ABOVE: Victor Ambros (left) and Gary Ruvkun (right) won the Nobel Prize for their discovery of an evolutionarily conserved post-transcriptional regulatory mechanism mediated by microRNA. Ill. Niklas Elmehed © Nobel Prize Outreach

Victor Ambros, a developmental biologist at the University of Massachusetts Chan Medical School, and Gary Ruvkun, a geneticist at Harvard Medical School, won this year’s Nobel Prize in Physiology or Medicine “for the discovery of microRNA and its role in post-transcriptional gene regulation,” the Nobel Assembly at the Karolinska Institute announced today (October 7). This discovery revealed a fundamental principle governing how gene activity is regulated.

“microRNAs are important for our understanding of embryological development, normal cell physiology, and diseases such as cancer,” said Olle Kämpe, vice chair of the 2024 Nobel Committee for Physiology or Medicine.

Every somatic cell in the body has the same set of genes, yet a brain cell is different from a liver cell. Differences in gene regulation across development drive cell diversity and the emergence of specialized cellular functions. By the early 1990s, scientists thought that they understood the basic principles of gene regulation, but then a series of unusual findings emerged.

Ambros and Ruvkun first met in the late 1980s when they were both postdoctoral researchers in the laboratory of the famous worm biologist Robert Horvitz at the Massachusetts Institute of Technology. They were studying the larval stages of Caenorhabditis elegans development. Horvitz’s team previously found that lin-4 mutants exhibited developmental abnormalities, such as missing structures and cell types.1 After he joined the group, Ambros discovered that lin-14 mutants exhibited a complete absence of larval programs and that lin-4 is responsible for turning off lin-14.2,3 

Ambros and Ruvkun wanted to learn more about the functions and products of these genes and how lin-4 blocks lin-14 activity. They decided to divide and conquer: Ambros would take on lin-4, while Ruvkun tackled lin-14. 

In his new laboratory at Harvard University, Ambros and his team cloned the lin-4 gene. But they noticed something unusual: the gene did not encode a protein. Instead, it produced two short transcripts, one of which was only 22 nucleotides long.4 Nearby, in his own laboratory at Harvard Medical School, Ruvkun came across another unexpected finding. Instead of interfering with lin-14 mRNA production, lin-4 appeared to interfere with protein production.5 Furthermore, he demonstrated how a small section of the lin-14 mRNA was necessary for lin-4-mediated regulation. 

During one late-night phone call, Ambros and Ruvkun pored over their sequences in search of answers to these mysterious observations. They noticed that the small lin-4 transcript matched complementary sequences in the 3’ untranslated region of the lin-14 mRNA. The duo appeared to have discovered a new principle of post-transcriptional gene regulation orchestrated by a small, unknown type of RNA. In 1993, they published their findings in the same issue of Cell.4,5 However, it was not met with much fanfare from the scientific community. 

“At the time, there was no framework for thinking about a very short antisense transcript,” Ambros previously said in a 2022 interview with Drug Discovery News. 

Many researchers also chalked it up to a worm oddity. “There was always a view that worms were quirky and weird,” Ruvkun said in the interview with Drug Discovery News.

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The tiny RNA remained shrouded in mystery until 2000 when Ruvkun and his team discovered another short 21-nucleotide RNA encoded by the gene let-7 which was involved in worm development.6  However, unlike the worm-specific lin-4, let-7 is evolutionarily conserved; it is found not only in sea sponges and worms, but importantly, also in mice and humans.7 

“A postdoc in my lab ran these northern blots on zoos of RNA, proving that these tiny RNAs were universal to animals,” Ruvkun said in the interview with Drug Discovery News.

If there were two of these small RNAs, the researchers reasoned that there must be more. Sure enough, in 2001, three papers published in the same issue of Science uncovered dozens of small RNAs, which the researchers called microRNAs.8-10

Nearly a decade after the discovery of the first microRNA, other scientists began to recognize this new type of regulatory RNA. Since then, aided by advances in molecular biology and sequencing, scientists have discovered thousands of microRNA genes in the human genome that orchestrate cell and tissue development and cell physiology. There is also a growing appreciation of how mutations in genes encoding microRNAs lead to conditions such as congenital hearing loss, eye and skeletal disorders, neurodegenerative diseases, and cancer. 

Ambros and Ruvkun’s seminal discovery of microRNA not only opened the door to a new dimension of gene regulation observed across the evolutionary sphere, but also highlights how studying simple models can lead to discoveries that are relevant to human health and disease. 

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  1. Chalfie M, et al. Mutations that lead to reiterations in the cell lineages of C. elegans. Cell. 1981;24(1):59-69. 
  2. Ambros V, Horvitz HR. Heterochronic mutants of the nematode Caenorhabditis elegans. Science. 1984;226(4673):409-416. 
  3. Ambros V. A hierarchy of regulatory genes controls a larva-to-adult developmental switch in C. elegans. Cell. 1989;57(1):49-57.
  4. Lee RC, et al. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843-854. 
  5. Wightman B, et al. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell. 1993;75(5):855-862. 
  6. Reinhart BJ, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000;403(6772):901-906. 
  7. Pasquinelli AE, et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000;408(6808):86-89. 
  8. Lagos-Quintana M, et al. Identification of novel genes coding for small expressed RNAs. Science. 2001;294(5543):853–858. 
  9. Lau NC, et al. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science. 2001;294(5543):858–862. 
  10. Lee RC, Ambros V. An extensive class of small RNAs in Caenorhabditis elegans. Science. 2001;294(5543):862–864.