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Silencing
Bad Genes
(This article was first printed in the Summer
2005 Special Edition of Newsweek,
Vol. 145, Issue 26A.)
Scientists are trying to harness a form of
RNA that interferes with the disease process.
The purple-petunia payoff.
A 6-year-old boy is suddenly engulfed by pain.
It is his first attack; he will suffer repeated
agony, along with breathlessness and debilitating
fatigue, for the rest of his short life. Over
the course of a few days, a 35-year-old lawyer
loses her appetite and energy, then the whites
of her eyes turn yellow. Trying to open a stuck
window, a 55-year-old nurse feels a sudden sharp
pain just above her wrist. The bone has broken,
weakened by cancer cells that have silently spread
there from her breast, and are multiplying uncontrollably.
In each case, wayward genes are the culprit.
The boy inherited a defective gene that makes
a misshapen version of the hemoglobin protein
inside his red blood cells, causing sickle cell
anemia. The lawyer has been infected by a hepatitis
virus that has commandeered her liver cells,
instructing them to make proteins from viral
genes instead of from human genes. The nurse
inherited a breast-cancer gene from her Ashkenazi
Jewish parents, and the gene is ordering the
cells to multiply.
Doctors have long dreamed of a magic bullet
that could travel harmlessly through the body
to diseased cells, enter those cells and switch
off the wayward genes that cause the suffering.
Now, new research holds out hope for just such
a treatment, through a technique called RNA interference.
Since the 1960s it has been the central tenet
of biology that a specific sequence of DNA (a
gene) makes a specific sequence of messenger
RNA, which in turn makes a specific protein.
This profoundly important insight led to an important
question, however. What controls that process?
All our genes are contained in each of our cells.
But in each cell, certain genes are expressed
while others remain dormant, which is why the
trillions of cells in the human body look and
function differently from one another.
Over the past 30 years, scientists have identified
various proteins that activate or silence genes.
However, those proteins are large and complex
molecules that are difficult to harness in order
to control disease. The surprise breakthrough
came in 1990. A team of plant scientists at the
University of California, Davis, and a company
called DNA Plant Technology were trying to make
a purple petunia even more purple by inserting
into it a gene for purple pigment. Instead of
turning a deeper purple, however, some of the
flowers were pale white and others were mottled.
The researchers discovered that the inserted
gene had stimulated the production of very small
RNAs, and that these microRNAs shut down the
gene activity that led to the production of purple
pigment. Other scientists then found microRNAs
in primitive animals and in humans. The microRNA
attaches to the messenger RNA and destroys it
before it can produce its designated protein,
thus "interfering with" or "silencing" the
instructions of the gene.
Considered just a curiosity at first, RNA interference
has since revolutionized biological research.
It allows scientists to silence specific genes
very precisely in cell cultures and even in animals,
like mice. Since science has now identified every
gene in humans, in several animals and in many
microorganisms that cause human disease, researchers
can systematically silence one gene after another,
and observe what happens to the cells or the
animals—a direct test of a gene's function,
including its role in causing a particular disease.
If a gene plays such a role, it becomes a target
for developing a conventional or novel drug treatment.
Could microRNA technology lead to the magic
bullet—drugs that silence wayward genes?
It's easy enough to produce microRNAs that silence
a particular gene. Such synthetically made RNAs
are called small interfering RNAs, or siRNAs.
The hard part is delivering the siRNA to the
cells deep inside the body, where the wayward
genes are causing mayhem. But progress is being
made. Scientists are figuring out ways to protect
the siRNAs from destruction as they circulate
through the body, and to allow them entry into
the target cells. In animal studies, siRNAs have
stifled autoimmune hepatitis, a neurological
disease called spinocerebellar ataxia, several
viral diseases and several types of cancer, and
have dramatically lowered cholesterol levels.
And, in human studies, siRNAs have recently shown
promise in the treatment of macular degeneration,
the leading cause of blindness in the elderly.
It's true that we already have conventional
drugs that inhibit the reproduction of some viruses,
slow the growth of cancer and lower cholesterol.
But RNA-interference technology offers a number
of advantages. For one thing, there are many
pathological genes for which no counteracting
drugs have yet been developed. And while the
process of looking for conventional drugs that
counteract the effects of wayward genes is getting
faster and more efficient, it's still ponderous
and expensive. Once scientists know the identity
and structure of a wayward gene, they can easily
make siRNAs to silence it. And, compared with
most conventional drugs, siRNAs are simple molecules
that should be very inexpensive to produce. Also,
since the immune system does not recognize siRNAs
as foreign, they would likely produce fewer side
effects than conventional drugs.
Though there are reasons to be optimistic that
this new technology will lead to powerful and
nontoxic new treatments, there are many obstacles
to overcome. It remains to be seen whether siRNAs
will be able to reach all their potential targets
deep in the body. And there is the possibility
of collateral damage; some siRNAs may silence
not only a wayward gene but several healthy genes
with similar structures as well. It is also uncertain
how durable the effect of this new form of therapy
will be. It's possible that in chronic diseases,
siRNAs, like conventional treatments, will need
to be given repeatedly in order to sustain a
beneficial effect. Eventually, gene therapy may
be used to express microRNAs throughout a patient's
life, but gene therapy has been plagued by difficulties.
While the value of RNA-interference therapy
in humans remains to be proved, the story of
its discovery is just the latest example of how
an investment in basic research can lead to completely
unexpected, and enormously beneficial, results.
Who could have imagined that trying to make a
petunia more purple would reveal a potential
new approach for shutting down the growth of
cancer? No one. That's why it's wise for a society
to invest in curious people who try to understand
how living things work.
By Anthony Komaroff, M.D. and Judy Lieberman,
M.D., Ph.D.
Dr. Komaroff is a professor at Harvard Medical
School. Dr. Lieberman is a professor at Harvard
Medical School.
(This article was first printed in the Summer
2005 Special Edition of Newsweek,
Vol. 145, Issue 26A.)
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