Nobel Prize in Physiology/Medicine 2024: Very Very Short RNA With a Big Impact

The 2024 Nobel Prize in Medicine or Physiology is awarded to Victor Ambros and Gary Ruvkun, “for the discovery of microRNA and its role in post-transcriptional gene regulation.”

A lot of a cell’s energy is spent on gene regulation – the processes that control what type of cell a cell will become. The genetic material of somatic cells is the same, but nerve cells have different functions than liver cells. Gene regulation is also affected by what happens in other parts of the body or in the surrounding environment. Malfunctioning gene regulation can lead to the development of diseases, such as cancer.

Experiments in Basic Science

microRNAs (miRNAs) are tiny RNA molecules (19 to 25 nucleotides long) that play an important role in gene regulation. The discovery of these molecules started out as a curiosity in basic science. In the 1980s, Ambros and Ruvkun were postdocs in the lab of Robert Horvitz at the Massachusetts Institute of Technology (Horvitz also won the Nobel Prize, in 2002). Horvitz’s research focused on the genetics of the nematode Caenorhabditis elegans – a soil worm about 1 mm in size and containing 959 cells, which for decades has been a model organism for genetic research. Ambros and Ruvkun set out to investigate two mutant strains of C. elegans, lin-4 and lin-14. The mutations led to developmental abnormalities in the worms. As Ambros later wrote, “we were simply curious about an interesting worm mutant, and everything we found out about it was unexpected.”

Very Very Short RNA

The project continued despite the researchers leaving Horvitz’s lab to set up their own: Ambros worked on the lin-4 gene at Harvard University and Ruvkun focused on lin-14 at Massachusetts General Hospital and Harvard Medical School. By that time, Ambros had established that lin-4 turned off the lin-14 gene. After cloning the lin-4 gene, it was found that it produced a very short RNA molecule that didn’t encode a protein. In his experiments on lin-14, Ruvkun demonstrated that lin-14 is not inhibited by lin-4 at the stage of mRNA production, but at the later stage of protein production.

The researchers shared the gene sequences between their labs and found that the lin-4 sequence matched complementary sequences in the lin-14 mRNA. As Ambros and colleagues later recalled, “Victor immediately called Gary; each of them read the complementary sequences to the other over the phone, practically in unison. That was a very happy shared moment.”

It was established that post-transcriptional regulation of genes was carried out by a small piece of RNA: microRNA. The research groups published two articles in the same issue of Cell in 1993, but there was very little response from the scientific community. The findings were largely dismissed as something that happened only in worms.

Not Just in Worms

It wasn’t until 2000, when Ruvkun and his team discovered another miRNA in C. elegans, encoded by the let-7 gene, that miRNA started to gain attention. It was soon found that, unlike lin-4, let-7 RNA transcripts are also expressed in human tissues. New miRNAs were discovered the following year, and since that time more than a thousand genes for miRNAs in humans have been identified. miRNA are involved in the most fundamental processes of cell functioning, and mutations of genes encoding microRNAs are linked to various disorders and conditions.

Not Going It Alone

“You can find out new things doing routine experiments,” said Ambros soon after being awarded the Nobel Prize. Both scientists have said that they didn’t consider these experiments as prizeworthy at the time, they were simply interested in solving the problem. There was no competition with other research groups, and the project itself lasted four years, providing the scientists with ample time to prove their findings were correct. What’s also remarkable is that Ambros, Ruvkun, and their colleagues shared their work and helped each other in many ways. And once their research became well-known, they were pleased to see the niche grow. “It was an unbelievable pleasure to participate in,” said Ruvkun. That attitude in itself is prizeworthy.