Celebrating Victor Ambros’ and Gary Ruvkun’s discoveries - a success for basic research.
Thirty years ago, Victor Ambros observed developmental abnormalities in a small, unassuming roundworm model when the so-called lin-4 gene was lost.
Alongside significant changes in the organism's development, he discovered that one specific gene, lin-14, was upregulated. The observation in itself was even for its time nothing out of ordinary, except for the fact that the repressive interaction between these genes was not based on a regulatory protein; lin-4 was not protein-coding.
Analysing the sequence, Ambros could show that lin-4 encoded two RNA molecules: a longer one and a 22-nucleotide fragment that is now known as a microRNA. This latter fragment piqued Gary Ruvkun’s interest. By deleting conserved elements in the 3’ untranslated region of the target mRNA, lin-14, Ruvkun began to unravel the microRNA-mRNA interaction. Noting the sequence complementarities between lin-4 microRNA and lin-14 3’ untranslated region, he subsequently demonstrated this mechanism by placing other mRNA species under the control of lin-4 by transferring these complementary lin-4 binding sites into their downstream untranslated regions.
This discovery was nothing less than a paradigm shift in our understanding of gene regulation, introducing a fundamentally new, RNA-interaction-based regulatory pathway.
In 1993, Ruvkun and Ambros published their groundbreaking findings in back-to-back articles in Cell , characterising microRNAs and their interaction with mRNA for the first time. Recently, their contributions were rightly recognized with the Nobel Prize in Physiology or Medicine in 2024 .
It would be hard to overstate the significance of their discovery.
To this day, microRNAs are known to function in both plants and animals, influencing numerous cellular processes, development, and disease.
Notably, microRNAs play a crucial role in cancer development and serve as important diagnostic and potential therapeutic targets. Yet again, this breakthrough originated from research in
Caenorhabditis elegans
, a model organism distant from practical applications, and it was based on a question entirely focused on the fundamentals of gene regulation. This success story underscores that we need to look beyond the scope of immediate application; scientific breakthrough requires thriving basic research - and of course suitable models like
C. elegans
, a gift that keeps on giving.
At the Cavalieri Ottolenghi Neuroscience Institute we study the genetic and molecular bases of neurodegenerative and neurodevelopmental diseases.
Using
C. elegans
as a powerful experimental model allows us to address these key issues more quickly and economically.
The great evolutionary conservation of molecular mechanisms makes it possible to translate this knowledge to humans, laying the foundations for new therapeutic strategies.
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