2024 Nobel Prize: the animal research behind the discovery of microRNA
The 2024 Nobel Prize in Physiology or Medicine has been awarded to two Americans, Victor Ambros and Gary Ruvkun, for their discovery in nematode worms that tiny pieces of RNA, called microRNAs, play a key role in controlling and regulating gene activity in animals and plants.
The C. elegans worm is once again in the spotlight of the Nobel Prize. The tiny worm had already been recognised for facilitating the discovery in 2002 of the genetic regulations of organ development and programmed cell death and in 2006 of RNA interference - gene silencing by double-stranded RNA. This year, the little nematode is involved in the ground-breaking “discovery of microRNAs and their role in post-transcriptional gene regulation.” This seminal work discovered a new and unexpected mechanism of gene regulation that helps our understanding of embryological development, normal physiology and diseases such as cancer.
The two new Nobel laureates, Victor Ambros from the University of Massachusetts Medical School in Worcester and Gary Ruvkun from the Massachusetts General Hospital in Boston, first came across the 1mm-long worm in the laboratory of another Nobel winner Robert Horowitz, who won his prize in 2002. Ambros and Ruvkun began postdoctoral fellowships with Professor Horowitz in the 1980s, in company with the crucial little animal.
At the time, researchers knew that to make proteins, DNA in the cell’s nucleus is transcribed into an intermediate molecule called messenger RNA or mRNA. This messenger is then carried outside the nucleus to the protein-making machinery and translated into proteins. But little was known about how the transcription factors triggered and regulated the protein-producing process so that different cell types can develop. All cells contain the same DNA but they develop into radically different types making different proteins and performing very different specialised functions such as muscle cells, intestinal cells, nerve cells and so on. Ambros and Ruvkun wanted to understand how that was done.
This is where nematodes came into play. Transparent and fast-growing, the C. elegans worm is composed of only around 1,000 cells, excluding gametes, but have as many different tissue types as humans. Simple yet diverse, they are the perfect animal model to study cell differentiation and how tissues develop and mature into multicellular organisms. The 2002 Nobel Laureate, Sydney Brenner had introduced the nematode worm Caenorhabditis elegans (C. elegans) to the world of genetic research over five decades previously. Two particular genetic strains caught Ambros and Ruvkun’s attention.
In the 1970s, teams led by Robert Horvitz, Sidney Brennes and John Sulston – all 2002 Nobel laureates – , had launched a vast genetic analysis of the nematode, inducing mutations in its genome. Two mutant lines in particular – named lin-4 and lin-14 –in which development seemed strongly disrupted intrigued Ambros, who took on the study of lin-4, and Ruvkun, who picked up lin-14.
Ambros found that the genomic sequence he was studying was transcribed into a tiny RNA molecule, unlike any other. It didn’t produce a protein. Instead the RNA fragment inhibited the function of the lin-14 sequence that Ruvkun was studying. Together, they showed in 1993 that the RNA from lin-4 was complementary to a non-coding portion of lin-14 mRNA. Lin-4 clearly encoded a new type of RNA, a “microRNA”, which regulated the translation of mRNA into protein by interacting with a neighbouring non-coding portion. The researchers had uncovered a crucial mechanism in which genetic expression was regulated.
At first, their discovery received little attention. Lin-4 only controls one gene, and the way it works implied that it was specific to nematode worms, likely irrelevant to humans and other more complex animals. However, in 2000, Ruvkun reported the discovery of yet another micro-RNA in C. elegans, called let-7, that this time controlled five genes. Database comparisons revealed a role for let-7 in insects, molluscs, annelids, crustaceans, and nematodes and matching sequences in fruit fly, zebrafish and humans, suggesting that the molecule could be found in most animals. Later, Let-7 microRNA was found in several human tissues indicating it could have a general relevance for gene expression in mammalian cells.
This hinted at the fact that microRNAs are in fact highly prevalent in the animal kingdom, which led to a huge interest in microRNAs. Soon after, the laboratory of Thomas Tuschl cloned novel microRNAs from human and fruit fly tissues, and both David Bartel’s and Ambros’s labs isolated new microRNAs from the nematode. The collective evidence was now compelling: a vast class of regulatory microRNA existed across animals, likely playing important roles in gene regulation.
Ambros and Ruvkun’s unexpected, seminal discovery in the small worm C. elegans revealed a new dimension to gene regulation, essential for all complex life forms. The control of when and where each gene should be used is a fundamental aspect of life. The fine tuning of microRNAs made possible the evolution of increasingly complex organisms from unicellular lifeforms, as cell-types acquired specialised functions. The essential role of microRNAs in animal development and tissue function has since been demonstrated in many animal models including mice, zebrafish and fruit flies.
Today, many thousands of microRNAs have been described in a wide array of organisms and animals, including humans, although most of their functions remain elusive. Some act within their “home” cells, others are released to affect other cells. Defects in microRNA regulation can lead to cancers, autoimmune diseases, congenital hearing and vision loss, as well as skeletal and many other pathologies. The presence or absence of microRNAs can also help diagnose certain medical conditions. For the moment, the medical use of microRNAs is exclusively for diagnostic purposes, as part of what is now called personalised medicine, but as we come to understand these microRNAs a little better, therapeutic possibilities are beginning to emerge and are attracting the attention of the pharmaceutical industry. Research groups are already working on treatments based on microRNAs, although so far none have yet been approved. But be ready, this isn’t the last time you’ll be hearing about MicroRNAs.
Last edited: 11 March 2025 17:00