Award for research on Rett syndrome

Huda Zoghbi and Adrian Bird receive the International Prize for Translational Neuroscience of the Gertrud Reemtsma Foundation for their findings on the causes of Rett syndrome

The brain is one of nature’s most complex structures. About 100 billion nerve cells work together to control vital functions as well as thinking and learning processes. When it comes to neurological diseases, it is often quite difficult to uncover the underlying changes. This year, the Gertrud Reemtsma Foundation is awarding the International Prize for Translational Neuroscience to two scientists for their work on Rett syndrome. Huda Zoghbi from the Baylor College of Medicine in the US has identified the MECP2 gene as the cause of Rett syndrome and studied its role in various neurons. Adrian Bird from the University of Edinburgh has uncovered the role of the MeCP2 protein in the regulation of genes and genetically modified mice so that Rett syndrome can be researched in them. The two researchers have thus made a substantial contribution to better understanding the disease and creating the basis for new treatment options. The prize will be awarded on 16 June 2022 at the Bucerius Kunst Forum in Hamburg.

Parents are usually the first to notice that something is wrong. A previously healthy toddler suddenly seems to have lost interest in their fellow human beings and the environment. First learned words disappear, and the child has difficulties with walking and balance.

Rett syndrome is a neurological disorder that includes various symptoms such as autism, epilepsy, and anxiety. Every year, about 50 children in Germany – primarily girls – are affected by this disease. After a normal first year of life, those affected increasingly lose their ability to speak and move. This makes them dependent on care throughout their lifetime.

Rett syndrome is often characterized by repetitive hand movements reminiscent of hand washing. The patients sometimes show strong autistic traits and suffer from anxiety and multiple physical symptoms such as breathing problems or spinal curvature. There is still no treatment for this serious disease.

Huda Zoghbi discovered trigger of the disease

When Huda Zoghbi diagnosed Rett syndrome in two girls within a short time at the beginning of her neurology training in 1983, relatively little was known about the disease. Zoghbi wanted to find the trigger of this complex disease. Because only one family member is affected at a time, spontaneously occurring changes in the genetic make-up seem to be the cause. Finding the gene responsible for this was an enormous challenge at the time – also because genetic analyses were still quite time-consuming and expensive.

For more than 10 years, Zoghbi studied the genetic material of the affected families and gradually narrowed down the possible genes. She finally found changes in a gene called MECP2 on the X chromosome in people with Rett syndrome. These mutations result in the production of a defective MeCP2 protein and thus trigger the disorder.

Adrian Bird analysed genetically modified mice without MECP2 gene

The MeCP2 protein was discovered a few years earlier by Adrian Bird. The scientist found that MeCP2 binds to specific sites on the DNA that are marked with methyl groups and can thus modulate expression of thousands of genes in neurons. MeCP2 thereby optimises levels of gene expression.

When it became known that many nerve cells in patients with Rett syndrome were unable to produce a functioning MeCP2 protein, Bird decided to investigate the its role in these cells in more detail. He developed genetically modified mice in which the MECP2 gene is switched off. These mice have typical characteristics of Rett syndrome and form an important basis for research into the disease.

The fundamental findings of Zoghbi and Bird made it possible to study the unusual clinical picture of Rett syndrome in greater detail. Affected children initially develop normally because MeCP2 is needed in higher concentrations in the nerve cells only from the second to third year of life. An absence therefore does not have a negative effect during this time. However, with increasing age, the lack of MECP2 drastically alters the transmission of stimuli in the nerve cells, and the first impairments start to appear.

The disease occurs mainly in girls because they have two copies of the X chromosome. Females silence one entire X chromosome early in development. As they are heterozygous for the disease mutation, this leads half their cells shutting down the normal gene, while the other half silence the chromosome carrying the mutant gene. The latter cells are normal with respect to MeCP2 function. Females with these mutations are rescued by X inactivation, but at the price of Rett syndrome. In male babies, on the other hand, all the nerve cells are damaged. They therefore usually die before or shortly after birth.

Huda Zoghbi and Adrian Bird are also trying to develop treatments that could improve the lives of Rett patients. Using the genetically modified mice, Zoghbi found that stimulating brain regions – using technology applied in Parkinson’s therapy – can correct deficits in learning and memory. Exercise and brain training of the mice before the onset of symptoms also mitigates the course of the disease.

Bird reactivated the production of MeCP2 in the nerve cells in the genetically modified mice. The mice that had already shown considerable impairments recovered and became almost completely healthy. This shows that this neurological disease is reversible and gives hope that Rett syndrome can one day be cured.

The prize winners

Huda Zoghbi studied biology and medicine at the American University of Beirut, Lebanon and received her doctorate in medicine from Meharry Medical College, Nashville, Tennessee in 1979. She then went on to Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas, where she trained in Pediatrics and Neurology, and then pursued postdoctoral research in molecular genetics. She became Professor of the Department of Pediatrics, Neurology, Neuroscience and Molecular and Human Genetics at Baylor in 1994, and an Investigator with the Howard Hughes Medical Institute in 1996. Since 2010, she has also been the Director of the Jan and Dan Duncan Neurological Research Institute at Baylor College of Medicine and Texas Children’s Hospital.

Adrian Bird studied biochemistry at the University of Sussex and obtained his PhD from the University of Edinburgh in 1971. He then had research residencies at the University of Zurich, Switzerland and Yale University. In 1975, he set up his own research in Edinburgh. From there, he went to the Institute of Molecular Pathology in Vienna, where he stayed from 1987 to 1990. In 1990, he returned to the University of Edinburgh, where he has held the Buchanan Chair in Genetics ever since.

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