The Shaw Prize in Life Science and Medicine 2016 is awarded to Adrian P Bird and Huda Y Zoghbi for their discovery of the genes and the encoded proteins that recognize one chemical modification of the DNA of chromosomes that influences gene control as the basis of the developmental disorder Rett syndrome. Genes are turned on and off in a precise order to achieve the intricate balance needed for human development. This process is orchestrated by the recognition of landmarks on chromosomes, including some chemical modifications of the DNA and of proteins that bind to DNA that suppress or activate gene function. Adrian Bird discovered that one such chemical change, the attachment of a methyl group to the C residue in DNA, serves to mark some genes to be turned off whereas the absence of that methyl group allows genes to be turned on. His research uncovered chromosome-binding proteins that recognize the methylC to switch off gene function. In the 1990s, Bird discovered five different proteins that have this binding activity, one of which, MECP2, makes contact with an enzyme that removes an acetyl chemical tag from histones, a major chromosome structure-forming protein. These two tags, methylC in chromosomal DNA and the absence of acetyl groups on histones cooperate to reinforce an off signal on genes and contribute to the ‘epigenetic’ marking of genes. Working completely independently on a seemingly unrelated biological problem, Huda Zoghbi, a trained neurologist, made a surprising connection between one of Bird’s methylC binding proteins, MECP2, and a challenging neurological disorder, Rett syndrome.
Rett disease was first described by Andreas Rett in the 1966, as an X-linked disorder that manifests itself as lethality in males that have only one copy of the gene and as a distinctive but variable neurobehavioral disease in females that have one mutant copy of the gene. The disease affects approximately 1 in 10,000 girls who show normal development for 6 months to 18 months, but as the disease takes hold, they become withdrawn, regress in their mental development, exhibit compulsive behavior such as wringing of the hands, and eventually lose all purposeful use of the hands. Mutations in this gene are now known to cause a variety of neurologic disorders including bipolar disease and schizophrenia. In 1999, Zoghbi and colleagues discovered that mutations in MECP2 are the primary cause of Rett syndrome. Her discovery allowed a confusing set of symptoms to be turned into a straightforward diagnostic genetic test of the disease. The Zoghbi and Bird groups independently produced a genetic animal-mouse-model of the disease and showed that the creation of a brain specific genetic defect reproduced the major symptoms of the disease. The MECP2 protein is quite abundant in nerve cells, approaching the level of the major chromosome-binding histones; thus a change in the balance of the MECP2 protein is likely to have a profound effect on chromosome structure in disease patients. Zoghbi showed that some of the learning and memory symptoms could be treated with a form of deep brain stimulation that is used on patients with Parkinson’s Disease. In dramatic contrast to the irreversible damage associated with most neurologic disorders, Bird’s group showed that the animal model of Rett Syndrome could be restored to normal by reintroducing the active gene that codes for the missing methylC binding protein. This discovery suggests a path to treatment of certain neurologic disorders using the emerging technology of gene editing. These highly complementary studies show, once again, the power of basic science to uncover the fundamental basis of human development and disease.