Nobel Prize in physiology or medicine awarded for discovery of microRNA

 Nobel Prize in physiology or medicine awarded for discovery of microRNA

American scientists Victor Ambros and Gary Ruvkun won the 2024 Nobel Prize in physiology or medicine Monday for the discovery of microRNAs, a class of tiny molecules that have been connected to heart disease, a wide variety of cancers and viral diseases.

Mutations in microRNAs, just like those in genes, can lead to diseases, and fixing or replacing mutant microRNAs may prove crucial to developing treatments.

Ambros and Ruvkun figured out that these small molecules have the power to reduce or block production of proteins, responsible for virtually every human action from breathing to thinking.

Not to be confused with messenger RNA — which acts as a “middleman” in the process of translating genetic material into proteins — microRNAs add a crucial, previously unrecognized layer to the process. MicroRNAs can bind on to the messenger RNA and are able to help cells regulate the kinds and amounts of proteins that are made.

Thomas Perlmann, secretary of the Nobel Committee for Physiology or Medicine, called the discovery of these molecules “truly fundamental for all physiology,” an insight that told scientists that the process of translating genes into proteins was more complex than they had thought.

Gunilla Karlsson-Hedestam, an expert in immunology and chair of the committee, said there are several ongoing microRNA trials trying to figure out how to combat cardiovascular and kidney diseases.

“Although there are no very clear applications available yet with microRNAs, understanding them, knowing that they exist, understanding their regulatory networks is always the first step,” Karlsson-Hedestam said.

Ambros is with the University of Massachusetts Chan Medical School; Ruvkun is at Massachusetts General Hospital and Harvard Medical School.

Ambros, at a news conference at UMass, said he slept late Monday and missed the initial call from the Nobel Committee. He said he found out about the award from his son, who called after the committee had reached out to him.

“Honestly, this was not something that I expected,” Ambros said, noting that he believed the 2006 Nobel Prize encompassed the phenomena he studied.

“The microRNAs are part of a broader sweep of regulatory mechanisms,” he added. “What the microRNAs really end up revealing for us is a way that parts of our genome can communicate with other parts of the genome. The significance of this discovery of microRNAs is that it allowed us to be aware of a very complex and nuanced layer of regulation whereby genes in our cells talk to each other.”

The genome is the genetic blueprint present in a living organism.

 

Ruvkun said he was sleeping when the telephone rang about 4 a.m. and he recognized Perlmann’s voice. As he received congratulations, he recalled, “my first thought was, ‘This changes everything.’” Although he and Ambros had won other prizes, he knew no other would have the impact of the Nobel.

 Ambros and Ruvkun, who had worked together as postdoctoral researchers in the lab of Nobel laureate Robert Horvitz at MIT, began making their discoveries in the 1990s after noticing anomalies in roundworms, a common model organism that researchers study to learn more about genomic and biological development.

Jon Lorsch, director of the National Institute of General Medical Sciences, part of the National Institutes of Health, said he was a graduate student early in the 1990s working in the lab upstairs from Ruvkun’s at Massachusetts General Hospital when Ruvkun showed those in the lab the gene involved in roundworm development.

“If you disturbed this gene, these worms didn’t develop properly,” Lorsch said. “They couldn’t figure out what it was doing. He said to us: ‘What’s going on here?’ We said: ‘No idea. That looks weird.’ Then he went back to his lab and now he’s won the Nobel Prize, which is fantastic.”

The gene that so puzzled Ruvkun would turn out to have been influenced by microRNA.

Both Ambros and Ruvkun showed interest in science from an early age. Growing up in Vermont, Ambros received a telescope-building kit from his parents. Ruvkun’s parents gave him a telescope and microscope.

In applying to MIT for undergraduate studies, Ambros submitted an essay consisting of just six words: “I want to be a scientist.”

As young researchers, they shared a distinguished scientific pedigree, with each studying under a Nobel-winning scientist. Ambros worked in the lab of David Baltimore, where he studied the structure of polio’s genetic blueprint. Ruvkun worked with Walter Gilbert, specializing in molecular genetics. (Gilbert helped pioneer the technology to read the sequence of DNA.)

In Horvitz’s lab, Ruvkun said, he and Ambros “just clicked” as scientific partners.

The path that would lead them to microRNAs started with an investigation into the curious relationship between two roundworm genes.

They learned that when the gene called lin-4 was broken or not sufficiently active, it caused the same developmental defects seen when the gene called lin-14 was too active.

The two men collaborated on this relationship between the two genes even as they went their separate ways: Ambros to start his own lab at Harvard, and Ruvkun at Mass General Hospital and Harvard Medical School. In previous interviews, both have stressed the important roles that others played in the work, including Rosalind Lee, who is a lead author on one of the publications honored by the committee and has supported Ambros both as a scientific collaborator and wife.

Thoroughly engrossed in the project, Ambros and Ruvkun compared the sequences of the two genes one night by telephone, according to an account of their work published by the science journalist John Rennie. Portions of the two sequences complemented one another, and although their relationship was not simple and exact, it was an important first step.

“That was just the first moment of our hitting a home run,” Ruvkun recalled.

The two scientists showed that lin-4 was binding to messenger RNA, encoding lin-14 and blocking it from being translated into protein in a never-before-seen mechanism for gene control, according to a news release from MIT.

Their findings were published in 1993 in the journal Cell. Seven years later, the discovery by Ruvkun’s lab of the second microRNA helped convince other scientists that microRNAs were not simply an oddity of roundworms, but fundamental to biology.

The National Institutes of Health has funded the work of the two scientists to the tune of more than $63 million over the years, and both had received a host of major scientific awards including the Albert Lasker Award for basic medical research and the Breakthrough Prize in life sciences.

Last year, Katalin Kariko, a Hungarian-born scientist, and American Drew Weissman won for discoveries that paved the way for the development of highly effective messenger RNA vaccines against covid-19.

On Tuesday, the Royal Swedish Academy of Sciences will announce the Nobel Prize in physics.