2024 Nobel Prize in Medicine Honors the Discovery of MicroRNA and Its Role in Gene Regulation

The 2024 Nobel Prize in Physiology or Medicine was awarded on October 10, 2024 to Victor Ambros and Gary Ruvkun for discovering microRNA and its role in post-transcriptional gene regulation.

Their work revealed a fundamental principle of how gene activity is regulated, revolutionizing our understanding of multicellular development and function. This major discovery identified a regulatory mechanism that allows genetic information to be controlled in a previously unknown way.

Regulating Genetic Information: The Basis of Differences Within the Human Body

All the cells in our body carry the same DNA information. Why, then, do cell types such as muscle and nerve cells have entirely different characteristics? The answer lies in gene regulation, which allows each cell to select and follow only the instructions appropriate to it. We know that genetic information generally flows from DNA to messenger RNA (mRNA), then to the protein production machinery. By processing the instructions needed to produce particular proteins, this flow enables each cell type to perform its specialized functions.

Errors in this system, however, can lead to serious disease. Cancer, diabetes, and autoimmune disease can result from such regulatory errors. Understanding how gene regulation works has therefore become a major research priority.

Figure 1: The flow of genetic information from DNA to mRNA and then proteins. The same genetic information is stored in the DNA of all our body's cells. However, gene activity must be precisely regulated so that only the appropriate set of genes is active in each cell type.

• Related topic: 2023 Nobel Prize in Medicine – Discoveries That Enabled mRNA Vaccine Development

The Discovery of MicroRNA: A New Dimension in Gene Regulation

While investigating the complex mechanisms of gene regulation, Victor Ambros and Gary Ruvkun discovered a new class of RNA called microRNA. MicroRNAs play a critical role in gene regulation by preventing expression of particular genes. This allows each cell to perform specialized functions even though genetic information is the same from cell to cell.

Ambros and Ruvkun first studied microRNAs in a relatively simple, 1 mm-long round worm called C. elegans. With many specialized cell types, including muscle and nerve cells, this model organism is well suited to studying multicellular development. Ambros and Ruvkun examined lin-4 and lin-14 mutant worms, investigating disruptions in the timing of activation of particular genetic programs in these two types of worms. lin-4 produced a short RNA molecule without protein-coding instructions, which was found to suppress lin-14. Ruvkun showed that this suppression occurred at the protein production stage rather than at the mRNA level.

IMPORTANT NOTE: MicroRNA (miRNA) is a small RNA molecule that regulates genes and does not encode protein. Messenger RNA (mRNA) carries the instructions required for protein production. MicroRNAs bind to mRNAs and suppress their function, thereby controlling protein synthesis.

These studies were published in 1993 in Cell and initially attracted little attention from the scientific community. The mechanism was then thought to apply only to C. elegans and be irrelevant to other organisms. In 2000, however, Ruvkun's group published a study showing that another microRNA, let-7, was conserved throughout the animal kingdom, drawing much greater attention to the universal role of microRNAs in gene regulation.

Figure 2: (A) C. elegans is a useful model for understanding how different cell types develop. (B) In experiments by Ambros and Ruvkun, lin-4 and lin-14 mutants were studied. Ambros had shown that lin-4 negatively regulates lin-14. (C) In a further finding, Ambros discovered that the lin-4 gene encodes a small non-protein-coding RNA called microRNA. Ruvkun cloned the lin-14 gene, and the two scientists recognized that the lin-4 microRNA sequence pairs with a complementary sequence in lin-14.

The Universal and Essential Role of MicroRNAs

We now know that most multicellular organisms, including humans, have more than a thousand microRNA genes and that these molecules have a universal role in gene regulation. MicroRNAs bind particular mRNAs, blocking protein production or causing mRNA degradation. One microRNA can regulate many different genes, and one gene can be regulated by several microRNAs. This allows gene networks to be coordinated and fine-tuned.

Figure 3: Ruvkun cloned a second microRNA-encoding gene, let-7. This gene is evolutionarily conserved, and microRNA regulation is now known to be universal among multicellular organisms.

This universal microRNA mechanism also helps protect plants against viral infections. Andrew Z. Fire and Craig C. Mello, who received the Nobel Prize in 2006, identified RNA interference, showing that particular mRNA molecules could be inactivated by adding double-stranded RNA.

MicroRNAs and Their Important Role in Understanding Disease

The discovery of microRNAs revealed their fundamental role in the development and function of organisms. Without them, cells and tissues cannot develop normally. Studies show that disrupted microRNA regulation can contribute to cancer, while mutations in microRNA-encoding genes can cause congenital hearing loss and eye and skeletal disorders. Another example of their importance is DICER1 syndrome: a mutation in a protein required for microRNA production causes this rare but serious syndrome, which leads to cancer in various organs and tissues.

Figure 4: The groundbreaking discovery of microRNAs was unexpected and revealed a new dimension in gene regulation.

Ambros and Ruvkun's unexpected discovery added a new dimension to gene regulation while deepening our understanding of the foundations of multicellular life. Their work shows that not only genetic information itself but also how it is used is critically important. Understanding microRNAs could therefore play a major role in treating future diseases and enable scientists to develop therapies targeting these molecules.

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Is There an Approved Cancer Drug That Uses MicroRNAs?

Although microRNA research has enabled new strategies in cancer treatment, there is not yet an approved cancer drug that directly uses microRNAs. However, microRNA-targeted therapies are in development, and these approaches hold considerable promise.

These strategies generally work in two ways:

1. MicroRNA Suppression (Antagonists): Certain microRNAs that are overactive in cancer disrupt normal cell regulation and contribute to tumor formation. Molecules designed to suppress them offer a strategy for inhibiting cancer cell growth. AntimiR antagonist molecules inhibit particular microRNAs and stop their function. For example, because some microRNAs such as miR-21 act as oncogenes, targeting this microRNA may be effective in cancer treatment.

2. MicroRNA Therapy (Agonists): MicroRNAs that lose their function during cancer development have tumor-suppressing properties. Reactivating them may stop cancer cell growth. MicroRNA mimics replace missing or suppressed microRNAs in an effort to restore normal function in cancer cells.

Clinical research into microRNA-targeted therapies continues, with some approaches showing promise in early trials. At present, however, no microRNA-based cancer drug has been approved for clinical use.

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Victor Ambros was born in 1953 in Hanover, New Hampshire, United States. He earned his doctorate in 1979 at the Massachusetts Institute of Technology (MIT), Cambridge, MA, and conducted postdoctoral research there from 1979-1985. In 1985, he became a principal investigator at Harvard University, Cambridge, MA. He was a professor at Dartmouth Medical School from 1992-2007 and is currently the Silverman Professor of Natural Science at the University of Massachusetts Medical School.

Gary Ruvkun was born in 1952 in Berkeley, California, United States. He earned his doctorate at Harvard University in 1982 and conducted postdoctoral research at the Massachusetts Institute of Technology (MIT), Cambridge, MA, from 1982-1985. In 1985, he became a principal investigator at Massachusetts General Hospital and Harvard Medical School and is currently Professor of Genetics at Harvard.

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The Scientific Papers Behind the Nobel Prize

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

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

Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kurodak MI, Maller B, Hayward DC, Ball EE, Degnan B, Müller P, Spring J, Srinvasan A, Fishman M, Finnerty J, Corbo J, Levine M, Leahy P, Davidson E, Ruvkun G. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000;408(6808):86-89. doi:10.1038/35040556