Medicine Nobel awarded for gene-regulating ‘microRNAs’

The 2024 Nobel Prize in Physiology or Medicine has been awarded to two geneticists who discovered microRNAs, a class of tiny RNA molecules that help to control how genes are expressed in multicellular organisms.
Victor Ambros, who works at the University of Massachusetts Medical School in Worcester, and Gary Ruvkun at Massachusetts General Hospital (MGH) in Boston share the prize pot of 11 million Swedish kroner (US$1 million), awarded by the Nobel Assembly at the Karolinska Institute in Stockholm.
MicroRNAs perform a multitude of tasks in complex organisms, from embryonic development to cell physiology. Researchers have speculated that they were involved in evolutionary leaps, such as humans’ bulging brains, and they have been implicated in the onset of cancers and other diseases.
Speaking at a press conference on 7 October, Ruvkun said he is looking forward to receiving his Nobel at the official ceremony later this year. He got a preview of the raucous celebration when he joined MGH biochemist Jack Szostack, who shared the 2009 medicine Nobel, on the trip to Stockholm. “They know how to party,” Ruvkun said.
Ambros and Rovkun, who were postdoctoral researchers in the same group, published their first key discoveries in 19931,2. They identified two genes — called lin-4 and lin-14 — involved in the development of the roundworm Caenorhabditis elegans. Mutations in these genes prevent roundworm embryos from developing properly. Ambros found that the lin-4 gene somehow blocked the activity of the lin-14 gene, but it was not clear how. Working in separate laboratories, Ambros set out to map the gene responsible for producing lin-4, whereas Ruvkun initially focused on lin-14.

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When Ambros identified the lin-4 gene, he was surprised to discover that it did not encode a protein, but instead produced an intriguingly short strand of RNA. Ruvkun’s work on the lin-14 gene — which does encode a protein — helped to complete the picture. The researchers found that the lin-4 RNA strand, later called a microRNA, attaches to a stretch of the lin-14 messenger RNA, preventing the protein from being made through a process known as translation.
For years, the discovery was viewed as a quirk unique to roundworms, without much relevance to other organisms. That view was shattered in 2000, when Ruvkun’s team identified another C. elegans microRNA that, unlike lin-4, was shared by humans, mice and most of the rest of the animal kingdom3.
In the press conference, Ruvkun recalled the moment he discovered that microRNAs weren’t unique to worms. Needing a distraction from writing a grant application at home, he used a slow dial-up modem to check if the draft human genome — still in the works — contained a second microRNA his lab had described. “It comes back matching the human genome, it was like ‘holy shit this is great’,” he said.
Although the human genome contains hundreds of microRNAs (around 600 distinct ones, more than any other organism), Ruvkun has been long intrigued by the fact that humans and other mammals appear to have jettisoned many small RNA molecules present in organisms such as scorpions, ticks, clams and his laboratory’s muse C. elegans. “[They’re in] the most badass organisms on the planet — and that makes our little worms badass,” he said.
The discovery that microRNAs are conserved across the tree of life caused the field to explode. “That was a watershed moment where everybody realised … we missed this whole layer of gene regulation completely,” says Eric Miska, an RNA biologist at the University of Cambridge, UK. “Our sieve for looking for genes was too big.”

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Studies that mutate microRNAs in mice show that they play critical roles in development, physiology, behaviour and other traits, says David Bartel, a molecular biologist at the Whitehead Institute in Cambridge, Massachusetts. But figuring out exactly how individual molecules act has been tricky. A single microRNA and its close relatives can alter the activity of hundreds of different genes, and many genes are controlled by more than one microRNA. “It gets complex very quickly,” Bartel adds.
The field of microRNA therapeutics is still in its infancy, but researchers hope to one day harness these master regulators for identifying and treating diseases. There are microRNA drugs in development, but delivering RNA molecules to cells has been a key challenge, says Miska.
The recognition of microRNAs with a Nobel Prize was a welcome surprise for some researchers. In 2006, the Nobel committee awarded the Medicine or Physiology prize to two researchers for their discovery of a cellular mechanism called RNA interference, which microRNAs and other non-coding RNA molecules employ to influence gene activity. “MicroRNA genes are now viewed as a whole new class of gene regulators in our genomes,” says Gunter Meister, a biochemist at the University of Regensburg, Germany.
”It’s a completely new physiological mechanism that no one expected,” said committee member Olle Kämpe, an endocrinologist at Karolinska, during the prize announcement. The work highlights the importance of curiosity in research, he added. “They were looking at two worms that looked a bit funny and decided to understand why. And then they discovered an entirely new mechanism for gene regulation. I think that’s beautiful.”