In every cell of the human body there is a complete and universal ‘kit’: the same set of genes, the same set of instructions. But the perfect machine of our organism is a ‘melting pot’ of different types of cells, from muscle to nervous cells, with very different characteristics. How is this possible? Magic of gene regulation, which allows each cell to select for itself only the relevant instructions from all those stored in the chromosomes. The directors of this process are the tiny molecules protagonists of the 2024 Nobel Prize for Medicine: microRNAs (miRNAs), a sort of ‘highlighters’ which in the ‘instruction manual’ of cells help to highlight the steps that count, and contribute to ensure that only the correct set of genes are active in each cell type.
Victor Ambros and Gary Ruvkun, this year’s honorees, were interested in just that: how different types of cells develop. And they discovered microRNAs, a new class of RNA molecules that play a crucial role in gene regulation. “Their revolutionary discovery revealed a completely new principle of gene regulation that proved essential for multicellular organisms, including humans”, explain the experts who decided to award them the most coveted recognition in the world of science.
It is now known that the human genome encodes over a thousand microRNAs. Their surprising discovery has revealed a whole new dimension, and miRNAs are proving to be fundamentally important to how organisms develop and function.
Thus cells control gene activity
This year’s Nobel Prize therefore focuses on the discovery of a vital regulatory mechanism used in cells to control gene activity. Genetic information flows from DNA to messenger RNA (mRNA), via a process called transcription, and then to the cellular machinery for producing proteins. There, mRNAs are translated so that proteins are produced according to the genetic instructions stored in the DNA. Since the mid-20th century, crucial scientific discoveries have explained how these processes work. Processes that allow different cells to express unique sets of proteins and for muscle, intestinal, nerve, and so on cells to carry out their specialized functions.
Furthermore, gene activity must continually be fine-tuned to adapt cellular functions to changing conditions in our bodies and the environment. If gene regulation goes wrong, it can lead to serious diseases such as cancer, diabetes or autoimmunity. 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 messenger RNAs are produced. Since then, thousands of transcription factors have been identified, and it was long believed that the fundamental principles of gene regulation had been resolved. However, in 1993, the newly awarded Nobel Prize winners Ambros and Ruvkun published unexpected results describing a new level of gene regulation, which proved to be highly significant and conserved throughout evolution.
The fundamental observation of a worm
Accomplice to their discovery was a small worm, which has always been precious for research, C. elegans. In the late 1980s, Ambros and Ruvkun – postdoctoral fellows in the laboratory of another Nobel Prize winner, Robert Horvitz (awarded in 2002) – pointed their microscopes at this 1-millimeter-long roundworm which, despite its small size, possesses many types of specialized cells also present in larger and more complex animals. 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. Their studies focused on two mutant strains of worms, lin-4 and lin-14, which showed defects in this activation timing. Ambros had previously shown that the lin-4 gene appeared to be a negative regulator of the lin-14 gene. However, it was not known how lin-14’s activity was blocked. With Ruvkun he faced these mysteries. Ambros analyzed the lin-4 mutant in his laboratory founded at Harvard University. There an unexpected discovery occurred: the lin-4 gene produced an unusually short RNA molecule that had no code for protein production. These results suggested that this small RNA of lin-4 was responsible for the inhibition of lin-14.
The discovery of micro RNA
But how did this process work? It was Ruvkun who put the other piece of the puzzle. Studying the regulation of the lin-14 gene in his laboratory at Massachusetts General Hospital and Harvard Medical School, he demonstrated that it is not the production of messenger RNA from lin-14 that is inhibited by lin-4. The regulation appeared to occur at a later stage in the gene expression process, through shutting down protein production. It was by comparing their findings that the 2 researchers had the intuition. Their further experiments therefore allowed them to demonstrate that the lin-4 miRna deactivated lin-14 by binding to complementary sequences in its mRna, blocking the production of the lin-14 protein. A new principle of gene regulation had been discovered, mediated by a previously unknown type of RNA, microRNA. The results were published in 1993 in 2 articles in the journal ‘Cell’, greeted – as recalled in the Nobel Prize note – with an “almost deafening” silence by the scientific community.
The perception changed in 2000 when Ruvkun’s research group published the discovery of another microRNA, encoded by the let-7 gene, highly conserved and present throughout the animal kingdom. The article aroused great interest and in the following years hundreds of different microRNAs were identified. Today we know that gene regulation by miRNAs is universal among multicellular organisms. In addition to the mapping of new microRNAs, experiments conducted by several research groups have clarified the mechanisms of how they are produced and delivered to complementary target sequences in regulated messenger RNAs. The binding of microRNAs leads to the inhibition of protein synthesis or degradation of mRNAs. Little curiosity: a single microRNA can regulate the expression of many different genes and, on the contrary, a single gene can be regulated by multiple microRNAs, thus coordinating and perfecting entire networks of genes.
Cellular machinery for producing functional miRNAs is also used to produce other small RNA molecules in both plants and animals, for example as a means of protecting plants from viral infections. Gene regulation via microRNA, first revealed by Ambros and Ruvkun, has been in place for hundreds of millions of years. This mechanism has allowed the evolution of increasingly complex organisms. Today we know from genetic research that cells and tissues do not develop normally without microRNA. Abnormal regulation via miRna may contribute to cancer and mutations have been found in genes that encode microRNA in humans and cause conditions such as congenital hearing loss, ocular and skeletal disorders. Mutations in one of the proteins necessary for the production of miRna lead to Dicer1 syndrome, a serious rare disease linked to cancer in various organs and tissues. “The fundamental discovery of Ambros and Ruvkun in the small worm C. elegans was unexpected – conclude the experts of the Nobel Assembly at Karolinska Institutet – and revealed a new dimension in gene regulation, essential for all complex life forms”.
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