Genetic Neurologist: A Profile of Huda Zoghbi

Turning to molecular genetics, the Baylor pediatric neurologist and geneticist works to discover the biological basis for the rare neurological diseases she sees in her patients.

Nov 1, 2018
Anna Azvolinsky
Huda Zoghbi
Professor, Baylor College of Medicine, Houston, Texas
Founding director of the Jan and Dan Duncan Neurological  
   Research Institute at Texas Children’s Hospital
Howard Hughes Medical Institute investigator
National Academy of Sciences member
Vilcek Prize in Biomedical Science, 2009
The Shaw Prize Laureate in Life Science and Medicine,
   The Shaw Prize Foundation, Hong Kong, 2016
2017 Breakthrough Prize in Life Sciences
Canada Gairdner International Award, 2017


In 1976, Huda Zoghbi (then Huda El-Hibri) was an eager first-year medical student at the American University of Beirut, Lebanon, her hometown. Halfway through that year, a civil war broke out. “Bombs were falling all around the medical campus,” the neuroscientist recalls. “I couldn’t commute 500 feet, let alone the two miles it took me to get home every day.” She and the other 62 students in her class decided that they, along with their professors, would live on campus—mostly underground, in double-walled rooms—to finish the school year.

Although the medical school was considered a safe zone, as both warring factions would send their wounded there for care, an occasional bullet or piece of shrapnel still pierced the campus. One afternoon, Huda had ventured out for a walk on campus with her boyfriend, William Zoghbi, a fellow medical student. They were holding hands and for no particular reason let go. In those few seconds, a bullet flew between them. Neither was hurt, but the young couple realized in an instant how close and serious the war really was.

Later, shrapnel wounded Huda’s younger brother while he was walking home from high school, so their parents decided to send them and another sibling to Texas, where their oldest sister was a professor of philosophy. The move was supposed to be temporary. But when the 1977 school year was to start in Lebanon, the civil war was still raging, and neither Huda nor her siblings could return home.

She was devastated that she could not continue medical school, and she worried about her parents, living in Beirut surrounded by war. But Huda was also resolute in continuing her education. She found a medical school, Meharry Medical College in Nashville, Tennessee, that allowed her to join even though its academic year had already begun.

Despite the tenuousness of her situation, Huda made do. She excelled academically. By this time, William had joined her for medical school in Nashville, and after graduation, they moved to Houston, Texas. There, Huda began a residency in pediatrics at the Baylor College of Medicine in 1979. She was initially fascinated by cardiology, but a rotation in neurology opened her eyes to the ways that neurodevelopment can go awry during childhood. “I kept being drawn back to these patients, thinking how fascinating the brain is and how as clinicians, we had to use logic to figure out which part of the brain’s anatomy has a problem and is driving the symptoms,” she says. She switched her specialty. She and William, a cardiologist, married soon after.

Since then, Huda Zoghbi has uncovered the molecular mechanisms of normal neurodevelopment and neurodegeneration by probing the complexities of rare neurological diseases, including Rett syndrome and spinocerebellar ataxia.

Literature, then research

Zoghbi was born in Beirut in 1954. Her mother raised her and her siblings while her father ran their family’s olive oil–based natural soap company. She recalls a simple and happy childhood by the Mediterranean Sea, playing outdoors, studying, and reading. She devoured Jane Austen, Shakespeare, and Fyodor Dostoevsky, as well as Arabic literature. She wanted to be a writer, but her mother convinced her that, with her excellent grades in math and the sciences, she should plan to go to medical school. Zoghbi entered the American University of Beirut as an undergraduate in 1973, majoring in biology.

“My love of literature has helped my research career,” she says. “My colleagues tell me that when I give scientific talks or write a paper, I always tell a story. So I ended up channeling my passion for writing into my science career.”

After her pediatric residency at Baylor, Zoghbi stayed at the Houston-based institution, starting a pediatric neurology fellowship in 1982. She was frustrated by the fact that medical science could only ease the symptoms of the many children she worked with who suffered from untreatable neurological disorders. It was then that a patient caught her attention: a girl with Rett syndrome, a rare, poorly characterized disorder that leads to severe learning disability and motor impairments, including ataxia—balance and coordination problems—loss of speech, seizures, and some autism-like behaviors, most distinctively repetitive hand-wringing movements.

Greatest Hits

  • Discovered the X-linked gene, MECP2, encoding a methyl-CpG-binding protein, a mutation in which results in Rett syndrome, a rare neurodevelopmental disorder that almost exclusively affects girls.
  • Created a mouse model of Rett syndrome and uncovered the cell type–specific requirements for Mecp2 in the brain.
  • Identified that low expression of Mecp2 results in Rett-like features, while overexpression of the gene results in a different neurodevelopmental disorder that includes autism- like symptoms.
  • Along with the lab of Harry Orr, discovered the gene mutated in spinocerebellar ataxia
  • Identified the Atoh1 gene, which encodes a transcription
    factor essential for development of inner ear hair cells and the Merkel cells of mammalian skin for the light-touch response, to discriminate shapes and textures.

“The children are born normal, acquire milestones, and then gradually lose them,” she says. “I saw two Rett patients in the same week, and this is a rare disease affecting about 1 in 10,000 girls.” In the scientific literature, there was no reporting of Rett patients in the US, so Zoghbi set out to find additional individuals with the disease. She studied six of them to understand the pathogenesis of the disorder and found that the girls had decreased circulating metabolites of key neurotransmitters, norepinephrine and dopamine in particular.

Those results, and Zoghbi’s work over the next few years, helped Baylor become a major Rett syndrome referral center. The disorder mostly afflicts female offspring of healthy parents, making it 99.5 percent sporadic from an epidemiological standpoint. Still, Zoghbi hypothesized that Rett syndrome disrupts a specific biological process and has a genetic basis, because the symptoms are consistent from patient to patient. She wanted to do additional Rett syndrome research, but she had no prior lab experience. So she decided to do a postdoc and zeroed in on the lab of Arthur Beaudet, also at Baylor, who studied genetic metabolic disorders.

Zoghbi laid out her case for pursuing the genetic basis of Rett, including her access to more than 100 patients. Beaudet told her that, although he would take her on as a postdoc, finding a genetic cause for the rare disorder was too tall an order and that she should find a more tractable project. She took the advice and wrote a proposal for the National Institutes of Health Mentored Clinical Scientist Research Career Development Award, also called the K08, which provides five years of support for a clinical researcher who aims to establish their own laboratory. Zoghbi suggested studying spinocerebellar ataxia (SCA) type 1, an autosomal dominant, usually adult-onset neurodegenerative disease for which a causative genetic mutation was not yet known.

“I wrote the proposal before I had any publications, when I had no clue how to do anything in the lab. But I had determination, and a good mentor and scientific question,” she says, noting that the award, which Zoghbi won in 1985, was a lucky break for her career. “I had five years of funding, and I told myself that I will give science these five years and won’t quit before then.”

By this time, she and William had a toddler and a four-month-old infant. She took graduate courses, learning molecular biology and genetic linkage mapping.

After three years, Zoghbi finally made progress: she approximately mapped the SCA locus to a region of human chromosome 6.

The biology of Rett syndrome

Beaudet eventually advised Zoghbi to apply for funding to start her own laboratory. In 1988, she became an assistant professor at Baylor. Deciding not to heed the advice of Beaudet and other colleagues, Zoghbi returned to studying Rett syndrome, convinced that she could map the causative gene, which she suspected was on the X chromosome. Over the next 10 years, she and her lab members began to collect tissue samples from families with two affected sisters, systematically comparing each of their X chromosome genes. This project helped Zoghbi’s lab, in 1992, to identify a region of the X chromosome that harbored the likely mutation. Then, in 1999, Zoghbi and her collaborators identified the exact gene, MECP2, which is mutated in Rett syndrome sufferers. The researchers showed that Rett was indeed an X-linked dominant disorder, meaning that just one mutated copy of MECP2, which normally encodes a methyl-CpG-binding protein, was enough to cause the disorder.

“There are three things that for me were crucial in my career: mentors that believed in me, a supportive family, and the sparse rewards of positive data.”

Then, in a mouse model of Rett’s syndrome that the lab developed, the team confirmed, in 2009, that a mutation in Mecp2, the mouse homolog of MECP2, results in a reduction of serotonin and other neurotransmitters, as Zoghbi had first observed in 1983 and reported in 1985. The lab also found that such a mutation partially disables excitatory neurons, and confirmed that practically all brain cells require the protein encoded by the gene.

This and other mouse models also taught the team that while eliminating the function of Mecp2 in just 50 percent of brain cells results in Rett syndrome symptoms, overexpression also caused a neurological disorder. Zoghbi and her lab mates supported the validity of their findings in mice by reporting that in human male cases, patients had an increased number of copies of the MECP2 gene, while other labs reported on the rare female cases. Those extra copies increased protein levels, leading to neurodevelopmental delays. “From our mouse models, we learned that the brain is really sensitive to the dose of this gene, which must be tightly regulated. Slightly less protein and slightly more protein can lead to disease,” Zoghbi explains.

Recently, in collaboration with a biotechnology company, Zoghbi’s lab has developed a potential therapy for decreasing MECP2 expression. The team is using an antisense oligonucleotide that binds MECP2 RNA and prevents its translation into protein, and is testing the oligonucleotide in animal models to identify the appropriate dosage to dial back MECP2 expression just enough—“too little will cause Rett-like problems,” Zoghbi says.

“When I started working on Rett, most researchers didn’t think that sporadic disorders could be genetic, but here we found a disease that is genetic but a result of a de novo, not an inherited, mutation,” she explains. “This has opened up the search for other genetic forms of disabilities that are sporadic but still caused by a genetic defect.”

Tackling other neurological diseases

In parallel to the Rett syndrome studies, Zoghbi’s lab also continued to work on SCA1. “With Rett syndrome, had we been waiting for a discovery for 16 years, I would have killed my career,” she says.

“Even what I considered as fun projects have revealed themselves to be medically relevant.”

When she started her lab, Zoghbi contacted Harry Orr, a University of Minnesota researcher who was also working on the genetics of SCA1. The two labs collaborated, identifying the mutation that caused the disease. First, they found the probable region of chromosome 6 where the SCA gene sits. Then, on the same spring day in 1993, the two groups realized that they had found the exact locus on chromosome 6: an unstable trinucleotide CAG repeat. “That was a sweet and exciting moment because both of our labs had been working on this for years,” Zoghbi says.

Zoghbi’s lab went on to create a mouse model for SCA1 that showed that certain neurons are more sensitive to mutant ataxin-1. “From this rare disease, we’ve learned a lot about factors that drive degeneration in neurons, which helps us to think about more common neurodegenerative diseases like Parkinson’s and Alzheimer’s,” Zoghbi says.

In the midst of these two major lab projects, Zoghbi says that she was craving a fun, basic-science project that did not carry the emotional weight of studying human diseases. Her Baylor colleague, a neurobiologist and fruit fly geneticist, Hugo Bellen, helped her zero in on atonal, which encodes a transcription factor and is required for the development of the peripheral nervous system. When mutated, atonal results in deaf and uncoordinated flies. Zoghbi’s lab began to search for the homologous gene in mice. In 1999, they discovered it—it’s called Math1 (or Atoh1) and is critical for the genesis of hair cells in the cochlea and vestibular system. And in 2009, they found that knocking out Math1 in mouse skin cells results in the loss of Merkel cells, part of the peripheral nervous system. These cells, the team found, are essential for discriminating among shapes and textures during touch, the so-called light-touch response. That same year, the lab also found that deleting the Math1 gene could prevent medulloblastoma, a type of brain tumor.

“Even what I considered as fun projects have revealed themselves to be medically relevant,” Zoghbi says.

Building science confidence

While successful now, Zoghbi says, she had no confidence that she would be successful when she started out. She just had a lot of determination. “There are three things that for me were crucial in my career: mentors that believed in me, a supportive family, and the sparse rewards of positive data that sustained me and allowed me to continue,” she says. “I don’t think my lack of confidence is unique, and it’s important for young scientists to realize that,” she says.

“You also need a life outside the lab, whatever that is, so that you have perspective and can face every day with a more positive attitude,” Zoghbi explains. For her, life outside the lab has been her husband, son, daughter, and her extended family in Lebanon. She and William began to take their children on visits to Lebanon as youngsters, to experience the country’s beaches, mountains, and culture, and they continue the tradition with their grown children and first grandchild.