This year’s Nobel Prize in Physiology or Medicine has been jointly awarded to two biologists who while studying worms decades ago discovered tiny pieces of genetic material called microRNAs and began to unravel their role in influencing the expression of genes in cells. Victor Ambros from the University of Massachusetts Chan Medical School and Gary Ruvkun from Harvard Medical School and Massachusetts General Hospital (MGH) received the award “for the discovery of microRNA and its role in post-transcriptional gene regulation,” the Nobel Assembly at the Karolinska Institute said in a press release this morning.
MicroRNAs are made of the same nucleotide bases as messenger RNAs (mRNAs), which carry the proteinmaking instructions encoded by DNA and were recognized in a Nobel Prize last year for enabling the first COVID-19 vaccines. However, microRNAs are much shorter, typically between 20 and 25 nucleotides, and play a different role in the cell: by binding to particular mRNAs transcribed from genes, they influence whether those mRNAs get translated into proteins. The finding of this class of molecules launched a new field to uncover microRNA’s roles in an organism’s development and, more recently, in diseases such as cancer, where microRNAs are often dysregulated.
The prize of 11 million Swedish krona (approximately $1.06 million), which will be divided equally between the two scientists, honors the discovery that mRNAs could themselves be modulated by molecular relatives, Olle Kämpe, a member of the Nobel Committee, said speaking after the announcement. “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.”
The Nobel is “very exciting news for those of us working in the microRNA field,” says Claudio Alonso, a developmental neurobiologist at the University of Sussex who began studying the gene regulators after hearing a talk by Ruvkun in the early 2000s. “That a discovery of this entirely new layer of gene regulation could take place in the late 1990s, early 2000s revealed that there were still many surprises awaiting to be discovered in … molecular biology.”
In the 1980s, Ambros and Ruvkun both worked as postdoctoral fellows in the lab of Robert Horvitz, who went on to share the 2002 Nobel Prize in Physiology or Medicine. There, they studied a roundworm, Caenorhabditis elegans, which is used as a model organism to show how cells and tissues develop into an animal. In particular, the pair carried out research on worms that carried specific mutations in their DNA that led them to develop abnormally.
The scientists had found that a gene called lin-4 seemed, somehow, to be blocking the expression of another gene, lin-14. But it wasn’t until the two scientists left to start their own labs that they shared data and discovered how. In 1993, Ambros’s group at Harvard University and Ruvkun’s group at MGH and Harvard Medical School revealed that lin-4 produced a short RNA molecule that didn’t code for any proteins and had a sequence that was complementary to lin-14, meaning it could bind to the latter’s mRNA.
“It was surprising that there could be enough information contained in only 22 bases in the genome for this microRNA to regulate another gene so precisely,” Ambros told reporters at a press conference this afternoon, dressed in a tiger-decorated shirt given to him by his wife Rosalind “Candy” Lee, a long-term scientific collaborator and co-author on one of the two key papers in 1993.
Those papers provided an explanation for how lin-4 could block lin-14 from making protein, and a novel way that genes could be effectively switched on and off inside cells. But it was thought to be an oddity until 7 years later, when Ruvkun discovered another microRNA called let-7 that, unlike the lin-4 microRNA, was found widely in organisms across the animal kingdom.
Publication of these results garnered far more interest, and biologists have since identified tens of thousands of microRNA-encoding genes, Kampe says. “They 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, and I think that’s beautiful.”
In the past 2 decades, researchers have studied microRNAs’ role not only in normal development for plants and animals, but in diseases such as cancer and skeletal disorders. “Components of microRNA pathways are mutated in dozens of diseases,” says Witold Filipowicz, a biochemist at the Friedrich Miescher Institute for Biomedical Research. Attempts to harness these findings for clinical applications have yet to reach late-stage clinical trials, and some studies have been shut down for reported toxic side effects. However, Filipowicz and others say they are optimistic that microRNA-based therapies will come.
Some of the furthest along efforts involve adjusting gene expression within diseased cells by targeting microRNAs with drugs or by using microRNAs themselves as therapeutics. Part of what makes this challenging—that each microRNA can potentially affect the translation of hundreds of different mRNAs—could end up being a key advantage compared with traditional approaches to treating complex diseases such as cancer, says Purdue University’s Andrea Kasinski, who researches microRNA’s role in cancer. “In cancer therapy, targeting one thing is never enough,” Kasinski says. “These microRNAs have the power to target many genes. We just have to make sure they’re the right ones.”
Researchers tell Science the Nobel is yet another win for so-called basic research and model organisms. “It’s striking that the work on the simple worm C. elegans is still resulting in Nobel Prizes,” says Dutch molecular biologist Ronald Plasterk, who worked on microRNA in the 1990s and 2000s but later became a politician. “So much basic biology has been discovered in this simple animal of only 959 cells.”
Lynne Maquat, a biochemist at the University of Rochester, echoes this sentiment, adding that, as in the case for mRNA research that eventually led to the COVID-19 vaccines, “I’m hoping that the general public will realize that these [fields] are decades in the making and they will ultimately benefit human health and mankind.”
In a conversation with a Nobel Prize representative this morning, Ruvkun emphasized that the work had been driven by curiosity. “At that moment … we weren’t thinking, ‘This is going to win a Nobel Prize,’ we were thinking, ‘This is really interesting,’” he said, adding that the field has been “an unbelievable pleasure to participate in.”
This year’s prize marks at least the fifth time that research on RNA has snagged a Nobel. In addition to this and last year’s prizes, researchers who discovered RNA interference, a process by which strands of RNA silence particular genes, won in 2006, and research on RNA’s role as enzymes was recognized in 1989. The discovery of mRNA itself received the Nobel Prize in Physiology or Medicine in 1965.
