What is RNA interference?
RNA interference (RNAi) is a natural process that cells use to
turn down, or silence, the activity of specific genes. Discovered
in 1998, RNAi has taken the biomedical community by storm.
Researchers quickly capitalized on the discovery and developed RNAi
into a powerful research tool that is now used in thousands of labs
High res. image (730 KB JPEG)
Scientists first used the transparent worm,
elegans, to study RNA interference.
How did we discover RNAi?
RNAi was first noticed in petunias, when plant biologists
attempted to deepen the flowers’ purple color by introducing
a pigment-producing gene. Instead of intensifying the color, the
gene suppressed it. The resulting flowers had white patches or were
A few years later, another group of researchers noticed the same
gene-silencing effect in C. elegans—a microscopic
worm commonly used to study cellular processes. These scientists
figured out that RNAi is triggered by double-stranded RNA, a type
of molecule not normally found in healthy cells. Two longtime NIGMS
grantees, Andrew Fire and Craig Mello, were awarded the 2006 Nobel
Prize in physiology or medicine for this discovery.
How does RNAi work?
RNAi works by destroying the molecular messengers that carry
information coded in genes to the cell’s protein factories.
These messengers, called messenger RNAs (mRNAs), carry out a
critical function, without which a gene is essentially
Upon entering a cell, the double-stranded RNA molecules that
trigger RNAi are cut into small fragments by an enzyme called
Dicer. The small fragments then serve as guides, leading the
cell’s RNAi machinery to mRNAs that match the genetic
sequence of the fragments. The machinery then slices these cellular
mRNAs, effectively destroying their messages and shutting off the
Why does RNAi exist?
RNAi is thought to have evolved about a billion years ago,
before plants and animals diverged. The process exists in many
living things, including single-celled organisms, plants and human
Current thinking suggests that RNAi evolved as a cellular
defense mechanism against invaders such as RNA viruses. When they
replicate, RNA viruses temporarily exist in a double-stranded form.
This double-stranded intermediate would trigger RNAi and inactivate
the virus’ genes, preventing an infection.
RNAi may also have evolved to combat the spread of genetic
elements called transposons within a cell’s DNA. Transposons
can wreak havoc by jumping from spot to spot on a genome, sometimes
causing mutations that can lead to cancer or other diseases. Like
RNA viruses, transposons can take on a double-stranded RNA form
that would trigger RNAi to clamp down on the potentially harmful
How can RNAi be applied to medicine and biomedical
Investigators are currently working intensely to understand
RNAi’s role in normal and diseased cells, and to harness the
mechanism for use in medical therapies.
Diseases that can be blocked by knocking down the activity of
one or several genes are the most promising targets for RNAi-based
therapies. Cancer, for example, is often caused by overactive
genes, and quelling their activity could halt the disease. Several
pharmaceutical companies are currently testing RNAi-based therapies
for various forms of cancer.
Viral infections are also important potential targets for
RNAi-based therapies. Reducing the activity of key viral genes
would cripple the virus, and numerous studies have already hinted
at the promise of RNAi for treating viral infections. In
laboratory-grown human cells, investigators have stopped the growth
of HIV, polio, hepatitis C and other viruses. RNAi-based therapies
against HIV and other viruses are expected to soon enter clinical
The strength of RNAi as a research tool will also have an
enormous potential impact on medicine. Knocking down a gene’s
activity yields a wealth of information about its functions in
cellular pathways. But prior to the discovery of RNAi, the process
was laborious and could take months.
Now, by harnessing RNAi, investigators can silence selected
genes quickly and easily, and can answer questions that were once
well beyond their reach. This technique promises to reveal key
players in normal and disease processes, and may lead scientists to
new drug targets.
Already, RNAi has taught biomedical researchers a few lessons.
For years, scientists had been intensely studying how proteins
regulate gene activity, focusing most of their attention on
proteins called transcription factors. Now RNA, through RNAi and
related processes, is recognized as a key partner in the
cell’s multi-layered approach to gene regulation.
Are there other cellular pathways similar to
Not long after RNAi was discovered, scientists uncovered a
related process called the microRNA (miRNA) pathway. Both pathways
involve double-stranded RNA, but the source of these RNAs differs.
Unlike the double-stranded RNA that triggers RNAi, miRNAs are
encoded in the genome. Additionally, miRNAs are not completely
double-stranded, but rather form hairpin-like structures that
contain double-stranded regions. While the miRNA pathway is
distinct from RNAi, it borrows extensively from RNAi’s tool
chest by making use of enzymes such as Dicer.
In contrast to RNAi, the miRNA pathway focuses on regulating the
cell’s own genes. Scientists believe that humans have more
than 200 miRNAs, and they are estimated to regulate as many as a
third of our genes.
NIGMS is a part of the National Institutes of Health that
supports basic research to increase our understanding of life
processes and lay the foundation for advances in disease diagnosis,
treatment and prevention. For more information on the Institute's
research and training programs, see http://www.nigms.nih.gov.
Content reviewed November 2012