2024 Nobel Laureates in Physiology or Medicine Victor · Ambrose and Gary · Ruffken
Summary: This year's Nobel Prize once again puts the spotlight on the field of life sciences, honoring two scientists who have made outstanding discoveries in the basic principles of gene regulation - Ambrose and Rufken, who discovered microRNA.
This discovery not only reveals how organisms precisely control gene expression to shape complex and diverse biological forms and functions, but also provides valuable clues for us to understand the nature of life and explore new ways to treat diseases.
Deep dive into science | Writing
Two miRNA discoverers were awarded the Nobel Prize
On October 7, Beijing time, the 2024 Nobel Prize in Physiology or Medicine was announced, and the prize was awarded to two scholars, Victor Ambros · Gary ·Ruvkun, who won awards for the discovery of microribonucleic acid (miRNA) and its role in post-transcriptional gene regulation. This discovery is of great significance for understanding the regulatory mechanism of gene expression, and also provides new ideas for the treatment of diseases.
In fact, genetic information is like a delicate script, transcribing DNA into messenger RNA (mRNA), which is then translated into actual proteins through the cell's protein-producing machine. This process, since the middle of the 20th century, has been revealed by a number of basic scientific discoveries.
However, while all cells carry the same genetic information about DNA, our organs and tissues are made up of many different types of cells, each expressing a unique combination of proteins. This wonderful phenomenon is a masterpiece of gene activity regulation.
Gene viability regulation ensures that each specific type of cell activates the correct set of genes to perform its specific function. For example, muscle cells, intestinal cells and different types of nerve cells are able to perform their respective functions and work together to maintain the normal functioning of living organisms.
In addition, gene activity needs to be fine-tuned to adapt to the changing environment in and around us. Deviations in this regulatory mechanism can lead to serious diseases such as cancer, diabetes, or autoimmune diseases. Therefore, understanding the regulatory mechanism of gene activity has been an important goal of scientific research for decades.
Back in the 60s of the 20th century, scientists discovered a special protein called a transcription factor, which is able to bind to specific regions of DNA and control the flow of genetic information by deciding which mRNA is produced. Since then, scientists have discovered thousands of transcription factors and at one time thought that the main principles of gene regulation had been solved.
However, in 1993, Ambrose and Rufken published a revolutionary discovery, miRNA, which opened up a whole new field. At the time, Ambrose and Rufken were intrigued by how different cell types developed, and in their continuous efforts and explorations, they eventually discovered miRNAs. This is a new class of miRNA molecules that play an important role in gene regulation, revealing not only a new principle of gene regulation, but also demonstrating the significance of this principle for multicellular organisms, including human beings.
After winning the award, Victor took a photo with his wife
Today, we know that there are more than 1,000 miRNAs encoded in the human genome. These tiny molecules, in their own unique way, shine on the stage of gene regulation, and they precisely regulate the expression of genes through a complex network of interactions, thus affecting the development and function of organisms.
From studying small nematodes to discovering miRNAs, the two scholars were left out in the cold for 7 years
At the end of the 80s of the 20th century, Ambrose and Rufken were the first to write about H. Postdoctoral researcher in Robert Horvitz's lab. Horvitz later won the Nobel Prize in 2002 alongside Sydney Brenner and John E. Sulston. Using nematodes as a research subject, Horvitz revealed how organ development and programmed cell death are genetically regulated.
Also under the influence of their mentors, in this lab, Ambrose and Rufken studied a seemingly inconspicuous 1 millimeter-long C. elegans (C. elegans). Elegans), despite its small size, possess many of the same specialized cell types as larger, more complex animals, such as nerve cells and muscle cells, and its short lifespan, easy control of growth conditions, transparency throughout, constant number of somatic cells, and fixed location of specific cells make it an ideal model for studying ontogenesis, developmental biology, genetics, and neurobiology.
Ambrose and Ruverken are very interested in genes that control the activation time of different genetic programs, which ensure that various cell types develop at the right time. They studied two mutant nematodes, lin-4 and lin-14, which were defective in the timing of activation of genetic programs during development. They want to identify the mutated gene and understand its function.
In previous studies, Ambrose had demonstrated that the LIN-4 gene appears to be a negative regulator of the LIN-14 gene. However, how LIN-14 activity was blocked was still unknown at the time. Ambrose and Ruverken became intrigued by these mutants and their potential relationships, and set out to solve the mysteries.
After leaving Horvitz's lab, Ambrose conducted an in-depth analysis of lin-4 mutants in a new lab at Harvard University. Through systematic genetic mapping, he successfully cloned the lin-4 gene and made an unexpected discovery. The lin-4 gene produces an abnormally short RNA molecule that lacks a code for a protein. These surprising results suggest that small RNAs from lin-4 are responsible for inhibiting lin-14. So, how does this work?
At the same time, in new labs at Massachusetts General Hospital and Harvard Medical School, Rufken studied the regulatory mechanisms of the LIN-14 gene. Unlike the known mechanisms of gene regulation at the time, Rufken found that mRNA production of lin-14 was not inhibited by lin-4, but that regulation appeared to occur at a later stage of the gene expression process, i.e., by shutting down protein production. The experiment also revealed a sequence in the lin-14 mRNA that is necessary for lin-4 to inhibit its activity.
Ambrose and Ruverken compared their findings and explored them together, leading to a breakthrough. They found that the short lin-4 sequence matched the complementary sequence in the key segment of the lin-14 mRNA. They further demonstrated that lin-4 miRNA shuts down lin-14 and blocks lin-14 protein production by binding to complementary sequences in lin-14 mRNA, and then they discovered a new gene regulation principle mediated by a previously unknown RNA type, miRNA. The results were published in two articles in the journal Cell in 1993.
However, the results of this publication initially received little response from the scientific community. Although the results are interesting, this unusual gene regulatory mechanism is thought to be just one trait of Caenorhabditis elegans and may not be relevant to humans and other more complex animals.
That perception changed in 2000, when Rufken's team published another miRNA they had discovered encoded by the let-7 gene. Unlike LIN-4, the let-7 gene is highly conserved throughout the animal kingdom. The article generated a great deal of interest, and over the next few years, hundreds of different miRNAs were discovered. Today, we know that there are more than a thousand different miRNA genes in the human body, and that miRNA-mediated gene regulation is ubiquitous in multicellular organisms.
How miRNAs are genetically regulated
miRNAs are an important class of non-coding RNA molecules that play an irreplaceable role in the regulation of gene expression. They achieve precise control of cell growth, development, and disease progression through complex regulatory mechanisms and delicate regulatory networks.
The biosynthesis of miRNA is a complex and precise process, which begins with the transcriptional process within the nucleus, which mainly includes two pathways: coding and non-coding. In the encoding process, the structure of the miRNA is encoded in the pri-miRNA transcribed by RNA polymerase II, which is processed to form a pre-miRNA, which is then transported to the cytoplasm, and finally a mature miRNA is generated by the cleavage of nucleases and Dicer enzymes. In non-coding interactions, miRNA sequences exist in the intron or exon regions of non-coding RNAs, and mature miRNAs are produced by intronic cleavage or exon cleavage.
Obviously, without the involvement of miRNAs, cells and tissues cannot develop normally. If there is an abnormality in the regulation of miRNAs, it may lead to serious diseases such as cancer. Mutations in the gene encoding miRNAs have caused a variety of conditions in humans, including congenital hearing loss and eye and bone diseases.
In addition, mutations in one of the key proteins in miRNA production can trigger DICER1 syndrome, a rare but serious disease that is closely associated with cancers of a variety of organs and tissues.
With the continuous development of research and technology, we are expected to have a more comprehensive understanding of the regulatory mechanism and mode of miRNA, and explore more targeted regulatory strategies, opening up a new chapter for life science research and medical treatment.
Profiles of two Nobel laureates
Ambrose is a highly respected United States developmental biologist, born in Hanover, New Hampshire, United States, in 1953, received his Ph.D. from the Massachusetts Institute of Technology (MIT) in 1979, and spent postdoctoral research at MIT from 1979 to 1985, where he gained extensive research experience and expertise.
In 1985, he became a principal investigator at Harvard University, where he began to lead research projects independently, with remarkable results in the field. He was a professor at Dartmouth Medical School from 1992 to 2007. Today, he is the Silverman Professor of Natural Sciences at the University of Massachusetts School of Medicine. It is worth mentioning that a Chinese scholar, Roselind Lee, was a Ph.D. student in Ambrose's lab and participated in almost all of Ambrose's important discoveries on miRNA in his early years.
Rufken is a scientist who has made outstanding contributions to the field of RNA regulation, and his research results have not only advanced the development of life sciences, but also provided new perspectives and methods for human understanding of gene expression, development and disease processes in living organisms.
Born in Berkeley, California, United States, in 1952, he received his Ph.D. from Harvard University in 1982 and did postdoctoral research at the Massachusetts Institute of Technology. In 1985, he became a principal fellow at Massachusetts General Hospital and Harvard Medical School in Boston, where he is currently a professor of genetics.
It can be said that the original discoveries of the two scholars in the field of miRNA not only open the door to understanding gene regulation, but also open up a new field of research in the field of miRNA, where countless molecular biologists around the world are engaged in research, and thousands of papers are published every year to reveal the mystery of life for us.
Resources
1.The Nobel Prize in Physiology or Medicine 2024
2.https://www.nobelprize.org/prizes/medicine/2024/press-release/
3. Just now, the 2024 Nobel Prize in Physiology or Medicine has been announced! Awarded to 2 discoverers of microRNA and gene regulation Deep in Science.
4.https://gruber.yale.edu/recipient/victor-ambros
5.https://gruber.yale.edu/recipient/gary-ruvkun
Review: Liang Ying, Associate Researcher of the Department of Pharmacy, the Second Affiliated Hospital of the Air Force Medical University
Producer: Science Popularization Department of China Association for Science and Technology
Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd