Every cell in our body starts out with the same set of genetic instructions, or DNA. Yet only some of these genes are expressed in each cell, leading to the production of proteins that perform the cell’s unique functions. The 2024 Nobel Prize in Physiology or Medicine was awarded on Monday to U.S. scientists Victor Ambros and Gary Ruvkun for the discovery of microRNA, a molecule that performs this important regulatory process.
The discovery opened up a new field in gene regulation, explaining how only some of the many genetic instructions in DNA result in functional proteins in different cells. The research was initially conducted in the tiny roundworm Caenorhabditis elegans, but the mechanism has since been found in the genes of humans and most other animals.
Ambros performed his part of the work at Harvard University, and he is currently a professor of natural sciences at the University of Massachusetts Chan Medical School. Ruvkun carried out his research concurrently at Massachusetts General Hospital and Harvard Medical School, where he is now a professor of genetics.
On supporting science journalism
If you're enjoying this article, consider supporting our award-winning journalism by subscribing. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today.
“The seminal discovery of microRNA has introduced a new and unexpected mechanism of gene regulation,” said Olle Kämpe, vice chair of the Nobel Committee for Physiology or Medicine 2024, while describing the research during a press conference in Stockholm on Monday.
In cells, genes are transcribed into messenger RNAs (mRNAs), which are then translated into proteins. Proteins perform the many vital functions within any cell, whether that cell is in nerve tissue, muscle or the immune system—or anywhere else. Problems with gene function can lead to conditions such as cancer, diabetes and autoimmune disease.
As early as the 1960s scientists had discovered that proteins called transcription factors could bind to genes and control what parts of those genes got transcribed into mRNA. This mechanism was thought to be the primary way genes were regulated. But gene regulation turned out to be more complicated than that.
In the 1980s Ambros and Ruvkun were working together as postdoctoral fellows at the laboratory of biologist Robert Horvitz, who shared the 2002 Nobel Prize in Physiology or Medicine for describing the genetic regulation of cell death in C. elegans. Researchers working with these organisms had previously discovered two “mutant” genetic forms of the roundworm that developed differently. One of the genes behind these forms, known as lin-4, resulted in a larger worm, whereas the other, lin-14, led to a smaller one. Ambros showed that the lin-4 gene was negatively regulating the lin-14 gene, but it wasn’t clear how it did so.
Later, at Harvard, Ambros worked to “clone” or make copies of the lin-4 gene—but this resulted in a very tiny RNA molecule that was too small to produce a protein. At the same time, Ruvkun, then at Mass General and Harvard, was studying lin-14. He found that lin-4 was not blocking the production of lin-14 at the mRNA level but was rather impeding its translation into protein at some later stage. Ruvkun and Ambros decided to compare their findings and found that part of the sequence of lin-4’s RNA matched that of lin-14’s mRNA’s end region, which isn’t involved in encoding a protein. They discovered that the binding of this lin-4 RNA to lin-14’s mRNA prevented the latter from producing a protein. This represented a newly found mechanism of gene regulation that was orchestrated by tiny molecules called microRNA.
At first, the researchers thought this mechanism might be unique to C. elegans. But in 2000 Ruvkun identified a second microRNA called let-7 that was present in humans and throughout the animal kingdom. Scientists now know that humans have more than 1,000 different microRNA genes and that the majority of genes are regulated by microRNA.
The disruption of these microRNA networks is believed to play a role in how cancers grow, pointing toward potential treatments.
The Nobel winners’ key research was published in three studies, including two papers published in 1993 in Cell and one published in 2000 in Nature.
“I was astonished and surprised, delighted” at the news of the win, Ambros said at a press conference at the UMass Chan Medical School on Monday morning. The significance of the discovery of microRNA is that it made scientists aware of “the very complex and nuanced layer of regulation whereby genes and our cells talk to each other,” he said. He emphasized the importance of laboratory organisms like the humble C. elegans, which he says are “absolutely the drivers of new knowledge in the life sciences.”
Ambros also noted that he and his wife Rosalind “Candy” Lee, who collaborated with him and co-authored one of the key studies, were the children of immigrants from Poland and China, respectively. “I’m standing here ... because of the legacy of the folks who came before us,” Ambros said.
At a press conference at Mass General on Monday, Ruvkun said, “It’s been a good morning,” adding that “the science turned out to be great in many different dimensions.” He thanked the lab colleagues he had worked with earlier, whom he said amounted to probably 100 people over 40 years.
Ruvkun added that he took an interesting route into science: "I was a disappointment to anybody who was thinking about where my career might go, because I lived in my van and planted trees in the Pacific Northwest and traveled in third-class buses to Tierra del Fuego for a year. But then in Cochabamba, Bolivia, I was bored with travel and I went to the Bolivian American Friendship something or other—that's probably a CIA front—and they had Scientific American magazines. And I spent a day reading Scientific American and it was a really a good day. And I said, you know what, maybe I'll go to graduate school. And that was '76—that was sort of the moment when recombinant DNA was really just starting to take off. And it was obvious that that was a revolution."
The groundwork for the discovery of microRNA was laid more than a decade before, in the early 1980s, says Bruce Wightman, a professor and chair of biology at Muhlenberg College. Wightman was a graduate student at Ruvkun’s lab at Harvard and co-authored one of the studies underlying that discovery. And when he and his colleagues described that study’s findings in 1993, their significance wasn’t immediately apparent. “There were some people who really thought that that was really interesting and were really excited about it,” he says. “But there were a lot of people who thought it was just some weird worm thing and wasn't going to lead to anything broader.” Later it became clear that microRNAs were conserved by evolution in most of the animal kingdom and that some of those in humans play a critical role in cancer and other diseases.
Ambros and Ruvkun “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,” Kämpe said at the press conference. “I think that’s beautiful.”