北京时间10月7日下午5点30分许，2024年诺贝尔生理学或医学奖揭晓。美国科学家 Victor Ambros 及 Gary Ruvkun 获奖，以表彰他们“发现mRNA及其在转录后基因调控中的作用”。
今年的诺贝尔奖表彰了两位科学家，他们发现了调控基因活性的一个基本原理。
存储在我们染色体中的信息可以类比为我们身体所有细胞生长分化的指导手册。每个细胞都含有相同的染色体，因此每个细胞都含有完全相同的一组基因和完全相同的一组指令。然而，不同类型的细胞，如肌肉细胞和神经细胞，具有非常不同的特性。这些差异是如何产生的？答案在于基因调控，它允许每个细胞只选择听从与其相关的指令。这确保了在每种细胞类型中只有正确的基因集是活跃的。
Victor Ambros 和 Gary Ruvkun，这两位杰出的科学家，一直对一个根本性的问题充满好奇：不同细胞类型是如何在生物体内发育起来的？他们最终揭开了microRNA的神秘面纱——这是一种新型的RNA分子类别，它在基因调控中扮演着不可或缺的角色。他们的开创性发现揭示了一种全新的基因调控原则。这一原则对于包括人类在内的多细胞生物来说，具有至关重要的意义。如今，我们了解到人类基因组中编码了超过一千种microRNA，这些microRNA在调控基因表达、细胞分化和组织发育等方面发挥着核心作用。
Essential regulation
This year’s Nobel Prize focuses on the discovery of a vital regulatory mechanism used in cells to control gene activity. Genetic information flows from DNA to messenger RNA (mRNA), via a process called transcription, and then on to the cellular machinery for protein production. There, mRNAs are translated so that proteins are made according to the genetic instructions stored in DNA. Since the mid-20th century, several of the most fundamental scientific discoveries have explained how these processes work.
Our organs and tissues consist of many different cell types, all with identical genetic information stored in their DNA. However, these different cells express unique sets of proteins. How is this possible? The answer lies in the precise regulation of gene activity so that only the correct set of genes is active in each specific cell type. This enables, for example, muscle cells, intestinal cells, and different types of nerve cells to perform their specialized functions. In addition, gene activity must be continually fine-tuned to adapt cellular functions to changing conditions in our bodies and environment. If gene regulation goes awry, it can lead to serious diseases such as cancer, diabetes, or autoimmunity. Therefore, understanding the regulation of gene activity has been an important goal for many decades.
The flow of genetic information from DNA to mRNA to proteins. The identical genetic information is stored in DNA of all cells in our bodies. This requires precise regulation of gene activity so that only the correct set of genes is active in each specific cell type. In the 1960s, it was shown that specialized proteins, known as transcription factors, can bind to specific regions in DNA and control the flow of genetic information by determining which mRNAs are produced. Since then, thousands of transcription factors have been identified, and for a long time it was believed that the main principles of gene regulation had been solved. However, in 1993, this year’s Nobel laureates published unexpected findings describing a new level of gene regulation, which turned out to be highly significant and conserved throughout evolution.
Research on a small worm leads to a big breakthrough
In the late 1980s, Victor Ambros and Gary Ruvkun were postdoctoral fellows in the laboratory of Robert Horvitz, who was awarded the Nobel Prize in 2002, alongside Sydney Brenner and John Sulston. In Horvitz’s laboratory, they studied a relatively unassuming 1 mm long roundworm, C. elegans. Despite its small size, C. elegans possesses many specialized cell types such as nerve and muscle cells also found in larger, more complex animals, making it a useful model for investigating how tissues develop and mature in multicellular organisms. Ambros and Ruvkun were interested in genes that control the timing of activation of different genetic programs, ensuring that various cell types develop at the right time. They studied two mutant strains of worms, lin-4 and lin-14, that displayed defects in the timing of activation of genetic programs during development. The laureates wanted to identify the mutated genes and understand their function. Ambros had previously shown that the lin-4 gene appeared to be a negative regulator of the lin-14 gene. However, how the lin-14 activity was blocked was unknown. Ambros and Ruvkun were intrigued by these mutants and their potential relationship and set out to resolve these mysteries.
(A) C. elegans is a useful model organism for understanding how different cell types develop. (B) Ambros and Ruvkun studied the lin-4 and lin-14 mutants. Ambros had shown that lin-4 appeared to be a negative regulator of lin-14. (C) Ambros discovered that the lin-4 gene encoded a tiny RNA, microRNA, that did not code for a protein. Ruvkun cloned the lin-14 gene, and the two scientists realized that the lin-4 microRNA sequence matched a complementary sequence in the lin-14 mRNA. After his postdoctoral research, Victor Ambros analyzed the lin-4 mutant in his newly established laboratory at Harvard University. Methodical mapping allowed the cloning of the gene and led to an unexpected finding. The lin-4 gene produced an unusually short RNA molecule that lacked a code for protein production. These surprising results suggested that this small RNA from lin-4 was responsible for inhibiting lin-14. How might this work?
Concurrently, Gary Ruvkun investigated the regulation of the lin-14 gene in his newly established laboratory at Massachusetts General Hospital and Harvard Medical School. Unlike how gene regulation was then known to function, Ruvkun showed that it is not the production of mRNA from lin-14 that is inhibited by lin-4. The regulation appeared to occur at a later stage in the process of gene expression, through the shutdown of protein production. Experiments also revealed a segment in lin-14 mRNA that was necessary for its inhibition by lin-4. The two laureates compared their findings, which resulted in a breakthrough discovery. The short lin-4 sequence matched complementary sequences in the critical segment of the lin-14 mRNA. Ambros and Ruvkun performed further experiments showing that the lin-4 microRNA turns off lin-14 by binding to the complementary sequences in its mRNA, blocking the production of lin-14 protein. A new principle of gene regulation, mediated by a previously unknown type of RNA, microRNA, had been discovered! The results were published in 1993 in two articles in the journal Cell.
The published results were initially met with almost deafening silence from the scientific community. Although the results were interesting, the unusual mechanism of gene regulation was considered a peculiarity of C. elegans, likely irrelevant to humans and other more complex animals. That perception changed in 2000 when Ruvkun’s research group published their discovery of another microRNA, encoded by the let-7 gene. Unlike lin-4, the let-7 gene was highly conserved and present throughout the animal kingdom. The article sparked great interest, and over the following years, hundreds of different microRNAs were identified. Today, we know that there are more than a thousand genes for different microRNAs in humans, and that gene regulation by microRNA is universal among multicellular organisms.
In addition to the mapping of new microRNAs, experiments by several research groups elucidated the mechanisms of how microRNAs are produced and delivered to complementary target sequences in regulated mRNAs. The binding of microRNA leads to inhibition of protein synthesis or to mRNA degradation. Intriguingly, a single microRNA can regulate the expression of many different genes, and conversely, a single gene can be regulated by multiple microRNAs, thereby coordinating and fine-tuning entire networks of genes.
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, where specific mRNA-molecules are inactivated by adding double-stranded RNA to cells.
Tiny RNAs with profound physiological importance
Gene regulation by microRNA, first revealed by Ambros and Ruvkun, has been at work for hundreds of millions of years. This mechanism has enabled the evolution of increasingly complex organisms. We know from genetic research that cells and tissues do not develop normally without microRNAs. Abnormal regulation by microRNA can contribute to cancer, and mutations in genes coding for microRNAs have been found in humans, causing conditions such as congenital hearing loss, eye and skeletal disorders. Mutations in one of the proteins required for microRNA production result in the DICER1 syndrome, a rare but severe syndrome linked to cancer in various organs and tissues.
Ambros and Ruvkun’s seminal discovery in the small worm C. elegans was unexpected, and revealed a new dimension to gene regulation, essential for all complex life forms.
Key publications
Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843-854. doi:10.1016/0092-8674(93)90529-y
Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell. 1993;75(5):855-862. doi:10.1016/0092-8674(93)90530-4
Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kurodak MI, Maller B, Hayward DC, Ball EE, Degnan B, Müller P, Spring J, Srinvasan A, Fishman M, Finnerty J, Corbo J, Levine M, Leahy P, Davidson E, Ruvkun G. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000;408(6808):86-89. doi:10.1038/35040556
根据诺贝尔奖官网显示，诺贝尔生理学或医学奖每年评选和颁发一次。下面我们一起来回顾近十年来（2014—2023）的诺贝尔奖成果，重温医学和生理学的激情岁月。
2023年诺贝尔生理学或医学奖颁给Katalin Karikó及Drew Weissman，以表彰“发现核苷基修饰，从而开发出有效的抗COVID-19 mRNA疫苗”的重要贡献。
2022年诺贝尔生理学或医学奖颁给了瑞典遗传学家斯万特·帕博（Svante Pääbo ），以表彰他在已灭绝的古人类基因组和人类进化方面的发现。
2021年诺贝尔生理学或医学奖颁给了戴维·朱利叶斯（David Julius）和雅顿·帕塔普蒂安（Ardem Patapoutian），以表彰他们对于温度和触觉感受器的发现。
2020年诺贝尔生理学或医学奖颁给了哈维·阿尔特(Harvey J. Alter)、迈克尔·霍顿(Michael Houghton)、以及查尔斯·赖斯（Charles M. Rice）。他们因发现丙肝病毒而获奖。
2019年诺贝尔生理学或医学奖获得者有三位，他们分别是来自哈佛医学院达纳-法伯癌症研究所的威廉·凯林（William G. Kaelin Jr.），牛津大学和弗朗西斯·克里克研究所的彼得·拉特克利夫（Peter J. Ratcliffe）以及美国约翰霍普金斯大学医学院的格雷格·塞门扎（Gregg L. Semenza），以表彰他们在理解细胞如何感知和适应氧气供应方面做出的贡献。
2018年诺贝尔生理学与医学奖由美国免疫学家詹姆斯·艾利森（James P. Alison）和日本免疫学家本庶佑（Tasuku Honjo）两人共享，以表彰他们在发现负性免疫调节治疗癌症疗法方面的贡献。
2017年诺贝尔生理学或医学奖得主为美国科学家杰弗里·霍尔（Jeffrey C. Hall）、迈克尔·罗斯巴什（Michael Rosbash）和迈克尔·扬（Michael W. Young），获奖理由为“奖励他们在有关生物钟分子机制方面的发现”，以表彰三人发现了控制昼夜节律的分子机制。
2016年的诺贝尔生理学与医学奖颁给了日本东京工业大学大隅良典（Yoshinori Ohsumi），奖励他在细胞自噬研究中的贡献，阐明了细胞自噬的分子机制和生理功能。
2015年的诺贝尔生理学或医学奖是最令国人印象深刻的，我国科学家屠呦呦获奖，成为第一位获得该奖的中国本土科学家！获奖理由为“有关疟疾新疗法的发现”。另外两名获奖科学家为爱尔兰的威廉·坎贝尔（William C. Campbell）和日本的大村智（Satoshi ōmura），获奖理由是“有关蛔虫寄生虫感染新疗法的发现”。
2014年的诺贝尔奖生理学或医学奖也很特别，出现了“夫妻档”。三位获奖得主分别为美国科学家约翰-欧基夫（John O’Keefe），以及挪威科学家梅-布莱特-莫索尔（May Britt Moser）、爱德华-莫索尔（Edvand Moser）夫妇，以奖励他们在发现大脑中组成定位系统的细胞方面所做的贡献。