Over the past year, the SciWhys column has explored a number of different topics, from our immune system to plants, from viruses to DNA. But why is an understanding of topics such as these so important? In short, using science to understand our world can help to improve our lives. In this post and the next, I want to illustrate this point with an example of how progress in science is providing hope for the future for one family, and many others like them.
By Jonathan Crowe
Carys is an angelic-looking two-year old, with a truly winning smile. At first sight, then, she seems no different from any other child her age. Yet Carys’ smile belies a heart-rending reality: Carys has Rett syndrome, a disorder of the nervous system that is as widespread in the population as cystic fibrosis, yet is recognised to only a fraction of the same extent. (I, for one, had never heard of it until just a few months ago.)
Rett syndrome is a delayed onset disorder — something whose effects only become apparent with time. When Carys was born, she appeared perfectly healthy, and developed in much the same way as any other healthy infant. Just as she began to master her first few words, however, she lost the power of speech, and soon lost the use of her hands too. The effects of Rett syndrome were beginning to be felt.
Over time, Rett syndrome robs young girls of their motor control: they lose the ability to walk, to hold or carry objects, and to speak. But there be other complications too: there may be digestive problems; difficulties eating, chewing, and swallowing; and seizures and tremors. It is a truly debilitating disorder.
So what causes Rett syndrome? What’s happened inside the body of young girls like Carys? We know that the syndrome is caused by as little as a single error (a mutation) in a single gene. (As I mention in a previous post, it’s quite unsettling to realise that just one error in the tens of millions of letters that spell out the sequence of our genomes is sufficient to cause certain diseases. Sometimes there’s very little room for error.) The normal, healthy gene (called MECP2) contains the instructions for the cell to manufacture a particular protein; the mutated gene produces a broken form of this protein, which no longer functions as it should.
But how can a single protein affect so many processes – from speech to the movement of limbs? The answer lies in the way the protein interacts with other genes, particularly in brain cells. Essentially, the protein acts like a cellular librarian by helping the cells in the brain to make use of the information stored in their genomes (their libraries of genes). If the protein is broken, the cells can no longer make use of all of the genetic information needed for them to work properly (a bit like trying to use an instruction manual with some of the pages blacked out), so normal processes begin to break down. The broken protein doesn’t just affect the ability of the brain cells to use one or two other genes, but a whole range of them – and that’s why the effects of Rett syndrome are so wide-ranging.
But the story of Rett syndrome runs deeper than this. The mutation that causes Rett syndrome occurs in sperm; it happens after the sperm is formed but before the sperm goes on to fertilize an egg. (So it’s not present in all the sperm produced by a particular male. It simply happens at random in a single sperm.) Specifically, the mutation occurs in a gene found on the sperm’s X chromosome (one of the two sex chromosomes). Mutations on other chromosomes wouldn’t be quite such a problem because we have two copies of every other chromosome, giving us a genetic back-up plan. If the gene on one of the chromosomes in a pair is broken, our bodies can often rely on the normal, healthy one, to act as a back-up so that no ill effect is felt.
However, the sex chromosomes, X and Y, are different. Males are defined by having one X and one Y chromosome; these chromosomes contain different genes and, so, different biological information. If a male’s only X chromosome has a serious error (such as the mutation causing Rett syndrome), the male in question is in trouble: they have no back-up plan. Consequently, males with Rett syndrome rarely survive to birth (which explains why Rett syndrome is generally seen only in females).
By contrast, females have two X chromosomes. So surely they do have a back-up plan and should be alright..? Well, no. Unlike other non-sex chromosomes, only one X chromosome is active in any one cell; the other is ‘switched off’ and its genes can’t be used. In what amounts to cellular Russian roulette, the deactivated X chromosome is selected at random. As a result, half of the cells in a female with Rett syndrome are likely to be normal, but the other half will be dysfunctional – their active X chromosome will be the one carrying the rogue mutation. The dysfunctional cells in a young girl with Rett syndrome simply ‘drown out’ the healthy ones, and the body is left unable to function as it should.
At face value, Rett syndrome has little rhyme or reason; it seems to be due to little more than chance – a chance that a father’s sperm picks up a single mutation. A chance that the mutated sperm is actually the one – from the millions released when a male ejaculates – that goes on to fertilise the egg. A chance that the normal X chromosomes in the baby that is born are switched off in a sufficiently large number of cells to trigger the onset of disease.
There are early signs, though, that we may not have to leave things to chance. We’ve come a long way in terms of our understanding of how and why Rett syndrome occurs. It is this understanding – and its use to inform medical research – that brings new hope for girls like Carys and their families, as I’ll explore in my next post.
Jonathan Crowe is Editor in Chief for Natural, Health & Clinical Sciences in the Higher Education Department at Oxford University Press. A biochemistry graduate, he manages OUP’s undergraduate textbook publishing programme across a range of science and science-related disciplines. He is also an author of Chemistry for the Biosciences, now in its second edition, and was a runner-up in the Daily Telegraph/BASF Young Science Writer Awards (in 2001, when he was still classed as being ‘young’). You can read more about OUP’s science books here.