Nobel Prize in Medicine Awarded to American Scientists for Discovery of microRNA

Written by: Ashley C. Morales & Jane Dai, Ph.D.

On October 7, 2024, the 2024 Nobel Prize in Physiology or Medicine was jointly awarded to two American scientists, Victor Ambros (of UMass Medical School) and Gary Ruvkun (of Harvard Medical School), for their discovery of microRNA, a new class of small noncoding RNA molecules, and the role microRNAs play in turning genes on and off, known as gene regulation.[1]

In the 1980’s, Ambros and Ruvkun worked as postdoctoral fellows in the laboratory of H. Robert Horvitz, an American biologist who won the 2002 Nobel Prize in Physiology or Medicine for his study of the roundworm Caenorhabditis elegans (C. elegans) and identification of two of the genes needed for programmed cell death to occur.[2]  As postdoctoral fellows, Ambros and Ruvkun also studied C. elegans, a transparent roundworm comprised of less than 1,000 cells used in basic research.[3]  Ambros’ and Ruvkun’s study focused on genes that control the timing of activation of different genetic programs.[4]  Specifically, Ambros and Ruvkun focused on two mutant strains of worms, lin-4 and lin-14, that had failed to develop properly due to defects in the timing of activation of genetic programs.[5] Ambros had determined that the lin-4 gene appeared to be a negative regulator of the lin-14 gene, but it was unknown at the time how the lin-14 activity was blocked.[6]

After the two finished their postdoctoral research, Ambros continued analyzing the lin-4 mutant, while Ruvkun focused on regulation of the lin-14 gene.[7] From his research, Ambros discovered that a small RNA from lin-4 might be responsible for inhibiting lin-14, while Ruvkun discovered that lin-4 did not inhibit the production of mRNA from lin-14 as expected, but instead the gene regulation occurred through the shutdown of protein production after the mRNA had been produced.[8]  The two compared findings and conducted additional research showing the lin-4 microRNA is responsible for turning off lin-14 by binding to the complementary sequences in its mRNA, blocking production of the lin-14 protein and leading to the observed abnormal development in the roundworm.[9]

Initially, the importance of Ambros’ and Ruvkun’s discovery was not recognized, as the scientific community thought the discovery might be irrelevant to more complex animals such as humans.[10]  However, in 2000, Ruvkun’s research group published its discovery related to cloning of a second microRNA, let-7.[11]  Unlike the lin-4 gene, the let-7 gene is present in humans and other complex animals, suggesting the importance of microRNAs in humans and complex organisms.[12]

Ambros’ and Ruvkun’s discovery spurred additional research, leading to the discovery of over 2500 microRNAs in humans, and recognition that gene regulation by microRNA is universal in multicellular organisms.[13]  Further research led to the discovery that abnormal gene regulation by microRNA can contribute to cancer, and that mutations in gene coding for microRNA can cause congenital hearing loss, eye and skeletal disorder.[14]

Ambros’ and Ruvkun’s research is paving the way for future developments in medicine.  The increase in research on the role of microRNA in human diseases and the characterization of various miRNA exclusively expressed or downregulated in specific human diseases have resulted in multiple microRNA based clinical trials, for example, for the treatment cardiovascular diseases, cancers, and neurodegenerative diseases.[15]  As microRNA therapies are beginning to gain significant traction, there is a growing belief that they could revolutionize the pharmaceutical landscape and become a major force in the future of medicine.