The Nobel Prize awarding body said on Monday that scientists Victor Ambros and Gary Rovkun won the 2024 Nobel Prize in Medicine for their discovery of microRNA (microRNA) and its role in regulating genes.
The Nobel Society said in a press release that this year’s award honors two scientists for their discovery that regulating gene activity is one of the basic principles that govern how gene activity is regulated.
She added that the information stored within our chromosomes can be likened to an instruction manual for all the cells in our bodies. Each cell contains the same chromosomes and therefore contains exactly the same set of genes and the same set of instructions. However, different cell types, such as muscle and nerve cells, have very distinct properties. How do these differences arise? The answer lies in gene regulation, which allows each cell to select only relevant instructions. This ensures that only the correct set of genes is active in each cell type.
Ambros and Rovkun were interested in how different cell types develop. They discovered microRNA, a new class of small RNA molecules that play a crucial role in gene regulation. Their pioneering discovery revealed an entirely new principle of gene regulation that turned out to be essential for multicellular organisms, including humans. It is now known that the human genome encodes more than a thousand microRNAs.
Basic organization
This year’s Nobel Prize focuses on discovering a biological regulatory mechanism used in cells to control gene activity. Genetic information flows from DNA to messenger RNA (mRNA) through a process called transcription, and then to the cellular machinery for protein production. There, the messenger RNA is translated so that proteins are made according to the genetic instructions stored in the DNA. Since the mid-20th century, several basic scientific discoveries have clarified how these processes work.
Our organs and tissues are made up of many different cell types, all of which have identical genetic information stored in their DNA. However, these different cells express unique sets of proteins. How is this possible? The answer lies in the precise regulation of gene activity so that only the right set of genes is active in each specific cell type. This enables, for example, muscle cells, gut cells, and different types of neurons to perform their specialized functions. Gene activity must also be constantly adjusted to adapt cellular functions to changing conditions in our bodies and environment. If the regulation of genes goes wrong, it can lead to serious diseases such as cancer, diabetes or autoimmunity. Therefore, understanding the regulation of gene activity has been an important goal for many decades.
In the 1960s, it was shown that specialized proteins, known as transcription factors, can bind to specific regions of DNA and control the flow of genetic information by determining which mRNAs are produced. Since then, thousands of transcription factors have been identified, and it was long thought that the main principles of gene regulation had been resolved. But in 1993, that year’s Nobel laureates published unexpected results describing a new level of gene regulation, which turned out to be extremely important and conserved throughout evolution.
Research on a small worm leads to a big breakthrough
In the late 1980s, Ambros and Rovkun were working in the laboratory of Robert Horvitz, who won the Nobel Prize in 2002, along with Sidney Brenner and John Sulston. In Horvitz’s lab, they studied a relatively humble, one-millimeter-long roundworm called C. elegans.
Despite its small size, C. elegans possesses many specialized cell types such as nerve and muscle cells that are also found in larger, more complex animals, making it a useful model for investigating how tissues develop and mature in multicellular organisms. Ambros and Rovkun were interested in the genes that control the timing of activation of different genetic programs.
The researchers studied two mutant strains of worms, “lin-4” and “lin-14,” which showed defects in the timing of activation of genetic programs.
The award winners wanted to identify mutant genes and understand their function. Ambros had previously shown that the LIN-4 gene appears to be a negative regulator of the LIN-14 gene. However, it was not known how the activity of the latter gene was blocked. Ambros and Rovkun were interested in these mutations and their possible relationship and set out to solve these mysteries.
Ambros analyzed the mutation in the “Lin-4” gene in his newly established laboratory at Harvard University. Systematic mapping allowed the gene to be cloned and led to an unexpected discovery. The lin-4 gene produced an unusually short RNA molecule that lacked a code for protein production. These surprising results indicated that this small RNA from Lin-4 was responsible for inhibiting Lin-14. How might this happen?
Meanwhile, Rovkun investigated the regulation of the LIN-14 gene in his newly established laboratory at Massachusetts General Hospital and Harvard Medical School. In contrast to how gene regulation was then known to work, Rovkun showed that it is not the mRNA production of the Lin-14 gene that is inhibited by the Lin-4 gene. The regulation appears to occur at a later stage in the gene expression process, by stopping protein production.
The experiments also revealed – a part of the mRNA of the “Lin-14” gene – that was necessary for its inhibition by the “Lin-4” gene. The two laureates compared their results, resulting in a groundbreaking discovery: The short LIN-4 gene sequence matched sequences complementary to the critical part of the LIN-14 mRNA.
Ambros and Rovkun conducted further experiments that showed that the Lin-4 gene’s microRNA turns off the Lin-14 gene by binding to complementary sequences in its mRNA, preventing the production of the Lin-14 protein. A new principle of gene regulation has been discovered, mediated by a previously unknown type of RNA, which is microRNA.
The results were published in 1993 in two articles in the journal Cell.
Initially, the published results were met with complete silence from the scientific community. Although the results were interesting, the unusual mechanism of gene regulation was considered to be characteristic of Caenorhabditis elegans, and perhaps unrelated to humans and other more complex animals. This perception changed in 2000 when the Rovcon research group published its discovery of another microRNA molecule encoded by a gene called “let-7”.
Unlike the LIN-4 gene, the LET-7 gene is conserved and present throughout the animal kingdom. The article generated great interest, and over the following years, hundreds of different microRNAs were identified. Today, we know that there are more than a thousand different microRNA genes in humans, and that gene regulation by microRNAs is common among multicellular organisms.
Deep importance
Gene regulation by microRNA, first revealed by Ambros and Rovkun, has been around for hundreds of millions of years. This mechanism has enabled the evolution of increasingly complex organisms. We know from genetic research that cells and tissues do not develop normally without microRNA.
The press release said that a disorder in microRNA can contribute to cancer, and mutations in the genes that encode microRNA have been found in humans, causing conditions such as congenital hearing loss, eye and skeletal disorders.
Mutations in one of the proteins required for microRNA production lead to DICER1 syndrome, which is a rare syndrome but highly associated with cancer in various organs and tissues.