Eureka moments are few and far between in the world of science. When they do
happen, however, they can turn an entire field on its head. A compelling
example is the discovery of RNA interference, or RNAi. Often
revolutionary discoveries come from scientists following an unusual
observation during their studies. For doctors Andrew Fire and Craig Mello,
that came when they saw a mutant strain of C. elegans, a type of worm commonly
used as an animal model, display an unusual twitching behavior. They had
been studying how gene expression is controlled, but to understand their
surprising observation, we first have to understand this critical process by
which DNA a is turned into proteins. First DNA, which is made up of two
complementary strands, is unzipped and a complex of proteins turns one of
these strands into a single strand of RNA known as messenger RNA, or mRNA.
This mRNA is then read by a different complex of proteins, resulting in the
assembly of a functional protein. So doctors Fire and Mello decided to see
if introducing various forms of RNA sequences that matched an RNA
responsible for a worm muscle protein would block production of that protein
and result in the twitching behavior. First, they introduced single-stranded
RNA, or ssRNA,
that was complementary to the target RNA, thinking that this would block the
cell's ability to read the RNA.
But to their surprise, the worms were completely normal. Then they tried
pairing the ssRNA with a partner strand to create double-stranded RNA and
injected this double-stranded RNA into the worms, as opposed to
single-stranded RNA. To their surprise, the double stranded RNA caused the
worms to twitch, signaling that the protein had been turned off or silenced.
This unexpected observation set off a chain of experiments which ultimately
revealed that double-stranded RNA is a signal for cells to initiate a series
of molecular events that leads to the destruction of a matched RNA sequence.
Doing so prevents production of the protein encoded by the RNA. This entire
process is known as RNA interference, or RNAi. Doctors Fire and Mello
published their initial findings in 1998 and won the Nobel Prize in
Physiology or Medicine in 2006. But why was this discovery so important?
In the years that followed Dr. Fire and Dr. Mello's initial findings,
scientists began to understand that RNAi is a process that naturally
evolved in many organisms for a variety of functions. For example, cells use it
as a defense mechanism against viruses. When viruses cause infection, they
inject their genetic material into cells. Many viruses have genomes made
up of double-stranded RNA, which activates the cell's RNAi machinery to
quickly degrade the viral RNA and prevent the spread of infection. RNAi
is also an elegant form of genetic regulation. MicroRNAs are small RNA
fragments encoded throughout the genome of many organisms, and they can bind to
certain RNA molecules creating double-stranded RNA, which ultimately
blocks protein production. MicroRNAs play critical roles in numerous
cellular functions, such as cell growth and differentiation, and have been
implicated in various diseases such as cancer.
Today RNAi is also used as a strategy to remove the function of a specific
gene and examine how that impacts the cell. For example, scientists can use
small interfering RNAs, or siRNAs, a type of RNAi technology, to pair with
and degrade a natural RNA in the cell.
Doing so allows researchers to identify the role of a specific protein by
studying the cellular outcomes in its absence.
RNAi also has found its way into medicine. In 2018, patisiran, an siRNA
molecule, was approved for a disease of the nervous system caused by hereditary
transthyretin-mediated amyloidosis (hATTR).
This disease is characterized by the abnormal build up of a protein called
transthyretin in the nervous system, which can impact movement, heart rate
and digestion.
Patisiran directly targets the RNA responsible for making transthyretin,
thereby limiting accumulation of the disease-causing protein. Patients who
received patisiran in a clinical trial had significantly improved muscle
strength and movement, compared to people receiving a placebo.
This landmark approval ushered in an entirely new class of medicines for
patients who had few options beforehand. Looking back, it's pretty incredible
that an entirely new class of medicines all started with some twitching worms.
But this is actually very typical of how science works. Breakthrough
discoveries begin with curious scientists following unusual
observations. Albert Einstein summed it up best by saying, "I have no special
talents, I am only passionately curious."