Mass General Hospital researcher Gary Ruvkun honored with 2024 Nobel Prize

Instead of being translated into proteins, as messenger RNAs are, the hundred-times-smaller microRNAs block gene expression by binding to regulatory segments in their target messenger RNAs. Current knowledge suggests that most plant and animal genomes, including the human genome, contain more than 1,000 microRNAs, which control many protein-coding messenger RNAs and may be involved in a broad range of normal- and disease-related activities.

Human microRNAs have been implicated in heart disease, in viral pathogenesis and in regulation of neural function and disease. Human therapies based on microRNAs are in clinical trials for heart disease, cancer, neurodegenerative diseases, and more.

The pair began investigating genes that control development in the C. elegans roundworm. As fellows at Massachusetts Institute of Technology, they worked together to isolate a gene called lin-14 that operates in concert with a gene called lin-4 to regulate the transition through key developmental stages.

After establishing his own laboratory in the MGH Department of Molecular Biology, Ruvkun continued collaborating with Ambros – then at Harvard – to uncover how the two regulatory genes interacted. They discovered that lin-4 did not block the activity of lin-14 through the protein for which it coded, but in a manner never seen before by direct interaction between the two genes’ RNA strands. The lin-4 RNA was also much smaller than any other RNA that previously had been studied, 22 nucleotides long.

In 2000, Ruvkun’s team discovered the second microRNA, let-7, that shuts down its target mRNA by base pairing to it in the same way that lin-4 silences lin-14. The Ruvkun lab also discovered that diverse animals, ranging from flies to fish to humans, have a let-7 microRNA that exactly matches the C. elegans let-7 microRNA, implying that this mechanism of translational regulation was present in the common ancestor to all animals and has been maintained by natural selection since these species diverged almost a billion years ago.

These findings established that microRNAs are universal to animals and not unique to C. elegans. Over the past two decades, research into the potential of microRNAs for the diagnosis, prognosis and treatment of disease has expanded from the two original papers published by Ruvkun and Ambros in 1993 to 176,000 papers today.

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, findings that may be applicable to important human neurodegenerative diseases.

It is significant, Ruvkun notes, that unlike the majority of U.S. university and hospital research units, the MGH Department of Molecular Biology fully supported his research expenses during the decade when this research was initiated.

Over the next decade, MGH-supplied research funds supported half of Ruvkun’s research budget. Much of the departmental research support was the result of a unique funding relationship between MGH and the German chemical company Hoechst AG. Ruvkun wishes to acknowledge how much this unique research support by his home institution empowered his research program.

Ruvkun is a professor of Genetics at Harvard Medical School, an investigator at the MGH Department of Molecular Biology and a member of the MGH Research Institute. He holds a bachelor’s degree in Biophysics from the University of California at Berkeley and a PhD in Biophysics from Harvard University.

In 2008 Ruvkun, Ambros and David Baulcombe of the University of Cambridge 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 MGH.

A member of the National Academy of Sciences, Ruvkun has co-led a NASA-funded Search for Extraterrestrial genomes, which has proposed using DNA sequencing techniques, commonly used to detect and classify organisms here on Earth, as part of the search for life on Mars or other planets.

About Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. MGH is a founding member of the Mass General Brigham healthcare system.