Take a Risk

Rice trustee emeritus Huda Zoghbi was awarded the prestigious 2022 Kavli Prize in Neuroscience for her pioneering work in “the discovery of genes underlying a range of serious brain disorders.” This includes her work on the genetic basis of spinocerebellar ataxia type 1 and Rett syndrome. Zoghbi splits the Kavli Prize with collaborators Dr. Jean-Louis Mandel of the University of Strasbourg, Harry Orr of the University of Minnesota Medical School, and Dr. Christopher Walsh of both Howard Hughes Medical and Harvard Medical School.

An Unknown Genetic Disorder

When Zoghbi first started working on Rett syndrome, the disorder had only been described a couple of times in medical literature and was thought to be extremely rare. “It was an encounter with a child that really intrigued me,” Zoghbi said. “She started life doing everything a typical girl will do, using her hands, walking, singing along with nursery rhymes, learning a few words, being very sociable, but then at 2 years of age, that stopped.” Patients with Rett syndrome develop normally in the first 6 to 18 months of life, only to hit a developmental plateau, after which they start regressing, with their symptoms affecting their ability to speak, walk, eat and breathe. One of the hallmark symptoms is near-constant, repetitive hand movements.

As it happened, the very next week, “another girl walked into my clinic, wringing her hands,” Zoghbi said. “Those were the two critical patients.” Although there were only a few described cases at the time, Zoghbi was soon able to locate additional patients with Rett syndrome, which suggested that it was much more common than previously thought. “I recognized that this was a syndrome that was really always the same in everybody,” Zoghbi said. “I recognized that this was a syndrome that was really always the same in everybody,” Zoghbi said. 

An X Chromosome Pattern

When Zoghbi met her first Rett syndrome patients, it was in the mid-1980s. At the time, all she had to go on was the hunch that because the disorder was primarily found in girls with a pattern of recognizable symptoms, it was probably caused by a single gene on the X chromosome. “The more I saw, the more I became convinced that this had to be genetic,” Zoghbi said. Although her hunch would later turn out to be correct, it was risky research to take on, because the techniques to locate the causative gene just weren’t there yet.

“It’s sort of like coming to the United States and trying to find someone when you don’t have their address and you don’t even have a map of the United States, and we didn’t have a map of the genome,” said Zoghbi, who immigrated to America herself in 1976, after her home country of Lebanon broke out in civil war. Eventually, Zoghbi and her collaborators were able to identify the MECP2 gene, which is located on the X chromosome, as being responsible for causing the syndrome.

Rett Syndrome and Autism Spectrum Disorder

“Up to that point, people would tell me to stop working on Rett syndrome, to work on autism instead, because it is more common,” Zoghbi said. “I said, ‘no,’ because with Rett I know I am working on the same disease (or on a uniform disease). The patients are teaching me.”

As it turns out, Rett syndrome is now recognized as one of the top genetic causes of autism spectrum disorder. “Today, we know of 1,000 genes that can cause intellectual disability and autism,” Zoghbi said. “If, back then, I had gone to look at autism, I would have failed, because it was so heterogenous, you were basically mixing apples and oranges. By focusing on Rett, I was able to narrow my search, in my brute force efforts, to just the X chromosome.”

Looking back, Zoghbi is grateful that she was able to take her chances all those years ago. “Every time I’ve gone into uncharted territory, it was challenging, and there was a lot of skepticism because I’m doing something no one has done before,” Zoghbi said. "I want young scientists to take a risk and to go into uncharted territory because that’s the only way we are going to make discoveries.”

— Rachel Fairbank