The award of the Nobel Prize in Medicine 2024 to Victor Ambros and Gary Ruvkun is a great success for the Swedish Academy. The contributions of Ambros and Ruvkun were a paradigm shift in our view of how the information contained in the genome is controlled, adding a new dimension. It was now revealed that genes were not only regulated by being turned on or off in chromosomes, but that their expression was also controlled by modifying the stability and effects of their immediate products (messenger RNAs).

His identification of small RNA molecules as post-transcriptional regulators revolutionised our understanding of the body development of complex multicellular organisms, such as humans, and was an essential element for understanding cell behaviour in pathological situations such as cancer.

This year's Nobel Prize in Medicine was awarded to Victor Ambros and Gary Ruvkun for the discovery of microRNAs. These RNA sequences play a fundamental role in gene expression, i.e. in which genes or DNA sequences are transcribed into RNA and translated into protein in each cell, giving a specific function to each cell type. It is called post-transcriptional regulation because, unlike other epigenetic mechanisms that also regulate gene expression, such as DNA methylation, it occurs after it has been transcribed from DNA to RNA.

The name microRNA comes from the fact that they are very small sequences, only 22 nucleotides, but their potential in the cell is enormous. In fact, increases or decreases in their expression are associated with various diseases. I am particularly excited about this award because in our research group we study how microRNA deregulation affects various diseases, such as tumors, and more specifically a rare disease, the 22q11 syndrome, in which a very important gene for the manufacture of these sequences is lost.

It was a great joy to learn about this year's recipients of the Nobel Prize in Physiology or Medicine. Ambros and Ruvkun revolutionized our understanding of the cellular programs that determine the identity of our cells, discovering that gene expression is determined not only in the nucleus but also in the cell cytoplasm, when RNA instructions are converted into protein. The crucial aspect of his discoveries is that the molecule that controls this step is another RNA, of very small size, which belongs to a type of molecule almost unknown until now: non-coding RNAs. These findings opened up a very important field in molecular biology, since these small RNAs are being used decades later as therapeutic tools to control genes or as disease markers in clinical practice. 

And I especially emphasize that the discovery of these small RNAs took place in tiny worms (1mm) with a complex name (Caenorhabditis elegans) and used in basic research, although a few years later it became clear that this new cellular mechanism is evolutionarily conserved and is of key importance in humans as well. Therefore, to recognize the work of these researchers is to highlight the essentials of basic research (including non-human model organisms), which is often undervalued by science policy decisions.

I find this Nobel Prize very interesting as it awards researchers who conducted basic research that has been shown to be very important for understanding the regulation of gene expression. Typically, we explain that genes are a sequence of DNA that codes for a specific protein, and that in order to decode genetic information, DNA is transcribed into RNA to be then translated into proteins. However, although all genes are transcribed, not all of them code for proteins. There are genes for which the RNA is not translated, but rather the RNA functions as such.

The Nobel Prize winners this year, Ambros and Ruvkun, discovered a genetic regulatory mechanism that is based on the use of very small RNAs, hence the name microRNAs, whose function is to bind to the RNAs of other genes to silence them and prevent them from producing protein. In other words, they perform the opposite function, preventing and blocking the translation of other genes. Ambros and Ruvkun discovered these genes in the nematode C. elegans, and at first, they were not given much attention because it was thought to be an exceptional mechanism that only acted in very specific organisms, until it was discovered that it is a highly effective and universal regulatory mechanism in multicellular organisms. Although microRNA genes are very small (21 to 25 nucleotides), there are hereditary genetic diseases caused by mutations in these genes, which consequently deregulate many different genes, potentially altering various signaling or metabolic pathways and affecting different organs.

I can safely say that today all scientists working in the field of epigenetics are tremendously happy to learn that the Nobel Prize in Medicine or Physiology 2024 has been awarded to those fascinating small non-coding RNA molecules: microRNAs.
Few molecules have been implicated in as many vital physiological processes as microRNAs, which through repression of their target genes are involved in immunological, carcinogenic, developmental or inflammatory processes, and are expressed in a wide variety of organisms.
It is a well-deserved award to the researchers who discovered the first microRNA, demonstrating once again that basic science is the first step to clinical translation.

This year's Nobel Prize in Medicine or Physiology goes to Victor Ambros and Gary Ruvkun, for the discovery of microRNAs and their role in post-transcriptional regulation of genes. MicroRNAs, as their name suggests, are small RNA molecules of 20-22 nucleotides that bind by base complementarity to larger RNA molecules, such as the messenger RNAs (mRNAs) that code for each of our proteins. By binding, microRNAs regulate the stability and translation efficiency of mRNA, conditioning protein levels in the cell and, consequently, cell physiology. Regulation by microRNAs is very important for maintaining healthy physiology, and failures in this regulation can not only cause problems during embryonic development, but also contribute to diseases such as cancer.   

I am delighted that this year's Nobel Prize went to the discovery of microRNAs for two reasons.First, because they were discovered in the worm C. elegans, and it is yet another example of how basic science is so fundamental to the advancement of medicine, and why governments should fund basic science.Second, because together with previous Nobel Prizes, such as last year's to Katalin Karikó and Drew Weissman for mRNA modifications that were essential for the development of vaccines against the COVID-19 pandemic, they highlight the relevance of RNA and post-transcriptional regulation. These are good times for RNA!

Although all the cells in our bodies contain basically the same genetic information, not all of them express it in the same way, and this process we call ‘regulation of gene expression’ is what allows cells to be different from one another. An epithelial cell and a neuron, for example, do not express the same genes. Nor does a healthy cell express the same genes as a cancer cell. There are many processes going on in the cell that contribute to making these differences possible, involving interactions between molecules.
The interest of the award-winning scientists' research lies in having highlighted the existence of a new mechanism, previously unknown, which is the participation of very small RNA molecules (microRNAs) that control the process through mechanisms that occur once the messenger RNAs, a copy of the information of some genes, have already been synthesised. Recognition between the messenger RNA and the microRNA is very simple, simply because their bases are complementary, but that directs a series of proteins towards that messenger, determining that it can be degraded and its information not expressed in the cell.
MicroRNAs are important tools in the diagnosis of certain types of cancer and have the advantage that they can be detected by liquid biopsy, in blood tests, and in the analysis of the blood. Their discovery has enabled the development of new tools for biological research in all fields. They can also be easily synthesised, which favours their potential therapeutic applications.

It seems to me a well-deserved Nobel Prize. The two laureates discovered small RNA molecules that post-transcriptionally regulate gene expression of the vast majority of genes. Ruvkun and Ambros identified these molecules by studying the development of the nematode C. elegans when they observed that a small RNA molecule, Lin-4, suppressed the expression of Lin-14 during the development process of this organism. Altered expression of these molecules is associated with numerous pathophysiological processes, including cancer, neurodegenerative and cardiometabolic diseases. The possibility exists to manipulate the expression of these molecules for the treatment of these diseases. On the other hand, the discovery of microRNAs is a very relevant finding, since these molecules control numerous basic cellular and physiological processes such as development, cell proliferation and cholesterol metabolism.

Personally, I am delighted that the Nobel Prize in Physiology or Medicine has been awarded to two great scientists, Victor Ambros and Gary Ruvkun, for their studies that they began in the 80's as postdoctoral students, and then continued as independent researchers on gene regulation and how it allows different cell types to develop or not at a given time.

My research also focuses on the fascinating world of microRNAs, small single-stranded non-coding RNA sequences (between 19-22 nucleotides) that regulate gene expression at the post-transcriptional level, either by inhibiting translation or promoting the degradation of messenger RNA (mRNA). Since their discovery, it has been revealed how a single microRNA can regulate more than 100 mRNAs, and likewise, how one mRNA can be regulated by several microRNAs. Furthermore, microRNAs are involved in both health processes and disease development.

I would like to highlight that microRNAs are very promising therapeutic targets and can be used as biomarkers for various diseases, especially in cancer and cardiovascular diseases. In fact, numerous preclinical studies have explored the overexpression or inhibition of certain microRNAs. Some of these studies have progressed to clinical trials, such as Miravirsen, the first drug specifically targeting a microRNA, which is currently in phase II (safety and efficacy evaluation) in patients. However, we must be cautious, as there is still a lot of research and development to be done.

Another aspect that I would like to highlight is that his studies are framed in basic research, specifically in models with small worms (C. elegans), which are often underestimated. It is essential to highlight the importance of these studies for the advancement of scientific knowledge.

It is a great success and a joy that this year's Nobel Prize in Medicine has been awarded to Victor Ambros and Gary Ruvkun for their discovery of microRNAs and their role in post-transcriptional gene regulation. This finding is of great importance, transforming our understanding of the regulation of gene expression and attributing critical functions to a fraction of the human genome that was previously considered 'junk DNA' because it does not code for proteins. These small non-coding RNAs play fundamental roles in virtually all cellular processes, including development, immunity and disease progression, by simultaneously regulating multiple genes, generating potent functional effects. The impact of microRNAs in medicine is evident, positioning them as key molecules in the development of new therapies for complex diseases, such as cancer and autoimmune diseases, among many others.

This Nobel Prize highlights the enormous relevance of microRNAs (miRNAs) in the post-transcriptional regulation of gene expression, a rapidly growing field with direct applications in precision medicine, thanks to advances in RNA therapeutics. Some of these advances have been recognised with Nobel prizes in previous years. Following the success of RNA vaccines administered to millions of people, RNA therapeutics has been shown to be an area full of promising possibilities. MicroRNAs, studied since the 1980s by Victor Ambros and Gary Ruvkun, who were postdoctoral fellows in the laboratory of Robert Horvitz - Nobel laureate in 2002 along with Sydney Brenner and John Sulston for their discoveries on the genetic regulation of organ development and programmed cell death - continue to reveal mechanisms fundamental to modern biology and medicine.

miRNAs are small non-coding RNA molecules, approximately 22 nucleotides in length, that regulate gene expression at the post-transcriptional level. These miRNAs act by binding to complementary sequences in the messenger RNA of specific genes, leading to their degradation or the inhibition of their translation, thus blocking protein production. This gene silencing mechanism is essential for the control of key biological processes, such as cell development, differentiation, and response to stress or disease, and is implicated in the regulation of multiple diseases, from cancer to cardiovascular diseases, which represent the leading cause of global mortality.

In addition, the identification of specific profiles of circulating miRNAs in blood is showing great potential for the early detection of difficult-to-diagnose cancers, such as pancreatic and lung cancer. Recent studies indicate that miRNAs could be used as biomarkers in cardiovascular diseases such as myocarditis, atherosclerosis, hypertension and cardiac fibrosis.

This recognition of Victor Ambros and Gary Ruvkun reinforces the importance of miRNAs, opening doors to therapeutic and diagnostic applications that could transform the management of devastating diseases such as cancer and cardiovascular pathologies.

Victor and Gary used the awesome power of C. elegans genetics to discover microRNAs.  At the time, they were working to understand how nematodes develop from embryos to adults and identified important genes that coded for RNA but not for protein—which was not how biology was thought to work at this time.  Victor and Gary’s work led directly to the realization that microRNAs are a crucial mechanism for gene regulation across the tree of life including humans.

The discovery of miRNAs, small RNA molecules that modulate the amount of protein produced by genes, was a true revolution in all fields of biology and medicine. First of all, they were a further step in deconstructing the dogma of molecular biology, since they showed that RNAs, not just proteins, could regulate the expression of genes in the genome. This opened the door to the discovery of more and more complex regulatory networks based on non-coding RNAs, including, for example, other longer RNA molecules. Second, as it became clear that regulation by miRNAs was not the exception but the rule, their relevance in virtually every field of biomedical research was studied and demonstrated: from the evolution of living organisms to embryonic development and the progression of cancer and other diseases. miRNAs turned out to be an essential part of almost all gene circuits and, therefore, all biomedical researchers have come across miRNAs, to a greater or lesser extent, at some point in our careers.

This award is a further recognition of the paramount importance of basic science, curiosity-driven research. As in many other cases, unexpected and potentially anecdotal observations led to an explosion of new practical opportunities and a revolution in our understanding of life.

This year's Nobel Prize in Physiology or Medicine has been awarded to two great scientists who discovered the existence of microRNAs. This discovery marked a turning point in the field of genetics, as it revealed a new biological and molecular mechanism by which cells regulate gene expression. The key importance lies in the fact that microRNAs are not an alternative mechanism to what is already known, but an additional level of gene regulation, which is added and combined with all the other mechanisms already known. Therefore, this discovery opened our eyes to a new world of previously unsuspected possibilities, initiating a new field of research that has and has had repercussions in many directions: in fundamental research, at the level of molecular mechanisms, evolution and even the origin of life, as well as in research applied to the healthcare system.

Since their initial discovery, thousands of different microRNAs have been identified, and we understand how they are produced by cells and what their effects are. One of the characteristics of miRNAs is the complexity of their mode of action: we know that these small molecules can act alone, or in groups, and that their mode of action and the effect they produce can vary enormously depending on the context: the type of cell or its state. All this has forever changed our traditionally deterministic way of looking at genetics.

Although they are small molecules, it has been discovered that they have existed for many millions of years and played key roles, both in the evolution of our brain, for example, and in its pathology, including childhood brain cancers that arise in the embryo itself.

For all these reasons, it is a prize that is more than deserved, and which highlights the value of science that 'only' advances knowledge, but apparently without immediate social utility, in a world that demands short-term profitability. Today the Nobel Committee awards a discovery by Victor Ambros and Gary Ruvkun that changed textbooks forever.

Victor Ambros and Gary Ruvkun have been awarded the Nobel Prize in Physiology or Medicine for the discovery of microRNAs. The central dogma of molecular biology says that from genes (DNA) a molecule called messenger RNA is produced (it looks very much like DNA but is not double-stranded and instead of ‘T’ in its sequence it has ‘U’), which is responsible for carrying the information to the cell factories (ribosomes) that produce proteins (haemoglobin, insulin, etc.).

There are several cracks in this dogma, and the above-mentioned researchers discovered one more: there are genes (about 1,000 in the human genome) that do not produce messenger RNA but a smaller RNA (21 to 25 pieces) called microRNAs that do not produce proteins. These microRNAs are the regulators of messenger RNAs: they bind to messenger RNAs by chemical complementarity and inhibit their function. This phenomenon contributes to the fact that, although all cells in the human body have the same DNA sequence, they can produce different amounts of protein: for example, the retina requires high expression of rhodopsin to see, while the skin expresses high levels of keratin.

The laureates' findings were initially described in a worm widely used in laboratories, Caenorhabditis elegans, in 1993; but later in 2000 they also showed that they occurred in humans. We now know that the expression patterns of microRNAs are altered in many pathologies such as cancer and their genes are mutated in some rare diseases. There is also very active pharmacological research to find drugs that act at the level of microRNAs. This is a well-deserved recognition!

This year's Nobel Prize in Medicine has been awarded to the two American scientists who discovered the regulation of gene expression mediated by microRNAs: Professors Victor Ambros and Gary Ruvkun. Although all the cells in our body have the same genome (the same genes), not all genes are active in all of them. One of the keys to understanding health and disease is the understanding of the mechanisms that govern which genes and to what degree they should be active at any given time in each cell, known as gene expression. In this regard, the awardees' work studying regulatory elements in the development of a small laboratory worm initiated the discovery of a previously unknown broad mechanism of regulation in living organisms.

These researchers discovered that genomes also produce very small RNA molecules (microRNAs) that regulate the expression levels of most genes by binding to specific sequences present in messenger RNAs. Since their discovery in 1993, more than 1,000 human microRNA genes have been identified, and the work of a multitude of laboratories has revealed that these molecules are involved in the regulation of virtually every aspect of our body, including aging, as our laboratory has shown.

This award to Professors Victor Ambros and Gary Ruvkun was long overdue. Their work has been key in the discovery of microRNAs, molecules that play a key role in regulating the activity of many of our genes. Furthermore, these discoveries led to the use of microRNAs as disease markers and new therapeutic targets - Dr. Santiago Vernia and Dr. Susana Rodriguez-Navarro work in the field of RNA at the Institute of Biomedicine of Valencia of the CSIC (IBV-CSIC).

It should be noted that these discoveries were largely possible thanks to the choice of the model organism Caenorhabditis elegans for their research. C.elegans is a small (1 mm) nematode that is easy to grow and manipulate in the laboratory but which, at the same time, shares with humans the main tissues and their regulatory mechanisms, constituting a very powerful tool for characterizing fundamental processes in the functioning of our cells -Dr. Nuria Flames and Dr. José Pérez are both specialists in this small model organism-. Similar strategies have already led to other Nobel Prize winners such as Mello & Fire (2006) who also used C.elegans to characterize other processes such as RNA interference, which has given rise to drugs that have already reached the clinic.