U.S. duo wins Nobel Prize in medicine for discovery of microRNA and gene regulation breakthrough

US scientists Victor Ambros and Gary Ruvkun won the Nobel Prize in Medicine on Monday for their discovery of microRNA and its role in how genes are regulated, solving a decades-old mystery, the Nobel Assembly at Sweden’s Karolinska Institute said.

If gene regulation goes awry, it can lead to serious diseases such as cancer, diabetes, or autoimmune illnesses.

“Their groundbreaking discovery revealed a completely new principle of gene regulation that turned out to be essential for multicellular organisms, including humans,” the jury said.

Ruvkun said he was shocked to win the prestigious prize.

“It’s quite a sea change,” the 72-year-old professor at Harvard Medical School told AFP after receiving the news in a call from the prize committee in the early hours of Monday.

“I’ve won other awards in the past, but those were very quiet in comparison.”

“There’s already been TV crews and photographers, and 300 email messages from friends!” he said, as his dog barked at the front door with more reporters arriving.

Ruvkun shared that he and Ambros are “buddies” and had a congratulatory video call that morning.

“We just FaceTimed to high-five. We’ve been friends for years.”

Ruvkun told AFP the pair would be “celebrating like crazy,” praising Ambros as “always positive and wonderful.”

The Nobel committee failed to reach Ambros by telephone to give him the news. He heard it instead from an SR reporter who called.

“Wow, that’s incredible! I didn’t know that,” the 70-year-old professor at the University of Massachusetts medical school said, adding: “Good. Wonderful.”

Speaking at a press conference organized by the University of Massachusetts Medical School—where Ambros is a professor—he said he had left his phone downstairs and slept until late in the morning.

“We get a call from my son who calls my wife…. and says, ‘If you get a call from somebody in Sweden, answer it’,” Ambros said, explaining people had started trying to reach his son instead.

Collaborating but working separately, Ruvkun and Ambros conducted research on a one millimeter roundworm, C. elegans, to determine why cell mutations occurred and when.

They discovered microRNA, a new class of tiny RNA molecules that play a crucial role in gene regulation, which in turn allows each cell to select only relevant instructions.

Their findings were published in two articles in 1993.

“The seminal discovery of microRNA has introduced a new and unexpected mechanism of gene regulation,” Thomas Perlmann, secretary general of the Nobel Assembly, told reporters.

“MicroRNAs are important for our understanding of embryological development, normal cell physiology and diseases such as cancer,” he said.

Medical trials under way

Gunilla Karlsson Hedestam, a biology professor at the Karolinska Institute, told reporters that “though there are no very clear applications available yet in microRNAs, understanding them, knowing that they exist, understanding their counter regulatory networks, is always the first step.”

“There are quite a lot of trials ongoing, not only against cancer but also other diseases, cardiovascular, kidney diseases,” she said.

“I think 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 and coordinate their activity,” Ambros told a press conference.

The Nobel Prize consists of a diploma, a gold medal and a $1 million check to be shared by the pair.

Last year, the medicine prize went to Katalin Kariko and Drew Weissman for work on messenger RNA (mRNA) technology that paved the way for COVID-19 vaccines.

The Nobel season continues this week with the announcement of the winners of the physics prize on Tuesday and the chemistry prize on Wednesday.

They will be followed by the much-anticipated prizes for literature on Thursday and peace on Friday.

The economics prize winds things up on Monday, October 14.

For Tuesday’s physics prize, Swedish public radio SR’s science experts suggested the honor could go to Swiss physicist Christoph Gerber, a pioneer in the development of the atomic force microscope.

“This is a microscope that gives 3D images on such an incredibly small scale that they sometimes are even atomic resolution,” said SR science reporter Camilla Widebeck.

The tool has become indispensable in nanotechnology and nano research, she added.

The Clarivate analytics group also highlighted David Deutsch and Peter Shor for their work on quantum algorithms and quantum computing.

——————

Nobel committee announcement:
The Nobel Assembly at Karolinska Institutet

has today decided to award the 2024 Nobel Prize in Physiology or Medicine jointly to

Victor Ambros and Gary Ruvkun
for the discovery of microRNA and its role in post-transcriptional gene regulation
This year’s Nobel Prize honors two scientists for their discovery of a fundamental principle governing how gene activity is regulated.

The information stored within our chromosomes can be likened to an instruction manual for all cells in our body. Every cell contains the same chromosomes, so every cell contains exactly the same set of genes and exactly the same set of instructions. Yet, different cell types, such as muscle and nerve cells, have very distinct characteristics. How do these differences arise? The answer lies in gene regulation, which allows each cell to select only the relevant instructions. This ensures that only the correct set of genes is active in each cell type.

Victor Ambros and Gary Ruvkun were interested in how different cell types develop. They discovered microRNA, a new class of tiny RNA molecules that play a crucial role in gene regulation. Their groundbreaking discovery revealed a completely new principle of gene regulation that turned out to be essential for multicellular organisms, including humans. It is now known that the human genome codes for over one thousand microRNAs. Their surprising discovery revealed an entirely new dimension to gene regulation. MicroRNAs are proving to be fundamentally important for how organisms develop and function.

Essential regulation

This year’s Nobel Prize focuses on the discovery of a vital regulatory mechanism used in cells to control gene activity. Genetic information flows from DNA to messenger RNA (mRNA), via a process called transcription, and then on to the cellular machinery for protein production. There, mRNAs are translated so that proteins are made according to the genetic instructions stored in DNA. Since the mid-20th century, several of the most fundamental scientific discoveries have explained how these processes work.

Our organs and tissues consist of many different cell types, all with identical genetic information stored in their DNA. However, these different cells express unique sets of proteins. How is this possible? The answer lies in the precise regulation of gene activity so that only the correct set of genes is active in each specific cell type. This enables, for example, muscle cells, intestinal cells, and different types of nerve cells to perform their specialized functions. In addition, gene activity must be continually fine-tuned to adapt cellular functions to changing conditions in our bodies and environment. If gene regulation goes awry, it can lead to serious diseases such as cancer, diabetes, or autoimmunity. Therefore, understanding the regulation of gene activity has been an important goal for many decades.

In the 1960s, it was shown that specialized proteins, known as transcription factors, can bind to specific regions in DNA and control the flow of genetic information by determining which mRNAs are produced. Since then, thousands of transcription factors have been identified, and for a long time it was believed that the main principles of gene regulation had been solved. However, in 1993, this year’s Nobel laureates published unexpected findings describing a new level of gene regulation, which turned out to be highly significant and conserved throughout evolution.

Research on a small worm leads to a big breakthrough

In the late 1980s, Victor Ambros and Gary Ruvkun were postdoctoral fellows in the laboratory of Robert Horvitz, who was awarded the Nobel Prize in 2002, alongside Sydney Brenner and John Sulston. In Horvitz’s laboratory, they studied a relatively unassuming 1 mm long roundworm, C. elegans. Despite its small size, C. elegans possesses many specialized cell types such as nerve and muscle cells also found in larger, more complex animals, making it a useful model for investigating how tissues develop and mature in multicellular organisms. Ambros and Ruvkun were interested in genes that control the timing of activation of different genetic programs, ensuring that various cell types develop at the right time. They studied two mutant strains of worms, lin-4 and lin-14, that displayed defects in the timing of activation of genetic programs during development. The laureates wanted to identify the mutated genes and understand their function. Ambros had previously shown that the lin-4 gene appeared to be a negative regulator of the lin-14 gene. However, how the lin-14 activity was blocked was unknown. Ambros and Ruvkun were intrigued by these mutants and their potential relationship and set out to resolve these mysteries.

After his postdoctoral research, Victor Ambros analyzed the lin-4 mutant in his newly established laboratory at Harvard University. Methodical mapping allowed the cloning of the gene and led to an unexpected finding. The lin-4 gene produced an unusually short RNA molecule that lacked a code for protein production. These surprising results suggested that this small RNA from lin-4 was responsible for inhibiting lin-14. How might this work?

Concurrently, Gary Ruvkun investigated the regulation of the lin-14 gene in his newly established laboratory at Massachusetts General Hospital and Harvard Medical School. Unlike how gene regulation was then known to function, Ruvkun showed that it is not the production of mRNA from lin-14 that is inhibited by lin-4. The regulation appeared to occur at a later stage in the process of gene expression, through the shutdown of protein production. Experiments also revealed a segment in lin-14 mRNA that was necessary for its inhibition by lin-4. The two laureates compared their findings, which resulted in a breakthrough discovery. The short lin-4 sequence matched complementary sequences in the critical segment of the lin-14 mRNA. Ambros and Ruvkun performed further experiments showing that the lin-4 microRNA turns off lin-14 by binding to the complementary sequences in its mRNA, blocking the production of lin-14 protein. A new principle of gene regulation, mediated by a previously unknown type of RNA, microRNA, had been discovered! The results were published in 1993 in two articles in the journal Cell.

The published results were initially met with almost deafening silence from the scientific community. Although the results were interesting, the unusual mechanism of gene regulation was considered a peculiarity of C. elegans, likely irrelevant to humans and other more complex animals. That perception changed in 2000 when Ruvkun’s research group published their discovery of another microRNA, encoded by the let-7 gene. Unlike lin-4, the let-7 gene was highly conserved and present throughout the animal kingdom. The article sparked great interest, and over the following years, hundreds of different microRNAs were identified. Today, we know that there are more than a thousand genes for different microRNAs in humans, and that gene regulation by microRNA is universal among multicellular organisms.

In addition to the mapping of new microRNAs, experiments by several research groups elucidated the mechanisms of how microRNAs are produced and delivered to complementary target sequences in regulated mRNAs. The binding of microRNA leads to inhibition of protein synthesis or to mRNA degradation. Intriguingly, a single microRNA can regulate the expression of many different genes, and conversely, a single gene can be regulated by multiple microRNAs, thereby coordinating and fine-tuning entire networks of genes.

Cellular machinery for producing functional microRNAs is also employed to produce other small RNA molecules in both plants and animals, for example as a means of protecting plants against virus infections. Andrew Z. Fire and Craig C. Mello, awarded the Nobel Prize in 2006, described RNA interference, where specific mRNA-molecules are inactivated by adding double-stranded RNA to cells.

Tiny RNAs with profound physiological importance

Gene regulation by microRNA, first revealed by Ambros and Ruvkun, has been at work for hundreds of millions of years. This mechanism has enabled the evolution of increasingly complex organisms. We know from genetic research that cells and tissues do not develop normally without microRNAs. Abnormal regulation by microRNA can contribute to cancer, and mutations in genes coding for microRNAs have been found in humans, causing conditions such as congenital hearing loss, eye and skeletal disorders. Mutations in one of the proteins required for microRNA production result in the DICER1 syndrome, a rare but severe syndrome linked to cancer in various organs and tissues.

Ambros and Ruvkun’s seminal discovery in the small worm C. elegans was unexpected, and revealed a new dimension to gene regulation, essential for all complex life forms.

Recent winners of the Nobel Medicine Prize

Here is a list of the winners of the Nobel Prize in Medicine in the past 10 years:

2024: US scientists Victor Ambros and Gary Ruvkun, for their discovery of microRNA and its role in how genes are regulated.

2023: Hungarian Katalin Kariko and Drew Weissman of the United States, for their work on messenger RNA (mRNA) technology, which paved the way for groundbreaking COVID-19 vaccines.

2022: Swedish paleogeneticist Svante Paabo, for his discoveries on the genomes of extinct hominins and human evolution.

2021: US duo David Julius and Ardem Patapoutian, for discoveries on human receptors responsible for our ability to sense temperature and touch.

2020: Americans Harvey Alter and Charles Rice, and Briton Michael Houghton, for the discovery of the Hepatitis C virus, leading to the development of sensitive blood tests and antiviral drugs.

2019: William Kaelin and Gregg Semenza of the US and Britain’s Peter Ratcliffe, for establishing the basis of our understanding of how cells react and adapt to different oxygen levels.

2018: Immunologists James Allison of the US and Tasuku Honjo of Japan, for figuring out how to release the immune system’s brakes to allow it to attack cancer cells more efficiently.

2017: US geneticists Jeffrey Hall, Michael Rosbash and Michael Young, for their discoveries on the internal biological clock that governs the wake-sleep cycles of most living things.

2016: Yoshinori Ohsumi of Japan, for his work on autophagy—a process whereby cells “eat themselves”—which when disrupted can cause Parkinson’s and diabetes.

2015: William Campbell, an Irish-US citizen, Satoshi Omura of Japan and Tu Youyou of China, for unlocking treatments for malaria and roundworm.

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