Adrian Bird - Hope for Rett Syndrome

Kat - You're listening to the Naked Genetics podcast with me Dr Kat Arney. Still to come, we'll be lighting up our lives with the gene of the month. But first, it's time to take another look at this month's topic of DNA methylation, or more specifically, Rett Syndrome - the rare but severe genetic disease caused by defects in the gene encoding a protein called MeCP2, which sticks to methylated DNA. Professor Adrian Bird, from the University of Edinburgh, has dedicated his career to studying DNA methylation and the molecules that recognise it - and is hopeful that his research might one day lead to new treatments, or even a cure for children affected by Rett syndrome.

Adrian - Rett syndrome is an autism spectrum disorder which is very distinctive. It was discovered by Andreas Rett in Vienna. But it is caused by mutations in a gene. So, it's a genetic disorder, but it just so happens that the gene that is mutated encodes a protein that is involved in epigenetic reading of the genome and specifically, what that protein is supposed to do is bind to methylated sites on DNA which is a methyl group. It's just like a little nutty knob that you can stick onto DNA and MECP2 recognises and binds to that. In the absence of that protein, the brain does not work properly.

Kat - So this protein, MECP2 is kind of recognising this mark on the DNA, involved somehow in turning genes off inside cells. What do we know about how this genetic fault is affecting brain cells and how are you trying to understand this disease and bring forward some treatments perhaps?

Adrian - Well, that's what makes - obviously, there's the human issue of dealing with the consequence of this that one would like to fix. But the attractive thing from a research perspective is that here, you have a complex disorder that affects cognition, understanding, behaviour, etc. and you know exactly at the molecular level what the cause is. Now, what one is trying to do is take little steps that you understand in going from the mutations that affect this protein to those complex outcomes and we have not yet joined them up. People are working down from the brain and what's happening in the brain. The nerves do not seem to mature properly. There are groups of people who are trying to work out why not. And then there's the bottom up approach where you start with the gene and find out what the protein interacts with and that's the approach we've largely taken. In the end, the idea is that those coming downwards and those coming upwards will meet. So far, that hasn't happened, but to me, it has all the ingredients that it's a good place to start looking for autism in general and intellectual disabilities, what their genetic roots might be.

Kat - Tell me about some of the results you've had trying to fix or repair this genetic fault?

Adrian - A feature of Rett syndrome is that it's not neurodegenerative. So in other words, the nerve cells, although they're rather simplified, they don't have as many branches as these cells usually do, they are alive. And so, this obviously raises the possibility that if you were to put back the protein, would they become mature now later in the day. The reason why this is an interesting question is because it was widely assumed that it would be too late. I think there's a general view that neurological disorders of all kinds are more or less irrevocable and that's really reinforced by the fact that there are hardly any effective treatments for any of these kinds of disorders. And so, there is the idea that the brain goes through this complex development, it does certain things at certain times and you need all the proteins to be there, and if you miss that, it's too late. You can't go back and redo it. So, we devised a way of testing this idea which was to make an animal model of Rett syndrome that did not have the MECP2 protein and it's a very good model in a lot of respects of the human disorder. And then we put it back. We did this through a genetic trick. So, we waited until the animals were ill and then we switched on the gene. The prediction of the critical period, critical window hypothesis would be that it wouldn't make any difference, but actually, it turned out that they got almost completely better. So, what that means is that there wasn't a critical window where you needed this protein. Actually, not having it makes the brain not work properly and if you put it back, the brain starts to work properly which was a totally surprising result to many people including us, I have to say. What it of course does mean that it raises the prospect that the human disorder will be curable. And certainly, it's fuelled a lot of research in many labs to try to act on that hopeful possibility.

Kat - There must be a huge number of families affected by this disorder who are really desperate for cures. How soon do you think this may get into human studies and are the families really interested in this kind of research?

Adrian - The families are extremely interested in this kind of research. At the moment, there is not meaningful therapy and this offers hope. As for being able to tell them when that hope will be realised, that's of course a very uncertain thing because until you actually have a therapy, you don't know. I could say, it would be very disappointing if in 10 years' time, there was not some therapeutic approach and I would be disappointed. But do I know that in 10 years' time there will be an approach? I don't. There's a lot of work going on and there are some quite hopeful preliminary results, but nothing, I would say, that makes you think, in two years, that will be in the clinic. Of course, getting from an idea or even a drug or a process into the clinic is a pretty difficult thing to do in and of itself even if you have the therapy there. I think all the preliminary work in Rett syndrome suggests that this disorder is one of the most promising ones for there to be therapy in the fullness of time. It's not the only one. Fragile X syndrome is also a common autism spectrum disorder. So, there is hope now as there never has been before I think.

Kat - That was Adrian Bird from the University of Edinburgh.