Two share Nobel Prize in Physiology or Medicine for microRNA discoveries

American biologists Victor Ambros from the University of Massachusetts and Gary Ruvkun from Harvard University have won the 2024 Nobel Prize in Physiology or Medicine. They share the prize for their discovery of microRNAs, a family of molecules produced in the body that can profoundly alter gene expression. 

In a press conference, Ruvkun remarked on his career in science, saying that “the joy of doing genetics . . . is the surprises. The surprises are what keep you young in science.” He also says of the model organism Caenorhabditis elegans, in which he helped discover microRNAs, that their potent small RNA system “makes our little worms badass . . . and I was asserting this before the Nobel stinkin’ Prize.”

Olle Kämpe, vice chair of the Nobel Committee for Physiology or Medicine, says of the prizewinning microRNA discovery, “It’s a completely new physiological mechanism that no one expected. It shows that curiosity research is very important.” He adds that the two scientists were “looking at two worms that looked a bit funny and decided to understand why. And then they discovered an entirely new mechanism for genetic regulation. I think that's beautiful.”

RNA biology is now the subject of a third Nobel Prize–winning discovery in the 21st century. Last year’s award in physiology or medicine went to Katalin Karikó and Drew Weissman for their work on messenger RNA (mRNA) vaccines during the COVID-19 pandemic. And in 2006, Andrew Fire and Craig Mello won the prize in physiology or medicine for their discovery of RNA interference. 

"Honestly, this was not something that I expected," Ambros said at a press conference. "In my opinion, the Nobel Prize to Mello and Fire encompassed all these phenomena that we studied. That was my sense and I was comfortable with that. So as you can imagine, I was astonished." He also thanked his wife, Rosalind “Candy” Lee for her crucial role in the discovery of microRNAs; Lee was a first author and Ambros last author on the Cell paper in which the production of a microRNA was first described (1993, DOI: 10.1016/0092-8674(93)90529-y).

Ambros and Ruvkun will share the 11 million Swedish kronor (about $1.1 million) prize, but it won’t be the first time they’ve shared recognition for their science; together they’ve previously won the Albert Lasker Award for Basic Medical Research, the Breakthrough Prize in Life Sciences, and the Dr. Paul Janssen Award for Biomedical Research for their work on microRNAs. 

Betty Chung, a pathologist studying RNA structure and function at the University of Cambridge, says in an email to C&EN that “both Victor Ambros and Gary Ruvkun are truly remarkable individuals. Their significant work has transformed the field of biology and inspired generations of scientists, including myself, to pursue this discipline.”

In the late 1980s, both Ambros and Ruvkun were postdoctoral scientists in the laboratory of 2002 Nobel laureate Robert Horvitz at the Massachusetts Institute of Technology. Horvitz tells C&EN that the two winners are, “brilliant, brilliant scientists . . . and wonderful human beings. [They’re] warm, caring, supportive of others, and phenomenally innovative.”

In Horvitz’s lab, the pair were studying two genes in the C. elegans genome named lin-4 and lin-14. When lin-14 was expressed, a lin-14 protein was produced, but when the lin-4 gene was expressed, it reduced the expression of the lin-14 protein. At the time Ambros and Ruvkun were studying this negative regulation, the mechanism of action was unclear.

Later, Ambros discovered that lin-4 produced a short RNA transcript that couldn’t be translated into protein. And Ruvkun established that lin-14 was still producing its own mRNA that wasn’t being translated into protein. Together the scientists found that the sequence of the short lin-4 RNA transcript was complementary to a part of the sequence in the lin-14 mRNA. The lin-4 RNA would bind to the mRNA of lin-14 and prevent translation from taking place (Cell 1993, DOI: 10.1016/0092-8674(93)90530-4).

That discovery would be the spark that ignited a whole new subfield of RNA biology—the study of microRNA gene regulation.

The discovery of these small molecules helped overturn the idea that noncoding DNA from which microRNAs and other small RNAs are produced was just junk, says André Fischer of the German Center for Neurodegenerative Diseases, who works on the epigenetic mechanisms of neurodegenerative and psychiatric diseases. Small RNA molecules like microRNA are involved in regulatory mechanisms that are important to biology, life science, and medicine, he says, and their discovery "opened the door to therapeutic interventions." The growth in RNA-targeting therapy in recent years is "truly amazing" he says, and is only set to continue.

Today, microRNAs are defined as single-stranded RNA molecules between 21 and 23 nucleotides long, and they’re found in animals, plants, and viruses. They are one of several classes of short RNAs that regulate gene expression. Scientists have been working toward unlocking the therapeutic potential of microRNAs as drug targets for small molecules or as therapeutic molecules in their own right. MicroRNAs can serve as biomarkers for diseases including bladder and breast cancer, Alzheimer’s disease, and HIV.

"It's an RNA world we live in," says Matthew Disney, a chemist at the University of Florida and scientific founder of Expansion Therapeutics, which is working on medicines that target microRNAs. "We've come through an era where RNA was the disease. SARS-CoV-2 has an RNA genome. And RNA is the cure: the mRNA vaccines."

"I think this is going to further cement the importance of RNA," he adds.

With additional reporting by Sarah Braner, Laura Howes, and Laurel Oldach.