Medicine Nobel: They found tiny RNA and how it regulates life’s complexity

NEW DELHI A muscle cell, a nerve cell or any other kind of living cell, for that matter, expresses different kinds of proteins. Yet the genetic information in the DNA of all cells of an organism is identical. How, then, does each cell know what kinds of proteins to express, so that it can perform its specialised functions?The answer lies in the precise regulation of gene activity, which involves processes that science has been decoding over the last few decades.This year’s Nobel Prize for Physiology or Medicine, announced on Monday, honours American biologists Victor Ambros, 70, of the University of Massachusetts Medical School, and Gary Ruvkun, 72, of the Massachusetts General Hospital for decoding a key aspect of the gene regulation process. In 1993, they published their findings about a new kind of RNA, called microRNA, and how it performs.To understand their work and its significance, it will help to look first at how cells make proteins.RNA, the intermediaryThe genome of all organisms is made up of DNA, which contains the encoded information for all the genes. The living cells use this information to make proteins, which perform most of the functions that define life. And ribonucleic acid (RNA) of various types plays the role of intermediaries in this process.The road from genes to proteins involves two key processes, transcription and translation. First, using the encoded information, the genes need to be transcribed into RNA, which will then translate into protein. Among the many types of RNA are messenger RNA (mRNA), now a familiar name, which carries the information from the DNA to the region where proteins are to be produced. And then there is microRNA, which is non-coding (it does not make protein) but regulates the performance of mRNA and genes.“The role of microRNAs is to make sure that the genes are transcribed into RNA which then translates into protein. Transcription and translation form the fundamental basis of life, and RNA is in the middle of all that makes life a reality,” said Dr Villoo Morawala Patell, a microbiologist and founder of Avesthagen Limited, a Bengaluru-based research and business organisation that works on several aspects of medicine and biology, including genomics.Although the role of mRNAs is widely studied now, it was unknown until three decades ago. And the process of discovery began with worms.The first discovery…C elegans is a roundworm just 1mm long, but it has long been a subject of research because it contains specialised cell types such as nerve and muscle cells that are also found in more complex animals. Ambros and Ruvkun were studying it in the 1980s in the laboratory of Robert Horvitz, who would go on to win a Nobel Prize in 2002.In particular, they wanted to learn which genes in the worm regulate which activity precisely to ensure that various cell types develop at the right time. To find out how something works precisely, researchers often look at what caused things to go wrong. In this case, Ambros and Ruvkun looked at two mutant strains of the worm with defective timing in genetic activity.Ambros showed that one of the mutant genes produced an unusually short RNA molecule, which lacked a code that would have led to protein production. The absence of this code implied that this small RNA in one mutant gene was responsible for inhibiting the other mutant gene.How did this work? Not by inhibiting the production of mRNA, as Ruvkun showed. The mRNA was indeed produced, but protein synthesis was shut down at a later stage. The two researchers then jointly established how the newly discovered microRNA binds to mRNA and blocks the production of protein.When they published their work in the journal Cell, however, it was not immediately considered a breakthrough.… and the clinching oneFor three decades up to the discovery, a key driver of precise gene regulation was thought to be a class of proteins known as transcription factors. Discovered in the 1960s, transcription factors can bind to specific regions in DNA, which determines what mRNAs are produced, which in turn controls the flow of genetic information.When Ambros and Ruvkun published their findings in 1993, the scientific community largely took microRNA as something unique to the roundworm C elegans, and not necessarily something characteristic of complex animals including humans.The argument was clinched in 2000, when Ruvkun’s research group discovered another microRNA in another gene. This gene was let-7, which is present not just in the worm but throughout the animal kingdom.Since then, more and more different microRNAs have been discovered. Today, some 3,000 microRNA molecules have been explored in the mammalian genome, of which over 2,000 belong to the human genome, according to a 2019 paper in the Indian Journal of Clinical Biochemistry.Why it mattersAcross multicellular organisms, microRNA has been established as a gene regulator, which in turn dictates cellular functions from development and growth to metabolism. It is gene regulation by microRNA that has enabled more and complex organisms to evolve.“This is not something that happened now. These non-coding RNAs have been around in our body for millions of years. They were created in multicellular organisms to exercise control over the process of transcription, to make sure everything works well,” Patell of Avesthagen said.When gene regulation is not precise, it can contribute to various diseases in humans.“Mutations in these microRNAs result in disease and development of cancers, neurodegeneration, deafness and metabolic disorders. The discovery of micoRNA has contributed to the understanding of evolution and will play a big role in understanding disease and finding new cures,” Patell said.Ambros and Ruvkun’s seminal discovery in a small worm, the Nobel Assembly noted, revealed a new dimension to gene regulation that is essential for all complex life forms.

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Medicine Nobel: They found tiny RNA and how it regulates life’s complexity

The Nobel Prize in Physiology honors Ambros and Ruvkun for discovering microRNA, key to gene regulation and vital for cellular functions and evolution.

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Medicine Nobel: They found tiny RNA and how it regulates life’s complexity

The Nobel Prize in Physiology honors Ambros and Ruvkun for discovering microRNA, key to gene regulation and vital for cellular functions and evolution.