The Epigenetics Revolution

But if a reader with any sort of background in neurogenetics read this article, two things probably struck them immediately. The first was that it’s very unusual – not unheard of but pretty uncommon – for girls to present with such severe autism. This is much more common in boys. The second thing that would have struck them was that this case sounded exactly the same as a rare genetic disorder called Rett syndrome, right down to the normal early development and the timing and types of symptoms. It’s just coincidence that the symptoms of Rett syndrome, and indeed of most types of autism, first start becoming obvious at around the same age as when infants are typically given the MMR vaccination.

But what does this have to do with epigenetics? In 1999, a group led by the eminent neurogeneticist Huda Zoghbi at the Howard Hughes Medical Institute in Maryland showed that the majority of cases of Rett syndrome are caused by mutations in MeCP2, the gene which encodes the reader of methylated DNA. The children with this disorder have a mutation in the MeCP2 gene which means that they don’t produce a functional MeCP2 protein. Although their cells are perfectly capable of methylating DNA correctly, the cells can’t read this part of the epigenetic code properly.

The severe clinical symptoms of children with the MeCP2 mutation tell us that reading the epigenetic code properly is very important. But they also tell us other things. Not all the tissues of girls with Rett syndrome are equally affected, so perhaps this particular epigenetic pathway is more important in some tissues than others. Because the girls develop severe mental retardation, we can deduce that having the right amount of normal MeCP2 protein is really important in the brain. Given that these children seem to be fairly unaffected in other tissues such as liver or kidney, perhaps MeCP2 activity isn’t as important in these tissues. It could be that DNA methylation itself isn’t so critical in these organs, or maybe these tissues contain other proteins in addition to MeCP2 that can read this part of the epigenetic code.

Long-term, scientists, physicians and families of children with Rett syndrome would dearly love to be able to use our increased understanding of the disease to help us find better treatments. This is a huge challenge, as we would be trying to intervene in a condition that affects the brain as a result of a gene mutation that is present throughout development, and beyond.

One of the most debilitating aspects of Rett syndrome is the profound mental retardation that is an almost universal symptom. Nobody knew if it would be possible to reverse a neurodevelopmental problem such as mental retardation once it had become established, but the general feeling about this wasn’t optimistic. Adrian Bird remains a major figure in our story. In 2007 he published an astonishing paper in Science, in which he and his colleagues showed that Rett syndrome could be reversed, in a mouse model of the disease.

Adrian Bird and his colleagues created a cloned strain of mice in which the Mecp2 gene was inactivated. They used the types of technologies pioneered by Rudolf Jaenisch. These mice developed severe neurological symptoms, and as adults they exhibited hardly any normal mouse activities. If you put a normal mouse in the middle of a big white box, it will almost immediately begin to explore its surroundings. It will move around a lot, it will tend to follow the edges of the box just like a normal house mouse scurrying along by the skirting boards, and it will frequently rear up on its back legs to get a better view. A mouse with the Mecp2 mutation does very few of these things – put it in the middle of a big white box and it will tend to stay there.

When Adrian Bird created his mouse strain with the Mecp2 mutation, he also engineered it so that the mice would also be carrying a normal copy of Mecp2. However, this normal copy was silent – it wasn’t switched on in the mouse cells. The really clever bit of this experiment was that if the mice were given a specific harmless chemical, the normal Mecp2 gene became activated. This allowed the experimenters to let the mice develop and grow up with no Mecp2 in their cells, and then at a time of the scientists’ choosing, the Mecp2 gene could be switched on.

The results of switching on the Mecp2 gene were extraordinary. Mice which previously just sat in the middle of the white box suddenly turned into the curious explorers that mice should be[24]. You can find clips of this on YouTube, along with interviews with Adrian Bird where he basically concedes that he really never expected to see anything so dramatic[25].