Nobel Prize in Physiology or Medicine 2024: Tiny RNAs with Big Impact

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The flow of genetic information from DNA to mRNA to proteins. The identical genetic information is stored in DNA of all cells in our bodies. This requires precise regulation of gene activity so that only the correct set of genes is active in each specific cell type. © The Nobel Committee for Physiology or Medicine. Ill. Mattias Karlén

The flow of genetic information from DNA to mRNA to proteins. The identical genetic information is stored in DNA of all cells in our bodies. This requires precise regulation of gene activity so that only the correct set of genes is active in each specific cell type. © The Nobel Committee for Physiology or Medicine. Ill. Mattias Karlén

Victor Ambros and Gary Ruvkun have been awarded the 2024 Nobel Prize in Physiology or Medicine for their groundbreaking discovery of microRNA and its role in gene regulation. This finding has revolutionized our understanding of how genes are controlled in complex organisms, including humans.

Summary: Ambros and Ruvkun discovered microRNA, a new class of tiny RNA molecules that play a crucial role in gene regulation, revealing a fundamental principle governing how gene activity is regulated in multicellular organisms.

Estimated reading time: 8 minutes

In a landmark decision, the Nobel Assembly at Karolinska Institutet has awarded the 2024 Nobel Prize in Physiology or Medicine jointly to Victor Ambros and Gary Ruvkun “for the discovery of microRNA and its role in post-transcriptional gene regulation.” This discovery has unveiled a new dimension in our understanding of how genes are regulated, a process crucial for the development and function of all complex life forms.

The journey to this Nobel-winning discovery began in the late 1980s when Ambros and Ruvkun were postdoctoral fellows in Robert Horvitz’s laboratory. Their work with the humble C. elegans, a tiny roundworm, led to an unexpected finding that would reshape our understanding of gene regulation.

The Power of Small: MicroRNAs Emerge

The researchers were initially studying two mutant strains of C. elegans, known as lin-4 and lin-14, which showed abnormalities in the timing of their developmental stages. Ambros and Ruvkun’s meticulous work led to a startling revelation: the lin-4 gene produced an unusually short RNA molecule that did not code for a protein.

This discovery challenged the prevailing understanding of gene regulation. Ruvkun’s work showed that this tiny RNA molecule from lin-4 was responsible for inhibiting the activity of lin-14, but not in the way scientists had expected. The regulation occurred after the production of mRNA, at the stage of protein production.

The breakthrough came when the two scientists compared their findings. They realized that the short lin-4 sequence matched complementary sequences in the lin-14 mRNA. Further experiments confirmed that the lin-4 microRNA turns off lin-14 by binding to these complementary sequences, effectively blocking the production of lin-14 protein.

This discovery, published in two seminal papers in the journal Cell in 1993, introduced the world to microRNAs and a entirely new principle of gene regulation.

From Silence to Sensation: The Impact of MicroRNA Discovery

Initially, the scientific community met these findings with skepticism. Many considered this unusual mechanism of gene regulation to be a peculiarity of C. elegans, likely irrelevant to more complex organisms. However, this perception changed dramatically in 2000 when Ruvkun’s research group discovered another microRNA, encoded by the let-7 gene.

Unlike lin-4, the let-7 gene was found to be highly conserved and present throughout the animal kingdom. This discovery ignited widespread interest, leading to the identification of hundreds of different microRNAs in various organisms. Today, we know that humans have more than a thousand genes for different microRNAs, and that gene regulation by microRNA is universal among multicellular organisms.

The Cellular Symphony: How MicroRNAs Orchestrate Gene Activity

MicroRNAs play a crucial role in fine-tuning gene expression. A single microRNA can regulate multiple genes, and conversely, a single gene can be regulated by multiple microRNAs. This intricate network allows for precise control of gene activity, essential for the development and function of different cell types in complex organisms.

The importance of microRNAs in human health has become increasingly clear. Abnormal regulation by microRNA can contribute to various diseases, including cancer. Mutations in genes coding for microRNAs have been linked to congenital hearing loss, eye and skeletal disorders. The DICER1 syndrome, a rare but severe condition linked to cancer in various organs and tissues, results from mutations in one of the proteins required for microRNA production.

From Worms to Humans: The Universal Language of Gene Regulation

The discovery of microRNAs has had far-reaching implications for our understanding of evolution and the development of complex life forms. As stated in the press release, “Gene regulation by microRNA, first revealed by Ambros and Ruvkun, has been at work for hundreds of millions of years. This mechanism has enabled the evolution of increasingly complex organisms.”

The journey from studying a small worm to uncovering a fundamental principle of biology applicable to all complex life forms underscores the importance of basic research. It demonstrates how seemingly obscure studies can lead to profound insights with wide-ranging applications in medicine and biotechnology.

Quiz

  1. What is the main function of microRNAs in cells?
  2. How did the discovery of the let-7 gene change the scientific community’s perception of microRNAs?
  3. What is one way that abnormal microRNA regulation can affect human health?

Answers:

  1. MicroRNAs play a crucial role in gene regulation by binding to complementary sequences in mRNA and inhibiting protein production.
  2. The discovery of let-7 showed that microRNAs were highly conserved and present throughout the animal kingdom, not just in C. elegans.
  3. Abnormal microRNA regulation can contribute to various diseases, including cancer.

Further Reading

  1. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843-854. doi:10.1016/0092-8674(93)90529-y
  2. Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell. 1993;75(5):855-862. doi:10.1016/0092-8674(93)90530-4
  3. Pasquinelli AE, Reinhart BJ, Slack F, et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000;408(6808):86-89. doi:10.1038/35040556

Glossary of Terms

  1. MicroRNA: Small RNA molecules that play a crucial role in gene regulation.
  2. Post-transcriptional gene regulation: Control of gene expression after the production of mRNA.
  3. C. elegans: A small roundworm used as a model organism in biological research.
  4. Transcription factors: Proteins that bind to specific regions in DNA to control gene expression.
  5. mRNA: Messenger RNA, which carries genetic information from DNA to the protein-making machinery of the cell.
  6. DICER1 syndrome: A rare condition caused by mutations in a protein required for microRNA production, linked to cancer in various organs and tissues.

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