Two scientists win Horwitz Prize for Rett syndrome breakthrough

Columbia University will award the 2026 Louisa Gross Horwitz Prize to Adrian Bird and Huda Zoghbi for their pioneering work on epigenetic regulation in the nervous system and its role in human neurological disease, particularly Rett syndrome. Bird and Zoghbi's work reshaped how scientists understand the roots of brain disease, showing that problems with gene regulation, not just gene mutation, can drive severe developmental conditions. 

Primarily affecting girls, Rett syndrome is a severe neurodevelopmental disorder that impacts nearly every aspect of life, including the ability to speak, walk, control hand movements, eat, breathe, think, and control seizures. Before the discoveries of Bird and Zoghbi, the disorder was poorly understood and considered untreatable. Their work has inspired international efforts to develop genetic therapies, culminating in a series of ongoing clinical trials.

Bird uncovered key principles of epigenetic regulation, a chemical process that turns genes on and off without altering their underlying code. In the 1980s, he discovered CpG islands, specialized DNA clusters present near the start of genes. A decade later, his lab identified MeCP2, a protein that scans for chemical tags called methyl groups attached to these clusters and, upon finding them, switches the nearby gene off, acting like a molecular "off switch" for gene activity in neurons and throughout the body.

Zoghbi discovered in 1999 that mutations in MeCP2 cause Rett syndrome, establishing the first direct link between epigenetics and a severe neurological disorder and enabling early detection of the disease by genetic testing. She also showed that MeCP2 levels must be precisely maintained for neurons to function normally. Too little MeCP2 causes Rett syndrome, while doubling MeCP2 levels causes neurological deficits. Later work revealed that MeCP2 mutations also contribute to a range of other neurological conditions, from autism to juvenile-onset schizophrenia.

Though Rett syndrome was thought to cause permanent brain damage, Bird and Zoghbi showed that it could be reversible. Bird's group engineered the first mouse model of Rett syndrome and, in 2007, showed that reactivating MeCP2 in these mice dramatically improved neurological symptoms. Zoghbi's team showed that the effects of abnormal levels of functional MeCP2 can be reversed in mice by oligonucleotide therapy. Based on this groundbreaking work, a new generation of gene replacement (TSHA-102 and NGN-401) and RNA-regulating (ION 440) drugs are now advancing through clinical development.

Together, these two scientists have forged a remarkable path from fundamental discovery to therapeutic possibility, exemplifying the highest ideals of biomedical research."

Laura Landweber, chair of Columbia's Horwitz Prize committee

"Their collective work has transformed our understanding of the molecular basis for a significant human disease and brought renewed hope to patients and families affected by devastating neurological disorders," added Henry Colecraft, a member of the prize committee.

Bird and Zoghbi are the 122nd and 123rd winners of the Horwitz Prize, which is awarded annually by Columbia University for groundbreaking work in medical science. Of the 121 previous Horwitz Prize winners, 55 have gone on to also receive Nobel Prizes.