The human genome project (HGP) is an international
research program that was set up to characterize
the genome of humans and other organisms;
to develop the new technology needed to
do so; and to address the ethical, legal,
and social issues (ELSI) that may arise
from the project. The possibility of sequencing
the human genome was first discussed in
the mid-1980s. The HGP officially started
in October 1990 and was completed in April
2003. The HGP has revealed that there are
probably 20,000-25,000 genes, much lower
than previous estimates of 80,000 to140,
000. The human genome contains 3.2 billion
chemical nucleotide bases. The average gene
consists of 3,000 bases, but sizes vary
greatly, with the largest known human gene
being dystrophin at 2.4 million bases. The
human genome also revealed that at least
80% of the genome does not code for proteins
and only about 1.5% of the genome is occupied
by protein-coding sequences, which raises
the question of what function the non-coding
DNA has. Sequencing the human genome will
have a great impact on the practice of medicine
and society. The field of medicine is building
upon the knowledge, resources, and technologies
emerging from the HGP to further understanding
of genetic contributions to human health.
As a result of this expansion of genomics
into human health applications, the field
of genomic medicine was born. Although this
genetic advance raises hope for new ways
to prevent diseases and promote wellness,
it also raises public concerns about the
privacy of health information and the potential
of discrimination. It is clear that there
is a need for society to understand, debate
and decide on the appropriate setting for
the use of genetic information (Dennis and
Gallagher, 2001; HGP, 2004).
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HUMAN GENOME AND THE PRACTICE OF MEDICINE |
The term genomic medicine has been recently
used to describe a new development in medicine
that holds promise for human health. This
new approach to health care uses the genetic
makeup of an individual to identify those
who are at a higher risk of developing certain
disease and to intervene at an earlier stage
to prevent these diseases (Hall et al.,
2004).
Genomic and common diseases
Information about the human genome sequence
must be applied to identify the particular
genes that play a role in the hereditary
contribution to common diseases. For a disease
such as diabetes mellitus, 5 to 10 (or maybe
more) genes are involved, all of which increase
disease risk only modestly because their
effects depend on interactions with other
genes and with the environment. Predictive
genetic tests for the vast majority of common
diseases are not yet available in medical
practice with the exception of breast and
colorectal cancer. But with increasing genetic
information about common diseases, this
kind of risk assessment will become more
generally available, and many primary care
clinicians will become practitioners of
genomic medicine, having to explain complex
statistical risk information to healthy
individuals who are seeking to enhance their
chances of staying well. This will require
substantial advances in the understanding
of genetics by a wide range of physicians,
nurses, and clinicians (Collins and McKusick,
2001; Hall et al., 2004).
Pharmacogenetics
People vary in their response to medication.
The variation between individuals in their
response to medicines is due to differences
in their genetic make-up. Although factors
like inaccurate prescription of medication,
the mixing of incompatible drugs, and poor
compliance by the patient can influence
the efficacy and toxicity of medicines,
understanding the role of genetic variation
in drug response could have important implications
for the improved safety and effectiveness
of treatment. Pharmacogenetics refers to
the study of DNA sequence variation that
affects an individual's response to drugs.
Pharmacogenomics refers to the use of genetic
information in order to target pharmaceutical
agents to specific patient populations in
the design of drugs. Clinical observations
of individual variation in relation to drug
toxicity and efficacy were first observed
in the 1950s (WHO and Nuffield council on
bioethics). Genetic variation in cytochrome
P450 genes, acetyltransferase genes, thiopurine
methyltransferase and dihydropyrimidine
dehydrogenase has clinical significance
because in each case it defines patient
populations that metabolize drugs at different
rates. The availability of genetic information
will provide important insight into the
variation in response and toxicity to many
drugs (Bell, 2004).
Despite the benefits of pharmacogenetics,
it may be accompanied by unintended negative
consequences. For instance, the introduction
of pharmacogenetics could lead to a further
stratification of the market for drugs,
discouraging pharmaceutical companies from
developing medicines that would provide
a significant benefit to only a small number
of patients. Wide-range programs of pharmacogenetics
may require obtaining extensive genetic
information, which raises concerns about
the appropriate protection of patients'
privacy and confidentiality. Furthermore,
the targeting of specific populations may
make it easier to unfairly discriminate
against some groups. Pharmacogenetics, which
is in its very early stages of development,
needs to be carefully evaluated in order
to determine its effectiveness relative
to existing methods, and also to judge how,
if applied, it would fit into the existing
health care framework (WHO and Nuffield
council on bioethics).
Nutrient-gene interaction
The concept of nutrient-gene relationships
is not new. Inborn errors of metabolism
provide familiar examples of nutrient-gene
relationships. For example, phenylketonuria
results from a specific mutation in both
copies of the gene encoding the enzyme phenylalanine
hydroxylase. This disease is characterized
by the accumulation of phenylalanine in
the blood because of the cells' inability
to convert phenylalanine to tyrosine. Affected
newborns are mentally retarded, unless they
are placed on a special diet, in which case
essentially normal intellectual development
can be expected. Another example of a nutrient-gene
relationship disorder is hemochromatosis.
Hemochromatosis is a condition in which
iron accumulates in tissues, which eventually
leads to organ damage. It results from a
mutation in both copies of the gene that
encodes the enzyme that regulates iron absorption.
Treatment includes phlebotomy and avoidance
of iron supplements (Kauwell, 2005).
The study of the relationship between a
specific genotype and the risk for developing
diet-related diseases, particularly common
chronic diseases such as cancer, diabetes,
and vascular disease, has been referred
to as nutrigenetics (Kauwell, 2005). An
interaction has been demonstrated between
folate status and a mutation of a key enzyme
in one-carbon metabolism, methylenetetrahydrofolate
reductase enzyme (MTHFR C677T). The reduced
MTHFR activity leads to an increased level
of cytosolic 5,10-methylenetetrahydrofolate
available for thymidylate synthesis, which
may protect cells from DNA damage induced
by uridylate misincorporation. Thus folate-replete
men who are homozygous for the TT mutation
are reported to have a two-fold reduction
in risk of colorectal cancer compared with
wild type or heterozygous individuals. However,
homozygotes with inadequate folate intake
have elevated plasma homocysteine, an independent
risk factor for atherosclerosis, which is
associated with increased risk of neural
tube defects and colon cancer (Fairweather-Tait,
2003).
Nutrient-gene interactions may also explain
why some individuals respond more favourably
to dietary interventions than others. For
example, blood pressure is controlled in
part by a vasoconstrictor-angiotensin. A
single nucleotide polymorphism (SNP) in
the gene that encodes the precursor form
of this polypeptide, angiotensinogen (ANG),
results in a guanine to arginine substitution
(G-6A) in the promoter region of the gene.
The AA genotype for the ANG G-6A polymorphism
has been associated with higher levels of
circulating angiotensinogen and essential
hypertension. Results taken from a sub-study
of subjects who participated in the Dietary
Approaches to Stop Hypertension (DASH) trial
revealed that subjects with the AA genotype
were more responsive to the DASH diet than
those with the GG genotype. Understanding
nutrient-gene interactions that modulate
the response to nutrition interventions
holds promise for improving our ability
to prevent and effectively treat chronic
diseases (Kauwell, 2005).
The human genome and psychiatric
disorders
There has been substantial epidemiological
evidence that psychiatric illnesses have
a strong genetic basis. Concordance rates
among monozygotic (MZ) twins for schizophrenia,
bipolar disorder, alcoholism and Tourette
syndrome are ~50%. Major psychiatric disorders
such as schizophrenia, bipolar disorder,
autism and alcoholism are multi-factorial
just like other multigenic disorders such
as hypertension and diabetes. Nevertheless,
in contrast to some other complex disorders,
no susceptibility loci for psychiatric disorders
have been unambiguously identified. The
availability of the human genome sequence
provides a starting point for the identification
and characterization of individual sequence
variation, including variation that confers
susceptibility to psychiatric illness (Stoltenberg
and Burmeister, 2000; Cowan et al., 2002).
While the HGP raises hope to improve health,
it also highlights many ethical, legal,
and social implications. Threats to privacy;
stigmatization; potential for genetic discrimination
in health insurance, life insurance, and
employment; and disruption of familial and
social relationships are now very real societal
issues (Tinkle and Cheek, 2002). The U.S.
Department of Energy (DOE) and the National
Institutes of Health (NIH) devoted 3% to
5% of their annual Human Genome Project
(HGP) budgets toward studying the ethical,
legal, and social issues (ELSI) surrounding
availability of genetic information. This
represents the world's largest bioethics
program, which has become a model for ELSI
programs around the world.
Genetic enhancement
The concept of eugenics came out by Sir
Francis Galton and Charles Davenport in
the late nineteenth and early twentieth
centuries, created an atmosphere of fear
on the social applications of genomic technologies
in this century. Eugenics (derived from
the Greek word meaning 'wellborn') is the
use of genetics to improve the quality of
humankind. Eugenic policies ranged from
restrictions on immigration to the involuntary
sterilization of jailed criminals or persons
institutionalized for reasons of "insanity
or feeblemindedness". This type of
thinking was also incorporated in the Nazi
German policy of racial cleansing which
lead to the mass extermination of millions
of Jews, Gypsies, homosexuals, and other
"disfavoured". Eugenic ideas are
not confined to the early twentieth century
and are still being applied today. For example,
the law in China forbids mentally retarded
people from marrying unless they have been
sterilized (Dennis and Gallagher, 2001;
Brown, 2002).
The ideas of the original eugenicists have
been largely discredited. However, there
are ethical concerns that a new form of
eugenics could emerge, whereby genomic technologies
may be used to help people select a desirable
trait for their children, such as physical
attributes, IQ and personality. This raises
the prospect of so-called "designer
babies". Fortunately, there are many
barriers blocking such development. Technically,
it is extremely difficult to find which
genes, in which combinations, create the
desirable trait. Moreover, environment and
upbringing play a big part of how a child
develops (Dennis and Gallagher, 2001).
Genetic discrimination
The potential use of genetic information,
particularly in health insurance, employment,
and medical research raises grave anxiety.
There are public concerns that a genetic
"underclass" might develop.
Public concern about the confidently of
genetic information may make people reluctant
to volunteer for studies involving disease
linked gene mutations or genetic therapy,
for fear that the results could result in
the loss of a job or the loss of insurance
coverage (Collins, 1999). Employers may
use genetic information to avoid hiring
workers who they believe are likely to take
sick leave, resign, or retire early for
health reasons. There are also concerns
that genetic information may be used to
deny insurance access. Several cases have
been reported where individuals with a genetic
disorder or predisposition have been refused
their health insurance, or had their enrolment
cancelled or premiums increased. In the
early 1970s, some insurance companies denied
coverage and charged higher rates to African
Americans who were carriers of the gene
for sickle cell anaemia, even though they
were healthy. There are worries that medical
expenses for those suffering from genetic
conditions will not be covered and children
at high risk of inheriting a genetic disease
may be excluded from coverage (Dennis and
Gallagher, 2001). Fortunately, laws are
being put into place to ensure the confidentiality
of genetic information and to ban the use
of genetic information in employment and
health insurance (Brown, 2002). However,
these laws are not always helpful in providing
adequate protection against genetic discrimination
since a woman's family history of having
numerous relatives with early onset breast
and ovarian cancer reveals almost as much
about her risk of future disease as her
own test results for mutations in BRCA1.
In actuality, she could be mutation-negative,
but still have elevated risk if the cancers
in her family were caused by mutations in
different genes or by environmental exposure
(Clayton, 2001).
Although genetic information is personal,
it could be made available without a person's
knowledge, or even against his or her wish.
For example, an employer or insurance provider
may require access to medical records, which
include the results of genetic tests. Disclosure
of genetic information may be considered
an invasion of privacy. Holders of genetic
information should be prohibited from releasing
it without the individual's prior authorization
and an individual's consent should be required
for each disclosure in order to protect
the use of genetic information for purposes
other than what it was originally collected
for (Dennis and Gallagher, 2001).
DNA data banking
The rapid growth of forensic science DNA
banking raises social concerns that genetic
information will be used for purposes other
than it originally collected for (Reilly
and Page, 1998; Dennis and Gallagher, 2001).
DNA has been a key 'witness' for several
trials, helping police and courts to identify
criminals and to exonerate the wrongly accused
(Dennis and Gallagher, 2001). DNA forensics
in the United Kingdom has grown very rapidly
since its inception in the mid-1980s. In
June 1998, the UK Forensic Science Service
had collected 320,000 samples for DNA analysis,
and had removed 51,000 samples from the
bank after suspects had been exonerated.
The social impact of DNA forensic data banking
are potentially much larger than those of
the old practice of collecting and storing
fingerprints of arrested individuals. A
fingerprint provides information relevant
only to identification. DNA forensic banks
retain whole DNA, and many laws permit research
on these samples. Such DNA archives will
be of huge interest to those who study human
behaviour, and especially to those who study
criminality. Suppose, for example, an association
study indicated that persons convicted of
vehicular manslaughter are ten-fold more
likely than those in a control group to
carry an allele thought to predispose to
alcohol abuse. If such correlations are
found, they will influence practices (for
example, sentencing and parole) in the criminal
justice system (Reilly and Page, 1998).
Who owns the gene?
A patent is a set of exclusive rights granted
by a government to an inventor for a limited
amount of time (normally 20 years from the
filing date), during which time others cannot
make, use or sell the invention unless the
inventor licenses it to do so. Patents were
developed to encourage investments, to reward
inventiveness and to make information about
inventions publicly available. Gene patenting
has, however, been controversial. There
are some debates about gene patenting to
whether a naturally occurring entity, such
as a gene be viewed as an invention. Patenting
offers an incentive for researcher to translate
genetic discoveries into genetic medicine.
On the other hand, patenting also pervades
health care delivery. The discovery of disease
genes requires the involvement of patients
and their families. However, when the gene
discovery is commercialized, the very same
patients find that they are unable to obtain
testing because some investigator or institution
exercises patent. These patients may be
required to pay what they perceive to be
unreasonable costs for tests and treatments
derived from the gene that they helped identify
(Clayton, 2001; Dennis and Gallagher, 2001).
The case of a US patient advocacy group
for Canavan disease represents a good example
of the social impact of gene patenting.
This patient advocacy group for Canavan
disease filed a lawsuit against the hospital
and the researcher who patented a gene that
is mutated in the degenerative disease.
They claim that the gene was discovered
using the genetic information and financial
resources provided by the Canavan families,
and that the hospital charged royalties
that limited the availability of testing
for the disease (Dennis and Gallagher, 2001).
Education
Genomic medicine is already making its
way into health care settings where health
care providers admittedly know very little
about the underlying science of genetics
or its role in human disease. Several surveys
of genetics knowledge among health care
professionals have shown that providers
are frequently asked for information about
genetics by their patients and that they
are uncomfortable relaying such information
(Fink and Collins, 1997). Unfortunately,
most medical schools did not anticipate
the changes that molecular genetics would
bring to modern medicine. As a result, the
ranks of medical geneticists are sparse,
and many physicians struggle with the new
biology. Furthermore, the nation's battalion
of genetic counsellors has never grown to
the size that would be needed in order to
compensate for these deficiencies. As a
result, doctors, nurses, and the public
will have to do some work on their own to
learn about the genes and genomes that will
progressively change medical practice. Initiatives
such as the National Coalition for Health
Professional Education in the United States
and the work of the Public Health Genetics
Unit in the United Kingdom are leading the
way in defining what primary care professionals
need to know (Burton, 2002; Kavalier and
Kent, 2003).
Predictive genomic medicine
The phrase 'predictive genomic medicine'
symbolizes a type of genomic medicine, which
proposes screening healthy individuals to
identify those who carry alleles that increase
their susceptibility to common diseases,
such as cancers and heart disease. Physicians
could then intervene even before the disease
manifests and advise individuals with a
higher genetic risk to change their behaviour
(e.g. to exercise or to eat a healthier
diet) or offer drugs or other medical treatment
to reduce their chances of developing these
diseases. However, predicting someone's
risk of developing a common polygenic disorder
also raises ethical, social and policy challenges
that science alone cannot address. Population
based genetic screening for a large number
of susceptibility alleles are only socially
and economically justifiable if physicians
can follow up on a diagnosis of increased
risk with an effective intervention to prevent
this disorder. For some common cancers,
such as colorectal and breast cancer, regular
monitoring and early treatment have been
shown to reduce mortality. Although preventive
medications and other treatments exist,
most interventions aimed at reducing disease
risk still depend on the patient changing
his or her behaviour. A question is raised:
how to present and explain information regarding
genetic risks for common disorders? Will
giving individuals this information motivates
them to change their lifestyle, such as
quitting smoking or reduce their weight?
Some researchers are concerned that inappropriate
communication of risks may instead result
in demoralization and reduce a person's
self-confidence in their ability to change
their health behaviour. Another concern
is that screening will unnecessarily raise
anxiety about disease risk in individuals
who are found to have susceptibility alleles,
but who are at low risk of developing the
disorder (Hall et al., 2004). Knowing that
one is at risk, even a small risk, could
give way to 'genetic fatalism', whereby
a person believes that his future health
is only determined by genes, irrespective
of changes to diets and behaviours (Dennis
and Gallagher, 2001).
The pace of knowledge development related
to genetics continues to progress exponentially.
Knowledge gained through the human genome
project will have a profound impact on the
practice of medicine and on society. Genomic
medicine holds the ultimate promise of revolutionizing
the diagnosis and treatment of many diseases.
Society on the other hand, is facing challenges,
especially regarding the impact of genetic
information (e.g. genetic information about
mental illness) on the self-confidence of
the individual, family relationship and
stigmatization as well as discrimination
in obtaining health insurance and in the
work place. Government should set rules
to protect the privacy and confidentiality
of genetic information and to ban the use
of genetic information in employment and
health insurance
