More than 30 years ago, as a pediatric resident at Texas Children’s Hospital and the Baylor College of Medicine, Huda Zoghbi first encountered patients with symptoms of a rare neurodevelopmental disorder that leads to a progressive loss of mobility and coordination early in a child’s life. In time, each patient’s story inspired Zoghbi to pivot from clinical medicine to research, where she felt she could make the biggest impact by searching for new treatments and, ultimately, a cure.
Known today as Rett syndrome, the disorder disproportionately affects more females than males, but it is especially aggressive in males; most boys with Rett syndrome do not survive infancy. Girls with the disease first develop normally but, before the age of three, they progressively lose the skills they’ve learned. In severe cases, girls with Rett syndrome lose their ability to talk and feed themselves, and they might experience seizures, teeth grinding, and difficulty breathing.
“The first [patient] who really grabbed my heart and attention was my first patient with Rett syndrome, who is now in her 40s,” Zoghbi said, noting that she remains in touch with her former patient still. “Rett syndrome is a very tough nut to crack. It’s a sporadic disease and [when I got started in research] the technology wasn’t there.”
Because of this roadblock, Zoghbi’s lab teamed up with Harry Orr’sexternal link, opens in a new tab group at the University of Minnesota to dig into studies of a balance disorder known as spinocerebellar ataxia type 1 (SCA1). After years of research, the two labs independently discovered the gene responsible for SCA1, and they continued to collaborate and used their findings to help decipher some of the mechanisms of neurodegeneration. All the while, Rett syndrome remained close to Zoghbi’s heart.
In 1999 – three years after Zoghbi was named a Howard Hughes Medical Institute Investigator – she and her lab identified the culprit in Rett syndrome: mutations in a multi-functional protein known as MeCP2.
“We learned that this protein is almost like the conductor of an orchestra,” Zoghbi said. “It really tells genes how to be expressed in our brain at the right time to execute the right functions. It’s almost like a beautiful symphony.”
But, when there is an absence of MeCP2, “it’s a cacophony,” Zoghbi said, noting also that MeCP2 is a “Goldilocks protein.” “When you have too little of it, you get Rett syndrome,” she said. In turn, when you double the amount of MeCP2, another devastating disease results: MECP2 duplication syndrome. Unlike Rett syndrome, MECP2 duplication syndrome primarily affects boys, and half of those affected die before the age of 25.
Armed with these new discoveries, Zoghbi and her team had a clearer view of their objective: to tackle these diseases, they now knew to target MeCP2.
“As our work progressed, we learned of ways where we can reverse the high level of the MeCP2 protein using small pieces of DNA as a technology to lower the amount of the protein,” Zoghbi said. “And it worked.” In animal models, Zoghbi and her lab showed that they were able to reverse the effects of MECP2 duplication syndrome. Their discovery led to the development of a treatment pathway that is set for clinical trials this year.
“This is very gratifying to see all these years of basic research finally bringing something that could help these children and adults, and their families,” Zoghbi said.
Human impact through basic science
“I’ve always been interested in science,” said Bakhos Tadros, a postdoctoral associate in Zoghbi’s lab. “Even during medical school, I learned about diseases, but I always wanted to understand why we see the symptoms we see in patients. I’ve always wanted to bridge the science to clinical medicine.”
In many ways, Tadros can relate to Zoghbi’s journey to the lab. Like Zoghbi, Tadros grew up in Lebanon with an immediate love of learning. “Even before coming to the lab, Dr. Zoghbi was a role model to me,” he said. “I think having representation of people from diverse backgrounds – and diverse backgrounds in science – is really important because you bring in so many different perspectives. You’re not looking at issues through tunnel vision.
Today, Tadros’s research centers on Alzheimer’s disease, a more recent addition to the Zoghbi lab “repertoire.” Just like for Rett syndrome and MECP2 duplication syndrome, Zoghbi’s group aims to discover new treatment or prevention pathways for Alzheimer’s. To do this, they’re diving deep into the basic science behind what drives the build-up of certain proteins – tau proteins – in the disease. When tau proteins accumulate in the brain, they form tangles inside neurons and block communication between neurons. Knowing this, Tadros is working to identify ways to target tau proteins as a pathway that could lead to new therapies to treat or slow the progression of Alzheimer’s disease.
‘I am but one person…’
“One of the main reasons Dr. Zoghbi’s research and her work in the field of Rett syndrome attracted me was because she works so closely with patients,” said Harini Tirumala, a postdoctoral researcher in Zoghbi’s lab who has met several children with Rett syndrome, as well as some of Zoghbi’s former patients. “It’s devastating how profound the impact of the disease is on the patients’ abilities. But you see the toll it takes on the entire family, not just the patient. That really motivates you, it drives you. While it’s devastating, it’s also very inspiring in the sense that I just want to wake up and do what I do with more rigor because these patients really need us.”
Further, Zoghbi’s mentorship is a major force that propels the lab forward, Tirumala said.
“Dr. Zoghbi is a phenomenal mentor,” she said. “The most important thing about her is that she cares about you as a person, beyond your contribution to the lab, to the science. She really listens and she remembers things that are important to you personally, as well as professionally.”
Although Zoghbi acknowledges that mentorship has always been important to her, it wasn’t until she had spent several years working in the lab that she realized how critical it is for expanding her lab’s impact.
“Somewhere about 10 years into my career I started realizing I am one person. I can only do so much,” Zoghbi said. “But, if I train my students [and members of my lab] to be the best possible scientists they can be, I can multiply myself 10 times, 100 times. Once that reality really woke me up, mentorship became a passion. I realized this is the most important thing I can do. If I really want to make a difference for my patients, if I really want to impact science, mentoring people is the most powerful, effective way I can do it.”