Gary Ruvkun with daughter Victoria Ruvkun (left), dog Barnaby, and wife Natasha Staller the morning of the announcement at their home in Newton. Image: Stephanie Mitchell/Harvard University
At a glance:
MicroRNAs are critical regulators of gene activity and of the proteins that these genes make.
Gene regulation by microRNA is an ancient mechanism that occurs in multiple organisms.
Understanding how microRNAs work can help illuminate how organisms function in health and how they malfunction in disease.
Gary Ruvkun, professor of genetics at Harvard Medical School and an investigator at Massachusetts General Hospital, has received the 2024 Nobel Prize in Physiology or Medicine for the discovery of microRNAs, a class of tiny RNA molecules that regulate the activities of genes in plants and animals, including humans.
Ruvkun shares the prize with his collaborator Victor Ambros, of the University of Massachusetts Chan Medical School. Ruvkun and Ambros discovered the first microRNAs in animals and demonstrated how microRNAs can turn off genes whose activities are crucial for development.
The two researchers’ discoveries revealed an entirely novel mechanism of gene regulation. Indeed, microRNAs are proving to be fundamentally important for how organisms develop and function, the Nobel committee said in its citation.
New twist in a classic plot
The code of life is stored in DNA, which is tightly guarded inside the cell nucleus. During cell division, DNA instructions from active genes get copied and carried outside the nucleus by messenger RNA into parts of the cell where they are translated into functioning proteins.
In the 1990s, Ruvkun’s and Ambros’ discoveries added a new twist to this classic plot. They identified thus-far unknown characters — microRNAs — that play a critical role, binding to specific messenger RNAs and shutting them down, thereby regulating which genes get translated into proteins and which genes get suppressed. By doing so, these tiny molecules can alter how organisms develop, mature, and function and malfunction.
As potent regulators of gene activity and of the expression of proteins made by these genes, microRNAs have profound implications for disease and health, and Ruvkun’s and Ambros’ discoveries have sparked a revolution in RNA medicine.
The scientists’ work revealed that microRNAs are pivotal regulators of normal development and physiology of animals and plants as well as key players in an array of human diseases, including coronary heart disease, neurodegenerative conditions, and many forms of cancer.
“Ruvkun’s and Ambros’ research elegantly combines evolutionary biology and genetics and reveals a completely novel dimension of gene regulation. This curiosity-driven research is a powerful example of how fundamental discovery can provide insights that illuminate causes of disease and consequently can benefit humanity,” said Harvard Medical School Dean George Q. Daley.
Ruvkun’s and Ambros’ discoveries ignited a wave of RNA exploration across the tree of life and led to the identification of the biochemical machinery by which RNAs of different classes are generated and regulate their target genes in many genetic pathways.
“Nobody who knows Gary or his work could be surprised by this recognition for his research on microRNA. A brilliant investigator, his curiosity has led him to one remarkable insight into fundamental biology after another,” said Harvard University President Alan M. Garber. “The implications of those discoveries aren’t always obvious at the outset. With promising medical applications of microRNA research on the horizon, we are reminded — again — that basic research can lead to dramatic progress in addressing human diseases.”
The story of the microRNA discovery
Ambros’ and Ruvkun’s initial research, conducted in the 1980s, was focused on the genetic mechanisms that regulate the specialization of cells at the larval stages in the worm Caenorhabditis elegans.
As postdoctoral researchers in the lab of Robert Horvitz — who himself later received a Nobel Prize — at MIT, Ruvkun and Ambrose studied how two genes, lin-4 and lin-14, regulate developmental timing in C. elegans.
The mutated forms of these genes led to aberrations in the timing of gene program activation during critical stages of development. Ambros and Ruvkun set out to understand how this happens.
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In 1991, Ruvkun showed that certain mutations in a non-protein-coding portion of the lin-14 messenger RNA (mRNA) allow it to ignore the “stop” signal from lin-4 and keep working.
Ambros and his team discovered that lin-4 did not encode a protein at all but instead encoded a tiny RNA composed of about 22 nucleotides, the building blocks of RNA and DNA. This was much shorter than most other RNAs, which are usually made of 200 nucleotides or more strung together. A key to interpreting this 22-nucleotide product was its placement in a genetic pathway.
Ambros’ genetic analysis showed that a lack of lin-4 caused excessive activity of the lin-14 target gene. Similarly, Ruvkun’s genetic analysis had shown that excessive lin-14 gene activity and related developmental defects stemmed from activating lin-14 RNA deletion mutations.
When Ambros and Ruvkun compared the RNA sequences of lin-4 and lin-14, they discovered that the 22-nucleotide lin-4 mRNA matched sections in the lin-14 mRNA and that activating mutations in lin-14 deleted these complementary regions. This complementarity to the lin-4 22-nucleotide RNA was imperfect — the duplexes contained multiple bulges and loops in both the lin-4 RNA strand and the lin-14 mRNA strand, like the secondary structures of the well-studied ribosomal RNAs.
Ambros and Ruvkun published back-to-back studies in the journal Cell in 1993 announcing the discovery of this first microRNA and of its mechanism of regulation of target mRNA translation by imperfect base pairing.
Ruvkun shares tales of his inauspicious start, scientific sea changes, and the power of worms. Video: Rick Groleau
A slow start to microRNA science
The discovery of the first microRNA (miRNA) and its mechanism of translational control did not generate great attention. The C. elegans lin-4 and lin-14 developmental timing genes did not have obvious homologues — corresponding genes — in other organisms, including humans.
The ubiquity of miRNAs emerged in 2000 when Ruvkun’s laboratory discovered the second miRNA, let-7. Ruvkun’s team found that many other creatures — humans, fruit flies, chickens, frogs, zebrafish, mollusks, and sea urchins — carried 100 percent conserved versions of let-7.
Furthermore, research showed that the let-7 miRNA also repressed the activity of its target gene through a part of mRNA known as the 3' untranslated region, with imperfect complementary sequences in the target mRNA. With that discovery, miRNAs finally broke through their designation as mere worm curiosities.
Because the let-7 miRNA was present in so many animal species, it meant that more miRNAs were likely to exist in other creatures as well. Multiple teams raced to discover new regulatory RNAs of approximately 22 nucleotides in length.
In 2001, Ambros’ group — as well as those of David Bartel from MIT and Thomas Tuschl, who was then at the Max Planck Institute for Biophysical Chemistry, Göttingen — discovered almost 100 additional candidate miRNAs in flies, humans, and worms.
Since then, the miRNA field has exploded — a growth evident in the peer-reviewed citations that grew from those two back-to-back references by Ambros and Ruvkun in 1993 to 147,583 references as of September 2022.
“Gary and Victor are outstanding scientists who fundamentally expanded our understanding of how genes are regulated. Their being honored with the Nobel Prize is richly deserved,” said Cliff Tabin, head of the Department of Genetics at HMS.
The clinical significance of the discoveries
Studies over the past few years have revealed that the human genome contains about 1,000 microRNAs that could collectively control the majority of our protein-producing genes.
miRNAs are now used in the clinic to determine tumor types and are implicated in heart disease, viral pathogenesis, regulation of neural function and disease, and the transition from so-called totipotent stem cells to differentiated cells.
Human therapies based on miRNA regulation are already in clinical trials for heart disease.
In plants, miRNAs mediate a variety of developmental and physiological transitions and turn out to have been key players in the actual domestication of corn, for example.
Ambros’ and Ruvkun’s original discoveries are still the paradigm by which the thousands of newly discovered miRNAs and their targets are viewed.
Looking where no one had looked before, Ambros and Ruvkun discovered an unforeseen universe of potent, tiny RNA molecules. Their work has elevated these hitherto unrecognized agents into the central dogma of biology and medicine.
“It is a great honor to congratulate Gary on his truly remarkable achievement and thank him for all of his contributions to science, to medicine, and to the health of people,” said Anne Klibanski, president and CEO of Mass General Brigham. “His work extends a legacy of innovation and inspires the next generation, so many of whom are here, as they pursue new discoveries with global impact.”
Additional background
In addition to continuing investigation of microRNA’s role in controlling gene expression, Ruvkun’s team studies other mechanisms involved in the development, metabolism, and longevity of C. elegans, including genes involved in the regulation and storage of fat.
In 2016 his team identified molecules essential to the ability of C. elegans cells to recognize dysfunction of the proteasome, a cellular component that degrades unneeded or defective proteins. The findings may be applicable to human neurodegenerative diseases.
In 2008 Ruvkun, Ambros, and fellow researcher David Baulcombe received the Lasker Award for Basic Medical Research for the work currently being honored. Among the many other awards Ruvkun has received — some shared with Ambros and Baulcombe — are the Franklin Medal, the Gairdner International Award, the 2012 Paul Janssen Award for Biomedical Research, the 2014 Gruber Genetics Prize, the 2015 Breakthrough Prize in Life Sciences, the 2016 March of Dimes Prize, and the 2008 Warren Triennial Prize from Mass General.
Ruvkun holds a bachelor’s degree in biophysics from the University of California at Berkeley and a doctorate in biophysics from Harvard University.
A member of the National Academy of Sciences, Ruvkun is also a principal investigator with the Search for Extraterrestrial Genomes, which has proposed using DNA amplification and sequencing techniques, commonly used to detect and classify organisms here on Earth, as part of the search for life on Mars or other planets.
“The joy of doing genetics … is the surprises,” Ruvkun said at a news conference at Mass General on Oct. 7. “The surprises are what keep you young in science. I’m constantly surprised, and my ignorance is bliss.”
Adapted in part from a Mass General news release.
