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Cracking the Code
Just how long can we live?
Grant R Sutherland
In June this year, United States President Clinton and British Prime
Minister Blair jointly announced that the human genome had been
sequenced. In another year or so, this information should be
assembled into a much more useful form than that in which it now exists.
The advances which will be made possible by the Human Genome Project
and new genetic technologies may well extend the human life span still
further.
MJA 2000; 173: 594-596
Genetic susceptibility to common diseases -
Cancer -
Infectious disease -
Aging genes -
A longer life? -
Acknowledgements -
References -
Authors' details
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The Human Genome Project will not be completed, in my view, until the
functions of all human genes have been determined, knowledge of
genetic variation between individuals is documented, and
interaction between genes and between each gene and the environment
and the contributions of these factors to human development and
disease are established. This may take much of the coming century;
however, substantial amounts of information of major importance to
health and wellbeing have begun to emerge.
In Australia, life expectancy rose by a little more than 20 years for
males and 22 years for females in the 20th century (Box 1). Similar
rises were recorded in most countries in which Western medicine was
fairly readily accessible. This increase was achieved without input
from the Human Genome Project, and involved factors that improved the
environment (eg, sanitation, seat belts), as well as medical factors
such as vaccines and antibiotics. How can the outcomes of the Human
Genome Project be expected to eventually affect life expectancy?
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There are more than 100 relatively common diseases for which there are
susceptibility genes present in the population (Box 2). Each of these
genes may have only a small effect, but the additive actions of unknown
numbers of such genes and their interactions with often unrecognised
environmental factors lead to disease. Almost all these common
diseases can shorten life, and many will be direct causes of death.
Major academic and industrial research efforts are currently aimed
at identifying susceptibility genes for these diseases.1
Genes that confer a marked increase in risk of a common disease are
fairly easy to find using standard genomic and molecular genetic
approaches. Good examples of such genes are BRCA1 and
BRCA2 for breast/ovarian cancer, and the DNA mismatch repair
genes which lead to non-polyposis colorectal cancer. Although these
genes are extremely important for those families in which they are
present, heritable variations in them appear to be minor causes of the
common diseases, accounting for less than 5%-10% of cases. Many
susceptibility genes, which may only individually increase or
decrease a baseline risk of disease by a few percent, are very
difficult to identify using current approaches.
This might change as a result of the Human Genome Project. There are two
emerging technologies for the identification of susceptibility
genes: SNP typing and DNA microarrays (Box 3).2
During the next few decades, these two approaches (and possibly new
ones) should identify most of the susceptibility genes for most
common human diseases. Once an understanding of the genetic basis of
susceptibility is obtained, intervention should be possible. Many
of the protein products of susceptibility genes will be novel targets
for the development of new drugs that may either delay the onset of
disease, or treat it once it is present, or both. There will be
opportunities to identify, before starting treatment, the most
appropriate treatment to use. This will be based both on an
understanding of the genetic variations contributing to disease and
on genetic variations that will determine drug side effects, dose and
efficacy.
Environment is certainly a key factor in much common disease, even if
the environmental factors that are important for any particular
disease are not known at all or are poorly understood. Once
susceptibility genes are found, further research may identify the
environmental factors that interact with them to increase the risk of
disease onset. Public health education aimed at lifestyle changes
may be targeted to genetically susceptible people, and be more likely
to be heeded than education aimed at the whole population.
Once genes are identified, diagnostic and therapeutic regimens will
be developed. Then combinations of drug treatment, environmental
modification (ie, lifestyle changes) and possibly even gene therapy
will be able to delay onset of disease and provide effective treatment
once onset occurs.
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Cancer at the cellular level is a genetic disease. The US National
Cancer Institute has established a Cancer Genome Anatomy Project
(http://www.ncbi.nlm.nih.gov/ncicgap), which will delineate the
genetic changes in cancer cells at a whole-genome level.
Understanding the cellular mechanisms of cancer will surely improve
disease classification and prognostication and provide many
therapeutic opportunities, including choice of the most
appropriate treatment. Eventually cancer may be no more of a threat to
life than is the common cold.
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Infectious diseases are still major causes of death, mainly in Third
World countries, but also (although perhaps to a lesser extent) in
First World countries. Genetic techniques have the potential to
prevent these diseases through DNA-based vaccines, as well as to
provide new treatments.
Genomic approaches to infection will lead to tests for rapid
identification of infecting organisms, allowing early
commencement of specific therapy. In addition, DNA microarray
analysis of gene expression in human macrophages is likely to
identify infecting organisms that are resistant to culture or can not
be identified by other means.
The genomes of most common human pathogens (including viruses,
bacteria and parasites) have already been sequenced. These genome
sequences are providing a range of new targets for the development of
novel antibiotics, antiviral and antiparasitic agents. The spectre
of multiple drug-resistant bacteria should soon fade. However, we
are likely to have to cope with the common cold and, more seriously,
HIV, for a long time, until there are new approaches to dealing with
highly mutable viruses.
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Genes involved in the aging processes in simple organisms have been
identified;7 however, in mammals, the
only intervention shown to delay aging is caloric
restriction,8 and the molecular
mechanisms by which this acts are just beginning to be
unravelled.9
I think it unlikely that knowledge of the genetic basis of aging will
lead to widespread anti-aging therapy in humans. However, this view
could be proven wrong and aging genes, when identified, may be targets
for the development of anti-aging drugs. If (when) gene therapy
becomes relatively simple and safe, there may be ways to modify the
actions of aging genes.
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From anecdotal press reports we learn of rare individuals who live for
about 120 years. Is this a genetically programmed maximum human
lifespan? If it is, why can not most of us achieve it? Barring accidents
(and there may be genes that promote risk-taking behaviours) or
suicide (and there are certainly susceptibility genes here,
possibly for suicide itself and certainly for a number of the
psychiatric disorders that too frequently lead to suicide), we
mostly die of common or infectious diseases before reaching 120
years.
With mastery to be gained over many of our pathogens and with
strategies to treat or to delay the onset of common diseases
(including cancer), it is likely that the 21st century will see a
similar increase in life expectancy to that witnessed in the 20th
century.
To be even more speculative, tinkering with our aging genes could add
yet another 20 years in the 22nd century and get most of us up to or beyond
120 years of age. Unfortunately, none of the readers of this article
will ever know the outcome of this speculation. And, if it is correct,
the 120-year-olds had better be sprightly, as there may be standing
room only on a grossly overpopulated planet.
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I thank Dr Eric Haan and Dr John Mulley for constructive criticism of an
earlier draft of this article.
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of the Human Genome Project. N Engl J Med 1999; 341: 28-37.
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Young RA. Biomedical discovery with DNA arrays. Cell 2000;
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Martin ER, Lai EH, Gilbert JR, et al. SNPing away at complex
diseases: analysis of single-nucleotide polymorphisms around APOE
in Alzheimer disease. Am J Hum Genet 2000; 67: 383-394.
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Kruglyak L. Prospects for whole-genome linkage disequilibrium
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Celera Genomics launches SNP reference database product with more
than 2.8 million unique SNPs [press release].
<http://www.pecorporation.com/press/
prccorp091300.html>. Accessed 14 November 2000.
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DeRisi JL, Iyer VR, Brown PO. Exploring the metabolic and genetic
control gene expression on a genomic scale. Science 1997;
278: 680-686.
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Vanfleteren JR, Braeckman BP. Mechanisms of life span
determination in Caenorhabditis elegans. Neurobiol Aging
1999; 20: 487-502.
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Weindruch R, Walford RL. The retardation of aging and disease by
dietary restriction. Springfield, Illinois: CC Thomas, 1988.
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Campisi J. Chromatin and food restriction -- connecting the dots.
Science 2000; 289: 2062-2063.
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Department of Cytogenetics and Molecular Genetics, Women's and
Children's Hospital, Adelaide, SA.
Grant R Sutherland, AC, FAA, FRS, Professor and Director.
Reprints will not be available from the author.
Correspondence:
Professor G R Sutherland, Department of Cytogenetics and Molecular
Genetics, Women's and Children's Hospital, 72 King William Road,
North Adelaide, SA 5006.
gsutherlandATmedicine.adelaide.edu.au
©MJA 2000
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3: Emerging technologies for identifying disease-susceptibility genes
SNP (single nucleotide polymorphism,
pronounced "snip") typing is yet to be widely applied. In principle,
typing large numbers of SNPs, perhaps up to 500 000 per individual, on
large groups of patients with the same common disease will reveal clusters
of SNPs that overlay susceptibility genes.3 This
process is known genetically as looking for linkage disequilibrium.4
Celera Genomics recently announced that it had a database of 2.4 million
proprietary SNPs, and had gleaned another 0.4 million from public databases,
and, for a fee, this collection could be viewed, and presumably used to
help find genes for common diseases.5
DNA microarrays come in several guises.
One form contains very large numbers of DNA samples spotted at high density
on glass slides. Most work to date has used arrays of the yeast genome
-- all the genes of this organism can be displayed on a 2 cm x 2 cm area
of glass.6 Arrays can then be used to determine
which genes are active in any tissue, or the relative levels of gene expression
in, say, normal compared with diseased tissue. For yeast, the response
of the entire genome to changes in physiological conditions of culture
(eg, temperature, nutrient stress) can be assessed with microarrays. For
humans, the response of the entire genome is now beginning to be explored.
The research question of which protein is involved in a particular process
is being replaced by the simultaneous detection of the regulatory response
of all proteins within a tissue in response to disease or experimentally
induced conditions.
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