By Todd Ackerman

The Houston Chronicle

Huda Zoghbi never dreamed her research into the rarest of rare brain disorders might one day lay the groundwork for promising therapeutic candidates for Alzheimer’s and autism.

She just wanted to help the patients she first encountered as a pediatrician-in-training in the 1980s, girls who mysteriously lost the ability to walk, speak and use their hands. Moved by their plight, Zoghbi set out to find solutions, even though it meant she’d need to reinvent herself as a geneticist.

“People become scientists for all sorts of reasons, such as science for science’s sake,” says Zoghbi, a professor at Baylor College of Medicine and the founding director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital. “I became one because I was heartbroken I had to tell parents nothing could be done about their child’s disease, frustrated by the state of neurology at the time.”

She laughs now at the naïveté that she could quickly find a disease’s cause and first-ever treatment, but Zoghbi went on to identify the genes responsible for two rare neurological disorders, discoveries that have shed light on the understanding of brain vulnerability at both ends of life. She calls the knowledge the Goldilocks Principle because it involves the brain’s need for the amount of certain proteins to be “just right,” neither too little nor too much. Testing of therapy based on the principle, a drug in design to tweak those protein levels, will begin in Alzheimer’s mouse models soon.

On Sunday, Zoghbi received the richest award in science, the Breakthrough Prize. Winners get $3 million, no strings attached, at a red-carpet ceremony in Silicon Valley that this year was hosted by Academy Award-winning actor Morgan Freeman and featured a performance by Grammy Award-winning singer-songwriter Alicia Keys.

The idea, the brainchild of “digerati” such as Facebook’s Mark Zuckerberg and Google’s Sergey Brin, is that celebrating scientists in a way similar to how movie stars are recognized at the Oscars will attract more young students to go into science. In that spirit, the winners were kept secret until the event.

The event, broadcast live on the National Geographic channel and to be re-aired on FOX Dec. 18, is now in its fifth year. MD Anderson Cancer Center professor Jim Allison, who discovered a brake on the immune system and developed a drug to unleash it so the body’s defenses can attack tumors, won one of the prizes in 2013; and Stephen Elledge, a geneticist at Harvard-affiliated Brigham and Women’s, joined Zoghbi in the winner’s circle this year for research he conducted at Baylor in the 1990s and early 2000s on how cells sense and repair DNA damage.

‘Charting new paths’

Brin and 23andMe’s Anne Wojcicki presented Zoghbi, a Lebanese-American, the award for “findings that have provided insight into the pathogenesis of neurodegenerative and neurological diseases.” Wojcicki extolled the brain as “a majestic mystery” but lamented the devastation when brains go wrong and Brin said that “as a Russian emigrant, it gives me great pleasure to give this award to a Lebanese emigrant.”

In her acceptance speech, Zoghbi cited the deaths she witnessed as a young doctor.

“I turned to research for answers, and today, together with collaborators and trainees we are charting new paths towards viable therapies,” said Zoghbi. “It’s thrilling to see we are beginning to understand the language of life and translate it to help mankind.”

In a video played before the presentation, Zoghbi said she will “not retire until I find a treatment for any of the diseases that I work on.”

Zoghbi has won a raft of awards in her career, at least one considered a predictor of a future Nobel and all of which have special meaning to her, she says. She likes the Breakthrough Prize in Life Sciences, she says, because it provides “a platform to inspire young people she probably wouldn’t normally reach.”

Zoghbi, 61, grew up in Beirut, speaking Arabic, English and French and enamored with Shakespeare and other literary figures. Her parents were businesspeople – her dad sold olive oil, soap, other items – who stressed ideas and education. When the young Huda went into the kitchen to help her mother, she was told to return to her studies.

Her mother also convinced her to study biology in college, a classic pre-med field. It would ensure independence and security for a woman in the Middle East, her mother advised.

In 1975, she entered medical school at the American University of Beirut, an education disrupted six months later when civil war broke out in Lebanon. She lived a mile from campus with her family, but it soon became apparent traveling even a short distance was too dangerous. Bombs were falling everywhere.

Zoghbi and classmates moved into the medical school.

“It was tough,” Zoghbi said in an interview in advance of the ceremony last week. “We’d sleep in double-walled rooms because you wouldn’t have been safe in rooms with windows. I slept in a tiny room within the ladies room.”

That summer, after her parents’ house was damaged by bombs and her brother was injured by shrapnel, Zoghbi was sent to stay with a sister in Texas. The plan was for her to return in the fall, but the war escalated so she instead found herself looking for a U.S. medical school that would take her after the new school year had started. She ultimately landed at Meharry Medical School, a historically black institution in Nashville.

A breakthrough

Zoghbi came to Baylor as a resident in pediatrics. It was there that she saw her first patient with Rett syndrome, now known to affect 1 in every 10,000 females, then little recognized in neurology clinics. Zoghbi diagnosed the condition in a 5-year-old girl at Texas Children’s, healthy until about her third birthday when her gait became uncoordinated, her head stopped growing normally and her language skills declined until she stopped speaking altogether. When Zoghbi saw a second patient with the same set of symptoms a week later and then, sifting through records, found five more patients, misdiagnosed, she determined she’d need a formal training in molecular genetics to tackle the disease.

But with little data about Rett available then, her first gene search instead focused on even rarer degenerative brain disease, spinocerebellar ataxia, which affects 1 in every 100,000. The condition usually appears in adulthood, attacking and destroying nerves in the brain and spinal cord and typically killing victims within 10 years of their first symptoms. In the 1980s, Zoghbi drove dusty roads in rural Texas and Louisiana on the hunt for patients, convincing families to open their doors to be interviewed and give blood, in which she hoped to find the code that programmed them for death.

Colleagues kept telling Zoghbi she was wasting her time, the diseases were so rare. It reached the point she stopped telling people what she was working on.

But Zoghbi’s doggedness paid off. In 1993, eight years after starting the hunt, she discovered the mutant gene that causes spinocerebellar ataxia. In 1999, 16 years after she diagnosed her first Rett patient, she discovered the gene responsible for it. Insights gained in the research are proving helpful in developing therapeutic targets for more common devastating diseases – Rett for autism and spinocerebellar ataxia for Alzheimer’s.

“It shows the importance of studying a rare but defined disease,” says Zoghbi. “You learn so much you can apply the knowledge to a more common, heterogeneous disease.”

The potential application for autism involves deep brain stimulation, an invasive technique sending electrical impulses through electrodes implanted in the brain that is currently used to ameliorate debilitating motor symptoms in people with Parkinson’s. In Zoghbi’s mouse models of Rett, the technique significantly improved memory and learning and the team is now working with other intellectual disability models. Zoghbi is hopeful that because stimulating network activity already worked in one such model, it can work in many autism spectrum disorders.

The application in Alzheimer’s could yield the most dramatic benefits. In an example of the Goldilocks Principle, Zoghbi’s team recently showed that stopping the build-up of a toxic protein that makes the brain vulnerable to degeneration prevented such symptoms in animal models. Zoghbi hopes a drug – multinational biopharmaceutical company UCB is currently developing one she will test in mice – eventually can work in patients at risk of dementia like statins act to control the accumulation of cholesterol in the blood vessels of heart patients.

‘Next generation’

Zoghbi has remained in Houston her entire career, despite frequently being approached for top jobs around the country. She says she is loyal to Baylor and Texas Children’s for taking a chance on her coming out of Meharry and loves the opportunities at the Neurological Research Institute, a first-of-its-kind center that employs 30 to 40 leading scientists dedicated to the development of treatments for childhood neurological diseases. Zoghbi has provided the vision, from the recruitment of scientists and setting of priorities to her insistence, long before the institute’s 2010 opening, that it absolutely had to be built near both Baylor and Texas Children’s.

Zoghbi plans to donate the majority of her $3 million Breakthrough Prize to support education and research initiatives.

“The idea is to honor people who’ve come before but focus on the next generation,” says Zoghbi. “They’re the ones who will make the next advances.”