Victor Ambros

Victor Ambros is the discoverer of microRNA — the founding class of small non-coding regulatory RNAs that have transformed the understanding of gene regulation and cancer biology, and for which he was awarded the Nobel Prize in Physiology or Medicine in 2024, jointly with Gary Ruvkun. His discovery, made in the nematode C. elegans in 1993, revealed an entirely unanticipated layer of post-transcriptional gene regulation that controls development across all animal life and is profoundly dysregulated in cancer. Ambros made his seminal discovery while studying the developmental timing genes of C. elegans as a postdoctoral fellow with H. Robert Horvitz and in his own laboratory at Dartmouth College. The lin-4 gene, known to control larval developmental stage transitions, was expected to encode a protein. Instead, Ambros and his team discovered that lin-4 produces a small, approximately 22-nucleotide RNA that base-pairs with complementary sequences in the 3' untranslated region of the lin-14 mRNA, repressing its translation without degrading the transcript. This was a completely unprecedented mechanism of gene regulation — a tiny RNA molecule acting as a post-transcriptional repressor through imperfect base-pairing with its target mRNA. At the time, lin-4 was considered a curiosity of invertebrate development. It was the subsequent discovery by Gary Ruvkun that let-7 — a second small RNA — is perfectly conserved from C. elegans to humans that established microRNAs as a universal regulatory principle. Ambros contributed to characterizing let-7 and demonstrated that miRNAs act through the RNA-induced silencing complex (RISC) in a mechanism related to, but distinct from, RNA interference. Ambros's laboratory has extensively characterized the biogenesis and function of microRNAs in C. elegans developmental circuits, elucidating the Drosha/Pasha (DGCR8) nuclear processing step and Dicer-mediated cytoplasmic maturation. His work defined the basic rules of miRNA-mRNA target recognition — particularly the critical role of nucleotides 2–8 of the miRNA (the "seed" sequence) in determining target selectivity — rules that underpin all computational and experimental miRNA target identification methods. In the cancer context, Ambros's discoveries established the conceptual foundation for understanding how miRNAs function as tumor suppressors (e.g., miR-15a/16, let-7 family members targeting RAS) or oncogenes (oncomiRs such as miR-21, miR-155, miR-17-92 cluster), and how global miRNA dysregulation is a near-universal feature of malignant transformation.

Victor Ambros 是 microRNA 的发现者——这一开创性的小非编码调控 RNA 类别彻底改变了对基因调控和癌症生物学的认识，他因此与 Gary Ruvkun 共同获得2024年诺贝尔生理学或医学奖。 1993年，他在研究线虫发育时序基因时发现：lin-4 基因并不编码蛋白质，而是产生一种约22个核苷酸的小RNA，通过与 lin-14 mRNA 3'非翻译区的不完全碱基配对抑制其翻译——这是一种前所未有的基因调控机制。他的工作定义了 microRNA 的生物发生规则（Drosha/Pasha 核加工步骤和 Dicer 细胞质成熟）及 miRNA-mRNA 靶标识别的"种子序列"原则，为所有 miRNA 靶标预测方法奠定了基础，也为理解 miRNA 在癌症中作为肿瘤抑制因子或癌基因的作用提供了概念基础。