American scientists Victor Ambros and Gary Ruvkun have been jointly awarded the Nobel Prize in medicine or physiology for their shared discovery of microRNA and the role it plays in post-transcriptional gene regulation.

At the announcement by the Nobel Assembly at the Karolinska Institutet in Sweden on Monday morning, Nobel Committee vice-chair Professor Olle Kämpe described the discovery of microRNA as "a tiny molecule that has opened a new field in gene regulation."

Though the pair worked in separate labs, their joint research focus led to them combining their resources to expand knowledge of microRNA and its role.

"The seminal discovery of microRNA has introduced a new and unexpected mechanism of gene regulation," said Kämpe.

"MicroRNAs are important for our understanding of embryological development, normal cell physiology and diseases such as cancer. As an example, tumors often perturb microRNA networks to grow."

Nobel Prize microRNA discovery started with a tiny roundworm

This Nobel Prize is all about foundational genetics.

At the heart of what makes a living organism function is the ability of double-stranded DNA to be translated by single-stranded RNA molecules. These "messenger" RNA (mRNA) create an "information molecule" from DNA and move into a cell’s protein factory — a ribosome — where amino acids align to this template and then fold into specialized proteins.

These proteins are the building blocks of all living organisms. But mutations or variations to genes can cause changes in function — often benign, but potentially disease-causing.

This general pathway to organism metabolism has been understood for a long time, but as Kämpe posed, "What determines that only the right genes are transcribed into messenger RNA and then translated into the right, tissue-specific proteins at the right time?"

The answer starts with one specific organism, the roundworm species Caenorhabditis elegans. Despite its size, the roundworm has 20,000 genes that code for proteins — about the same number as a human, making it an ideal lab ‘model’ for physiological research.

Different mutations to C. elegans genes were found to cause growth changes. One triggered excessive growth via a repeating developmental pathway. Another restricted growth due to a different gene variation.

Ambros found the enlarging "lin-4" variant in 1993, with Ruvkun isolating the "lin-14" mutation present in the miniature worms a year later. What wasn’t clear was how these variations interacted and influenced cell regulation. The pair joined forces to find the answer.

A micro discovery leads to big implications for science

Ambros and Ruvkun found their respective mutations interacted — specifically, that a sequence of code on the lin-4 gene corresponded to part of a lin-14 sequence.

This was the critical moment when microRNA was determined to exist, as a distinct form of RNA.

"At this point they had discovered a novel and unexpected mechanism of gene regulation — microRNA," said Kämpe. "For a long time, however, microRNA was believed to be an oddity peculiar to C. elegans."

It required more evidence to confirm their findings.

It came in 2000, when Ruvkun found another gene — "let-7" — which was found not just in roundworm, but in humans and most animals.

Many microRNAs, it turns out, are highly conserved across animals, plants and fungi, meaning that they are largely unchanged from species-to-species and across hundreds of millions of years of biological evolution.

More than 1,000 microRNA genes have been found in humans.

"Every microRNA regulates several genes," said Kämpe. "And each mRNA is regulated by many distinct microRNAs, creating a robust system for gene regulation."

When did RNA enter the public spotlight?  

RNA was thrust into the public consciousness with the rise of RNA-based vaccine technology at the height of the COVID-19 pandemic.

These vaccine products could be developed relatively quickly by creating imitation proteins based on small sections of genetic code from the SARS-CoV-2 virus.

When used in a vaccine, these proteins provide a non-disease-causing target for the human immune system to find and create antibodies ready for the real virus.

Katalin Kariko and Drew Weissman were awarded last year’s prize for their work developing mRNA vaccine technology.

However while last year’s prize was very much in recognition of work that had led to direct medical applications, this year’s is more research focused.

"This year’s prize is definitely a physiology prize," said Professor Gunilla Karlsson Hederstam, chair of the Nobel Committee for Physiology or Medicine. "Last year, of course, [was] much a more applied discovery that was translated into vaccine development, so two quite different prizes.

"Although there are no very clear applications available yet, understanding them, knowing that they exist, understanding their regulatory networks is always the first step."

Why type of products are being developed which utilize microRNA technology?   

So while this year’s prize is very much focused on discovery rather than application, the realization of the Ambros-Ruvkun research may not be far away. There are currently several vaccine-type products in clinical trial stage for cancer, cardiovascular and other diseases that use microRNA technology.

The challenge is hitting the right target. Take a cancer cell. There may be a specific gene that a vaccine needs to address, but microRNAs regulate many different genes. The risk is that a product may act more like a bulldozer than a scalpel.

"But there might be ways around that," said Kämpe, "Tumors quite often perturb the microRNA networks and they can do that by deleting the genes or mutating the genes that process the microRNA.

"In [this] case there are promising first tests to see if you can modulate the RNA-binding proteins, but to deliver microRNAs to cells and think you get one effect, I think will be very difficult."

Two more Nobel science prizes will be awarded this week, with the physics laureate to be revealed on Tuesday, and chemistry prize on Wednesday.

What is the history of the Nobel Prize in Physiology or Medicine? 

This year's Prize, set at 11 million Swedish kronor (about $1.06 million USD), is yet another recognition of genetic discovery. 

Arthur Kornberg and Severo Ochoa were recognized in 1959 for identifying the synthesis mechanisms of DNA and RNA, while the famed trio Crick, Watson and Wilkins were awarded the prize in 1952 for unravelling the DNA Double Helix.

Fire and Mello (2006), and Karikó and Weissman (2023) have also had their work on RNA recognized.

Famed Austrian neurologist and founder of psychoanalysis Sigmund Freud (1856-1939) was nominated for his work in Physiology and Medicine but was never named as a recipient.

At 31, Canadian surgeon and pharmacologist Frederick G. Banting is the youngest recipient of the Prize in Physiology or Medicine. He was recognized in 1923 for his discovery of insulin.

The American pathologist Francis Peyton Rous is the oldest, receiving his award in 1966 aged 87 for his discovery of tumor-inducing viruses.

The prize has been declined once. In 1939, Gerhard Domagk was prevented by Germany's Nazi Government from receiving his award for his discovery of an antibiotic against Streptococcus infections. He was later able to receive his diploma and medal in 1947.

Edited by: Wesley Dockery