Nobel Prize in Physiology or Medicine 2024: Which research won the prize? | Explained

The story so far: The 2024 Nobel Prize in Physiology or Medicine was awarded to Victor Ambros and Gary Ruvkun on Monday (October 7, 2024) by the Nobel Assembly at the Karolinska Institutet in Stockholm, Sweden. The scientists won the prestigious award for the discovery of microRNA and its role in post-transcriptional gene regulation.

Both Ambros and Ruvkun are American biologists. Ambros is currently working in the Molecular Medicine Program at the University of Massachusetts in the USA. Ruvkun is a professor of genetics at Harvard Medical School and studies microRNA and RNA interference mechanisms in the Ruvkun Lab at Massachusetts General Hospital.

Also read: The Nobel Prize 2024 – an interactive guide

Although their research area is similar, Ambros and Ruvkun have not worked together since they were postdoctoral fellows in the laboratory of H. Robert Horvitz, who won the Nobel Prize in Physiology or Medicine in 2002. “Then they went to Harvard University and Harvard Medical School, setting up their own labs and working on various aspects of microRNA regulation. Ambros was the first to clone a microRNA, and Ruvkun cloned the second. As far as I know, they didn't work together much after their postdoctoral work, but they (shared some data) and that was the key to this Nobel Prize,” Olle Kämpe, a member of the 2024 Nobel Committee for Physiology or Medicine, said in an interview after the price announcement.

What are microRNAs?

MicroRNAs or miRNAs are small, non-coding RNA molecules. They are typically about 19 to 24 nucleotides long and play an important role in determining how much messenger RNA (mRNA), which carries genetic information, is ultimately translated into protein.

The body makes proteins in a complex process with two major steps. In the transcription step, a cell copies a DNA sequence into messenger RNA (mRNA) in the cell nucleus. The mRNA travels from the cell nucleus through the cell fluid and attaches to the ribosome. In the translation step, another type of RNA called transfer RNA (tRNA) brings certain amino acids to the ribosome, where they are linked together in the order specified by the mRNA to form the protein.

MicroRNA or miRNA regulates the production of proteins by binding to the mRNA and then silencing it at an appropriate point. The process is called post-transcriptional gene regulation.

Nobel Prize-winning research: a brief history

In the late 1980s, Ambros and Ruvkun examined a 1 mm long roundworm, Caenorhabditis elegans which, despite its small size, had specialized cell types such as nerve and muscle cells. That did C. elegans an important model for studying tissue development in multicellular organisms, including humans.

Ambros and Ruvkun studied two mutant strains, Lin-4 and Lin-14, both of which had abnormalities – their genetic programming that controls development did not work as expected. Ambros' previous studies proved that lin-4 suppressed the activity of lin-14, but could not say how this happened.

After their postdoctoral research, the biologists individually examined how Lin-4 influences the activity of Lin-14. Ambros analyzed the lin-4 mutant, cloned the gene and found that it produced an unusually short RNA molecule that lacked a code for protein production. The results suggest that this small RNA molecule may be responsible for inhibiting Lin-14.

Around the same time, Ruvkun was studying the regulation of the lin-14 gene in his laboratory and found that lin-4 did not block the production of lin-14 mRNA. Since the late 1960s, gene regulation has been understood as a process that determines which mRNAs are produced and thus how genetic information flows. Ruvkun found that regulation of lin-14 mRNA occurred later in the gene expression process by inhibiting protein production. His experiment also revealed an important segment in the lin-14 mRNA that is essential for its inhibition by lin-4. The short lin-4 sequence that Ambros discovered in his research matched complementary sequences in the critical section of the lin-14 mRNA, meaning they can pair together like keys fit into locks.

The two biologists conducted further experiments and found that Lin-4 microRNA, the “unusually short” RNA molecule, binds to Lin-14 mRNA and blocks the production of Lin-14 protein. In this way, microRNA was discovered and the results were published in two articles in 1993 cell Magazine.

Although the results were significant, they were not enthusiastically received by scientists because the behavior was assumed to be specific C. elegansand therefore irrelevant to complex animals and humans. However, in 2000, Ruvkun's research group published the discovery of another microRNA encoded by the let-7 gene. The let-7 gene is found throughout the animal kingdom and this discovery sparked interest in microRNAs and their role in protein synthesis.

“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,” the Nobel Assembly said in a statement.

Applications

A single microRNA can regulate the expression of many genes, alternatively a single gene can also be controlled by multiple microRNAs. This leads to fine-tuning of different cell types despite similar genetic information. Abnormal regulation by microRNA can contribute to cancer, and mutations in genes encoding microRNAs have been found in humans, which can lead to conditions such as congenital hearing loss, eye and skeletal diseases, the Nobel Assembly noted. However, Gunilla Karlsson-Hedestam, chair of the 2024 Nobel Committee on Physiology or Medicine, said there are no clear applications of miRNAs yet. Understanding them is the first step toward further research, she said, answering a question after the announcement.