Ambros, Ruvkun Win the Nobel Prize in Physiology or Medicine for microRNAs

Their work over the past three decades has opened up a new dimension to gene regulation through establishing a focus on how microRNAs control the translation and degradation of mRNA in the cytoplasm—in contrast to proteins in the nucleus regulating RNA transcription and splicing.

Today, we know that there are more than a thousand genes for different microRNAs in humans, and that gene regulation by microRNA is universal among multicellular organisms.

This is the third Nobel prize awarded to work from the C. elegans field. In 2002, the award was given to Sydney Brenner, Robert Horvitz, and John Sulston for establishing C. elegans as an experimental model system. In 2006, Andrew Fire and Craig Mello won for the discovery of RNA interference—also done using C. elegans.*

Ambros and Ruvkun’s paths have been both similar and shared. The two long-time collaborators were postdocs together, in the 1980s, in the Horvitz lab at MIT. Since then, Ruvkun has run a lab at Massachusetts General Hospital and Harvard Medical School and Ambros’ lab moved from Harvard University to Dartmouth College. Since 2007, he has been a professor of molecular medicine at UMass Chan Medical School in Worcester, MA.

During their post-doc, Ambros and Ruvkun were interested in genes that control the timing of activation of different genetic programs, ensuring that various cell types develop at the right time. Two mutant strains of worms, lin-4 and lin-14, were known to display defects in the timing of activation of genetic programs during development. The lin-4 mutant becomes larger because a developmental program is repeated. The lin-14 mutant skips stages and becomes smaller.

Ambros investigated lin-4. He started by cloning the gene, which took several years, and showed that lin-4 made a tiny RNA that did not encode a protein. He also showed that the lin-4 gene negatively regulated lin-14. However, how the lin-14 activity was blocked was unknown.

At the same time, Ruvkun was investigating lin-14, and showed that it is not the production of mRNA from lin-14 that is inhibited by lin-4. Experiments also revealed that the negative control involved the terminal segment of the lin-14 mRNA—an area that is not translated. In addition, deletions of this region abolished the effect of lin-4.

The two scientists compared their findings, which resulted in a breakthrough discovery. The short lin-4 sequence matched complementary sequences in the critical segment of the lin-14 mRNA in the terminal region. The Ambros and Ruvkun labs went on to show that the lin-4 microRNA binds to lin-14 by binding to the complementary sequences in its mRNA and blocks the production of lin-14 protein.

It was at this point that a new principle of gene regulation, mediated by microRNA—a previously unknown type of RNA—had been discovered.

The results were published back to back, in 1993, in Cell: “The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14,” by the Ambros lab and “Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans,” by the Ruvkun lab.

The published results were not immediately recognized for their impact, and some considered the role of microRNA to be specific to C. elegans (and likely irrelevant to humans and other more complex animals).

That perception changed in 2000 when Ruvkun’s team identified a second microRNA, encoded by let-7. Unlike lin-4, the let-7 gene was highly conserved and present throughout the animal kingdom. This opened the door to further investigation and over the following years, hundreds of different microRNAs were identified. Today, it is understood that the majority of genes are regulated by microRNAs, every microRNA regulates several mRNAs, and each of those are regulated by multiple microRNAs—creating a robust system for gene regulation. MicroRNAs are not only important to our understanding of embryological development, normal cell physiology, they are also a key component to our understanding of diseases such as cancer.

As far as the early morning phone call goes… was the Nobel committee able to reach the new laureates early this morning? Thomas Perlmann, secretary of the Nobel committee, answered that question in the news briefing by stating that it is harder now when people have their mobile phones on silent. But, he noted that he was able to wake up Gary Ruvkun. “I think he had a landline. I was able to reach him, his wife answered, and it took a long time before he came to the phone and sounded very tired. But he quite rapidly was quite excited and happy when he understood what it was all about. He was so enthusiastic.” Perlmann was not able to reach Ambros, but says that he left him a message and he hopes that he gives him a call soon.

*Martin Chalfie, PhD, a C. elegans researcher at Columbia University, won the Nobel Prize in 2008 as part of the team that discovered and developed GFP.

PackGene Biotech is a world-leading CRO and CDMO, excelling in AAV vectors, mRNA, plasmid DNA, and lentiviral vector solutions. Our comprehensive offerings span from vector design and construction to AAV, lentivirus, and mRNA services. With a sharp focus on early-stage drug discovery, preclinical development, and cell and gene therapy trials, we deliver cost-effective, dependable, and scalable production solutions. Leveraging our groundbreaking π-alpha 293 AAV high-yield platform, we amplify AAV production by up to 10-fold, yielding up to 1e+17vg per batch to meet diverse commercial and clinical project needs. Moreover, our tailored mRNA and LNP products and services cater to every stage of drug and vaccine development, from research to GMP production, providing a seamless, end-to-end solution.

Related News

Related Services