Analysis: inside the fascinating world of figuring out what genes named Tinman, Ken and barbie and C5orf30 actually do

By Emma Dorris, UCD

In addition to being beloved cartoons from the 1980s and 1990s, SONIC Hedgehog, SMURF1 and SMURF2 are all also human genes. Many genes were first found in flies and fly scientists have, well, a particular sense of humour.

Whereas a gene may be amusing and linked to the culture at the time of its discovery, trouble arises when the human versions of these genes become linked to serious and life-threatening illnesses. The comedy quickly drains out of quirky names when a doctor has to counsel patients about genetic defects with names like "NEMO" and "Lunatic Fringe" (both names have since been changed in Humans).

In the genetic age, human gene names are now tightly regulated with oversight from the Human Gene Nomenclature Committee, a part of the Human Genome Organization. Human gene symbols can no longer form known words and must be named after the gene function.

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From RTÉ Radio 1's Today with Sean O'Rourke show, a discussion on the Human Genome Project with Dr John Greally (Albert Einstein College of Medicine, New York) and Dr Gianpiero Cavalleri (Royal College of Surgeons)

In defence of the fly guys

Scientists are often considered dull. One American study found that scientists were perceived as highly competent but not warm. Other studies have routinely reported perceived stereotypes of scientists as socially inept, eccentric and cold.  As creatures steeped in evidence-based research, we feel comfortable with numbers and metrics and often don’t focus on our softer skills and building trust. Often, we reinforce our "the ivory tower" by using sterile language (like the new gene name rules) and focusing on defending science rather than building relationships with the public.

I lament the loss of the weird and wonderful names gifted by our fly scientists. The gene Ken and barbie was named because mutants in the gene produced flies without genitalia. Tinman was so named because without it flies couldn’t develop a heart. This link to culture is also found in genes first discovered in mice. Nanog is a gene involved in ageing, named after Tír na nÓg from the Irish myth of tale of Oisín and Niamh.

These names linked science within society and showed personality, creativity and whimsy. I completely understand the need to change these names in humans - these genes may be linked to a medical condition that can be devastating and these names may cause undue stress - yet I cannot help but bemoan this lost link with culture.

It was nearly 10 years ago that a large genetics study first identified that C5orf30 was linked to rheumatoid arthritis.

What do you call a human gene if you don’t know what it does?

When the function of a gene is unknown it is given a temporary symbol, based very simply on where in the DNA it is located. The technology for reading our DNA sequence has developed so fast that we have many stretches of DNA code that look like genes, yet we don’t know what the gene actually does. Our chromosomes are numbered 1-22, in order of decreasing size, with our sex chromosomes called X or Y. The gene that I was interested in was called C5orf30, which it means it was the 30th sequence of DNA code that looked like a gene on chromosome 5, the 5th biggest chromosome in our cells.

How do you figure out what a gene does?

Usually we ask: does it look like a duck, walk like a duck and quack like a duck? We tend to use high powered computers and work with scientists that specialise in using computers to predict biology to figure this out. If the answer is yes, then we hypothesize it’s a duck and carry out experiments in the lab to prove or disprove this. However, it’s not always easy. Our computer programmes only work when our DNA code shares similar features to genes whose function we do know.

C5orf30 did not look like a duck. In fact, it looked like nothing else in the genome (the term for all our DNA code). In this case, it was a long process to discover what C5orf30 actually did. It was nearly 10 years ago that a large genetics study first identified that C5orf30 was linked to rheumatoid arthritis. Since then work has been underway to figure out what it actually does.

So, what does the gene actually do?

The C5orf30 gene is now called MACIR for macrophage immunometabolism regulator and is important for our immune system. The immune system is crucial for the normal functioning of the body. A type of immune cell, called a macrophage, has a role in inflammation, but also in normal growth and healing. These cells are like conductors of an orchestra: they tell the other immune cells when to turn on inflammation or fight infection but also when to turn off "fight" mode and to turn on "healing" mode. When they stop working properly, the whole immune system can go out of tune.

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Without MACIR, the macrophages went very out of tune. They were no longer able to properly switch from "fight" mode to "healing" mode. This is partly because MACIR tells the immune cells how to use their energy (called immunometabolism). People with rheumatoid arthritis have less MACIR compared to people that don't have an autoimmune condition. When people with rheumatoid arthritis have more inflammation, they also tend to produce less MACIR.

What's next?

This is truly new and novel research. Given the little knowledge about MACIR structure and function, MACIR could never have been considered low hanging fruit. Without the recognition by the funding agencies for the value of undertaking fundamental, basic and preclinical lab-based research this would still be an uncharacterised gene and would not have this piece of the immune system puzzle.

Investment in this type of research can have enormous long-term benefit, though that can sometimes be difficult to quantify. Will MACIR be useful in developing new medicines for rheumatoid arthritis and the immune system? We don’t know yet. But we now have the opportunity to find out. And, of course, enact a nice little piece of history for Irish science.

Dr Emma Dorris is a Molecular Biologist at the UCD Centre for Arthritis Research in the UCD School of Medicine. She is an Irish Research Council awardee 

The views expressed here are those of the author and do not represent or reflect the views of RTÉ