Natural sciences [2024-10-18]

MicroRNA – A Nobel-Winning Discovery

— Dariusz Jan Smoliński

The revelation of microRNA and the understanding of its pivotal role in post-transcriptional gene regulation have heralded a new era in molecular biology, agriculture, and medicine, as remarked by Professor Dariusz Jan Smoliński, commenting on this year's Nobel Prize in Medicine.

In 2024, the Nobel Prize in Physiology or Medicine was awarded to Victor Ambros and Gary Ruvkun for their discovery of microRNA (miRNA) and its function in the post-transcriptional regulation of genes.

MicroRNA – A Revolution in Gene Regulation

Not all genes encode protein products. For instance, small microRNAs act as regulators of other genes. The discovery of miRNA was a breakthrough in molecular biology and genetics. This class of molecules, ranging from 21 to 23 nucleotides in length, plays a crucial role in controlling gene expression, potentially resulting in phenotypic alterations in an organism. The biological significance of these molecules is being rigorously studied, as they offer deeper insights into the mechanisms of gene regulation.

MicroRNAs bind to messenger RNA (mRNA), molecules that encode proteins, reducing their levels. These miRNAs are present in both animal and plant organisms.

Ambros and Ruvkun uncovered that miRNAs—small, non-coding RNA molecules—play an essential role in regulating genes at the post-transcriptional level. They function by binding to complementary sequences in mRNA, leading to mRNA degradation or inhibition of protein translation. This discovery revealed a novel genetic control mechanism, illustrating that gene regulation is far more intricate than previously thought.

In the late 1980s, Victor Ambros and Gary Ruvkun worked in Robert Horvitz's laboratory at the Massachusetts Institute of Technology (MIT). Horvitz, a Nobel laureate in 2002 for his work on genetic regulation of development in Caenorhabditis elegans, fostered a stimulating research environment for young scientists.

Ambros and Ruvkun focused their research on C. elegans, a model organism that, despite its simplicity, shares many characteristics with more complex life forms. They were particularly interested in the lin-4 and lin-14 genes, mutations of which caused significant disruptions in the worm's larval development. These genes were pivotal for understanding when and how decisions about the timing of genetic programs during development are made.

The Discovery of microRNA

In his studies on the lin-4 gene, Victor Ambros discovered that it does not encode a protein but produces a short, non-coding RNA only 22 nucleotides long. At the same time, Gary Ruvkun analyzed the lin-14 gene and found that its expression was regulated post-transcriptionally.

At that time, it was widely believed that the regulation of protein-coding gene expression occurred primarily at the transcriptional level within the gene itself. When the scientists compared their results, they discovered that lin-4 miRNA binds complementarily to the 3'UTR region of lin-14 mRNA, inhibiting its translation. This groundbreaking discovery demonstrated that such a short RNA molecule could serve a significant biological function—regulating protein synthesis post-transcriptionally by interacting with mRNA. This marked the first discovery of miRNA and simultaneously introduced a novel mechanism of post-transcriptional gene regulation.

The Discovery of Conserved microRNA let-7

Another milestone came in 2000 when Gary Ruvkun discovered another miRNA—let-7. Unlike lin-4, let-7 was found to be evolutionarily conserved across many species, including humans. This confirmed that the miRNA regulatory mechanism is a fundamental aspect of gene regulation in multicellular organisms.

To underscore the critical role of microRNA, it is worth noting that the most evolutionarily conserved microRNA genes, such as let-7, have been preserved for hundreds of millions of years and are widely present in animals—from worms and insects to all vertebrates, including humans. These miRNAs function in early embryonic development. Similarly, evolutionarily conserved miRNA genes exist in plants. On the other hand, microRNA genes specific to narrow evolutionary groups play a role in regulating tissue-specific gene expression in adult organisms, rather than in their embryonic development.

The Significance of microRNA in Biology and Medicine

Today, it is known that the human genome encodes over a thousand different miRNAs, which play critical roles in regulating gene expression. miRNAs are involved in controlling the cell cycle, cell differentiation, embryonic development, and the response to stress and external signals.

Abnormal miRNA expression is associated with numerous diseases, such as cancer, cardiovascular, neurodegenerative, and metabolic disorders. For example, disruptions in the activity of specific miRNAs can lead to uncontrolled cancer cell growth or dysfunction in the nervous system.

Research on miRNA has opened new diagnostic and therapeutic possibilities. miRNAs can serve as biomarkers for diseases, enabling early detection and monitoring of disease progression. Targeted therapies focused on miRNA hold promise for treating various disorders by modulating their expression in cells.

In plants, miRNAs also play a variety of roles, including regulating developmental processes such as flowering, organ formation, and leaf shaping. They also influence plant immunity by regulating the expression of genes related to pathogen responses. Moreover, miRNAs are involved in intercellular signaling, where they can be transported between cells or even across tissues to serve signaling functions, influencing various biological processes throughout the organism. Research on plant miRNAs has practical applications in agriculture. Manipulating miRNAs can lead to the development of crops with desirable traits, such as higher yields or disease resistance, contributing to increased agricultural productivity.

Although over 30 years have passed since the discovery of miRNA, much remains to be understood. Current research focuses on identifying new miRNAs, their molecular targets, and regulatory mechanisms. Particularly intriguing are studies on miRNA's role in diseases and therapeutic potential.

Modern technologies, such as next-generation sequencing, CRISPR/Cas9 gene editing, and advanced animal models, are accelerating progress in this field. The development of bioinformatics and tools for analyzing large datasets is helping to identify complex regulatory networks involving miRNAs.

The work of Victor Ambros and Gary Ruvkun is an excellent example of how fundamental research can lead to discoveries of immense significance for science and medicine. The discovery of miRNA revolutionized our understanding of post-transcriptional gene regulation.

Dariusz Jan Smoliński – professor of molecular biology, director of the Institute of Biology, and head of the Department of Cellular and Molecular Biology at the Faculty of Biological and Veterinary Sciences at Nicolaus Copernicus University in Toruń. He specializes in RNA genetics and biochemistry. Between 2020 and 2023, his team achieved significant scientific successes recognized nationally and internationally. In 2023, he received three prestigious awards, including two main prizes from the Polish Society for Experimental Plant Biology for the best scientific publications. He also won the Faculty II of Biological and Agricultural Sciences Prize of the Polish Academy of Sciences for his research on the molecular mechanisms of microRNA biogenesis in plant cells. His research focuses on post-transcriptional gene regulation mechanisms and the use of modern molecular techniques and RNA bioimaging in biology.