Four neuroscientists win Kavli Prize for discovering genes behind serious brain disorders

Four neuroscientists who discovered the genes involved in a host of serious brain disorders on Wednesday won this year’s $1 million Kavli Prize in neuroscience, honoring arduous work undertaken long before sequencing of the human genome accelerated investigations of what goes wrong in the brain.

Together, research by the four winners — Jean-Louis Mandel of France, Harry Orr of the U.S., Christopher Walsh of the U.S., and Huda Zoghbi of Lebanon and the U.S. — revealed the genetic underpinnings of Fragile X syndrome, spinocerebellar ataxia, Rett syndrome, and rare forms of epilepsy and autism spectrum disorder.

“Understanding inherited brain disorders has been made possible by the novel genetic approaches developed by this year’s laureates,” Kristine Walhovd, chair of the Kavli Prize Neuroscience Committee, said at the award ceremony in Oslo. “Together, these four scientists uncovered the genetic basis of multiple brain disorders and in doing so, paved the way to the development of diagnostic tools and improved care for those affected.”

The prize is awarded by the Norwegian Academy of Science and Letters.

Collectively, the scientists’ work charted the way forward into research, diagnosis, and treatment for these disorders. Here are their award-winning contributions, and the scientists’ remarks from videos recorded for the ceremony:

Mandel, of the University of Strasbourg, found an unusual mutation in a gene on the X chromosome that causes Fragile X syndrome, an inherited form of intellectual disability that also includes autism and usually occurs in males. The mutation was a string of triple-letter repeats that disrupted the FMR1 gene so that it couldn’t produce the FMRP protein, which is vital for brain function. The unstable repeat expansions that Mandel discovered are now known as the mechanism behind more than 50 genetic disorders, getting worse as they accumulate over generations. As the number of repeats increases, symptoms arise earlier and are more severe. Mandel’s work has led to improved diagnostic tools for Fragile X and become a model for other neurological diseases.

“We had been working for eight years, from 1983 to 1990, trying to locate where exactly in the genome was this Fragile X mutation. And when in 1991 we started to look with more precision in the place we had located, we started to see, using a technique that allowed visualization of the results on X-ray film, … anomalies in the genome,” he said. “Suddenly we could visualize, like in a picture, what was going on in these families.”

Orr of the University of Minnesota and Zoghbi of Baylor College of Medicine collaborated to discover ATXN1, the gene whose mutations are responsible for spinocerebellar ataxia 1, in which neurons in the cerebellum degenerate and eliminate balance and coordination. The disease is progressive, permanent, and often fatal. Working together, Orr and Zoghbi found that repeat expansions make proteins misfold and clump together in cerebellar neurons, eventually leading to death.

“As Harry and I were marching to find the mutation that caused the disease, we learned that there’s some rare diseases like myotonic dystrophy or Fragile X with repeats,” Zoghbi said. “That’s what Harry and I saw in our families, so we pooled our resources.”

On the same day — April 8, 1993 — they both discovered the CAG repeat expansion in ATXN1.

“That day was the most exciting day when we made that discovery together,” Zoghbi said.

Arriving there was not easy, Orr said.

“The gene for SCA1 was cloned from humans, and it was done prior to the sequencing of the human genome,” he said. “So this meant we had to use what are now relatively archaic techniques of genetic linkage, isolating DNA from family members, looking for variation in this DNA and which of these variations covariated with whether the individual was affected or unaffected.”

Zoghbi also discovered the gene MECP2, whose abnormal levels cause Rett syndrome, a rare genetic neurological disorder typically found in young girls that shows up as autism-like symptoms and causes serious motor and cognitive symptoms. Zoghbi demonstrated that MECP2, as a repressor of gene expression, is essential for many types of neurons to function normally in the brain. MECP2 is one of the first identified epigenetic causes for a brain disorder, meaning it controls other genes. MECP2 affects hundreds of neurons and genes, her work revealed, and normalizing MECP2 levels with genetic therapies may reverse the gene’s effects.

Walsh of Boston Children’s Hospital discovered more than three dozen genes implicated in neurological disease, including “double cortex” syndrome, a rare neuronal migration disorder that causes seizures and intellectual impairment, almost exclusively in females. He found other genetic mutations underlying disorders that affect the cerebral cortex, leading to structural malformations that can be subtle or profound, including some forms of epilepsy and autism spectrum disorders. Walsh made these discoveries by studying recessive mutations in geographically isolated families. In some children, mutations appeared in some but not all their brain cells, somatic mutations that slowly built up during brain development.

“What our work has been focused on is understanding genetic disorders that disrupt the development of a child’s brain,” Walsh said. “We found in the old days, when it was very expensive to sequence the whole genome, that the most efficient way to find these genes was to work with families where the parents had a shared ancestor. … This was a really amazing way of trying to help people in all different parts of the world in ways that were the most technologically feasible at the time.”

The Kavli Prizes, considered Nobel predictors along with the Lasker and Gairdner prizes, are awarded every two years in astrophysics and nanoscience as well as neuroscience. To name two instances: Emmanuelle Charpentier, Jennifer Doudna, and Virginijus Šikšnys won the Kavli nanoscience prize in 2018, and Charpentier and Doudna were honored with the Nobel in medicine in 2020. (On the day it was announced, Šikšnys called the Nobel Prize committee’s decision “a well deserved recognition for the field.”) And David Julius and Ardem Patapoutian won the 2021 Nobel Prize in medicine or physiology after sharing the 2020 Kavli award in neuroscience for their discovery of receptors for temperature and pressure.

This story has been updated with remarks from the award ceremony.