The 2024 Nobel Prize in Physiology or Medicine has been awarded to Victor Ambros (University of Massachusetts Medical School) and Gary Ruvkun (Harvard Medical School/Massachusetts General Hospital) for their groundbreaking discovery of microRNA and its critical role in post-transcriptional gene regulation. Their work has unveiled a new mechanism by which gene activity is regulated, reshaping our understanding of genetic function.
About the Laureates
Victor Ambros was born in Hanover, New Hampshire, in 1953. He earned his PhD from MIT in 1979 and conducted postdoctoral research there from 1979 to 1985. After establishing his laboratory at Harvard University in 1985, he later joined Dartmouth Medical School (1992-2007) and has been with the University of Massachusetts Medical School ever since.
Gary Ruvkun was born in Berkeley, California, in 1952. He received his PhD from Harvard University in 1982 and completed his postdoctoral work at MIT from 1982 to 1985. He established his laboratory at Harvard Medical School and Massachusetts General Hospital in 1985, where he continues his research.
The Mystery of Gene Regulation
Our chromosomes store the blueprint for every cell in our body, yet different cell types, such as muscle and nerve cells, exhibit dramatic functional differences. This discrepancy is due to gene regulation-the process that ensures each cell activates only the genes relevant to its function, keeping other genes inactive. Ambros and Ruvkun were particularly intrigued by how different cell types develop and discovered a novel class of RNA, microRNA (miRNA), which plays a key role in this regulation.
Their revolutionary discovery revealed an entirely new principle of gene control, one that is vital for the development and functioning of multicellular organisms, including humans. Today, it is known that the human genome encodes more than 1,000 different microRNAs, underscoring the profound importance of their work.
A New Dimension of Gene Control
This year's Nobel Prize highlights the discovery of a crucial regulatory mechanism in cells that controls gene activity. Traditionally, gene expression was understood as the flow of genetic information from DNA to messenger RNA (mRNA), which is then translated into proteins. However, Ambros and Ruvkun uncovered a regulatory step that occurs after transcription, where small RNA molecules, such as microRNAs, influence which mRNAs are translated into proteins.
Since the 1960s, scientists believed they had largely uncovered the mechanisms of gene regulation, particularly through the action of transcription factors-proteins that control the production of mRNA. But in 1993, Ambros and Ruvkun challenged this view by discovering a new level of regulation involving microRNA, which would soon be recognized as a highly conserved and essential biological process across species.
A Tiny Worm, a Major Breakthrough
In the late 1980s, Ambros and Ruvkun were postdoctoral researchers in the laboratory of Robert Horvitz, who won the 2002 Nobel Prize for his work on programmed cell death. Their model organism was the nematode Caenorhabditis elegans-a tiny worm, just 1mm long, with specialized cells like neurons and muscle cells. This made it an ideal model for studying the development of multicellular organisms.
Ambros and Ruvkun were particularly interested in two genes, lin-4 and lin-14, which appeared to control the timing of developmental processes in these worms. Ambros' earlier research suggested that lin-4 negatively regulated lin-14, but the mechanism was unclear. Through systematic analysis, Ambros discovered that lin-4 produced an unusually short RNA molecule that lacked the ability to code for proteins.
At the same time, Ruvkun was studying how lin-14 was regulated and found that lin-4 did not prevent the production of lin-14 mRNA but instead blocked the translation of lin-14 into protein. They realized that this short RNA from lin-4 was binding to a complementary sequence on the lin-14 mRNA, preventing the production of lin-14 protein.
A New Regulatory Mechanism
Their breakthrough was the discovery that lin-4 RNA, later classified as a microRNA, regulated gene expression by binding to complementary sequences on mRNA, controlling its translation into protein. This new form of post-transcriptional regulation added an unexpected layer of complexity to gene expression.
Although their 1993 discovery was initially met with skepticism-many believed it was specific to C. elegans and not relevant to humans-their findings soon gained traction. Seven years later, Ruvkun discovered a second microRNA, let-7, which, unlike lin-4, was highly conserved across the animal kingdom. This revelation ignited widespread interest, and within a few years, hundreds of microRNAs were identified.
microRNAs: Tiny Molecules with Big Impact
We now know that microRNAs are expressed by over 1,000 genes in humans, playing a key role in regulating gene expression in all multicellular organisms. They bind to complementary sequences on target mRNAs, either inhibiting their translation or promoting their degradation. Remarkably, a single microRNA can regulate multiple genes, while one gene can be controlled by several microRNAs, allowing for a highly coordinated gene regulatory network.
The discovery of microRNAs has profound biological significance. It is now clear that without microRNAs, cells and tissues cannot develop normally. Abnormal microRNA regulation is linked to diseases such as cancer, congenital hearing loss, and bone disorders. Mutations in the enzyme Dicer1, which is required for microRNA production, cause DICER1 syndrome, a rare condition associated with multiple forms of cancer.
Groundbreaking Research with Enduring Impact
Ambros and Ruvkun's work has opened a new frontier in the study of gene regulation. Their findings revealed a novel mechanism that has shaped the evolution of complex organisms. Their research has not only advanced our understanding of cellular development but also paved the way for new approaches to treating diseases caused by disrupted gene regulation.
Their seminal papers, published in Cell in 1993 and Nature in 2000, have become cornerstones of modern genetic research.
