. GENOMICS AND NUTRITION
With the advent of genomic technologies such as
transcriptomics, proteomics, and metabolomics, nutrition
research has finally been provided with the necessary tools to
decipher the complex mechanisms involved in successful
metabolic regulation [5], [6]. Despite nutritional science
recognizing at an early stage that diet and specific nutrients
influenced the transcription of genes, the interdependence
between metabolic pathways and gene transcription had
always been unclear [1]. Furthermore, although extensive
studies in nutrition research attempted to clarify the unknowns,
the approach in which the studies were conducted was
misleading. In the past, nutritionists focused their efforts on
understanding the specific molecular details of how certain
nutrients in the diet exerted their effects on a biological
system. However, this approach limited the scope of their
understanding to a particular mechanism operating under
specific parameters; thus reducing their ability to comprehend
the complexity of the overall biochemical pathways involved.
The disparity of this approach can be vividly illustrated by the
inability of nutrition to solve the growing problems of
metabolic disregulation in humans with atherosclerosis,
obesity and diabetes [8].
Being that nutrition is a
multidisciplinary field, by adapting a more global perspective,
the application of functional genomics to nutrition research
provides a more informative means of improving health
through diet. As such, functional genomics has allowed for a
paradigm shift from a reductionists strategy to a more holistic
perspective - commonly termed a systems approach [1], [3],
[5], [8]. The result of this approach has stemmed a new
‘–oemic’ technology, nutrigenomics.
A. Nutrigenomics - Goals
Nutrigenomics or nutritional genomics, can be defined as
the study of how naturally occurring chemicals in foods alter
molecular expression of genetic information and how the
variation in individual genotypes affects phenotypic
expression, all as a function of diet [2], [8]. Recently, Vernon
Young [6] from the School of Science at the Massachusetts
Institute of Technology, concisely summarized the goals of
nutrigenomics at the Annual Meeting of the American Society
for Nutritional Sciences 1) explore the roles(s) and
mechanism(s) of action of nutrients; 2) establish quantitative
nutrient requirement values and understand the molecular and
cellular basis for individual variation in requirements; 3)
predict, with an increased precision, the nature of genotypeenvironmental interactions, especially in relation to chronic
disease and its nutritional antecedents; and 4) optimize food
production and the nutritional value of foods for specific
populations in given ecological/cultural/social settings [6].
B. Nutrigenomics –Genomic Technologies
Nutrigenomics utilizes a wide range of genomic
technologies to investigate the effect dietary intake has on
metabolic and genetic regulation (Fig. 2) [1], [2]. Despite the
innovative approach of nutrigenomics, this is still a relatively
novel area where the specific methodology of these functional
genomic technologies to nutritional science needs to be
worked out. However the potential of this approach can be
exemplified by the rapid adoption of these technologies to
disciplines such as pharmaceuticals, toxicological and clinical
research [1]. Nevertheless, obstacles to nutrigenomics do exist.
For instance, a challenge nutrigenomics will most likely face is
the design of meaningful studies in which to use these genomic
techniques. More specifically, the design of studies capable of
deciphering the complex interactions between individuals’
genetic differences, their predisposition to disease and the
compound-gene interactions and lastly, the integration and
examination of the vast sets of data that such studies will
produce [1].
C. Benefits of Nutrigenomics
The output from all the functional genomic technologies, as
depicted in Fig 2, can ideally be integrated in a database of
known genomic sequences and correlated with the genetic
variability from individual to individual, to allow for the gene
expression of thousands of different genes to be studied
simultaneously. Given that different genes or gene
combinations respond differently to changes in environmental
factors such as exercise, smoking and diet, the generated
genetic profile would enable individuals to adopt habits that
would minimize their risk of developing a disease [9]. Thus,
nutrigenomics embodies the possibilities of improving public
health through the prevention of disease. Nutrigenomics also
presents the possibility of personalizing ones diet (also known
as intelligent nutrition) by catering ones nutritional intake to
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prevent or delay the onset of disease and thus, optimizing ones
health [1], [5], [9]. Having access to such powerful and
informative knowledge would not only be beneficial for
nutritional scientists but also for future generations where the
risk of disease would be minuscule.
Regulation by diet
Gene expression process Functional genomics
techniques
DNA
Transcription, RNA
processing and
stability
RNA
Translation,
modification, and
stability
Protein
Cell
Genomics (gene or
promoter sequences
and polymorphisms)
Transcriptomics
(DNA arrays)
Proteomics
Metabolites
Metabolomics,
metabonomics,
bioassays
Health
Fig 2. Schematic representation of the step involved in gene expression
(center), the stages at which diet can modulate these processes (left), and the
functional genomics techniques used to analyze each stage (right) [1].
III. GENETIC VARIATIONS
The sequencing of entire genomes has revolutionized the
scientific community by providing scientists with an incredible
amount of insight into the relationship between biological
processes and gene function. Surprisingly, the Human Genome
Project revealed that for the most part the vast majority of
human genetic information is similar from person to person
[4], [6], [8]. For example, the DNA sequence of two
individuals is 99.9% similar – or there exists about 1
difference in every 1000 base pairs in their sequence [4]. The
relatively small differences in DNA sequences are responsible
for human diversity such as hair and skin colour, height and
weight potential and all other ‘gene-based’ variations.
Additionally, these minor differences also involve many
important medical variations that may alter an individual’s
susceptibility to a disease [4]. Specifically, these variations at
the molecular level alter gene structure, and thus function.
Many of the sequence variations are single nucleotide
polymorphisms (SNPs). It is believed that SNPs, acting
individually or in groups, alter the regulation of gene
expression, mRNA processing and protein and enzymatic
activity [2], [4]. Recently, it has been reported that
approximately 1.42 million SNPs have been discovered in the
human genome and can be linked to discrete locations in the
genome [8]. A number of studies have correlated various
SNPs of importance, to particular phenotyptic patterns of
nutritionally related health disorders such as homocystenemia,
high/low cholesterol, or variations in HDL and LDL
cholesterol and their subunits [2], [8]. In addition, progress is
slowly being made to correlate SNPs to genotypic variation
[8]. As a result, SNPs can provide a powerful molecular tool
for investigating the role of nutrition in human health and
disease. Thereby, the recent developments of genetic
polymorphism databases and high throughput genetic
screening made possible through functional genomic
technologies, are providing a means of integrating this
knowledge into clinical, metabolic and epidemiologic studies
that will therefore contribute enormously to the goal of
‘intelligent nutrition’ [1], [8].
Scientists have long hypothesized that the inter-individual
genetic differences were responsible for the variations in
response to environmental factors such as diet [2]. For
instance, knowledge about disorders such as lactose
intolerance, alcohol dehydrogenase deficiency as well as the
variability among individual’s blood lipid profiles and health
outcomes due to the consumption of high fat diets, presented
scientists with valid reasoning for their suspicions [2], [9].
However, the direct connection and understanding of the
mechanisms involved continued to perplex them. The recent
introduction of nutrigenomics has started to aid scientists in
their understanding.
Moreover the variability in the response to dietary intake
among ethnic and racial groups within society, also presented
scientists with compelling evidence of the interdependence of
genetic variations and dietary intake. For example, this can be
demonstrated through the disproportionately high incidences
and morbidity rates due to diabetes, obesity, asthma,
cardiovascular diseases (CVD) and certain cancer, among
certain minority populations. Based on a 1985 U.S. survey of
dietary habits and health status conducted through the National
Health and Nutrition Examinations Survey (NHANES), it was
found that that older African Americans and Mexican
American women as well as African American men were at
greatest risk for CVD which consequently heightened the risk
of CVD among younger ethnic minority populations.
Furthermore it was found that CVD risk factors included
plasma lipids as well as dietary fat, obesity, hypertension and
diabetes, which were highly evident in these minority
populations [4].
Unfortunately, few research groups to date have undertaken
the task of correlating specific SNPs to genotypic variations.
Despite the small number of studies conducted, there has been
important knowledge gained from their observations.
However, it has been critiqued by some researchers that in
order for nutritional genomics to acquire a more accurate
prediction of the mechanisms driving the connection between
diet and phenotype according to specific genetic variations,
nutritional researchers must take a more proactive stance in
this particular subject matter [8]. However, according to a
review paper by Young R (2002) [6], it has also been
suggested that SNPs may not be sufficiently strong to affect
the requirement/function/cell response due to the complexity
of the numerous pathways involved in metabolic regulation.
Thus, discrepancies among nutritional researchers do exist
while they attempt to determine the most optimal approach in
which nutrigenomics should proceed. Nevertheless, the
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multidisciplinary perspective that genomic technologies
inherently bring to scientific research will not only expose
nutrition research to a more well rounded idea of how to
identify and decipher genotype-environmental interactions
more accurately. Also, it will provide them with the capability
to efficiently use high throughput screening strategies that
ultimately will place nutrigenomics in a suitable position to
unveil the mystery of successful metabolic regulation.
IV. BIOMARKERS
In traditional medicinal approaches, individuals are
diagnosed based on the presence of a variety of biomarkers.
However, as mentioned previously, this conventional strategy
is not applicable to detecting metabolic diseases since the
detection of these particular biomarkers is identified too far
along the disease process [1], [3], [5]. Nonetheless, the
methodological approach inherent to nutritional genomics
provides a suitable manner to develop molecular biomarkers
for early, pivotal changes between health maintenance and
disease progression [1]. Recently, two distinct approches have
been proposed for the identification of metabolic diseases (Fig.
3) [1].
Earliest markers of food
bioactivity
Alternative approaches
to nutritional genomics
research
Cascade of changes in
gene expression with
scope for return to healthy
state through dietary
modification
Reduced scope for return
to healthy state through
dietary modification
natural components of foods that we ingest can have both
beneficial and adverse effects. These may impinge on quite
different health or disease processes and at overlapping doses.
For example, moderate to low intake of alcohol is associated
with a reduced risk of heart disease but an increased risk of
cancer. As such, the novel approaches that nutrigenomics is
offering to nutritional scientists, will ultimately have to be
fine-tuned in accordance to these effects in a manner that
enables them to determine maximum benefit and minimal risk
[1].
V. CONCLUSIONS
The multidisciplinary approach that embodies systems
biology allows for the concurrent monitoring of complex
metabolic pathways as well as the capacity to measure small
perturbations introduced into the pathway that may result from
nutritional influences. Although incredible progress is being
made in nutritional science through the application of
functional genomics technologies, the challenges that this area
of research will most likely face are not technologically based
[3].
For example, infrastructural changes in research
institutions and universities will need to occur in order for
disciplines to integrate their knowledge more conveniently and
for these teams to conduct innovative scientific research. The
impacts on the food industry will also need to be fully
investigated in order to minimize any potential risks that could
be presented to the overall well being of society. Furthermore,
the socio-economic impacts of conducting routine genetic
screening for many genes as well as the opinions and ethical
issues associated with such screenings will have to be vitally
considered. Nutrigenomics is still in its naïve stages of
development. Consequently, it is crucial that at this pinnacle
stage, this technology considers all facets of its impacts on
society, not only its advantages but perhaps more imperatively
all its disadvantages.
REFERENCES
[1]
Fig 3. Schematic representation of proposed chronic disease development
process and the alternative nutritional genomics approaches [1].
[2]
The first approach focuses on the disease state and tracks
back through the mechanism of development to identify the
earliest genes involved. The identified genes are then used as
targets to determine nutritional agents that are capable of
modulating the gene expression. The second approach begins
with a healthy normal condition and examines the effect of
dietary components on global patterns of gene expression
without any hypothesized outcomes. The ideology behind
these approaches is that the specific effect on patterns of gene
expression will guide nutritional scientists to the links of
disease development.
The advantage of these approaches is that they do not need
to be mutually exclusive and may be complementary, thereby,
potentially meeting at the level of the key early genes.
However this task may be complicated by the fact that the
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[5]
[6]
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[8]
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vol. 324, pp. 1438-1442, 2002.
N.F. Johnson & J. Kaput, “Nutrigenomics: An emerging scientific
discipline,” Food Technology, vol. 57, no. 4, pp. 61-67, 2003.
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NCMHD Center of Excellence for Nutritional Genomics,
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Available: http://nutrigenomics.ucdavis.edu
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[9]
N. Fogg-Johnson & A. Merolli, “Nutrigenomics: The next wave in
nutrition
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Available:
http://www.nutraceuticalsworld.com/marapr001.htm