Why is it Necessary to Understand the Molecular Biologist ?
Marília Cravo, M.D., Ph.D.
Centro de Nutrição e Metabolismo, Faculdade de Medicina de Lisboa, Portugal
phone +351-21-7200422, fax +351-21-7229855, email: mcravo.cplancha@mail.telepac.pt
Learning Objectives
 To get acquainted with the terminology and technology of medical genetics
 To understand what genetic polymorphisms and susceptibility genes are
 To understand how nutrients can control gene expression
 To understand what individualised, genetically tailored medicine is
Since the 1970s, nearly all avenues of biomedical research have led to the gene, for
genes contain the basic information about how a human body carries out its duties from
birth to death [1]. During lifetime, the health of an individual will be determined by the interaction between his genetic background and a number of environmental factors. Nutrition
is one of the environmental factors of major importance.
DNA Analysis Technology and its Potential Application to Clinical Practice
In the year 2001, the Human Genome Project was completed which will revolutionise
science and medicine. The transition from genetics to genomics marked the evolution from
an understanding of single genes and their individual functions to an understanding of the
actions of multiple genes and their control of biologic systems [2].
There was a tremendous improvement in DNA technology in the past few years. Whereas,
at first, the Human Genome Project mainly focused on identifying single genes, it rapidly
moved to the genomic-scale analysis of the human organism. The so-called DNA chip
technology currently provides one promising approach to genome-scale studies of genetic
variation, mutation analysis and gene expression [3]. The result of an adaptation of dot blot
hybridization techniques, DNA chips, also called microarrays, generally consist of a thin
slice of glass or silicon usually about the size of a postage stamp on which threads of
synthetic nucleic acid are arrayed. Samples probes are then added to the chip, and
matches are read by an electronic scanner. The capacity of DNA chips increases constantly so that hundreds of thousands of genes can now be analysed simultaneously on a
single chip. Microarray technology has been applied to the detection of DNA variations as
well as expression of messenger RNA in individual cells and tissues.
As we will see below, microarrays may become widely used in a near future for establishing a person's risk of contracting common, adult-onset disorders. A base-line genome scan
could provide helpful information about a person's risk profile and point to the prevention
strategies -if available- that should be used.
Genetic Variability and Human Diversity
The Human Genome Project clearly showed that not all men are created equal (except for
identical twins). And the reason for this genetic diversity is due to single base changes
scattered throughout the genome [2,4]. There are now thousands of these so-called single
nucleotide polymorphisms (SNPs) located in coding and non-coding regions of DNA. Each
SNP can be classified by whether they alter the sequence of the protein encoded by the
altered gene. Changes that alter protein sequences can be classified by their effects on
protein structure. And non-coding SNPs can be classified according to whether they are
found in gene-regulating segments of the genome - many complex diseases may arise
from quantitative, rather than qualitative, differences in gene products [2]. More important
than just identifying these SNPs, was the discovery that these variations in genome sequences underlie differences in our susceptibility to, or protection from, all kinds of diseases, in the age of onset and severity of illness and in the way our bodies respond to
treatment, namely to nutritional challenges. These are called susceptibility genes and they
explain different patterns of responses, observed in different individuals, to the same nutritional challenges. Thus, in respect to choleterol metabolism, McCombs and coworkers [5]
showed that the apo A-IV-2 allele attenuates the hypercholesterolemic response to the
short-term ingestion of a very-high cholesterol diet, whereas Bouchard et al [6] observed
that the response to long-term overfeeding differed greatly among different individuals, but
very little between identical twins [6].
We may antecipate that studies of SNPs and diseases will be a high topic for research in
the forthcoming years. Such research will be the basis for «genetic medicine» in which
knowledge or our uniqueness will alter many aspects of medicine. By identifying variation
across the whole genome, the SNP map may be our best route to a better understanding
of the roles of nature and (not versus) nurture [2]. It is now widely accepted that the large
difference in the tolerance of and needs for nutrients observed in different individuals, can
be largely accounted by the diversity observed in their genetic heritage [7].
Levels of nutritional intervention
Nowadays, we may identify several levels of nutritional intervention: in the community, in
the family, as a human being, at the level of body systems, organ, tissue, cell, organelle,
and finally, at the molecular level. Changing nutrient composition of foods through biotechnology may alter nutrient interactions, nutrient-gene interactions, nutrient bioavailabilty, nutrient potency and nutrient metabolism. Pediatrics will be one of the first medical
specialities to benefit from the outcome of this project, as recombinant DNA manipulations
will replace diet therapies [8]. This is especially true as more emphasis is placed on the
prevention, rather than the treatment, of chronic degenerative and metabolic diseases.
There is a new emerging field of biotechnology and potential nutritional implications for
children. The tools of biotechnology have enormous potential to develop new, safe, and
nutritious foods that could benefit the immediate and long-term nutritional and health
needs of the pediatric population.
Coming down to a molecular level, the topic of my talk, the effects of nutrition can be exerted at many stages between transcription of the genetic sequence and production of a
functional protein.
Nutrition has a marked influence on gene expression and an understanding of the interaction between nutrients and gene expression is important in order to provide a basis for
determining the nutritional requirements on an individual basis. For this reason, the regulation of gene expression by specific nutrients is a major aspect of modern nutrition. An
example of this was given by Jean Girard in his recent review on the regulation of gene
expression by nutrients [9] and consists in the inhibition of cholesterol biosynthesis by excess cholesterol. Previous studies showed that the transcription of a number of genes involved in both cholesterol biosynthesis and in the cellular uptake of cholesterol-rich low
density lipoprotein is inhibited by dietary sterols. This is performed by a unique transcription factor named sterol regulatory element binding protein (SREBP) which is turned on
and off according to levels of circulating cholesterol. In this same issue of Current Opinion
in Clinical Nutrition and Metabolic Care [10,11,12], there are five more reviews illustrating
how several nutrients namely, glucose, long-chain fatty acids, arginine and vitamins A and
D, regulate the expression of several genes.
Moreover, besides influencing gene expression at a transcriptional level, dietary factors,
both macro- and micronutrients, can also exert an effect at the post-translational level,
particularly mRNA stability. In a recent review, Hesketh and colleagues [13], present the
effect of several nutrients on the regulation of gene expression by post-transcriptional
mechanisms. The function of the regulatory signals in the untranslated regions of the
mRNA is highlighted in relation to control of mRNA stability. It is concluded that nutrients
can influence gene expression through control of the regulatory signals in these untranslated regions and that the post-transcriptional regulation of gene expression by these
mechanisms may influence nutritional requirements [13].
There are a number of other examples clearly showing that regulation of gene expression
by nutrients in mammals is an important mechanism allowing them to adapt to the nutritional environment.
Why Do Nutrition Professionals Need to Understand the Molecular Biologist?
Identifying human genetic variations and their relations to clinical phenotypic, will eventually allow physicians to adapt therapies, including nutritional care, to the individual patient.
There may be treatments which are efficient in some patients, which carry some specific
genetic traits, and largely inefficient in others who have a different genetic background.
These observations led to the development of a new field of pharmacogenomics, which
attempts to use information about genetic variation to predict responses to drug or nutritional therapies [1].
In the next decade or so, we can imagine a scenario where, there will be the so-called genetically based, individualised preventive medicine, according to which a number of preventive strategies, including nutritional intervention, will be tailored for each specific individual, according to his genetic background. For this to happen it will be necessary that physicians, dietitians, nurses and other health care providers become familiar with the
emerging field of genetics. Not only with its broad contents but also with its language, the
methodologies used, as well as with its limitations. There will still be specialists on the
matter who will be needed to solve the more complex problems, but genetic medicine will
be practiced for the most part by primary care providers.
In this respect, a number of surveys have shown that currently we are not prepared for this
since a large proportion of medical doctors did not receive genetics as part as their formal
training. To meet this urgent need for education in medical genetics, the National Coalition
for Health Professional Education in Genetics has been created (NCHPEG accessible at
http://www.nchpeg.org) with the aim of promoting professional education and access to
information about advances in human genetics [1].
References
1. Collins FS. Shattuck Lecture - Medical and societal consequences of the Human Genome Project. N Engl J Med
1999; 341;1: 28-37
2. Chakravarti A...to a future of genetic medicine.. Nature 2001;409: 822-3
3. Wang DG, Fan J-B, Siao C-J et al. Large scale identification, mapping and genotyping of a single-nucleotide polymorphisms in the human genome. Science 1998; 280:1077-82
4. Collins FS, Guyer MS, Chakravarti A. Variations on a Theme: cataloging human DNA sequence variation. Science
1997; 278:1580-1
5. McComb RJ, Marcadis DE, Ellis J, Weinerg RB. Attenuated hypercholesterolemic response to a high-cholesterol
diet in subjects heterozygous for the apolipoprotein A-IV-2 allele. N Engl J Med 1994; 331:706-10
6.
7.
8.
9.
10.
11.
12.
13.
Bouchard C, Tremblay A, Despres J-P et al. The response to long-term overfeeding in identical twins. N Engl J Med
1990. 322: 1477-82
Berdanier CD. Nutrient-gene interactions: today and tomorrow. FASEB J 1994; 8: 1
Young AL, Lewis CG. Biotechnology and potential nutritional implications for children. Pediatr Clin North Am 1995;
42:917-30
Girard J. The regulation of gene expression by nutrients. Curr Opin Clin Nutr Metab Care 1998;1:321-2
Foufelle F, Girard J, Ferre P. Glucose regulation of gene expression. Curr Opin Clin Nutr Metab Care 1998;1:323-8
Pegorier J-P. Regulation of gene expression by fatty acids. Curr Opin Clin Nutr Metab Care 1998;1:329-4
Tissue-selective expression of enzymes of arginine synthesis. Wakabayashi Y. Curr Opin Clin Nutr Metab Care
1998;1:335-9
HeskethJ, Vasconcelos MH, Bermano G. Regulatory signals in messenger RNA: determinants of nutrient-gene
interaction and metabolic compartmentation. Br J Nutr 1998; 80: 307-21