The Lyon Queen -- Dead, But Never Forgotten

01/09/2015 03:47 pm ET Updated Mar 11, 2015

In 1992 I completed a PhD in Virology, after my BSc in Immunology. There were far fewer people studying for PhDs back then, which is the only reason I can imagine why I managed to get a post-doctoral position in a really successful group working in human genetics. I hadn't studied genetics in the ten years since I'd been at school, but I liked the idea of working in the field so off I went.

One day the lab head suggested I should go to a set of seminars being held that evening. I listened to a couple of interesting if slightly baffling talks and then the last speaker began her presentation. Even now, I can't decide if I am more embarrassed or amused at what happened next. Like the previous speakers, this quiet elderly lady was talking about a process known as Lyonization. I distinctly remember thinking "Ha, she's talking about something called Lyonization and her name is Mary Lyon. What are the chances of working on something that has the same name as you?" It was at least ten minutes before a few synapses went into action and I realised I had got the relationship the wrong way around. Lyonization was named after this woman, and there was a reason why everyone else in the audience who was not a completely uninformed moron was looking at her with absolute awe and reverence.

Mary Lyon had worked out the principles behind a baffling genetic problem. In mammals, gender is determined by genetic material, carried on specific chromosomes. Males have a large X chromosome and a small Y chromosome. Despite its diminutive size, the Y chromosome determines gender because it drives development down the male route. Females have two of the large X chromosomes. But that shouldn't be possible, because it means females should express twice as much material from the genes on the X chromosome as males. Such a huge imbalance in gene expression is normally incompatible with healthy life.

It was Mary Lyon who formulated how cells in females manage this double-dosage issue. In every cell with two X chromosomes, one is randomly switched off during development. In this way, females have the same X chromosome-driven gene expression in their cells as males. There are examples of female mammals, including humans, where there has been a genetic defect and the cells all contain three X chromosomes. In this instance, two are switched off. If a female cell has a different mistake which means it contains only one X chromosome, that chromosome is never inactivated. Basically, mammalian cells can count, and act appropriately on this information when silencing an entire chromosome. This process happens early in development, and the copy of the X chromosome that is switched off is arbitrary. But once it has been inactivated, it is never switched on again, even if that cell gives rises to millions of daughter cells. All those daughter cells will switch off the same one out of their pair of X chromosomes.

Mary Lyon worked all of this out -- the counting, the early inactivation, the random selection, the passing on in daughter cells and the way the whole event is reversed and then started again when an egg fuses with a sperm to create a new female, with her own unique pattern of X chromosome silencing.
If all of this is sounding a bit esoteric, here are some real-life examples of the significance of X chromosome inactivation. It's one of the things that protects women from developing symptoms of many of the genetic diseases that are carried on the X chromosome and usually only afflict males. But sometimes the inactivation may be skewed, leading to remarkable situations where one of a pair of genetically identical female twins has all the symptoms of an X-linked genetic disease and the other is completely healthy.

Are you a cat lover? The orange and black fur patches on tortoiseshell (calico) cats exist because of X inactivation -- almost all of these types of cats are female and the orange and black fur color genes are carried on the X chromosomes. The patches of color are because the cells that produce the orange or black color switch off one or other of the X chromosomes early in development, and all the daughter cells switch off the same copy. Early developmental events followed by stable inheritance, just as Mary Lyon predicted. You can clone one of these cats, taking a cell back to the ground state where both X chromosomes are briefly active, and then start the whole developmental process all over again. If you do this, the coat pattern will be completely different between the first cat and the clone, even though they are genetically identical. The "choice" of which X chromosome is switched off is completely random. As Mary Lyon predicted.

X inactivation has yielded huge insights into how cells control gene expression, and has been the founding model system for two of the most controversial research areas in biology -- epigenetics and junk DNA. Mary Lyon stimulated one of the most amazing field in biology and yet the sad thing is that unless you work in genetics, you may never have heard of her. And part of that is because of a travesty. Despite her scientific status and extraordinary impact, she was never awarded the Nobel Prize. And I don't know anyone who understands why not.

There is no doubt about the magnitude of the impact of Mary Lyon's work. Her achievements are all the more remarkable when you learn about the level of discrimination she faced as a woman in science, right from the beginning of her career when she could not be awarded a "proper" degree from the University of Cambridge because women were not eligible in the 1940s.

Good scientists change what we know. Great scientists change how we think. That, most fundamentally, should be what the Nobel awards recognize. But it is too late now, because the prizes are never awarded posthumously. Mary Lyon died peacefully on Christmas Day.