The Gene Genies: Unpacking the Power of microRNA

Victor Ambros and Gary Ruvkun won the 2024 Nobel Prize in Physiology or Medicine for their discovery of microRNA and its importance in gene control. This finding is a basic part of the knowledge surrounding how genes are controlled within cells, which has broader implications relating to development and biology in many organisms.

Both of them were at MIT and Harvard in the late 1980s, and early 1990s when they started on their research quest. In an important study on the roundworm C. elegans, they showed that two genes lin-4 and lin-14 regulated in just this way—by mirroring one another as microRNA molecules sitting at opposite ends of a transcription unit at a given gene locus. Unfortunately, no one knew about this new mechanism: the microRNA could bind messenger RNA and then stop protein translation. These findings were led by them and were published in 1993, in the journal of Cell, which is being considered as the final date stamp where one could define that this ground-breaking mechanism was discovered.

Such research has led to a major breakthrough in the molecular biology field and it confirms miRNA plays a key role in regulating gene expression from yeast to humans, where over 1000 different miRNAs have been identified. Their finding has broad implications for cancer research, developmental biology, therapeutics, and in many other medical and biological research areas.

Though the Nobel Prize was in 2024, Ambros and Ruvkun's work actually had its origins in the early '90s — well before any of this long-tail action took place.

Here’s a chronological order showing the mountains of effort behind the award:

Creating the Discovery: Collaboration in the Infancy of Endeavor

Two energetic researchers, Victor Ambros and Gary Ruvkun, started their postdocs in the laboratory of H. Robert Horvitz at MIT back in the late 1980s. They were investigating the gene regulation mechanisms of Caenorhabditis elegans—a model organism for genetics. This first cooperation enabled them to make groundbreaking discoveries in molecular biology.

A brief history of lin-4 and lin-14.

While working on this, in the early 1990s Ambros made a critical observation. He found that lin-4 was not a protein-coding gene—contrary to what researchers had believed—but instead produced an RNA that was only 22 nucleotides long. It turned out that this RNA blocked the production of an essential gene called lin-14, which controls when various cell types develop in the worm. The latter was surprising as it implied a new type of gene control.

Publication and Recognition: The 1993 Cell Paper

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In 1992, the partnership between Ambros together with Ruvkun stronger. This led Ambros to suggest that whatever was causing lin-14 inhibition, it could not be a protein —though he admitted not knowing what it might be28. This fostered substantial sharing of data between their labs, and ultimately verification of this hypothesis. Their work revealed that lin-4 RNA did not affect transcribing of lin-14 to messenger RNA, but rather blocked the translation of this mRNA into the protein. This was a new mechanism — microRNA being able to regulate post-transcriptional and gene regulation.

Publication and Recognition: The 1993 Cell Paper

Together, their joint discovery was published in 1993 in Cell. The study laid out the process by which lin-4 RNA attached itself to sites on the lin-14 mRNA that were complementary in sequence and could no longer be translated into protein. This proved to be the first example of microRNA mediated gene regulation that remained an unknown mechanism and also unveiled a novel layer of genetic control.

Expansion of the Field: Post-1993 Discoveries

After the original microRNA discovery, Ruvkun in 2000 identified yet another type of microRNA, let-7, which is common across species and may well have significant implications. The identification of let-7 bolstered the view that microRNAs have key functions in animal gene control.

Nobel Recognition: 2024 Award

The Nobel Prize shared by Ambros and Ruvkun in 2024 was for a discovery that completely revolutionized our view of how genes are controlled in cells. Their findings have since led not only to new avenues of research in genetics, developmental biology, and medicine but also helped form the basis for therapeutic approaches that include microRNAs as targets in many diseases, including cancer.

Images from the database illustrate this extended journey starting in the late 1980s and passing through meaningful milestones of the 1990s with continued persistence and innovation to define transformative discoveries

The discovery by Victor Ambros and Gary Ruvkun of microRNA heralds the dawn of a new era in medicine and biology. In human cells, microRNAs are central players in the regulation of gene expression by controlling a huge number of cellular processes ranging from cell differentiation to apoptosis. This insight may create new directions for therapies, especially in diseases involving gene expression regulation failures like cancer, heart disease, and various genetic conditions. Scientists hope that, by distinguishing exactly which microRNAs a disease process activates, they can gain the ability to finely tune the expression of appropriate gene products in order to design therapies for biological conditions. Other uses for microRNAs also include being biomarkers for early disease diagnosis and intervention in pathologies. While we can now learn more about those processes, according to Matreyek the discovery has future implications beyond that, promising a potential transformation for personalized medicine and hope for improved (and less invasive) precision treatments.