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Understanding
of human nutrition has followed developments in the sciences,
primarily chemistry, biochemistry and physiology. During the
“Naturalistic Era” (400 B.C.-1750 AD), Hippocrates hypothesized
about the body’s “innate heat”; during the next 500 years, little
happened in either the development of scientific knowledge or
nutrition science.
The late 1700’s ushered in the
“Chemical-Analytical Era” (1750-1900) highlighted by Lavoisier’s
calorimetry studies1. He discovered how food is metabolized by
oxidation to carbon dioxide, water and heat. He also invented the
calorimeter, crucial to further understanding of heat energy. In the
19th century, Liebig recognized that carbohydrates, proteins and
fats are oxidized by the body and calculated energy values for each.
While chemists were examining the composition of foods and
metabolism, physicians were studying the mechanisms and process of
digestion, the means by which food is converted to useful,
oxidizable components.
The “Biological Era” (1900-present)
was founded on advances in chemistry, biochemistry and understanding
of the metabolic pathways1. In the early 20th century, considerable
research had been done on energy exchange and on the nature of
foodstuffs. Nutrition science took a leap forward as evidenced by
publication of the “laws of nutrition” by Langworthy. Once
understanding of macronutrients was developed and better tools
developed, nutrition scientists turned attention to the
understanding of micronutrients, mineral and vitamin nutrition2.
Most work during the last half of the 20th century (post 1955), the
“Cellular Era,” focused on understanding functions of essential
nutrients and the roles of micronutrients (vitamins and minerals) as
cofactors for enzymes and hormones and their subsequent roles in
metabolic pathways. The roles of carbohydrates and fats in diseases
such as diabetes and atherosclerosis were discovered and actual and
potential mechanisms have been uncovered3.
Even in those
observations of health and disease, puzzles existed. Why can some
individuals consume high fat diets and yet show no evidence of
atherosclerotic disease? Genetic differences certainly were
suspected, but elucidating and proving cellular, molecular and
ultimately genetic-level mechanisms in both healthy and unhealthy
individuals proved to be a challenge.
With the continuing
developments in tools that enable molecular level exploration of
cause-effect phenomena, scientists have begun to develop hypotheses
and conduct experiments to lay the foundation for a deeper level of
understanding of gene-diet interaction. Today, an emerging field of
nutritional research focuses on identifying and understanding
molecular-level interaction between nutrients and other dietary
bioactives with the human genome during transcription, translation
and expression, the processes during which proteins encoded by the
genome are produced and expressed.
The Next Step:
Nutrigenomics
Continuing and accelerating
discoveries in genomics present possibilities for an ever more
dynamic era of scientific investigation based on understanding the
effects of nutrients in molecular level processes in the body as
well as the variable effects nutrients and non-nutritive dietary
phytochemicals have on each of us as individuals. We call this the
new era in nutritional science the genetic era, or nutrigenomics. On
one hand, it represents a logical extension of biotechnology,
molecular medicine and pharmacogenomics, while on the other, it is a
revolution in how nutrition and diet are viewed.
Enabling
science and technology platforms and techniques are essential for
development of knowledge and advancements in science. Table 1 shows
the key developments that are propelling nutritional science to the
genetic level.
Application of the tools and techniques listed
in Table 1 forms the basis of a relatively recent approach to drug
research and development known as pharmacogenomics, the use of
genetic information to predict the safety, toxicity and efficacy of
drugs in individual patients or groups of patients. “Personalized
medicine” developed through growing knowledge of pharmacogenomics
has generated a lot of well-deserved enthusiasm as an important tool
for the pharmaceutical industry. Collaborations have been
extensively established.
Karl Thiel, staff writer for
Biospace.com, creates an interesting scenario4: “You go to the
hospital with complaints of chest pain. A doctor diagnoses you with
chronic angina and recommends drug therapy. But instead of giving
you a prescription, she gives you a quick pinprick blood test.
Placed in a small machine, the sample is rapidly, automatically
prepared for analysis and through a speedy hybridization or mass
spec assay, a relevant portion of your genotype is determined. The
results show that you have a genetic polymorphism that makes you
unsuitable for the most common type of angina medication—its
efficacy will be marginal and you will be likely to have significant
side effects.”
The application of similar tools and methods
to examination of individual responses to macro/micronutrients is at
its infancy. But we predict that nutrigenomics will be the next
technological and commercial frontier emerging from genomics. How
will this happen?
• Individual genetic differences in
response to dietary components have been evident for years: lactose
intolerance, alcohol dehydrogenase deficiency, individual and
population differences in blood lipid profiles and health outcomes
after consumption of high fat diets.
• Genomic
information—including proteomics and SNP’s—will be used to
understand the basis of individual differences in response to
dietary patterns.
• The resulting nutrigenomic data also
will provide a sound basis for development of safe and effective
diet therapies for individuals or subgroups of the population.
• Genomics can aid diet development and health outcomes from
dietary patterns by defining specific sub-populations of patients.
• Refined models of disease mechanism based on understanding
the genome may provide new lines of research and possibly new diets.
The elaboration of physical and genetic linkage maps combined with
techniques to catalog massive databases of genetic information will
uncover genes that may interact with diet to influence disease.
“Nutrigenomics will revolutionize wellness and disease
management,” said Guy Miller M.D., Ph.D., chairman and CEO of
Galileo Laboratories, Inc., a biotech company working on cell-based
therapeutic nutritionals. “Specifically, by being able to elucidate
genetic profiles of individuals, diets will be formulated from crop
to fork to confer prevention or retard disease progression. As basic
science advances converge with e.commerce, new opportunities will
emerge to deliver to consumers, whose genetic susceptibility to
specific diets and diseases are known, products tailored to
individual dietary needs.
“One driving force for
nutrigenomics will be cost savings realized by consumers, employers,
government and third party providers, through retarding and
preventing disease,” he continued. We are embarking on a new era to
deliver to consumers exciting technologies to enable wellness.”
Mapping Out The
Possibilities
Genetic variations occurring in more
than 1% of a population would be considered useful polymorphisms for
creating a chromosome map showing the relative positions of the
known genes on the chromosomes of a given species. A consortium of
pharmaceutical companies and academic institutions has undertaken
the task of mapping human SNP’s. While the initial target of this
effort is drug development, diagnostic applications are already
developing. Can nutritional applications be far behind? We think
not. Dave Evans, president and CEO, Wellgen, Inc., a startup company
commercializing Rutgers University technology, agreed, “In less than
10 years, you’ll be able to go to a lab and complete a set of
genetic tests to identify your personal disease susceptibilities.
When you leave you’ll be armed with a list of foods to eat and foods
to avoid and a recommendation of dietary supplements to help prevent
your diseases.”
Suppose the person with angina noted above
has testing to understand the genetic polymorphisms that interact
with diet to influence inception and development of a certain set of
conditions or diseases. Specific diets could then be created to
retard or block such development. If we have this information early
enough, we could benefit future generations with markedly reduced
risks of disease.
For instance, if we knew all the genes
involved in cardiovascular health—detrimental ones, protective ones
and how much each contributes individually and in combination, we
might be able to reduce a person’s likelihood of cardiovascular
disease based on his or her genetic profile, as well as on age,
gender and lifestyle habits. A genetic profile would enable
individuals to adopt the habits most likely to reduce risk—because
different genes or gene combinations respond differently to changes
in diet, exercise, smoking, alcohol consumption.
Dr. Ronald
Krauss, head of the Molecular Medicine Department at the Lawrence
Berkeley National Laboratory, UC Berkeley, observed, “When a large
group of people go on the same diet low in saturated fat and
cholesterol, their LDL levels can vary widely.” The question is
“why?” Dr. Krauss further claims that, “recent evidence indicates
that genetic factors can contribute to differences in dietary
response.” Studies with large samples do not satisfactorily predict
individual responses due to unique genotypic differences. Dr. Krauss
predicts the results of research on the interaction of genes and
diet may lead to diet plans and /or drug regimens tailored to an
individual’s genetic predisposition to heart disease and stroke5.
Richard B. Weinberg, M.D., professor of internal medicine at
Wake Forest University Baptist Medical Center reported in the New
England Journal of Medicine6 that subjects with the variant gene
(apo A-IV-2) showed lower increases in cholesterol and LDL than
subjects with the more common gene (apo A-IV-1) when fed high egg
diets. He hypothesizes that the variant gene affects dietary
responsiveness by altering the efficiency of intestinal absorption
of cholesterol. These findings may lead to better understanding of
the larger normal population and how to control cholesterol
absorption.
Dr. Jose M. Ordovas, Jean Mayer USDA Human
Nutrition Research Center on Aging at Tufts University in Boston,
Massachusetts, has identified several of the 40 or so genes so far
known to affect cardiovascular health. He estimates that there may
be hundreds of genes that will ultimately go into a risk-analysis
database. Dr. Ordovas explains that four main components under
genetic control contribute to coronary artery disease risk, known as
“syndrome x”7:
• high blood lipids—total and LDL
cholesterol, triglycerides
• impaired glucose tolerance and
diabetes
• high blood pressure
• obesity (in the
abdomen).
Whether the genes for any of these components are
manifest depends on an individual’s habits as well as age, Dr.
Ordovas says. Moreover, manifestation is interrelated. For example,
in an obese person, a gene for obesity can trigger a normally
beneficial gene for blood lipids to express high LDL cholesterol and
triglycerides. However, if the person stays lean, the beneficial
gene could prevail—all other things being equal.
Someday,
health professionals will have a complete profile of the human genes
involved in raising or lowering risk, says Dr. Ordovas. Children
could be tested early in life so that diet and other lifestyle
changes would be started before damage begins.
Relationships
between individual differences in the ability to process milk
proteins and highly puzzling neurological diseases such as autism
and schizophrenia have been postulated. According to Dr. J. Robert
Cade, University of Florida, an intestinal enzyme flaw in some
individuals may lead to absorption of beta-casomorphin-7, a portion
of the casein molecule. These individuals absorb the 12 amino acid
peptide rather than free amino acids. The peptide produces
exorphims, morphine-like compounds and are taken up by portions of
the brain linked to autism and schizophrenia8.
Dr. Jo
Freudenheim, SUNY at Buffalo, studies the role of diet in cancer,
particularly breast cancer, risk9. She has examined the role of
genetic polymorphism in genes for metabolic enzymes as modifiers of
the effect of exposures such as diet and alcohol in cancer risk.
According to Dr. Freudenheim, there appears to be an effect of a
genetic factor related to alcohol dehydrogenase activity that
influences the association between alcohol consumption and breast
cancer risk. Among premenopausal women with both the genetic factors
related to increased enzymatic activity and who have higher alcohol
consumption, there was increased cancer risk. There was no such
association for women with lower alcohol consumption or who had the
other genotype.
The search for genetic markers for breast
cancer susceptibility has led to an increasing number of
epidemiological studies of relatively common genetic polymorphisms.
These polymorphically expressed genes code for enzymes that may have
a role in the metabolism of estrogens or detoxification of drugs and
environmental carcinogens. Although the clinical significance and
causality of associations with breast cancer is unclear, genetic
polymorphisms may account for why some women are more sensitive than
others to environmental carcinogens.
Where To From Here?
We certainly
can envision concentrated, single bioactive compounds that could be
delivered in a variety of forms. These could be enzymes that counter
the effects of absent or decreased activities relevant to disease
inception or development, autism or schizophrenia, for example. For
instance, if a person lacking the intestinal enzyme to hydrolyze the
indicated portion of the casein molecule, could take it in pill form
prior to consumption of milk products, this may lead to improved
quality of life for those suffering from certain neurological
disorders. The same may be true for susceptible females who may need
to intake alcohol dehydrogenase before consumption of alcohol. The
possibilities are manifold.
We can see the development of
food/beverage products either as preventive agents or as treatments
specific for those with a propensity for disease. The most prevalent
current example is the ketogenic diet used for treatment of
pediatric epilepsy patients considered intractable, non-responsive
to pharmaceutical regimens. The possibilities extend to important
segments such as those with propensities for cardiovascular, cancer
and others described above.
What does this burgeoning new
field of understanding presage? Beyond the obvious improvements to
quality of life and health, we see a new mode for market
segmentation. Imagine the possibility to identify small subgroups
based on their individual genome, create products to satisfy their
needs and then to market diets and products directly to them. The
technology to accomplish in an economically feasible way is rapidly
becoming a reality. According to Dr. B. Michael Silber, Pfizer, “it
costs $150 or more to identify each of a person’s S.N.P.’s. The
goal, he adds, is to get the price down to pennies, which he calls
feasible. Some challenge that consumers do not want to know. We
think that the drive for prevention and prolongation of life quality
will prevail, particularly when costs permit wide diffusion into our
culture.
Who will do this? Certainly, the academic community,
rich with new tools, is making relevant discoveries daily. Small,
entrepreneurial start-up companies who are willing to make the
needed investment and take the risk will most likely be first to
market. Food processors marketing mainstream products will wait for
the products to be created and demand to be established. We will
then see them applying their extensive marketing skills to reach
ever more segmented groups. Rather than the current demographic or
psychographic segmentation tools, the future belongs to those who
can adapt to deliver products based upon new applications of genomic
tools.
References
1”A History of
Nutrition”, E.V. McCollum 1957 QU 145 McCol.
2Nutrition; An
Integrated Approach, Ruth Pike and Myrtle Brown, John Wiley &
Sons, 1975, pp 4-8.
3”Fundamentals of Nutrition”, Course
Syllabus, University of Vermont.
4Biospace.com
“Pharmacogenomic Medicine: Technology Outpacing the Health Care
System.”
5AAAS symposium on “Gene-diet Interactions in
Coronary Heart Disease,” AHA press release
2/14/98.
6“Attenuated hypercholesterol response to a
high-cholesterol diet in subjects heterozygous for the
apolipoprotein A-IV-2 allele,” Weiberg et al, N Engl J Med, Vol.
331, No.11, pp 706-710.
7“Attacking Heart Disease at Its
Genetic Base”, Agricultural Research, 7/99.
8Autism and
Schizophrenia: Intestinal Disorders, Cade R et al. Nutritional
Neuroscience, in press 1999.
9Symposium: Interactions of diet
and Nutrition with Genetic Susceptibility in Cancer, Journal of
Nutrition, Vol. 129, 2/99, pp 550S-551S. |
