 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 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 results in the twitching behavior. First, they introduced single-stranded RNA or SS RNA 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 SS RNA 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 proteins 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 combine 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 SI RNAs, 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, Pizzeran, an SI RNA molecule, was approved for a disease of the nervous system caused by hereditary transtherodin-mediated amyloidosis, HATTR. This disease is characterized by the abnormal buildup of a protein called transtherodin in the nervous system which can impact movement, heart rate, and digestion. Pizzeran directly targets the RNA responsible for making transtherodin, thereby limiting accumulation of the disease-causing protein. Patients who received Pizzeran 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.