Roundworm oddity
I have a personal connection with microRNAs: I worked on them as a graduate student. In fact, in the scientific background article the Nobel Assembly released to inform the public about microRNAs, I recognized authors whose work was being referenced as people who had been on my thesis committee. Back then, microRNAs had a clear relevance to human health and many of us were scrambling to figure out ways in which these tiny molecules could be used to diagnose or treat diseases.

But when they were discovered, microRNAs looked to be an oddity of the roundworm.

Its Latin name is Caenorhabditis elegans, or C. elegans for short. And short it certainly is: the worm is one millimetre in length, which is a little more than the thickness of a credit card. In the second half of the twentieth century, this tiny worm became a model organism in scientific research. Not only was it transparent, which made it easy for researchers to see what was going on inside, its time between generations was a few days, compared to our 20 to 30 years between generations. But most importantly, an adult C. elegans worm had 959 cells. Not 958, nor 960, but exactly 959. Understanding how humans develop from embryos into adults is tricky because of our trillions of cells, but 959? That’s a lot easier to keep track of.

Hence this teensy roundworm became a workhorse of developmental biology laboratories, and researchers mutated some of its genes to see what impact it would have on organ development. The hope was that understanding their function in the worm would shed a light on our own development.

In the 1970s, one of these mutated worms drew the attention of a particular lab. The worm’s development had been grossly altered, and these changes were traced to a mutation in one of its genes. The gene was called lin-4.

At this point, it’s important to mention a foundational bit of knowledge to which these researchers had access and which guided their thinking. DNA makes RNA, and RNA makes proteins. The DNA molecule has segments called genes which contain the instructions to build a particular protein. Genes are transcribed into RNA, which can be thought of as a flimsy, condensed, and disposable copy of the gene, and this RNA is translated into a protein in much the same way that a chef translates a recipe into an actual cake. (For the sake of simplicity, I will not mention other types of RNA molecules which are not translated into proteins.)

But this DNA-to-RNA-to-protein production line is not always on, in much the same way that a chef does not robotically produce cake after cake until they die of exhaustion just because the recipe is in front of their eyes. This chain of events is regulated. In fact, another worm with a mutation in a gene called lin-14 was subsequently discovered, and scientists figured out that the lin-4 gene, the first one, regulated the lin-14 gene.This type of regulation was known to happen via proteins, so it was thought that the lin-4 protein would interfere in some way with the production of the lin-14 protein.

That was not the case. Something much more special was actually happening.

RNA regulating RNA 
The RNA made from lin-4 was surprisingly small, so it was unlikely to code for a protein, much like how a one-sentence-long recipe is unlikely to allow you to build a three-tiered wedding cake. So how was lin-4 regulating the activity of the lin-14 gene?

Gary Ruvkun and Victor Ambros had met as post-doctoral fellows in the 1980s in the laboratory of Robert Horvitz. After their post-docs, they became faculty, with Ambros ending up at Harvard University and Ruvkun at Massachusetts General Hospital and Harvard Medical School. They had been studying this strange lin-4/lin-14 gene regulation mechanism in the worm and on the evening of June 11, 1992, they looked at the sequences of the RNA made from those genes. DNA is made up of a specific string of nucleotides, commonly referred to as letters: A, C, T, and G. (RNA is made of the same molecules, except that T is replaced by U.) You will remember that DNA is a double helix: it has two strands joined together in a spiral staircase shape. This shape is largely due to nucleotides “holding hands” with each other. If one strand has an A, the other strand must have a T, and the A and the T hold hands. Likewise, C and G bind to each other. This is known as complementarity.

What Ruvkun and Ambros saw that fateful evening was that the small lin-4 RNA molecule—so small one might call it a microRNA—would theoretically bind to the tail end of the lin-14 RNA. They had complementarity. This was confirmed by actual experiments, which led to two papers published in 1993 in the celebrated journal Cell.

There was only one problem: this was work done in worms. What about humans?

Seven years went by before a second microRNA would be discovered. Like lin-4, it had been found in the C. elegans worm, but unlike lin-4 it was also present in a broad range of animals, including humans.

We now know that regulating the pipeline of DNA-to-RNA-to-proteins is very complex and does not simply involve proteins. MicroRNAs are made inside our cells, transcribed from our DNA, and these tiny bits of RNA will bind to longer RNA molecules and prevent them from being translated into proteins (or simply reduce the number of proteins made from these RNA molecules). They’re like ball boys in tennis running into your kitchen and grabbing that recipe from the counter before you have a chance to get started, and this is to prevent your kitchen from being overrun with Boston cream pies.

MicroRNAs have been found in 271 different living organisms, including plants, and even some viruses have them. Close to 2,000 microRNAs have been catalogued in humans alone. So, can we harness them in the service of medicine?

As soon as microRNAs were detected in the blood, researchers began to look for signatures. If, let’s say, ten specific microRNAs were always present at elevated levels in the blood of people with melanoma, then that signature in the blood could be used to diagnose people with this skin cancer. Signatures were being published left and right for all sorts of cancers, as either diagnostic, prognostic, or predictive tools, the latter meaning that a signature would predict a patient’s response to a particular treatment. But the problem with these signatures is that they often could not be reproduced, a fact I noticed and published about. If you test a small enough number of patients for a large enough number of molecules, you will find a signature by chance alone. Still, circulating microRNAs continue to hold the promise of being used in such a way. We just need more rigorous data that replicates.

And microRNAs could also be used to treat people. A handful of clinical trials are currently registered, using modified microRNAs to treat conditions like hepatitis C and a rare blood cancer affecting the skin known as mycosis fungoides.

Source: 

https://www.mcgill.ca/oss/article/technology-general-science/tiny-micrornas-win-big-nobel-prize#:~:text=It%20may%20surprise%20you%20but,Prize%20in%20Physiology%20or%20Medicine