Nobel prize in medicine awarded to micro-RNA discoverers

This year’s Nobel prize in physiology or medicine has been awarded to Victor Ambros and Gary Ruvkun, the pioneering scientists who discovered microRNAs (miRNAs) and elucidated their role in regulating gene expression.
MicroRNAs are a class of small RNA molecules, 21 to 23 nucleotides long, that reduce the expression of specific genes by binding to and disrupting their corresponding mRNAs. This regulation of gene expression pattern by miRNAs plays a key role in driving cell differentiation and determining cell fate.
Mutated or dysregulated microRNAs are implicated in the development of various diseases including cancers and severe congenital malformations. The discoveries of this year’s Nobel laureates are likely to pave the way for novel cancer therapies that utilize miRNAs, either as tools or therapeutic target.

The Nobel Assembly at Karolinska Institute awarded the 2024 Nobel prize in physiology and medicine to Victor Ambros and Gary Ruvkun who discovered a new class of small RNA molecules called microRNAs, and elucidated their role in post-transcriptional regulation of gene expression. This decision was motivated by a profound importance of the discovered molecules to organism’s physiology and an enormous potential for future therapeutic applications.

The two laureates have devoted their careers to unraveling the process of cell differentiation. Specifically, they struggled to answer the intriguing question of how cells containing identical genetic information are able to develop into a wide array of cell types performing vastly different functions. In an effort to solve this mystery, they studied C. elegans roundworms with mutations in two genes, lin-4 and lin-14, which control the organism’s development. During their work, they discovered that lin-4 acts as an inhibitor of lin-14, but initially they couldn’t link this interaction to any biological mechanism known at that time. The transcription of lin-14 proceeded uninterrupted in presence of lin-4, so the researchers reasoned that its regulation must occur at post-transcriptional level, after mRNA is already formed. Their hypothesis proved to be correct. In a series of breakthrough experiments, Ambros and Ruvkun demonstrated that lin-14 expression is blocked by a small RNA molecule derived from lin-4 gene, only 21 nucleotides long, that contains a sequence complementary to 3’ untranslated region (UTR) of lin-14 mRNA. This molecule, named microRNA (miRNA) due to its short length and elusive nature, bound to lin-14 mRNA and prevented its translation into protein. MicroRNAs were thus found to modify the pattern of gene expression and constitute one of the mechanisms that allows cells to differentiate into various cell types without incurring any changes to the genome. Ambros and Ruvkun published their findings in 1993 in the renown journal Cell, opening up the new discipline of miRNA research. Since then, numerous experiments have confirmed the crucial role of these molecules as drivers of cell fate specification and differentiation.

The formation and function of microRNAs.

MicroRNAs are now understood to silent target genes via three different mechanisms: cleavage, destabilization or reduction of mRNA translation. The human genome is estimated to encode nearly 2,000 miRNAs capable of silencing about 60% of all genes. Given their abundance, it is not surprising that many of miRNAs were found to be critical for normal development and functioning of human body. Mutations in specific miRNAs are known to cause several inherited disorders such as hereditary progressive hearing loss or keratoconus with anterior polar cataract. Disruption of one of the proteins responsible for microRNA production leads to the so-called DICER1 syndrome, which predisposes individuals to early-onset cancer affecting multiple organs and tissues. Additionally, miRNA deregulation seems to be associated with the development of certain sporadic cancers such as chronic lymphocytic leukemia. This might happen for example when overexpression of particular miRNA causes the excessive silencing of tumor repressor genes.

Due to their significant physiological roles and associations with many human disorders, the microRNAs discovered by this year’s Nobel laureates hold great promise for therapeutic innovations that work by modifying the expression of genes associated with disease development. MicroRNAs could be used either as a tool, silencing mRNAs that code for implicated proteins, or as a target, which disruption restores the normal gene activity. One of the first candidates for miRNA-based therapy is miR-506, which was found to selectively kill lung cancer cells and act as a tumor suppressor in cervical cancer cells in vitro.

For more information on 2024 Noble prize laureates and the science of miRNAs, visit the official Nobel prize website.

2024 NOBEL PRIZE LAUREATES IN MEDICINE OR PHYSIOLOGY

VICTOR AMBROS

was born in 1953 in Hanover, New Hampshire, USA. He received his PhD from Massachusetts Institute of Technology (MIT), Cambridge, MA, in 1979 where he also did postdoctoral research 1979-1985. He became a Principal Investigator at Harvard University, Cambridge, MA in 1985. He was Professor at Dartmouth Medical School from 1992-2007 and he is now Silverman Professor of Natural Science at the University of Massachusetts Medical School, Worcester, MA.

GARY RUVKUN

was born in Berkeley, California, USA in 1952. He received his PhD from Harvard University in 1982. He was a postdoctoral fellow at Massachusetts Institute of Technology (MIT), Cambridge, MA, 1982-1985. He became a Principal Investigator at Massachusetts General Hospital and Harvard Medical School in 1985, where he is now Professor of Genetics.

Prepared by:

Adam Tuszyner

Sources and further reading

The Nobel Prize press release: The Nobel Prize in physiology or medicine 2024. Link: https://www.nobelprize.org/prizes/medicine/2024/press-release/.
Allison, Lizabeth A. Fundamental molecular biology. John Wiley & Sons, 2021.