MicroRNA discovery wins 2024 Nobel Prize in Physiology

An unexpected discovery about what made a tiny worm refuse to grow has now led to the 2024 Nobel Prize in physiology or medicine.

Victor Ambros, now at the University of Massachusetts Chan School of Medicine in Worcester, and Gary Ruvkun, of Harvard Medical School, discovered that small pieces of RNA called microRNAs can help control protein production throughout the body. . These small RNAs can play a major role in health and disease.

“The seminal discovery of microRNA has introduced a new and unexpected mechanism of gene regulation,” said Olle Kämpe, vice-chairman of the Nobel Committee for Physiology or Medicine at the Karolinska Institute in Stockholm on October 7 when announcing the prize. MicroRNAs play important roles in cancer, pain and itch, eye disease, and in controlling the mix of microbes that live in the human colon (SN: 4/7/19; SN: 13.8.18; SN: 4/2/13; SN: 19.1.16).

“[The discovery] it helps our basic understanding of all the things you’ve heard about how cells differentiate and become specialized,” said committee chair Gunilla Karlsson Hedestam. “Having a basic understanding is, of course, the first step toward developing applications.”

Much of the important work in cells—contracting muscles, processing medicine, digesting food, transmitting signals to the brain—is done by proteins. The instructions for making these proteins are encoded for long-term storage in DNA.

MicroRNAs play a key role in the steps between reading those instructions and making proteins.

The original DNA is too valuable and too large to be converted directly into protein, so cells copy the stored information into molecules called messenger RNA, or mRNA. Transcription or copying is literally what cells do when they rewrite DNA instructions into RNA. “It’s like a monk transcribing a passage in Latin into Latin,” says Jon Lorsch, director of the US National Institute of General Medical Sciences in Bethesda, Md. The mRNA instructions are then read by the cellular machinery and translated from the nucleic acid “language”. ” of DNA and RNA into proteins.

It is the step between transcription and translation where microRNAs function (SN: 1/10/02).

These small RNAs — only 21 or 22 nucleotides, or letters, long — bind to much longer mRNAs. Messenger RNAs that have microRNAs attached to their backbones are degraded, preventing proteins from being produced on their instructions. MicroRNAs “are not on-off switches,” says Tamas Dalmay, a molecular biologist at the University of East Anglia in Norwich, England. Instead, they function as a dimmer switch to dampen protein production.

In this way, microRNAs are similar to small interfering RNAs, or siRNAs, which were awarded the 2006 Nobel Prize in Physiology or Medicine.SN: 10/4/06). “They are very similar, but microRNAs are made by our genomes,” says Luisa Cochella, a molecular developmental biologist at the Johns Hopkins School of Medicine. “In most cases, RNAi, or small interfering RNA, arises from RNA that comes from outside the cell.”

But microRNAs were there first, says H. Robert Horvitz, a biologist at MIT in whose lab Ambros and Ruvkun worked as postdoctoral students. The two newly minted Nobel laureates “are both brilliant scientists and wonderful people,” he says. And both gambled promising scientific careers to work in Horvitz’s lab on a tiny transparent worm called Caenorhabditis elegans. The pair worked to discover key steps in the worm’s development guided by two genes called line-4 AND line-14.

Worms with a mutation in line-4 repeated some steps in larval development and failed to make some adult parts, Ambros said on Oct. 7 at a news conference.

He carefully narrowed down the location of line-4 in the worm’s genome, but found no protein-producing gene there. “We stumbled over and over trying to test different hypotheses,” Ambros said. He remembered seeing the little RNA show up in his experiments, but he brushed it off as some kind of crap. “And it turned out to be the microRNA we’re all talking about, but [it was] something so unexpected that we had dismissed it for a while as just, you know, schmutz.”

In 1993, Ambros discovered this line-4 creates a microRNA. Except then it wasn’t called microRNA, Dalmay says. This name came later. At the time, it was called a short-time RNA because it was only made at a precise time during the worm’s development. Ruvkun found that line-4 microRNA attaches to a part of line-14 messenger RNA and reduces its protein production. The lin-14 protein, in turn, regulates other genes involved in worm development.

The mechanism for controlling protein production was unexpected and completely new. “Surprisingly, it wasn’t taken too seriously because it was in this little worm, C. elegans. And people thought that was something these funny worms do,” says Cochella.

Seven years later, Ruvkun went on to discover that a microRNA called let-7 is present throughout the animal kingdom, including humans. “That’s when people noticed,” says Cochella. “A frenzy began to find all the microRNAs that are present in animals.”

It took time, David Brown, president of Mass General Brigham Academic Medical Centers in Boston, said at a press conference honoring Ruvkun. “The critical role that microRNAs play in health and disease has become increasingly apparent. It takes time and their therapeutic applications are in clinical trials now for heart disease, cancer, neurodegenerative diseases and many others.”

More than 1,000 microRNAs are now known to regulate genes in humans. Non-human animals and plants also use microRNAs. Some microRNAs are evolutionarily ancient, Dalmay says. Those ancient microRNAs tend to regulate basic biological processes that are fundamental to all plant and animal cells. But during evolution, new microRNAs have also appeared. Novels tend to regulate processes that are specific to certain species or to particular branches of the evolutionary tree.

“It is a completely new physiological mechanism that no one expected. Completely out of the blue! And that shows that curiosity research is very important,” Kämpe said. “They were looking at two worms that looked a little funny and decided to figure out why. Then, they discovered a whole new mechanism for gene regulation. I think it’s beautiful.”

Ambros and Ruvkun will share the prize of 11 million Swedish kronor, or about $1 million.