The worm that turned … into a transformational scientific discovery

Most readers will be familiar now with RNA thanks to the development of the Covid vaccine, with the two scientists whose research into RNA enabled the vaccine’s development winning the Nobel Prize for physiology and medicine in 2023. Readers would be forgiven for missing the fact that research into RNA won the same prize this year, announced on October 7, for the discovery of microRNA, tiny RNA molecules that play a crucial role in gene regulation.

Victor Ambros of the University of Massachusetts Chan Medical School and Gary Ruvkun of Harvard Medical School discovered these tiny RNA molecules control gene expression in many species across the animal kingdom, from a tiny worm called C.elegans to humans.

I mention those two species specifically because it was the serendipitous discovery of a single microRNA in the nematode in 1992 that led us to an understanding of how microRNAs affect human health. The prize is awarded to fundamental science, but this discovery (like the research done by last year’s winners) has significant health implications.

Allow me to go back to the beginning, of all known forms of life that are based on the same fundamental biochemical organisation: genetic information encoded in Deoxyribonucleic acid (DNA), the genes that are safely stored in chromosomes inside the nucleus of a cell. When a gene is activated, it is transcribed into another form of nucleic acid – messenger Ribonucleic acid (mRNA) which then departs the cell nucleus to be translated into protein by the ribosome residing in the cell cytoplasm.

The path of DNA to mRNA to protein is fundamental to life and represents the mechanism for the faithful reproduction of the genetic code governing all life on earth. How and when genes are turned on or off determines all aspects of life, whether a cell becomes a liver cell for instance, or a brain, bone or blood cell, or a cancer cell.

The intricate control of gene expression was thought to be mostly at the first step of DNA to RNA but Ambros and Ruvkun’s discovery revealed another means of controlling gene expression that we now know to be ubiquitous across all species.

This was not an overnight discovery by any stretch of the imagination. It can be traced back to 30 years ago, when Ambros and Ruvkun, working as friendly scientific collaborators in Boston, simultaneously and independently published two papers in the journal Cell describing a gene they had discovered called lin4 that controlled the fate of many cells in the flatworm C. elegans, a tiny nematode that is used as a model in the field of developmental biology.

C. elegans is a powerful scientific model because it has fewer than 1000 cells, grows fast and is transparent when viewed under the microscope, making changes in growth and cell patterns obvious to the naked eye. What mystified the two scientists was there was no way the nematode’s lin4 gene could code for a protein, yet it still exerted control over the fate of many cells in C. elegans from the embryo to the adult.

What they were able to show, described by Ruvkun as their eureka moment, was that the lin4 gene coded for tiny bits of RNA (22 and 64 nucleotides long for those who understand nucleic acid structure). These short bits of RNA complemented the sequence of another gene called lin14 that was essential for cell development in C. elegans.

They deduced that the tiny lin4 RNA molecules attached themselves to the lin14 RNA molecule to control how much lin14 protein could be made – a crucial step in the development of C. elegans. This was the first example of what we now know to be a fundamental mechanism of gene control, not just in cell development but for many other cellular functions, with obvious implications for understanding how cancer, neurological and autoimmune diseases develop, and new ways to treat them.

Not many scientists paid much attention at the time. As so often happens in science, their discovery in 1992 of lin4/lin14 was met with relative silence except within the tightly knit C. elegans science community. Most biologists thought it was interesting, but probably unique to C. elegans with little relevance to any other species.

It took years to find other examples of microRNAs at work, because they are so small and very hard to find using conventional techniques. Fast forward 30 years and thousands of different microRNAs have been discovered controlling all manner of cell functions in all species from worms to man and pretty much every other life form in between.

The discovery of lin4/lin14 in C. elegans ranks among the great recent discoveries in biology and medicine and is another great example of how medicine is transformed by serendipitous discoveries made from basic scientific research that often take years to realise – which we scientists would point to as exemplifying the value of basic curiosity-driven research that is not applied to any expected outcome.

The Nobel prize for physiology or medicine is awarded for discoveries that transform medicine and human health so what is the impact of RNAs on medicine? We know for example that microRNA can regulate tumours, which means they can be used as a biomarker for cancer, or open up new treatments. We also know that microRNAs regulate several neurodegenerative diseases such as Alzheimer’s which again means diagnostic markers and novel treatments.

The world of microRNA research is now vast and new discoveries are made on a regular basis – all thanks to the research done by scientists into a tiny strip of RNA first identified in a transparent 1mm-long nematode.