The Nobel Assembly at the Karolinska Institute has taken a liking to RNA. The committee has awarded two American biologists the 2024 Nobel Prize in Physiology or Medicine for their discovery of microRNA, the small RNA molecules that regulate genes, one year after the prize went to scientists who conducted foundational work on mRNA vaccines.
The laureates are Victor Ambros, Ph.D., and Gary Ruvkun, Ph.D. Ambros is a professor at UMass Chan Medical School, while Ruvkun is a professor at Harvard Medical School.
The central idea of molecular biology is that genes are transcribed into mRNA, which then gets translated into proteins that go on to serve vital functions in our cells. Scientists knew that cells use proteins called transcription factors to control when genes are turned on and off, dictating when and in what cells proteins are made.
“For many years, it was believed that the main principles of gene regulation had been elucidated,” Olle Kämpe, M.D., Ph.D., vice chair of the Nobel Committee for Physiology or Medicine 2024, said in the award announcement. “The mechanism would, however, turn out to be more complex. For this year's Nobel Prize, an elegant little organism was the key.”
That elegant little organism is the nematode Caenorhabditis elegans, which is commonly used as a model organism in biology. Researchers had previously identified two C. elegans genetic mutants that experience errors in the timing of their development; the lin-4 mutant becomes larger than a typical nematode, while the lin-14 mutant skips some developmental stages and ends up smaller than average.
Ambros’ team spent years attempting to identify the nature of lin-4, while Ruvkun’s focused on lin-14. Ambros’ team discovered that the lin-4 gene doesn’t code for an mRNA that becomes a protein, as many other genes do, but instead encodes a small molecule of RNA. The lin-14 gene, on the other hand, does become an mRNA and then a protein. Ambros and Ruvkun knew each other from their postdoctoral researcher days, and shared the sequences of the genes they were working on with each other.
From this collaboration, the researchers realized that there was overlap in the sequences of the lin-4 microRNA and the lin-14 mRNA. In 1993, Ambros’ team published a pivotal paper showing that the lin-4 microRNA binds to the lin-14 mRNA and prevents it from being translated (PDF) into a protein.
“At this point, they had discovered a novel, and unexpected, mechanism of gene regulation: microRNA,” Kämpe said. “For a long time, however, microRNA was believed to be an oddity peculiar to C. elegans.”
It took seven more years for Ruvkun’s group to identify another microRNA, let-7, that is found not only in C. elegans but across the animal kingdom, including in humans. We now know that humans have more than 1,000 types of microRNA and that virtually every gene is regulated at the mRNA level by several microRNAs.
While both this prize and last year’s prize went to research on RNA, Ambros and Ruvkun’s prizes skew toward physiology rather than medicine. MicroRNAs are not used therapeutically, at least not yet, though Kämpe noted that microRNA regulatory networks are often disrupted in cancer cells.
“Having a basic understanding is, of course, the first step towards developing applications,” Gunilla Karlsson-Hedestam, Ph.D., chair of the Nobel Committee, said in the announcement. “This could still take a while. There are quite a lot of trials ongoing, and not only against cancer, but also in other diseases, [like] cardiovascular, kidney diseases.”
Several companies are endeavoring to turn microRNAs into drugs. Curamir Therapeutics, for example, launched in 2019 with a near-term goal of using microRNAs to target cancer, according to its website. And TAmiRNA develops microRNA biomarkers for age-related diseases like liver disease and cardiovascular disease.
The discovery of microRNA “shows that curiosity research is very important,” Kämpe said. Ambros and Ruvkun might have never made their paradigm-shifting discoveries if they hadn’t taken an interest in some strange-looking nematodes.