The Deeper Meaning of the 2024 Nobel Prize in Physiology or Medicine

On October 7, 2024, the Nobel Assembly of the Karolinska Institute awarded this year's Nobel Prize in Physiology or Medicine to Victor Ambrose and Gary Ruvkun “for the discovery of microRNA and its role in post-transcriptional gene regulation” (https://www.nobelprize.org/prizes/medicine/2024/press-release/). The prize-winning research was published in back-to-back 1993 papers in Cell demonstrating in the nematode worm C. elegans that the lin-4 microRNA regulates the translation and degradation of lin-14 mRNA post-transcriptionally in the cytoplasm during the transition from the first to the second stage of larval developments by base-pairing to the target mRNA. When Ruvkun and colleagues later identified and characterized the more evolutionarily conserved let-7 microRNA to play a similar post-transcriptional regulatory role during the transition from late larval to adult stages in animals from mollusks to vertebrates (but not in plants, yeast, bacteria, jellyfish or sponges), the scientific community began to accept microRNAs as part of the canonical developmental regulatory machinery of multicellular organisms [1]. “Cellular machinery for producing functional microRNAs is also employed to produce other small RNA molecules in both plants and animals, for example as a means of protecting plants against virus infections. Andrew Z. Fire and Craig C. Mello, awarded the Nobel Prize in 2006, described RNA interference (RNAi), where specific mRNA-molecules are inactivated by adding double-stranded RNA to cells.” In fact, the Nobel committee's detailed scientific explanation of the 2006 prize mentioned the work of Ambrose and Ruvkun as exemplifying the potential of RNAi-like mechanisms, although it turns out that the story is more complex, since post-transcriptional control microRNAs (unlike siRNAs) have only partial sequence complementarity with their target mRNAs and interact with protein cofactors not involved in RNAi (https://www.nobelprize.org/prizes/medicine/2006/advanced-information/). “The fundamental principles for the regulation of gene expression were identified more than 40 years ago by the French Nobel Laureates François Jacob and Jacques Monod. Today, we know that similar principles operate throughout evolution, from bacteria to humans (https://www.nobelprize.org/prizes/medicine/2006/summary/).” “Whereas proteins in the nucleus regulate RNA transcription and splicing, microRNAs control the translation and degradation of mRNA in the cytoplasm. This unexpected layer of post-transcriptional gene regulation has critical importance throughout animal development and in adult cell types and is essential for complex multicellular life https://www.nobelprize.org/uploads/2024/10/advanced-medicineprize2024-2.pdfm.” The Nobel Prize committee appears to be reserving the key job of regulating nuclear genome expression to proteins, based on the lac operon model of the 1965 Nobel Prize winners, and relegating the regulatory RNA functions to the cytoplasm. But today, we know that it appears there is little to no selfish junk DNA. The mammalian genome is pervasively transcribed [5-7]. ncRNAs play key roles in the nuclear regulation of transcription and post-transcriptional processing of protein-coding pre-mRNA and mRNA molecules [8]. For example, enhancer elements are transcribed into noncoding eRNAs that help establish the proper chromatin configuration for transcription to occur from target promoters [9, 10]. Although most transcripts currently under study for their diverse functionalities are long noncoding RNAs (lncRNAs) and circular RNAs, it was the microRNAs recognized in the 2006 and 2024 Nobel Prizes that led the way in our understanding that RNA molecules could be more than passive intermediates between DNA and protein. Since the coding regions for many ncRNAs contain repeat copies of abundant mobile genetic elements, including retroviruses and transposons, and the ncRNAs determine so many important phenotypes, such as nervous system development and function [11], we may have to think in new ways about genome evolution in complex multicellular organisms. Transposable element transcripts themselves have important regulatory consequences [12] and their sequences can constitute functional domains for ncRNAs [13, 14]. The evolution of ncRNAs may thus involve the formation of LEGO-like combinations of different repeat and single-copy sequences. It is not difficult to imagine how the insertion of mobile elements into a sequence encoding a regulatory ncRNA can occur physically by transposition or retro-transposition. But mobile repeat elements are the most volatile components in genome evolution [15], and 95% of ncRNAs in mammals are also taxonomically “volatile” [16, 17]. I suggest that this volatility contrasts with the basic maintenance of conserved physiology, morphology, and behavior as new species arise, adapting to our changing environment. How do rapidly changing regulatory ncRNAs affecting virtually every feature of the organism maintain the taxon's basic phenotype, or is their purpose to promote adaptability necessary to sustain life? That question is only one of many that molecular genomics will confront as we enter the new realm of multifunctional RNAs. We can anticipate many more Nobel Prizes for research on RNA coding in the genome, RNA regulation, and RNA evolution. James A. Shapiro: Writing–original draft (lead). The author declares no conflicts of interest. All data are available in the manuscript. The peer review history for this article is available at https://publons.com/publon/10.1002/ntls.20240037.