Fundamental and pioneering. This is how the selection committee for the prestigious and internationally-recognised Lundbeck Foundation Brain Prize has described the work of 2020 prize-winners Prof. Sir Adrian Bird and Prof. Huda Zoghbi. Having both made outstanding contributions to the field of neuroscience, they will now share the 10 million DKK (around £1.17 million) prize, known as the ‘Nobel’ of neuroscience. The researchers, working from the University of Edinburgh and Baylor College of Medicine in the US respectively, were nominated by their peers for revealing the underlying mechanisms behind the neurodevelopmental disease Rett Syndrome.
Whilst rare, having been estimated to affect just over 1,000 people in the UK, Rett is a severe and debilitating autism spectrum disorder. The vast majority of those affected are female. This is because the responsible gene MECP2 – identified by Professor Zoghbi – is on the X chromosome. Male foetuses receive only one copy of the gene, and if this is faulty the effect tends to terminate the pregnancy. In females a second X chromosome, and so a second copy of MECP2, enables development to continue as normal until one or two years of age. Onset of Rett Syndrome then impedes normal development; a seemingly healthy toddler will begin to develop difficult and persistent neurological symptoms, and will require extensive assistance for the rest of her life. There is a 50% likelihood she will never develop the ability to walk.
As a disease that stems from a single gene mutation, Rett Syndrome demonstrates the profound effect individual genes can have on our entire development. A functioning MECP2 gene is undoubtedly vital for normal neurological development – but why exactly? Although he had no idea initially of the relevance of his work to Rett Syndrome, this is the question answered by Sir Bird, who was knighted in 2014 for services to science.
Considered a pioneer in epigenetics, Sir Bird and his colleagues’ discoveries have shed light on core mechanisms of multiple congenital diseases. Epigeneticists study modifications to our genetic code that change not the DNA itself, but how it is read and interpreted in cells. In 1992, he found that particular proteins in our cells govern these epigenetic modifications, which themselves are encoded in DNA. Damage to a gene encoding one of these vital proteins would have a widespread effect, changing how DNA is interpreted at multiple different locations. A specific type of these proteins, abundant in cells of the nervous system, were revealed by Bird to be encoded by MECP2 which explains the extensive symptoms of Rett.
To be able to study the genetics of diseases, researchers rely on animal models. They are able to edit genes to discover causes and find out whether the issue is treatable. Sir Bird was able to create a mouse model of the disease and discovered that by replacing the faulty copy of MECP2 with a healthy copy, the mouse could be cured of Rett-like symptoms. The mouse model demonstrates a direct link between a loss of protein production from MECP2 and the onset of neurodevelopmental problems – a link that could be exploited in future research in treating or even curing Rett Syndrome.
Although effective in the mouse model, gene editing in humans is not regarded by the scientific community as a feasible treatment option. The long term effects of gene editing are poorly understood and it is only intended as a tool in highly protected laboratory settings, where edited organisms cannot leak their DNA to wider populations. This is a generally accepted rule among geneticists, famously flouted by He Jiankui who revealed that he had attempted to engineer the genomes of twin girls in 2018 to delete a gene that allows HIV to enter cells. It is yet to be seen whether this controversy has helped or hindered gene editing research, but nonetheless gene editing is unlikely to be a human treatment any time soon. Instead researchers will undoubtedly seek alternative ways to compensate for the protein deficiency caused by MECP2 damage.
This is the second time in its ten year history that The Brain Prize, which is open to nominees of any nationality, has been awarded to an Edinburgh researcher. In 2016 it was awarded to Professor Richard Morris, along with two others, for an exceptional contribution to understanding the basis of memory and complex brain conditions including autism, schizophrenia, depression and addiction.
The purpose of the award is not only to honour the researchers, but also to inspire new research in brain function and disorders. Having made significant contributions to the world of neuroscience, the joint prize-winners will now engage with the research community through site-visits, speaking at conferences, and other outreach activities. Now internationally recognised for their work, they have brought the world’s attention to the epigenetic and genetic basis of Rett Syndrome and have paved the way for further research into a treatment and perhaps a cure.
Written by Claudia Carter and edited by Ailie McWhinnie.