Rett Syndrome Research Award

Huda Zoghbi and Adrian Bird receive the “International Award for Translational Neuroscience” from the Gertrud Reemtsma Foundation for their findings on the development of Rett syndrome

The brain is one of the most complex structures in nature. About 100 billion nerve cells work together to control the functions necessary for survival, but also the processes of thinking and learning. In brain diseases, it is often very difficult to discover the underlying changes. This year, the Gertrud Reemtsma Foundation awards the “International Prize for Translational Neuroscience” to two scientists for their work on Rett syndrome. Huda Zoghbi of Baylor College of Medicine in the United States has the gene MECP2 identified as the cause of Rett syndrome and studied its function in different types of nerve cells. Adrian Bird of the University of Edinburgh discovered the role of the MECP2 protein in the regulation of genes and genetically modified mice to study Rett syndrome. The two researchers thus made a significant contribution to better understand the disease and create the basis for new therapeutic options. The prize will be awarded on June 16, 2022 at the Bucerius Kunst Forum in Hamburg.

Parents are usually the first to notice that something is wrong: their previously healthy baby suddenly seems to lose interest in his fellowmen and the environment. The first words learned disappear and he has difficulty walking and balancing.

Rett’s syndrome is a neurological disorder that includes a variety of symptoms such as autism, epilepsy, and anxiety disorders. Around 50 children, mostly girls, get sick in Germany every year. After a normal first year of life, those affected increasingly lose the ability to speak and move. As a result, they depend on treatment for the rest of their life.

Repetitive hand movements that resemble hand washing are characteristic of Rett’s syndrome. Patients sometimes display strong autistic traits, suffer from anxiety disorders, and a variety of physical ailments such as breathing problems or spinal curvature. There is currently no treatment for this serious disease.

Huda Zoghbi discovered the trigger of the disease

When Huda Zoghbi quickly diagnosed Rett’s syndrome in two girls in 1983, early in his neurological training, very little was known about the disease. Zoghbi wanted to find the cause of this complex disease. Since only one family member is affected in each affected family, the changes in the genome appeared to occur spontaneously. Finding the gene responsible for this was a huge challenge at the time, not least because genetic analysis still required a lot of time and money.

For more than ten years, Zoghbi has been examining the genome of affected families and narrowing down possible genes in ever more precise ways. Eventually, she found changes in a gene on the X chromosome in people with called Rett’s syndrome MECP2. These mutations result in the production of a defective MeCP2 protein and trigger disease.

Adrian Bird analyzed genetically modified mice lacking the MECP2 gene

The MeCP2 protein was discovered by Adrian Bird a few years earlier. The scientist found that MeCP2 binds to specific sites in DNA marked with methyl groups, thereby regulating and optimizing the activity of thousands of genes in nerve cells.

When it became known that functional MeCP2 could not be produced in many nerve cells in patients with Rett syndrome, Bird wanted to study its role in these cells in more detail. He developed genetically engineered mice with turned off MECP2-Gene. These mice have typical features of Rett syndrome and form an important basis for research on the disease.

The key findings of Zoghbi and Bird allowed a closer look at the unusual clinical picture of Rett syndrome. Affected children initially develop normally, as MeCP2 is only needed in higher concentrations in nerve cells from the second to third year of life. Therefore, an absence during this period does not have a negative effect. With advancing age, however, the lack of MeCP2 drastically changes the transmission of stimuli in the nerve cells and the first impairments appear.

The disease occurs mainly in girls because they have two copies of the X chromosome. One of them is deactivated early in development. This causes half of their cells to switch off the normal gene, while the other half inactivates the chromosome carrying the mutated gene. These latter cells then produce a sufficient amount of MeCP2 protein. The female embryos with these mutations thus remain alive thanks to the inactivation of the X chromosome, albeit at the expense of Rett syndrome. In boys, however, all nerve cells are damaged, so they usually die before or soon after birth.

Huda Zoghbi and Adrian Bird are also trying to develop therapies that could improve the lives of Rett’s patients. Using the genetically engineered mice, Zoghbi found that stimulation of brain regions, as also used in Parkinson’s therapy, can remedy learning and memory deficits. Movement and brain training of mice before symptoms appear also alleviates the course of the disease.

Adrian Bird, in turn, reactivated the production of MeCP2 in the nerve cells of the genetically modified mice. As a result, the mice that had already shown significant disabilities recovered and became almost completely healthy. This shows that this neurological condition is reversible and gives hope that one day there will be a cure for Rett’s syndrome.

The award winners

Huda Zoghbi studied biology and medicine at the American University of Beirut, Lebanon, and received her doctorate in medicine in 1979 from Meharry Medical College, Nashville, Tennessee. She then attended Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas, where she completed training in pediatrics and neurology. You then carried out postdoctoral research in the field of molecular genetics. In 1994 she became a professor in the Baylor Department of Pediatrics, Molecular and Human Genetics, Neurology and Neuroscience and in 1996 a researcher at the Howard Hughes Medical Institute. Since 2010 she has also been 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 received his PhD from the University of Edinburgh in 1971. He then spent research stays at the University of Zurich, Switzerland and Yale University in the United States. From 1975 he started his own research in Edinburgh, but then went to the Institute of Molecular Pathology in Vienna, Austria, from 1987 to 1990. In 1990 he returned to the University of Edinburgh and has since held the Buchanan Chair in Genetics. .

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