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Imagine a riddle with over 2,5 billion parts ... can you see it? Now, add to
this the extra challenge of not being able to see the parts – unless you look
at them under a super-duper microscope – and that is the Human Genome Project
(HGP). Doesn’t sound like the kind of riddle that could ever be solved, but the
sequencing of the human genome – which is all the DNA in our cells – is on the
verge of completion, with an accuracy of 99,99% (fewer than one mistake for
every 10 000 letters). Those who initiated the project believe that it is going to
drastically change the face of medicine and the way that doctors go about treating
their patients in the future.
The HGP began in the United States in 1990, when the National Institute of Health and the
Department of Energy joined forces with international partners to decipher the massive amount
of information contained in our genomes. Frequently ahead of schedule, HGP scientists have
produced an increasingly detailed series of maps that help geneticists navigate through human
DNA. They have mapped and sequenced the genomes of important experimental organisms. They
completed a working draft covering 90% of the human genome in 2000 and, by the end of 2003,
they will finish the sequence.
The HGP, the international quest to understand the genomes of humans and other
organisms, will shed light on a wide variety of questions, like:
- How many genes do we have? (it is currently estimated that we have between 35 000
and 100 000 genes)
- How do cells work?
- How did living things evolve?
- How do single cells develop into complex creatures?
- What exactly happens when we become ill?
It is also believed that the HGP will give us insight into the fundamental mechanisms
of life and lead to an era of molecular medicine, with precise new ways to prevent,
diagnose and treat disease.
Genomics is the study of all the DNA – or genome – of an organism. This includes mapping and
sequencing the genome, as well as any variations or mutations or changes in DNA spelling that prevent
proteins from functioning normally and result in health problems.
- To map and sequence the human genome.
- To map and sequence the genomes of important model organisms
such as: e-coli, yeast, the roundworm, the fruit fly and the mouse.
- To collect and distribute data. This includes the commitment to:
- release within 24 hours all sequence data that spans more than
2 000 base pairs;
- create and run databases;
- develop software for large-scale DNA analysis; and
- develop tools for comparing and interpreting genomic information.
- To study the ethical, legal and social implications of genetic research.
- To develop technologies that make large-scale sequencing faster and
cheaper, and technologies for finding sequence variations.
In "The story of DNA" on page 11 it was explained that DNA is
made up of nucleotides distinguished by their bases, which are
Adenine, Thymine, Cytosine and Guanine. There are over 2,5 billion
nucleotides in human DNA which occur in different sequences.
Sequencing the DNA involves recording the order in which the
nucleotides are arranged in their chromosome pairs. By doing this, the
HGP scientists are able to build genetic and physical maps spanning the
human genome.
The mapping of the human genome involves recording the
sequence of nucleotides of all the human genes (which consist of
segments of DNA which are typically several thousand base pairs long).
It also includes the charting of variations in DNA spelling among
human beings.
So, it is not only a matter of recording the order in which the
nucleotides are found, but also involves deciphering what the sequence
means and how it relates to the functioning of the human body.
Genes usually code for a particular
protein. This means that when given the
right stimuli the gene will initiate the
production of a molecule of RNA which
will carry the "recipe" for a particular protein
out of the nucleus into the cytoplasm where
the protein will be made up of 20 different
amino acids.
Proteins make up essential parts of tissues
and guide chemical reactions in living things.
However, if there is a misspelling in the
DNA sequence of the gene, this could prevent
the protein from functioning normally
and result in disease.
Alterations in our genes are responsible
for an estimated 5 000 clearly hereditary
diseases, like Huntington’s disease, cystic
fibrosis and sickle cell anaemia. The spellings
of many other genes influence the development
of common illnesses that arise
through the interaction of genes with
the environment.
During the sequencing and mapping of
the human genome, scientists discovered
one-letter variations in the DNA sequence,
which are known in scientific terms as
single-nucleotide polymorphisms (or SNPs).
SNPs (pronounced "snips") contribute to
differences among individuals. The majority
have no effect, others cause subtle differences
in countless characteristics of our appearance,
while some affect the risk for certain diseases.
All areas of medicine will be affected from diagnosis to prognosis. It
is also hoped that, as we gain a better understanding of genetics, it
will become easier to prevent a disease before it can do any damage.
DIAGNOSIS: Genetic analysis can now classify some conditions, like
colon cancer and skin cancer, into finer categories. This is important
since classifying diseases more precisely can suggest more appropriate
treatments.
Pharmacogenomics is a new word that scientists and drug developers
use to describe the idea of tailoring drugs for patients. These
drugs would be designed specifically for the patient based on genetic
fingerprinting which would be carried out beforehand. For example,
cancer patients facing chemotherapy may experience fewer sideeffects
and improve their prognosis, by first getting a genetic fingerprint
of their tumour. This fingerprint can reveal which chemotherapy
choices are most likely to be effective.
PROGNOSIS: Diagnosing ailments more precisely will lead to more
reliable predictions about the course of the disease. For example, a
genetic work-up can inform a patient with high cholesterol levels
how damaging that condition is likely to be.
Gene therapy involves replacing a misspelled
gene with a functional gene. Small groups of patients
have undergone gene therapy in clinical trials for
more than a decade, but this remains an experimental
treatment. Unfortunately, the procedure of gene
therapy recently suffered a major setback when a second
child in a pioneering French gene therapy trial,
developed leukaemia as a result of the treatment.
The trial was testing a treatment for "bubble boy"
disease, or X-SCID (X-chromosome-linked Severe
Combined Immunodeficiency). Boys with X-SCID
have no resistance to infection due to a faulty copy
of an X-chromosome gene that makes an immune
protein called interleukin-2. Using a virus, the
therapy introduces the correct copy of the gene into
the patient's cells. The treatment appears to have
cured a number of boys, so the two cases of
leukaemia have come as a great disappointment.
Scientists are now looking into the possibility
of whether the technique used on the boys may
have been the problem. In the meantime, a number
of United States gene therapy trials have been put on
hold as a result of the news.
Once scientists figure out what DNA sequence changes in a gene
can cause disease, healthy people can be tested or screened to see
whether they risk developing conditions like heart disease, diabetes
or prostate cancer later in life.
Unfortunately, our ability to predict a disease sometimes
precedes our ability to prevent or treat it. For example, a genetic
test has been available for Huntington’s disease for years, but no
treatment is yet available.
There are two types of screening that are already used, but
that will become more commonplace in future:
NEWBORN SCREENING: A particular type of predictive testing,
newborn screening can sometimes help a great deal. For example,
babies in the United States and a few other countries are routinely
screened for phenylketonuria (PKU), a metabolic disorder that
prevents the breakdown of phenylalanine, one of the building blocks
of proteins and a component of the artificial sweetener Aspartame.
Excess phenylalanine in the body is toxic to the nervous system.
Children with the condition become severely mentally retarded,
but the screening programme identifies children with the enzyme
deficiency, allowing them to grow normally on a diet that strictly
avoids phenylalanine.
CARRIER SCREENING: For some genetic conditions, people who
will never be ill themselves can pass a disease to their children. For
example, carrier testing for Tay-Sachs disease, which kills young
children and is particularly common in some Jewish and Canadian
populations, has been available and widely used for years.
In many cases, instead of trying to replace a gene, it will
be more effective and simpler to replace the protein the
gene would give rise to. Alternatively, it may be possible
to administer a small molecule that interacts with the
protein - as many drugs do - and change its behaviour.
Instead of having to rely on chance and screening thousands
of molecules to find an effective drug, which is how
most drugs we use today were originally found, scientists
will begin the process of drug discovery with a clearer
notion of what they are looking for. And because rationally
designed drugs are more likely to act very specifically,
they will be less likely to have damaging side-effects.
One of the first examples of gene-based therapy
which targets a genetic flaw, was in the case of chronic
myelogenous leukemia (which mostly affects adults).
An unusual joining of chromosomes 9 and 22 produces
an abnormal protein that spurs the uncontrolled growth
of white blood cells. Scientists have designed a drug that
specifically attaches to the abnormal protein and blocks
its activity. In preliminary tests, blood counts returned to
normal in all patients treated with the drug, and the
patients only experienced very mild side-effects.
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