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There is a growing need to harness miRNA biology to develop new technologies and focus on its translational applications
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The central dogma of molecular biology—the theory that outlines the flow of genetic information in cells—initially marked RNA as a simple intermediary between DNA and protein. Little did scientists know then that RNA is an extremely versatile molecule with diverse functions. So far, three Nobel Prizes have been awarded to RNA biology—RNA interference or gene silencing, mRNA vaccines against COVID-19, and now, microRNAs and the regulation of gene expression.
This year’s Nobel Prize winners in Physiology or Medicine, Dr Victor Ambros and Dr Gary Ruvkun identified specific RNA molecules—microRNA (miRNA)—that are essential to the expression of genes. While this discovery enabled a greater understanding of cellular and developmental biology, its greatest impact has been in understanding disease states, including cancer, hypertension, hepatitis, and cardiovascular diseases, and in catalysing the research and development of biomarkers and therapeutics.
The amount of a particular kind of protein at any given point of time is reflective of that protein’s biochemical pathways, i.e., its production and synthesis.
Each cell contains genetic information—or genes—that give instructions to cells. These instructions are provided in the form of proteins. The amount of a particular kind of protein at any given point of time is reflective of that protein’s biochemical pathways, i.e., its production and synthesis. Controlling the amount of protein produced from a gene is referred to as gene expression and is critical to the functioning of living organisms. For instance, some genes are turned ‘on’ all the time and produce proteins that maintain essential cellular functions (also referred to as housekeeping genes), while other genes that are specialised, are expressed only under certain conditions. The regulation of gene activity has always been central to the working of researchers because its dysregulation leads to the development of diseases.
Until the early 1990s, scientists believed that gene expression was controlled solely by proteins within the nucleus of cells. While studying developmental abnormalities of the nematode, Caenorhabditis elegans, Nobel Laureates, Dr Victor Ambros and Dr Gary Ruvkun, along with Dr Ambros’ wife, Rosalind C Lee and other researchers, discovered that one of the genes required for its development was silenced (not expressed) by an RNA molecule (miRNA). Moreover, the miRNA was able to affect the timing and expression pattern of a protein involved in the post-embryonic development of the nematode. This was considered a novel discovery at that time because RNA molecules were not known to play a role in regulating gene expression.
The miRNA was able to affect the timing and expression pattern of a protein involved in the post-embryonic development of the nematode.
Over the next decade, researchers identified that miRNAs were present in plants and other animal species, including humans, indicating that they are highly evolutionarily conserved. They were found to play a crucial role in regulating gene expression. By 2001, miRNAs were characterised as small RNA molecules that regulated gene expression by inhibiting an intermediate step in protein production.
Essentially, if a particular miRNA is found in high amounts in cells, the expression of the protein it regulates will be low, while protein expression will be high if the miRNA that controls it is under-expressed. Genes that miRNAs control include those involved in cell death, cell cycle, secretion of hormones, such as insulin, and the differentiation of cells into specific ones. Thus, the production of miRNAs within cells is also tightly regulated.
The relevance of miRNAs comes into play in disease conditions. Dysregulated levels of miRNA have been observed in cancer, cardiovascular disease, diabetes, certain viral infections, and neurological diseases.
In cancers, the levels of certain miRNAs are abnormal. These create ‘unique signature patterns’ that allow the identification of different kinds of cancers and their progression. This makes it an ideal biomarker—a molecule found within the body that can indicate whether biological processes are functioning adequately or if there is an underlying condition, disease, or abnormality—for cancer diagnosis and prognosis during therapy.
They are attractive biomarkers because they exhibit specificity for their target, their levels are stable in body fluids and under different storage conditions (during lab analyses), and offer a non-invasive or minimally invasive method of access. Many miRNAs are in various stages of research and development for use as biomarkers.
miR-21 levels were found to be associated with progressive heart disease, such as hypertrophy and myocardial infarction.
miRNA-21 (miR-21) is an extensively studied one that is ubiquitously expressed and performs essential cellular functions. Its levels are found to be stable in bodily fluids, making it a reliable indicator of injury or a disease state. miR-21 levels were found to be associated with progressive heart disease, such as hypertrophy and myocardial infarction. Experimental studies have demonstrated that serum levels of miR-21 can be used as a non-invasive method to predict heart disease.
In the same vein, miRNAs are dysregulated in neurological diseases, including Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). Most of the therapies available for these neurological diseases are symptomatic treatments. These diseases are often debilitating and significantly diminish the quality of life. Health efforts currently target innovative diagnostic tools. Some studies indicate that neuronal changes occur 10-20 years prior to the onset of symptoms. Biomarkers that can detect disease before the onset of symptoms would enable clinicians to administer therapies more effectively.
A naturally occurring miRNA, miRNA-122 (miR-122), was found to enhance the stability of the Hepatitis C Virus (HCV) genome and contributed to the development of hepatocellular carcinoma (HCC). While miR-122 is used as a biomarker to detect HCV infection and HCC progression, therapeutics comprising molecules that bind to miR-122 are currently undergoing clinical trials against HCV infections.
While miR-122 is used as a biomarker to detect HCV infection and HCC progression, therapeutics comprising molecules that bind to miR-122 are currently undergoing clinical trials against HCV infections.
Several miRNA-based therapies are in various stages of pre-clinical and clinical development. A significant challenge miRNA-based therapies face is that a single miRNA may target many genes and its functionality varies by disease stage as well. There are over 2,000 miRNAs that control more than 60 percent of the human genome. This makes targeted therapeutic approaches challenging for researchers. Other obstacles are related to their physical properties for instance, miRNAs may be degraded by naturally occurring enzymes within the body, may be poorly delivered to target sites, run the risk of eliciting immune responses, and may be rapidly cleared from the blood.
Several diseases, such as acute myeloid leukaemia and PD, require unique therapies as patients face drug resistance and delays in diagnoses, contributing to morbidity and mortality. The discovery of miRNAs represents a significant turn for biotechnology. Its diagnostic and therapeutic potential offers substantial opportunities for further research in pre-clinical and clinical studies, and biopharmaceutical development. Considerable research lies in developing suitable mi-RNA delivery systems, including nanoparticles, viral vectors, and polymers that can deliver miRNAs to specific targets.
India can endeavour to carry out studies on miRNA biology with the aim of producing clinically relevant molecules and diagnostics under the new Bio-E3 and Bio-RIDE policies.
Biopharmaceutical research needs to be directed towards developing mi-RNA delivery vehicles that are specific, pose no or low levels of toxicity, and display potent clinical efficacy. India can endeavour to carry out studies on miRNA biology with the aim of producing clinically relevant molecules and diagnostics under the new Bio-E3 and Bio-RIDE policies. In addition, international collaborations, such as ones similar to Cancer Moonshot—the Indo-US cooperation on cancer—can be implemented to fast-track the development of novel therapies and diagnostics. The Nobel Prize signifies the importance of harnessing miRNA biology to develop novel technologies and highlights the need for academic and clinical research to focus on the translational applications of miRNA biology.
Lakshmy Ramakrishnan is an Associate Fellow at the Observer Research Foundation.
The views expressed above belong to the author(s). ORF research and analyses now available on Telegram! Click here to access our curated content — blogs, longforms and interviews.
Lakshmy is an Associate Fellow with ORF’s Centre for New Economic Diplomacy. Her work focuses on the intersection of biotechnology, health, and international relations, with a ...
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