ON October 7, US scientists Victor Ambros of the University of Massachusetts Medical School and Gary Ruvkun of Massachusetts General Hospital and Harvard Medical School, were awarded the Nobel Prize in Physiology or Medicine for their discovery of microRNAs, or miRNAs, as key regulators of gene expression, which is a novel physiological mechanism. So far no confirmed applications have emerged from this discovery, despite considerable potential and research.

Every cell contains DNA molecules that house genetic information in the chromosomes. Segments of the DNA, called genes, are transcribed or formed into messenger RNA, and then translated into proteins, the workers of the cell. Although every cell shares the same chromosomes and genes, cells vary in their functions. For instance, there are muscle cells and nerve cells. This is because of the regulation of genes which ensures that only the necessary genes are switched on or off and that the required level of proteins are present in each cell type. This permits a cell to react to changes in the body and environment to attain optimal functioning. An interruption of this process can result in diseases such as cancer, diabetes, and auto-immune disorders.

MICRO RNAs

In the 1960s scientists discovered transcription factors, that is proteins that bind to genes and control which ones are transcribed into mRNA. At that time this was the only known method of gene regulation. In the 1980s, Ambros and Ruvkun were working in the lab of Robert Horvitz, who was awarded the 2002 Nobel Prize for his investigations into genetic regulation of cell death in C. legans, a species of roundworm, now extensively used in research as a model organism. Researchers found that there are two mutant forms of this nematode, one 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 it was not known how it did so.

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 that a section of lin-4 RNA bound part of lin-14's mRNA (messenger RNA), 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, Ambros resigned from Harvard University in 1992, where he had been since 1984, when his tenure application was rejected. Ambros began the next chapter of his career at Dartmouth College, and then at the University of Massachusetts. Former students of Ambros have described him as 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 partly explain why tenure was denied to him.

KEY REGULATORS IN DEVELOPMENT AND DISEASE

When Ambros and Ruvkun first made their discoveries, the scientific community ignored them on the grounds that perhaps the noted feature was a peculiarity of C. elegans and irrelevant in 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. Over the following years, hundreds of different miRNAs were identified in various species.

At first, it was thought that miRNAs inhibited translation without any effect on the stability of mRNA. An important publication in 2005 from Amy Pasquinelli’s laboratory showed that certain miRNAs such as let-7 and lin-4 also hasten the degradation of mRNA. These two modes of miRNA regulation of gene expression, that is  repression of translation as well as degradation of mRNA,  allowed for tighter control of protein production in cells.

MiRNAs are present in all kingdoms of life including animals, plants, and viruses. They 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, the focus is not on what the miRNAs regulate, but rather on 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 malfunctioning of these miRNAs could result in developmental abnormalities and diseases such as auto-immune disorders, metabolic syndrome, and cardiovascular disease.

POTENTIAL USES

Research into miRNAs holds a lot of therapeutic promise. Targeting miRNAs may uncover new therapeutic strategies for conditions like cancer, cardiovascular disease, and neuro-degenerative 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 tumors. For cardiovascular disease, miRNAs like miR-208a and miR-1 might have the potential to regulate heart muscle function and prevent heart failure. In neuro-degenerative 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 important contributors related to miRNA discovery have been missed in the Nobel Committee’s decision. Nobel laureate Venki Ramakrishnan mentioned David Baulcombe, whose laboratory was the first to report a 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 some other names conspicuous by their absence although they continue to be an integral part of the research on miRNA. This reflects a long history of women's discoveries remaining unacknowledged. For example, Rosalind Franklin was excluded from the 1962 Nobel Prize for the structure of DNA. 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.

The under-representation of women in Nobel Prizes is, of course, longstanding. Between 1901 and 2024, only 13 laureates in Physiology or Medicine were women and only 65 out of 653 Nobel Laureates in the sciences. This mirrors systemic bias with white men being favoured, particularly in STEM fields, and the Nobel Committee plays a role in the furtherance of this inequality. But with growing awareness, exclusion in science on the basis of gender and race is drawing increasing attention.