US scientists Victor Ambros and Gary Ruvkun have been awarded the Nobel Prize in Physiology or Medicine 2024 for their pioneering discoveries around microRNA.
MicroRNAs are an influential force in dictating how genes within organisms are controlled; and are currently the subject of clinical trials for potential heart disease, cancer, neurodegenerative disease treatments.
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.
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 US university and hospital research units, the MGH Department of Molecular Biology fully supported his research expenses during the decade when this research was initiated.
