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Gary Rubcon and Victor Ambrose won the 2024 Nobel Prize in Medicine for the discovery of microRNA and its effect on gene regulation (extension)

The two scientists were recognized for their contribution to the understanding of genetic regulatory mechanisms through the discovery of microRNAs - tiny RNA molecules that play an essential role in the processes of development and function in cells

The mechanism of the flow of genetic information from the DNA molecule to microRNA molecules and from there to proteins. The identical genetic information is stored in the DNA of all cells in our body. This situation requires precise regulation of gene activity so that only the correct set of genes is active in each type of cell. Courtesy of the Nobel Prize Committee
The mechanism of the flow of genetic information from the DNA molecule to microRNA molecules and from there to proteins. The identical genetic information is stored in the DNA of all cells in our body. This situation requires precise regulation of gene activity so that only the correct set of genes is active in each cell type. Courtesy of the Nobel Prize Committee

The winners of the Nobel Prize in Medicine were announced: Prof. Victor Ambrose and the Jewish Prof. Gary Robkon for the discovery of micro RNA - small RNA molecules. A decade ago, the Israeli Wolf Prize was won with the Israeli-Canadian researcher Prof. Nahum Sonnenberg - who did not win the Nobel with them. Ambrose and Robkon were together in post-doctoral training at the Massachusetts Institute of Technology (MIT), the laboratory of Robert Horvitz, the 2002 Jewish-American Nobel laureate.

The 2024 Nobel Prize was awarded to two scientists for their discovery of a fundamental principle that controls the activity of genes. The information stored inside our chromosomes can be linked to a kind of operating manual for all the cells inside our body. Every cell in the body contains identical chromosomes, so every cell contains the same set of genes and the same operating instructions. And yet, different cell types, for example muscle cells or nerve cells, have very different characteristics. How do these differences emerge? The answer is gene regulation, which allows each cell to choose only the instructions relevant to it. This mechanism ensures that only the correct set of genes are activated in each and every type of cell.

Prof. Gary Rubkon and Prof. Victor Ambrose wondered how different types of cells develop. They discovered the molecule called micro-RNA, a new type of tiny RNA molecules responsible for an essential role in gene regulation. Their groundbreaking and revolutionary discovery revealed an entirely new principle in the field of gene regulation essential to multicellular organisms, including humans. Today it is known that the sequences of the human genome encode more than one hundred thousand microRNAs. Their surprising discovery revealed a whole new dimension for honest regulation. MicroRNAs have been shown to be fundamentally significant to how organisms develop and function.

The essential regulation of genes at the heart of this year's Nobel Prize in Medicine focuses on the discovery of an essential regulatory mechanism in cells used to control gene activity. Genetic information flows from DNA to messenger RNA (mRNA) through a process called "transcription" and in the next step through a cellular mechanism for the production of proteins. At this stage, microRNAs are replicated and thus enable the production of proteins based on the genetic instructions stored in the DNA itself. Since the middle of the twentieth century some of the basic scientific discoveries have explained how these processes work. Our organs and tissues are made up of many different types of cells, all of which contain the same genetic information stored within their DNA. At the same time, these different cells express unique collections of proteins. How is this possible? The answer lies in the precise regulation of gene activity, so that only the "correct" collection of genes is active in each type of cell. This mechanism enables, for example, the creation of muscle cells, intestinal cells, and different types of nerve cells, which perform their unique functions.

In addition, the genetic activity must always be controlled in order to adapt to cellular functions so that they adapt to changing conditions in our body and environment. If the genetic regulation goes wrong, this deficiency can lead to serious diseases such as cancer, diabetes, or diseases of autoimmunity. Therefore, understanding the regulatory mechanism of gene activity has been an essential goal for many decades.

 

 

 

 

In the nineties it was known that unique proteins, known as "transcription factors" bind to specific regions in DNA and control the flow of genetic information by determining the microRNA that is produced. Since then thousands of transcription factors have been identified and a long time later researchers believed that the main principles of gene regulation had been fully revealed.

However, in 1993 the Nobel laureates for that year published unexpected findings describing a new level of gene regulation, which proved to be extremely significant and even conserved throughout evolution.

 

Research on tiny worms has led to a huge breakthrough

In the eighties of the last century, the two researchers were postdoctoral fellows in the laboratory of Robert Horvitz, who received the Nobel Prize for 2002, together with Sydney Brenner and John Sulston. In Horowitz's laboratory, they studied tiny roundworms, a roundworm only 4 mm long. Despite its tiny size, the worm C. elegans has many cell types such as nerve cells and muscle cells, cells also found in larger and more complex animals, which made them a useful model for testing the mechanism of development and growth of multicellular organisms. The two researchers were interested in the genes that control the timing of the activation of various genetic "programs", a mechanism that ensures that different cell types develop at the right time. They studied two mutant strains of worms [lin-14 lin-4] that expressed defects in the timing of the activation of genetic programs during cellular development. The two Nobel laureates wanted to identify the mutant genes and understand their functions. Ambrose previously showed that the lin-4 gene is a negative regulator of the lin-XNUMX gene.

 However, how the activity of this gene was blocked was unknown until then. Both researchers were interested in these mutants and their potential to solve these mysteries.

A review of *C. elegans* and a genetic study on lin-4 and lin-14 mutations. Courtesy of the Nobel Prize Committee for Medicine, 2024


A review of *C. elegans* and a genetic study on lin-4 and lin-14 mutations. Courtesy of the Nobel Prize Committee for Medicine, 2024

After his postdoctoral phase, researcher Victor Ambrose analyzed the lin-4 mutant in his new laboratory at Harvard University. Systematic mapping and cloning of the gene led to the discovery of an unexpected finding - a short RNA molecule that does not contain a code for protein production. These surprising results imply that this small RNA produced by Lin-4 was responsible for the inhibition of Lin-4. How can this happen?

At the same time, Prof. Gary Rubcon studied the regulation of the Lin-4 gene in his new laboratory at Massachusetts General Hospital and Harvard Medical School. Unlike what was commonly assumed at the time about the function of genes in the framework of genetic regulation, Robcon showed that it was not the product of a microRNA produced from Lin-14 that was inhibited by Lin-4. It seems that the regulation occurs at a later stage in the gene expression process, through turning off the production of the protein. Further experiments revealed a segment within the lin-14 microRNA that was necessary for its inhibition by lin-4. The two researchers compared their findings, a fact that led to a breakthrough discovery. The short sequence of lin-4 corresponded to suitable (complementary) sequences within the essential segment of the microRNA of lin-14. The two researchers performed additional experiments that showed that the Lin-14 microRNA was turned off following binding to the appropriate sequences in the microRNA. while blocking the production of the Lin-14 protein. A new principle in the field of genetic regulation, mediated by RNA that was not known until then, microRNA, was discovered at this moment. The findings were published in 1993 in two articles in the scientific journal Cell.

 

The published findings were initially received with silence among the scientific community. Although the findings were interesting, the unusual mechanism of gene regulation is considered a unique feature only of the specific worm examined, C. elegans, meaning that the findings are probably not relevant to humans and other complex animals. The scientific perception in the field changed in 2000 when Robcon's research group published its discovery of another microRNA encoded by the let-7 gene. Unlike the previous gene, lin-4, the lat-7 gene was particularly conserved during evolutionary development and was found to exist in all the animal kingdom. This article actually received a lot of interest, and during the years that followed, hundreds of different microRNA molecules were discovered. Today, we know that there are more than a thousand genes encoding different microRNAs in humans, and that genetic regulation by microRNAs is a universal mechanism among multicellular organisms.

 

In addition to the mapping of new microRNAs, experiments conducted by several research groups have shown how microRNA mechanisms are produced and deliver corresponding target sequences in a regulated manner. The discovery of microRNA leads to the inhibition of protein synthesis or the degradation of microRNA. Interestingly, a single microRNA can regulate the expression of many different genes, and in parallel, a single gene can be regulated by several microRNAs so that the mechanism is coordinated and adjusted in order to include networks of genes. The cellular mechanism of producing functional microRNAs is also used to produce other small RNA molecules in both plants and animals, for example as a means of protecting plants against viral infections. Researchers Andrew Z. Fire and Craig C. Mello, who won the Nobel Prize in 2006, described an RNA interface, where specific microRNA molecules are silenced by adding double-stranded RNA to cells.

Genetic production between species shows the evolutionary conservation of miRNAs such as let-7 over 500 million years. Courtesy of the Nobel Prize in Medicine Committee
The evolutionary conservation of miRNAs such as let-7 for 500 million years. Courtesy of the Nobel Prize Committee for Medicine

 

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