"Biology Has Become One Huge Canvas" – An Interview With Brain Prize Winner Sir Adrian Bird
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The annual announcement of the Lundbeck Foundation’s Brain Prize represents the largest yearly award for brain research. Laureates, who share a €1 million ($1.13 million) sum, are recognized for their outstanding contribution to neuroscience.
This year’s laureates are two geneticists, University of Edinburgh professor Sir Adrian Bird and Baylor College of Medicine professor Huda Zoghbi. They are recognized for their work towards understanding the inherited brain disorder Rett syndrome.
Bird's lab made the first identification of a gene, MECP2, mutations in which were later determined to be causative in Rett syndrome by Zoghbi's clinical lab years later.
Their work, conducted independently, has led research to the brink of clinical trials for the syndrome and may have resonance far beyond this rare condition. Technology Networks recently spoke to Sir Adrian to discuss his lab’s contribution towards decoding the origins of Rett syndrome.
Ruairi Mackenzie (RM): What is Rett syndrome?
Adrian Bird (AB): Rett syndrome is a profound neurological disorder that is caused by mutations, in nearly all cases, in the MECP2 gene. It's characterized by a period of normal development, followed by, at the age of 18 months or so, a crisis, when the child obviously becomes distressed. At this point, skills such as walking and speech, which may have been learned prior to this point, are lost and they never return. In addition, the children can't walk, and they grow into adults who are wheelchair-bound. There are breathing difficulties in the sense that the children have apneas – that is they hold their breath quite often for a distressingly long time. And there are other issues, such as tendency to scoliosis, seizures and sleep irregularity. It's a serious disorder for which there is absolutely no cure.
Rett syndrome affects girls predominantly. The reason for that is that the MECP2 gene is on the X chromosome. Mutations on the X chromosome are not less severe in males than in females; they are more severe. In Rett syndrome, they're so severe that males generally do not survive with these mutations. There is no common Rett syndrome in males. There are a few cases, but the vast majority of cases affect girls who have one mutated copy of the gene, and one unmutated copy of the gene and it's this combination that allows them to survive, but at the price of Rett syndrome.
RM: What’s the prevalence of Rett syndrome?
AB: Roughly one in 10,000 births. I'm not sure how that translates into numbers in the world, but it's neither exceptionally rare nor highly frequent.
RM: Could you tell us about your research into the MECP2 gene?
AB: My lab was a basic, blue skies lab that was and still is interested in how gene expression is regulated – how different genes can be switched on and off to make the different cell types in the body.
One of the mechanisms that was of interest at that time was DNA methylation, whereby a small methyl group is attached to cytosine residues in the DNA. We were involved in studying that from quite an early time. The question was, “What is it good for? Is it a signal that can be read?” To answer that question, we looked for proteins that might be able to recognize methylated DNA and distinguish it from unmethylated DNA.
That's how we came across MECP2, because this protein binds preferentially to DNA that has these methyl groups attached and so that was a potentially a reader, if you like, of the DNA methylation signal. We got interested in it as a way of trying to understand what DNA methylation did. We thought that by finding the proteins that read it, we could then ask what they do. And that would tell us about what DNA methylation does as well.
RM: How has your field of research changed in the three decades since the MECP2 publication?
AB: It has changed dramatically, because of all sorts of technologies; not only DNA sequencing, but also techniques in microscopy and mass spectrometry. The armory that we have available to address questions now bears no comparison with the way it used to be. We, for example, had to purify the MECP2 protein. For that we used classical protein purification methods, which are still sometimes used. Once we got the protein, we had to break it up with enzymes and then determine the amino acid sequence at the very tips of those broken fragments. We then worked backwards to work out what the DNA must have been that encoded the fragments. That allowed us to purify a copy of the mRNA and that allowed us to subsequently go and find the bit of the genome that encoded the mRNA. Many, many steps that today would be virtually instant because the whole genome is sequenced and you can PCR every bit of it in a day, if not one or two days. So yes, it's totally transformed.
RM: You shared the prize with Dr. Huda Zoghbi from Baylor College of Medicine. It seems to me to be a great example of collaboration between basic and translational science. Does it seem to you like these kinds of collaborations have become more common in recent years as opposed to back in the 90s?
AB: Huda is a clinician who sees patients with Rett syndrome. She was interested in it as a disorder, whereas we came from the opposite direction; we were interested in proteins, DNA methylation and gene regulation. The protein we found happened to be the protein that is involved in Rett syndrome. It was the Zoghbi lab that actually made that connection. We had no idea we were working on something clinically relevant. As to whether or not that kind of collaboration is more common, I think it definitely is. Biology used to be much more siloed – molecular biologists or structural biologists or geneticists or microscopists operating with a relatively small number of techniques within a community that all did more or less the same thing. The new technologies have really broken down those barriers. And importantly, they've broken down the barriers with medical science. Medicine is now accessible much more quickly and directly than it ever was before. Biology has become one huge canvas rather than a small number of vignettes.
Professor Sir Adrian Bird. Credit: University of Edinburgh
AB: We wanted the mice to grow up without any MECP2 and then we wanted to put it back, to see whether or not the defects that arose as a result of not having it could be fixed if you made it available later on.
The way we did this was to "knock-in", to manipulate the natural gene. We didn't add an extra gene; we simply manipulated the gene that was already there. We inserted what's called a stop cassette, a piece of DNA that stops a gene from being expressed while it's present. On either side of that stop cassette, we had sites that would allow it to be cut out when we wanted it to be cut out.
We injected these mice with tamoxifen, because tamoxifen triggered the activation of a system, derived from bacteria, that would chop out the stop cassette whenever we wanted. This worked brilliantly. It's the sort of experiment that you scribble on an envelope, and you think, "But there are five steps there. And we need them all to work perfectly. And life very often isn't like that." But in fact, in this case, every single step worked very well. We were able to create mice that had no MECP2, because their MECP2 gene was stopped. Then, after the tamoxifen injection, their gene was activated and then they got better. That’s really how we did it.
RM: That’s a really exciting finding. But the great challenge is trying to apply that animal-based finding to human patients. Could you summarize the advances the field has made in the last 13 years?
AB: Of course, it's frustratingly slow. I should make the point that the animal model of Rett syndrome developed in mice is an extremely good mimic of the human disorder. With many diseases of this kind, the mouse and the human are not necessarily very equivalent. There are differences; mice are not people. It’s very important in this case that what MECP2 does in mice, it also does in people. The fact that we could get it to reverse in this way really strongly suggested that it was going to be curable in humans. But in mice, we use genetic tricks, which I previously described, and you can't do those genetic tricks in humans.
You need to somehow add a functional gene into the brain. And this is not trivial. But the most important thing I just want to say is that no one expected any brain disorder that arose during development, as this one does, to be reversible. The assumption was that all such disorders were irrevocable, and you would never be able to do anything about them. That’s really the notion that the 2007 paper overturned. It had this dramatic effect of attracting people to the possible ways, and there are several, of fixing this mutation.
One of the most obvious and sort of, in a sense, the most crude way is to do gene therapy, whereby you go in with a virus that you've hijacked. In place of its own genome, you've inserted the MECP2 gene. The problem with this is you can't really regulate how much goes into individual cells. You need a virus that goes to quite a large number of neurons. You can't do that with the current viruses that we have available, though that is a little bit controversial. Some people disagree with that.
The second problem is that you do not want to put too much MECP2 in, because there is another disorder called MECP2 duplication syndrome, which as the name suggests, is where there are two copies of the gene where you should have only one. This is at least as bad as Rett syndrome. So that tells you that too much MECP2 is toxic and too little is toxic, so you need to put in the right amount and with gene therapy that's not easy to manage.
That sounds hopeless. But, in fact, experiments in mice have suggested that it works remarkably well. Putting back some MECP2 protein is hugely beneficial in a way that no drug has ever approached. So there is leeway, a window of opportunity if you'd like, to put in a safe amount that stays low and doesn't ever go high. And the situation now is that clinical trials are being planned, but they have not yet been started. So we're waiting with bated breath to see what happens with the first clinical trials. There is a plethora of private and academic labs that are trying to find different ways of curing Rett syndrome. One would like to be 10 years down the line when hopefully some of them will have managed to do that.
RM: Do you think the etiology of Rett syndrome means that it’s likely to be among the first of the autism spectrum disorders that we are able to cure? How do the genetics of Rett disorder compare to these other disorders?
AB: The first point I should make is that not everyone agrees it's an autism spectrum disorder. People get quite excited about names and words. In the latest edition of the DSM [DSM-V, released in 2013] it is not classed as an autism spectrum disorder. But autism is so incredibly broad that it's very difficult to define where the edges are. It’s now pretty clear from the genetics, that autism isn't one disorder, it isn't even ten disorders, it's probably hundreds of disorders, all differing depending on the root cause.
As to whether or not Rett syndrome will be among the first of these disorders that we cure – I would like it to be among the first tried. But if other disorders of this kind are the first cured, I wouldn't really feel as though any meaningful race had been lost.
As for the genetics of other disorders – I think with the explosion of exome sequencing and, more recently, whole genome sequencing, there are lots of single gene disorders that are turning up that people didn't realize were caused by single gene. But the question is, to what extent is the reversibility of Rett syndrome a peculiarity of this disorder? And to what extent is it actually the thin end of a wedge that will include large numbers of autism spectrum disorders? I'd like to think that lots of them will be reversible. But you've got to do the experiments. It’s actually taken quite a while for people to look, but it looks as if it's turning out that some are reversible. Only a handful have been looked at properly. Some are reversible and some don't seem to be. The data isn't always utterly convincing, but some of it is.
Predicting the future and how things will go is not always a useful thing to do. But I can't believe that there won't be lessons to be learned from Rett syndrome that won't be of relevance for other neurological disorders as well.
Professor Sir Adrian Bird was speaking to Ruairi J Mackenzie, Science Writer for Technology Networks. Interview has been edited for length and clarity.
