June 24, 2021

I, Science

The science magazine of Imperial College

India Renziehausen saw Professor Adrian Bird present his prize winning work on Rett syndrome at the Royal Society ...


When Professor Adrian Bird received the GlaxoSmithKline prize for original contributions to medical and veterinary sciences it drew a big crowd. The prize is a nice gold medal and an even nicer cheque for £2,500, but the recipient first has to present their work at a Royal Society evening lecture.

Professor Bird researches epigenetic processes and his laboratory investigates the role DNA methylation plays in disease and development. They recently identified CpG islands as gene markers and used this information to discover more about Rett syndrome.

Approximately 1% of the genome contains clusters of unmethylated cytosine-guanine sequences called CpG islands. These are interesting because they sit right on top of gene control regions. In about 10% of these regions the CpG islands are methylated and this methylation silences the gene making it completely inactive. Professor Bird used this trait to switch off genes.

After introducing these CpG islands, Professor Bird discussed how they relate to Rett syndrome. This autism-spectrum disorder only affects females as males die before birth and symptoms include the loss of expressive language, repetitive hand movements and breathing abnormalities. The syndrome only becomes noticeable 6-18 months after birth and affected individuals have a life expectancy of about 40 years. Up until now there has been no effective treatment.

Previously, Rett syndrome had been studies by searching for genes specifically affecting the brain but Professor Bird’s lab found the cause is actually a basic housekeeping protein called MeCP2 that reads DNA methylation and is expressed in every cell type, including brain cells.

Now their main question was: can the symptoms be reversed? To answer that, Professor Bird and his team stopped the transcription of MecCP2 in wild type mice so they developed Rett syndrome, then reactivated MeCP2 expression. They found the symptoms could be reversed.

To investigate this further, they took a male mouse that was in the death stage of Rett syndrome and injected it with tamoxifen that allowed MeCP2 to be expressed in the mouse. Again the mouse recovered. However, male mice are not an ideal model for Rett syndrome as human males with Rett syndrome don’t survive. They then took female mice that were heterozygous for the trait and, again, the symptoms could be reversed.

The implication that Rett syndrome is potentially a curable condition opened the door for gene therapy. Professor Bird discussed how his team then treated female mice that had Rett-like symptoms with Adeno-associated virus (AAV) as a gene therapy vector that delivered the MeCP2 gene into the mice’s cells. This again relieved the symptoms.

Although this sounds promising in theory, Professor Bird was cautions about saying the therapy could quickly be used in humans as the AAV viral load would need to be colossal because relatively small amounts are likely to reach the brain. It may take time to find a robust treatment for human Rett syndrome but Professor Bird’s research has brought advances in the field well-worthy of the notable GlaxoSmithKline prize, and that may provide curative therapies in the future.

The event Genetics, Epigenetics and Disease took place at The Royal Society on 22 January 2013.


IMAGE: ghutchis, flickr