Tuning in is key to control of disease

A group of researchers at TCD is studying the molecules behind volume control systems – microRNAs – which can tune a disease process up or down

SUPPOSE YOU went to listen to an orchestra, but during the concert the volume control on individual sections went awry. First the strings section was muted. Next the decibels from the woodwind and percussion sections went so high they hurt your ears. You’d be asking for your money back.

In a similar way, if the volume control on biochemical processes is disrupted, it can throw our cells into disarray and possibly contribute to disease. That’s why a group at Trinity College Dublin is looking at the molecules behind this cellular volume control, known as “microRNAs” .

MicroRNAs are a recent discovery and research into them has exploded in the last few years, explains Luke O’Neill, professor of biochemistry at Trinity, who is looking at their roles in the immune system and disease.

First reported in roundworms, microRNAs are short stretches of RNA encoded by genes. These particular RNA molecules can put the brakes on the activities of proteins and thereby help to turn the noise up or down on biochemical processes that underpin normal development or disease.

The discovery of this odd RNA in roundworms was initially seen as something of a mystery, says O’Neill. “It was published and it was ignored – people thought it was a quirk of the worm,” he says. “But then people found plants had a similar system and then it was found in mammals. This opened up a new world as a whole new level of control, and we now know microRNA is a key modulator, it’s a fine-tuner of proteins of cells.”

The field has now mushroomed and identified around a thousand microRNAs in humans, says O’Neill, who has recently turned his attention to how microRNAs are involved in disease and the immune system.

“Probably every biological process has a microRNA or set of microRNAs behind it, but when we began our work about three or four years ago nothing much was known about them in the immune system at all,” he says.

“Then we began to find them in the immune system. We began to find they were very strongly regulated by Tolls , and Toll Four was inducing loads of them.”

In particular, their research pointed to microRNAs having roles in keeping inflammation under control.

“We have found that microRNA is very important for dampening down the inflammatory process – through a negative feedback effect they fine tune the system,” says O’Neill. “We have stumbled into a set of molecules that are probably important for the resolution phase of inflammation, so microRNAs are very important for returning the body to normality after an infection.”

This summer, O’Neill’s team will start another research project on microRNAs in the immune system, teasing out a potential tug of war between microRNA 155 and microRNA 21 during inflammation. So far this work, which was funded by Science Foundation Ireland, has looked at how the microRNAs affect cells. But with a grant from the European Research Council, O’Neill can now progress the research to more complex preclinical models to get a more complete picture.

“We are very much on a frontier here,” says O’Neill. “We are really fishing now in the world of microRNAs, to see are they relevant and can they affect disease outcome.”

And knowing more about the mechanics of the volume control will help inform the use of microRNAs in diagnosing and treating disease, he adds.

“How can you understand disease if you don’t know the control? It’s like playing music but you don’t know where the volume control is. We knew a disease would be loud or quiet but we didn’t know how, and these microRNAs are another piece in the puzzle,” he says.

“Almost every disease will have microRNAs in them and the dream would be that they could be manipulated therapeutically. What we are doing is basic research, we are still trying to figure out the mechanics of it.”

How can you understand disease if you don’t know the control? It’s like playing music but you don’t know where the volume control is