- 10
- Dec.
- 2024
Every year, the Nobel Prize award ceremony takes place on December 10 in Stockholm and Oslo, honoring those who, in accordance with Alfred Nobel's last will, work towards the progress of humanity. On this occasion, This is Beirut highlights the revolutionary discovery of microRNAs through an exclusive interview with Victor Ambros, co-recipient of the 2024 Nobel Prize in Physiology or Medicine for this groundbreaking advancement.
“All of my remaining realisable assets are to be disbursed as follows: the capital, converted to safe securities by my executors, is to constitute a fund, the interest on which is to be distributed annually as prizes to those who, during the preceding year, have conferred the greatest benefit to humankind.” These were Alfred Nobel's final wishes, outlined in his will written in Paris on November 27, 1895. He died on December 10, 1896, and since then, the Nobel Prize award ceremony has been held annually on this date to honor this philanthropist, driven by a deep desire to advance the human condition. Today, as all eyes turn to Stockholm to celebrate the new laureates, This is Beirut takes a closer look at one of the major discoveries that revolutionized our understanding of molecular genetics and, more generally, the functioning of the human organism: the discovery of microRNAs. And it is precisely with Victor Ambros, co-discoverer of microRNAs and co-recipient of the 2024 Nobel Prize in Physiology or Medicine, that we revisit this pivotal scientific breakthrough.
Non-Coding Molecules
To better grasp the significance of this discovery, it is essential to define certain fundamental biological concepts. Genetic information is encoded in DNA (deoxyribonucleic acid), a molecule located in the cell's nucleus, containing the instructions necessary for the development and functioning of the organism. DNA is transcribed into RNA (ribonucleic acid), a molecule that serves as a messenger to transfer this information to the cytoplasm, the intracellular fluid surrounding the nucleus, where many biochemical reactions occur. The RNA produced is then translated into proteins, which perform various structural and functional roles within the cell. These were the basic principles of molecular genetics as understood until the early 1990s. But this was about to change…
In 1993, while Victor Ambros, in collaboration with Rosalind Lee and Rhonda Feinbaum, all researchers at Harvard University, was studying Caenorhabditis elegans (C. elegans), a tiny worm often used as an experimental model, he encountered a rather unexpected result. He was studying a gene called lin-4 which, according to studies published by Chalfie et al. in 1981 and Ambros and Horvitz in 1987, was involved in the animal’s larval development. Much to his surprise, lin-4 does not code for a protein, as most genes do; instead, it produces only... a small piece of RNA. However, this molecule can regulate the expression of another gene, lin-14, by specifically binding to its RNA. This was unprecedented! These results, published on December 2 in Cell, shook established paradigms and quickly became the catalyst for a scientific revolution.
The authors of the study concluded, “lin-4 may represent a class of developmental regulatory genes that encode small antisense RNA products, but such genes might be difficult to identify by standard genetic approaches.” A few years later, another team led by Gary Ruvkun, co-recipient of the 2024 Nobel Prize in Physiology or Medicine, demonstrated the presence of another gene, let-7, still in C. elegans, which shared characteristics similar to lin-4. These discoveries led to the introduction of the term microRNA to describe this type of regulatory RNA.
Healthy Skepticism
In an exclusive interview with This is Beirut, Professor Victor Ambros explains, “microRNAs are a form of small regulatory RNA that enable parts of the genome to regulate information flow from other parts of the genome by nucleic acid complementarity (the building blocks of genes, forming DNA and RNA, that contain genetic information—Ed.).” “The discovery of microRNA was unexpected because there was no particular reason to predict that there should be such small regulatory RNAs that control gene expression post-transcriptionally.” However, after numerous studies aimed at elucidating the function of these key molecules in different plants and animals, it has become clear that microRNAs provide a rich layer of gene regulatory interactions that act independently of transcriptional regulation. “This enables gene regulatory networks to be highly connected and coordinated in ways that endow cells with the potential for increased complexity, and for more robust responses to stress,” adds the Nobel laureate.
The concept that RNA could regulate gene expression —without coding for a protein— appeared not only unlikely but also contrary to the understanding of many scientists at the time, including Ambros himself. “I reacted to the initial result with (what I would call) healthy skepticism of my own,” recalls the American researcher. “I was concerned that we might have missed something, like a very short open reading frame (a sequence of DNA or RNA that could potentially be translated into a small, unconventional peptide—Ed.) encoding an unconventional small peptide.” He continues, “We therefore took measures to experimentally rule out those other possibilities before reporting the small noncoding RNA product of lin-4. After that, we did not experience skepticism from the community, because we had done a good job of ruling out alternatives.”
Therapeutic Prospects
Over the past two decades, studies have revealed that microRNAs are involved in major biological processes, such as cell development, stress response, aging and carcinogenesis, a domain in which their involvement is particularly significant. As key regulators of gene expression, these molecules could offer promising therapeutic prospects for treating cancers, neurodegenerative and cardiovascular diseases, as well as for regenerating damaged tissues. However, they remain in the initial stages of advancement. “I am not an expert in the field of therapeutics development, so I do not really understand, in professional terms, why microRNA-based therapeutics have not been as forthcoming as one might have hoped,” shares Victor Ambros.
Indeed, for microRNAs to become part of the therapeutic arsenal, several complex challenges need to be addressed. “My understanding is that for all therapeutic programs, the challenges are great, and in this context, the especially difficult issue is the specific delivery of oligonucleotide therapeutics (the mircroRNAs in question—Ed.) to desired organs and cell types. My sense is that headway is being made on these delivery challenges, such that we may soon see accelerated emergence of therapies based on microRNA inhibition or supplementation, for example in the context of anticancer treatments.”
Ethical Obstacles
Gene therapy, aimed at correcting genetic mutations or inhibiting pathogenic genes, represents an ambitious research avenue, though it faces considerable technological and especially ethical obstacles. In this regard, Professor Ambros advocates for precise and firm regulation. “I think it is wise for the scientific community to pay close attention to potential ethical issues related to new technology, and to deliberately conduct open discussions of the issues,” he states. According to the septuagenarian biologist, scientists must strive to find an ethically grounded consensus and use it as a basis for informing the public and advising policymakers accordingly. “I believe that ethical issues around new technologies are less about dangers – although dangers can be real – and more about access to new therapies that emerge from new technologies,” he points out, adding that the “cost of new therapies can be prohibitive for general accessibility, and so it seems that more attention needs to be paid to engineering affordability.”
Scientific Philosophy
When a researcher makes a groundbreaking discovery, do they anticipate eventually receiving the Nobel Prize? The new laureate shares his philosophy, “I don’t think it is advisable to aim for the Nobel Prize, or to expect it after making a discovery. That sort of approach to science is a recipe for heartbreak. However, one never knows. It can take a relatively long time for certain discoveries to reveal their importance. I certainly did not expect this award, but after it happened, I came to understand the Nobel Committee’s reasoning.” Finally, Victor Ambros outlines the approach researchers should adopt to push the frontiers of knowledge and uncover new scientific horizons: “I think it is important to build your confidence by welcoming opportunities to: learn about new fields of inquiry, experience new settings and experimental approaches, and work with people of diverse backgrounds, expertise and skill sets,” he emphasizes. And the 2024 Nobel laureate in Physiology or Medicine concludes, “Learn to collaborate effectively, and to trade ideas openly and brainstorm freely.”
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