An unexpected discovery about what made a tiny worm refuse to grow up has now led to the 2024 Nobel Prize in physiology or medicine.
Victor Ambros, now at the University of Massachusetts Chan Medical School in Worcester, and Gary Ruvkun, of Harvard Medical School, found that small snippets of RNA called microRNAs can help control production of proteins throughout the body. These minuscule RNAs may play an outsize role in health and disease.
“The seminal discovery of microRNA has introduced a new and unexpected mechanism of gene regulation,” Olle Kämpe, Vice Chair of the Nobel Committee for Physiology or Medicine at the Karolinska Institute in Stockholm said October 7 during the announcement of the prize. MicroRNAs play important roles in cancer, pain and itchiness, eye diseases and in controlling the mix of microbes living in people’s colons (SN: 4/7/19; SN: 8/13/18; SN: 4/2/13; SN: 1/19/16).
“[The discovery] 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 towards developing applications.”
Much of the important work in cells — making muscles contract, processing drugs, digesting food, transmitting signals to the brain — is done by proteins. Instructions for making those proteins are encoded for long-term storage in DNA.
MicroRNAs fill a key role in the steps between reading those instructions and making the proteins.
The DNA originals are too valuable and much too big to be converted directly into proteins, so cells copy the stored info into molecules called messenger RNA, or mRNA. Transcription or copying is literally what cells do when rewriting DNA instructions into RNA. “It’s like a monk transcribing a passage in Latin into Latin,” says Jon Lorsch, director of the U.S. National Institute of General Medical Sciences in Bethesda, Md. The mRNA instructions are then read by cellular machinery and translated from the nucleic acid “language” of DNA and RNA into proteins.
It’s the step between transcription and translation where microRNAs work (SN: 1/10/02).
These little RNAs — just 21 or 22 nucleotides, or letters, long — latch on to much longer mRNAs. Messenger RNAs that have microRNAs clinging to their backs get degraded, preventing proteins from being made from 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 work like a dimmer switch to dampen production of proteins.
In that way, microRNAs are similar to small interfering RNAs, or siRNAs, which were honored for the 2006 Nobel Prize in physiology or medicine (SN: 10/4/06). “They’re very similar, but microRNAs are generated from our own genomes,” says Luisa Cochella, a molecular developmental biologist at the Johns Hopkins School of Medicine. “In most cases, RNAi, or small interfering RNAs, arise 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 fellows. 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 governed by two genes called lin-4 and lin-14.
Worms with a mutation in lin-4 repeated certain steps in larval development and failed to make some adult parts, Ambros said October 7 in a news briefing.
He carefully narrowed the location of lin-4 in the worm’s genome, but found no protein-producing gene there. “We were repeatedly stymied in trying to test various hypotheses,” Ambros said. He remembered seeing tiny little RNA showing up in his experiments, but he brushed it off as some sort of grime. “And it turned out that was the microRNA that we’re all talking about, but [it was] something so unexpected that we had kind of ignored it for a while as just, you know, schmutz.”
In 1993, Ambros discovered that lin-4 makes a microRNA. Except it wasn’t called a microRNA then, Dalmay says. That name came later. At the time, it was dubbed a short temporal RNA, because it was made only at a precise time during worm development. Ruvkun found that the lin-4 microRNA latches on to part of the lin-14 messenger RNA and turns down production of its protein. The lin-14 protein, in turn, regulates other genes involved in worm development.
The mechanism for controlling protein production was unexpected and entirely new. “Surprisingly, it wasn’t really taken super seriously because it was in this little worm, C. elegans. And people thought this was something that these funny worms do,” Cochella says.
Seven years later, Ruvkun went on to find that a microRNA called let-7 is present throughout the animal kingdom, including in humans. “That’s when people noticed,” Cochella says. It “started a frenzy to find all the microRNAs that are present in animals.”
It has taken time, David Brown, president of the academic medical centers of Mass General Brigham in Boston, said at a news conference honoring Ruvkun. “The critical role that microRNAs play in health and disease has become more and more apparent. It takes time, and their therapeutic applications are in clinical trials now for heart disease, cancer, neurodegenerative disease, and so many others.”
More than 1,000 microRNAs are now known to regulate genes in people. Nonhuman animals and plants also use microRNAs. Some microRNAs are evolutionarily ancient, Dalmay says. Those old microRNAs tend to regulate basic biological processes that are fundamental to all plant and animal cells. But during evolution, new microRNAs have also appeared. The new ones tend to regulate processes that are specific to certain species or to particular branches of the evolutionary tree.
“It’s a completely new physiological mechanism that no one expected. Completely out of the blue! And it shows that curiosity research is very important,” Kämpe said. “They were looking at two worms that looked a bit funny and decided to understand why. Then, they discovered an entirely new mechanism for gene regulation. I think that’s beautiful.”
Ambros and Ruvkun will split the prize of 11 million Swedish kroner, or about $1 million.