The 2024 Nobel Prize in Physiology or Medicine was awarded to Victor Ambros and Gary Ruvkun in recognition of their seminal discovery of microRNAs (miRNAs) and their regulatory role in gene expression. This article, published in Blood Science, reflects on the path from the initial identification of miRNAs to their broad biological relevance and emerging therapeutic potential.Historical Foundations and Discovery
The origins of miRNA research trace back to the early 1990s, when Ambros and Ruvkun, both postdoctoral fellows in H. Robert Horvitz’s laboratory at MIT, investigated genes involved in temporal development in Caenorhabditis elegans. Mutations in lin-4 and lin-14 were known to disrupt developmental timing, but the molecular underpinnings remained elusive. In 1993, Ambros’s team revealed that lin-4 was not a protein-coding gene, but a small non-coding RNA derived from a precursor with a stem-loop structure. The mature lin-4 molecule, only 22 nucleotides in length, marked the first identified miRNA. Shortly thereafter, Ruvkun’s group demonstrated that lin-4 post-transcriptionally suppressed lin-14 by imperfect base pairing with its 3′ untranslated region—introducing an entirely new paradigm in gene regulation.
Initial skepticism followed, as many viewed the mechanism as a nematode-specific curiosity. That changed in 2000 with the identification of let-7, a second miRNA that regulates lin-41 and is conserved across a wide range of animal species. This discovery signaled that miRNA-mediated regulation was evolutionarily conserved and broadly significant.
Impact on Hematology and Disease Biology
Since their discovery, miRNAs have been implicated in diverse biological processes, including hematopoiesis and immune regulation. Their roles in blood physiology and disease continue to generate transformative insights. For instance, miRNAs contribute to the intrinsic malaria resistance observed in sickle cell disease. In a 2012 study, researchers found that a miRNA highly expressed in sickled erythrocytes could be transferred into Plasmodium falciparum, where it bound parasitic mRNAs and inhibited their translation—highlighting an extraordinary cross-species regulatory mechanism.
Moreover, miRNA dysregulation is now linked to inherited hematological disorders. A 2023 Science report demonstrated that USB1, an exoribonuclease mutated in poikiloderma with neutropenia (PN), regulates miRNA stability. Defective USB1 leads to the accumulation of unprocessed miRNAs essential for hematopoietic development, providing a molecular explanation for the clinical phenotype of PN.
Mechanistic Advances and Ongoing Innovation
While the basic biogenesis and functions of miRNAs were elucidated in earlier decades, recent years have brought a deeper understanding of the machinery and dynamics governing miRNA pathways. Investigations have revealed that specific RNA-binding proteins, including QKI5 and KSRP, orchestrate selective miRNA maturation and thereby influence lineage commitment during hematopoiesis. Studies employing single-cell transcriptomics and CRISPR-based functional genomics have expanded our knowledge of how miRNAs fine-tune gene expression at the cellular level.
In parallel, long non-coding RNAs (lncRNAs) such as H19 have emerged as important regulators, often working in tandem with miRNAs to guide developmental processes. Such findings suggest a complex, multilayered regulatory network where small RNAs exert precise temporal and spatial control over gene expression.
Conclusion
From their initial discovery in nematodes to their current status as central players in gene regulation, miRNAs have revolutionized molecular biology. Their relevance spans developmental biology, cancer, infectious diseases, and hematologic disorders. As technologies such as cryo-electron microscopy, high-throughput screening, and single-molecule imaging continue to evolve, new dimensions of miRNA biology are being uncovered. Looking ahead, miRNAs are poised not only to serve as powerful biomarkers but also as therapeutic agents in precision medicine, further solidifying their place in the molecular lexicon of human health and disease.
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