Nobel for MicroRNA Work: Recognising Basic Science, Open Research

On October7 , the Nobel Prize in Physiology or Medicine was awarded to US scientists Victor Ambros of the University of Massachusetts Medical School and Gary Ruvkun of Massachusetts General Hospital and Harvard Medical School for their key discovery that miRNAs are major gene expression regulators, thereby providing a new physiological mechanism.

Although this encompasses tremendous potential and what could appear to be an uninterrupted study on miRNAs, no practical application has been established based on such a discovery to date.

Every cell has DNA molecules containing genetic information on chromosomes. Segments of this DNA, known as genes, are transcribed into mRNA and then translated into proteins that constitute the cell's functional parts. If the same chromosomes and genes are found in every cell, why do cells have different functions-like muscle versus nerve cells? Because of gene control. It ensures that only the right genes are activated or deactivated, thereby maintaining proper protein levels in each cell type. This allows cells to adapt to changes in the body and the environment for optimal performance. Dysregulation of the process can lead to diseases as diverse as cancer, diabetes, and autoimmune disorders.

MicroRNAs

In the 1960s, scientists discovered transcription factors—proteins that bind to genes and control which areas are transcribed into mRNA, a phenomenon believed then to be the most important approach of gene regulation.

In the 1980s, as post-doctoral fellows, Ambros and Ruvkun were working in the lab of Robert Horvitz, who was awarded the 2002 Nobel Prize for his investigations on genetic regulation of cell death in C. elegans. Researchers found that there are two mutant forms of this nematode, one for where the lin-4 gene resulted in a longer nematode and the lin-14 gene produced a smaller one. Ambros showed that lin-4 repressed lin-14 but how it did so was undetermined.

Later, Ambros, as an independent researcher at Harvard University, worked on duplicating the lin-4 gene but only obtained an RNA molecule too small to code for a protein. Around the same time, Ruvkun, at Massachusetts General Hospital and Harvard Medical School, studied lin-14. He discovered that lin-4 did not block lin-14 transcription but interfered with the protein production.

Ruvkun and Ambros discussed and shared their findings - a hallmark of not for profit, open science. They found a section of lin-4 RNA bound part of lin-14's mRNA, preventing its translation into protein. This revealed a new gene regulation mechanism using short RNA molecules. Their studies were published in the journal Cell in 1993. In 2001, Ruvkun coined the term microRNA (miRNA) for these 21-25 nucleotide-long RNA molecules that regulate mRNAs without coding for proteins.

Interestingly in 1992, Ambros resigned from Harvard University, where he had become a young professor since 1984, after his tenure application was rejected. During the same period, his collaborator and co-Laureate Ruvkun got a permanent tenure at Harvard.

Ambros further progressed and began this new chapter of his career first at Dartmouth College and then at the University of Massachusetts. Former students of Ambros have described him as a pioneering scientist but an incredibly hands-on mentor. Unlike most principal investigators, who opt out of direct lab work to focus on administrative and funding matters, Ambros wanted to remain directly involved at the bench. From some accounts, his highly collaborative nature might have clashed with personalities at Harvard, which may be part of the reason why his tenure was denied.

When Ambros and Ruvkun first made their discovery, the scientific community basically ignored it, stating that perhaps it was a peculiarity of C. elegans only and thereby irrelevant to more complex organisms. Then in 2000, Ruvkun's group identified another miRNA, let-7, which is highly conserved across the animal kingdom. This generated a lot of interest, and in the following years, hundreds of different miRNAs were identified in various species.

Researchers initially thought that miRNAs repressed translation but did not affect mRNA stability. It was the seminal 2005 study by the lab of Amy Pasquinelli that surprised everyone in showing that miRNAs such as let-7 and lin-4 also triggered degradation of their mRNA targets. That moved the understanding to a point where it indicated that a dual mechanism is responsible for miRNA regulation of gene expression: translation repression and induction of mRNA degradation. Such a mechanism allows for a tight control over protein production in cells.

It has been found that miRNAs are present in all kingdoms of life, including animals, plants, and viruses. These molecules function to regulate growth and environmental stress responses in plants. In viruses like Epstein-Barr virus, miRNAs have been discovered controlling host immune evasion through regulation of gene expression.

In developmental biology, it's not what the miRNAs regulate but rather the timing of the key processes. In C. elegans, lin-4 and let-7 regulate developmental transitions. In mammals, for example, miR-1 and miR-133 control muscle development while miR-9 controls neurogenesis. Also, it has been found that miRNAs exist in breast milk.

Apart from development, miRNAs have been found to play roles in regulating other physiological processes. These include miR-146a that has been linked with control of inflammation; miR-155 that has been associated with regulation of inflammatory responses; and miR-33, a cholesterol regulator. These indicate that absence or misfunctioning of these miRNAs could result in developmental abnormalities and diseases, such as autoimmune disorders, metabolic syndrome, and cardiovascular disease.

Potential Uses

Research into miRNAs also has lot of therapeutic promise. Targeting miRNAs may uncover new therapeutic strategies for conditions like cancer, cardiovascular disease, and neurodegenerative disorders. Therapeutic approaches could either be to repress pathologic miRNAs or to restore beneficial miRNAs.

For example, in the case of cancer, introduction of mimics of let-7 miRNAs may become useful because of their tumour suppressing activity. Oncogenic miRNAs, such as miR-21, could be blocked to delay the progression of tumours. For cardiovascular disease, miRNAs like miR-208a and miR-1 might have the potential to regulate heart muscle function and prevent the failing heart. In neurodegenerative diseases, miRNAs play important roles in the regulation of neuronal survival and function.

Beyond this, the miRNAs are also being explored for their use as diagnostics. As they are stable in the body's fluids, for example, blood and urine, these might prove to be helpful in the early diagnosis of diseases. For instance, an upregulation of a particular miR-141 in plasma relates with prostate cancer while changes in the level of miR-122 relate with a number of pathologies in the liver.

Point for Concern

Some of the major contributors to the research on miRNAs, did not receive consideration. Nobel Laureate Venki Ramakrishnan mentioned David Baulcombe, whose lab had discovered the closely related gene-silencing phenomenon in plants. Baulcombe shared the 2008 Lasker Award with Ambros and Ruvkun.

Amy Pasquinelli, whose 2005 paper changed the understanding of the function of miRNA; and Rosalind Lee, married to Ambros and first author on the Ambros 1993 paper cited in the prize award, are the other names conspicuous by absence although they continue to be an integral part of the research on miRNA.

This exclusion reminds of several instances whereby discoveries by women went unacknowledged, such as Rosalind Franklin, who was left out in the Nobel Prize in 1962, when Watson, Crick, and Wilkins were awarded for discovering the DNA structure. In RNA biology, independent scientists Louise Chow and Sara Lavi were first co-authors and important contributors to the work that resulted in the 1993 Nobel Prize for Physiology or Medicine on split genes to Richard Roberts and Philip Sharp.

This history of under-representation of women amongst Nobel Prize winner is worrisome. Between 1901 and 2024, for example, only 13 of 229 Physiology or Medicine laureates were female. There are just 65 women among the 653 Nobel Laureates in the sciences. These facts are partly explained by systemic bias favouring white men, especially in STEM fields.

It has been a part of this tradition of favouring white men in the Nobel Committee. After all, along with the growing awareness of women's contributions, their legacy of exclusion based on gender and race has been a contentious issue within science.

The writer is a retired Professor, School of Biotechnology, Madurai Kamaraj University. He is in the All-India People’s Science Network. The views are personal.