The 2024 Nobel Prize in Physiology or Medicine has been awarded jointly to Victor Ambros and Gary Ruvkun for the discovery of microRNA and its role in post-transcriptional gene regulation. Ambros is a professor at the UMass Chan Medical School, while Ruvkun is a professor at Harvard Medical School and also affiliated with Massachusetts General Hospital in Boston. In the late 1980s, Ambros and Ruvkun undertook post doctorate studies in the laboratory of Robert Horvitz, himself a Nobel Prize winner in 2002, conducting gene experiments on the roundworm Caenorhabditis elegans. Their ground-breaking discovery of microRNA, a new class of tiny RNA molecules revealed a completely new principle of gene regulation.
MicroRNAs and their mode of gene regulation remained completely unknown until the discovery by Victor Ambros and Gary Ruvkun in 1993. The two Nobel laureates investigated mutant C. elegans nematodes with developmental defects caused by alterations at the lin-4 and lin-14 genetic loci. Ambros’s laboratory cloned the lin-4 gene and made the surprising discovery that it did not code for a protein. Instead, it encoded a short 22-nucleotide noncoding RNA. In parallel, Ruvkun’s laboratory determined that lin-4 regulates lin-14 via multiple elements in its 3’UTR. Upon comparing sequence information, they defined partial sequence complementarity between the short non-coding lin-4 RNA and the 3’UTR elements of lin-14. This provided a first glimpse into a conceptually novel type of regulatory RNAs: microRNAs.
The next breakthrough came when the Ruvkun lab found that the let-7 gene, unlike lin-4, was evolutionarily conserved across a wide range of animals. Comparing the let-7 microRNA sequence against nucleotide databases revealed matching sequences in both the fruit fly and human (Pasquinelli et al., 2000). Furthermore, let-7 microRNA was found across several human tissues indicating its relevance for gene expression in mammalian cells in general. Discovery of the evolutionarily highly conserved let-7 greatly increased the interest in microRNAs as post-transcriptional regulators of gene expression.
Studies conducted in other laboratories revealed that each microRNA likely regulates multiple protein-coding genes. MicroRNAs have important functions in cell lineage formation and cell-type stability in multicellular organisms. The specific regulatory roles of microRNAs during animal development include developmental timing, the formation and stability of cell fates, general physiology, and homeostasis.
Advances in molecular biology and sequencing technologies have since led to the identification of over a thousand microRNA genes in the human genome. Currently, miRBase, a database for microRNA genes, comprises over 38,000 hairpin precursors and 48,860 mature microRNA gene sequences across 271 organisms (Kozomara, Birgaoanu and Griffiths-Jones, 2019).
Thanks to the seminal discovery by Ambros and Ruvkun, and the many colleagues who built on their findings, a new dimension to gene regulation has been revealed. Whereas proteins in the nucleus regulate RNA transcription and splicing, microRNAs control the translation and degradation of mRNA in the cytoplasm. This unexpected layer of post-transcriptional gene regulation has critical importance throughout animal development and in adult cell types and is essential for complex multicellular life.
Excerpts taken from: Advanced information. NobelPrize.org. Nobel Prize Outreach AB 2024. Sat. 12 Oct 2024.
https://www.nobelprize.org/prizes/medicine/2024/advanced-information/
https://www.nobelprize.org/uploads/2024/10/advanced-medicineprize2024-2.pdf
