The story so far: The 2024 Nobel Prize in Physiology or Medicine was awarded to Victor Ambros and Gary Ruvkun by the Nobel Assembly at Karolinska Institutet in Stockholm, Sweden, on Monday (October 7, 2024). The scientists won the esteemed prize for the discovery of microRNA and its role in post-transcriptional gene regulation.
Both Ambros and Ruvkun are American biologists. Ambros currently works at the Programme in Molecular Medicine at the University of Massachusetts in the U.S. Ruvkun is a professor of genetics at the Harvard Medical School and researches microRNA and RNA interference mechanisms at the Ruvkun Lab at Massachusetts General Hospital.
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While their area of research is similar, Ambros and Ruvkun haven’t worked together since they were postdoctoral fellows in H. Robert Horvitz’s laboratory, who won the 2002 Nobel Prize in Physiology or Medicine. “After that, they went to Harvard University and Harvard Medical School and set up their own labs and worked on different aspects of microRNA regulation. Ambros was the first one to clone a microRNA and Ruvkun cloned the second one...they haven’t collaborated a lot after their postdoctoral work as much as I know...but they did [share some data] and that was the key to this Nobel Prize,” Olle Kämpe, member of the Nobel Committee for Physiology or Medicine 2024, said in an interview after the prize announcement.
What are microRNAs?
MicroRNAs, or miRNAs, are small, non-coding molecules of RNA. They are typically around 19-24 nucleotides long and play an important role in determining how much messenger RNA (mRNA), which carries genetic information, eventually gets translated into protein.
The body makes proteins in a complex process with two broad steps. In the transcription step, a cell copies a DNA sequence into messenger RNA (mRNA) in the nucleus. The mRNA moves from the nucleus, through the cell fluid, and attaches itself to the ribosome. In the translation step, another type of RNA called transfer RNA (tRNA) brings specific amino acids to the ribosome, where they are linked together in the order specified by the mRNA to make the protein.
Micro RNA, or miRNA, regulates the production of proteins by bonding with and subsequently silencing the mRNA at an appropriate juncture. The process is called post-transcriptional gene regulation.
Nobel-winning research: a brief history
In the late 1980s, Ambros and Ruvkun studied a 1 mm-long roundworm, Caenorhabditis elegans which, despite its small size, had specialised cell types such as nerve and muscle cells. This made C. elegans an important model to investigate how tissues develop in multicellular organisms, including humans.
Ambros and Ruvkun studied two mutant strains, lin-4 and lin-14, both of which exhibited abnormalities -- their genetic programming that controls development was not functioning as expected. Ambros’ previous research proved that lin-4 suppressed the activity of lin-14, but could not tell how it did so.
After their postdoctoral research, the biologists individually researched how lin-4 affected the activity of lin-14. Ambros analysed the lin-4 mutant and cloned the gene and found out that it produced an unusually short RNA molecule that lacked a code for protein production. The findings suggested that this small RNA molecule could be responsible for inhibiting lin-14.
Around the same time, Ruvkun investigated the regulation of the lin-14 gene in his lab and found that lin-4 did not block the production of lin-14 mRNA. Since the late 1960s, gene regulation was understood as a process that determined which mRNAs are produced, and hence, how genetic information flows. Ruvkun found that the regulation of lin-14 mRNA occurred later in the gene expression process by inhibiting protein production. His experiment also revealed an important segment in the lin-14 mRNA that was essential for its inhibition by lin-4. The short lin-4 sequence that Ambros discovered in his research matched complementary sequences in the critical segment of the lin-14 mRNA, which means that they can pair together like keys fit into locks.
The two biologists conducted further experiments and found that lin-4 microRNA, the “unusually short” RNA molecule, attaches to lin-14’s mRNA and blocks the production of lin-14 protein. This is how microRNA was discovered, and the results were published in 1993 in two articles in the Cell journal.
The results, although significant, were not enthusiastically accepted by scientists as the behaviour was thought to be specific to C. elegans, and therefore irrelevant to complex animals and humans. However, in 2000, Ruvkun’s research group published discovery of another microRNA, encoded by the let-7 gene. The let-7 gene is present throughout the animal kingdom, and this discovery sparked interest in microRNAs and their role in protein synthesis.
“Todays, 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,” the Nobel Assembly said in a statement.
Applications
A single micro-RNA can regulate the expression of many genes, and alternatively a single gene can also be controlled by multiple micro-RNAs. This leads to fine tuning of different types of cells despite similar genetic information. Abnormal regulation by microRNA can contribute to cancer, and mutations in genes coding for microRNAs have been found in humans, causing conditions such as congenital hearing loss, eye and skeletal disorders, the Nobel Assembly noted. However, Gunilla Karlsson-Hedestam, chairperson of the Nobel Committee for Physiology or Medicine 2024, said that there are no clear applications of miRNAs yet. Understanding them is the first step towards further research, she said while answering a question after the announcement.
Published - October 07, 2024 10:03 pm IST
