The 2024 Nobel Prize in Physiology or Medicine went to Victor Ambros (University of Massachusetts Medical School) and Gary Ruvkun (Harvard Medical School/Massachusetts General Hospital) for the discovery of microRNA and its role in post-transcriptional gene regulation. Their work described a mechanism of gene control that had not been part of the standard account, and it changed how genetic function is understood.
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. He established his laboratory at Harvard University in 1985, 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 the body, yet cell types as different as muscle and nerve cells carry out very different functions. Gene regulation accounts for that difference: it keeps each cell running only the genes its function requires and leaves the rest inactive. Ambros and Ruvkun wanted to know how distinct cell types arise, and that question led them to a class of RNA nobody had described, microRNA (miRNA).
That finding pointed to a principle of gene control that was new at the time, one that matters for the development and function of multicellular organisms, humans included. The human genome is now known to encode more than 1,000 different microRNAs.
A New Dimension of Gene Control
This year's Nobel Prize recognizes a regulatory mechanism in cells that controls gene activity. Gene expression was traditionally understood as a one-way flow from DNA to messenger RNA (mRNA) and then to protein. Ambros and Ruvkun found a step that happens after transcription, where small RNA molecules such as microRNAs influence which mRNAs are translated into proteins.
Since the 1960s, transcription factors, the proteins that control the production of mRNA, seemed to account for most of gene regulation. In 1993, Ambros and Ruvkun added a level below that by discovering a new form 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 worm about 1mm long with specialized cells such as neurons and muscle cells, which made it an ideal system 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 found that lin-4 produced an unusually short RNA molecule that could not code for proteins.
At the same time, Ruvkun was studying how lin-14 was regulated. He found that lin-4 did not prevent the production of lin-14 mRNA; it blocked the translation of lin-14 into protein. The short RNA from lin-4 was binding to a complementary sequence on the lin-14 mRNA, preventing production of lin-14 protein.
A New Regulatory Mechanism
The result was that lin-4 RNA, later classified as a microRNA, regulated gene expression by binding to complementary sequences on mRNA and controlling its translation into protein. This form of post-transcriptional regulation added a layer to gene expression that had not been accounted for.
Their 1993 discovery was initially met with skepticism, since many researchers assumed it was specific to C. elegans and irrelevant to humans, but the findings gained traction. Seven years later, Ruvkun discovered a second microRNA, let-7, which unlike lin-4 was highly conserved across the animal kingdom. Interest built quickly, and within a few years hundreds of microRNAs had been identified.
microRNAs: Tiny Molecules with Big Impact
microRNAs are now known to be expressed by over 1,000 genes in humans and to regulate gene expression in all multicellular organisms. They bind to complementary sequences on target mRNAs, either inhibiting their translation or promoting their degradation. A single microRNA can regulate multiple genes, and one gene can be controlled by several microRNAs, which allows for a coordinated gene regulatory network.
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.
Impact on Gene Regulation Research
Ambros and Ruvkun's work opened a new area in the study of gene regulation. Their findings described a mechanism that has shaped the evolution of complex organisms. The research advanced the understanding of cellular development and pointed toward new approaches to treating diseases caused by disrupted gene regulation.
Nobel Prize official website listed three core papers of the two winners.
Their papers, published in Cell in 1993 and Nature in 2000, remain core references in genetics.
