Spotlights

Huda Y. Zoghbi, M.D.


By Texas Medical Center | July 1, 2015

Huda Y. Zoghbi, M.D., professor in the Department of Molecular and Human Genetics at Baylor College of Medicine and director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, has had an exceptional career. From her early days as a medical resident in pediatric neurology to her research role in the discovery of the gene for Rett syndrome, Zoghbi has always had a desire to give families the answers they need when faced with a devastating diagnosis.

Q | Can you tell us a bit about your formative years?
A | I was born in Beirut, Lebanon, and was fortunate to have a family who valued scholarship. My parents always encouraged me to study and my bibliophile dad would spend hours reading in his huge library. His library was filled with books from floor to ceiling, a room I enjoyed spending time in as well.

I attended school in Beirut. I fell in love with English literature in high school and decided to declare it my major once I enrolled in a university. My mom disagreed. She felt that literature was not the right path for me, which led to quite a few arguments. She would say, ‘I can’t believe that you are so good in biology but you are going to study English literature just because you like reading and writing. You can do that as a hobby and focus on medicine professionally. For a woman it will be much better to have a career in medicine than to be a writer.’ I eventually began to understand her point, and after much discussion, ultimately entered the pre-med program at the American University of Beirut.

Q | What led you to Houston?
A | I completed my pre-med degree at the American University of Beirut and then began medical school there. I was very happy living in Beirut. The city was at its peak, a dream place to be. When the civil war began, however, the quality of life in Beirut quickly deteriorated.

Towards the end of my first year of medical school, Beirut was becoming quite dangerous and my parents suggested that I spend the summer with my sister who was living in Austin, Texas, at the time. I arrived in Texas thinking that my stay would only last through the summer. Unfortunately, the war continued to escalate during those months and I decided to transfer to a medical school in the United States. I ultimately enrolled in Meharry Medical College in Nashville, Tennessee.

While in Nashville, I traveled to Houston for electives at Baylor College of Medicine. During one of my trips, I met Dr. Ralph Feigin, chairman of pediatrics at Baylor and physician-in-chief at Texas Children’s Hospital. He encouraged me to consider the program here and asked, ‘What can I do to get you to come to Baylor?’ He didn’t have to do much as I quickly knew Baylor was the right choice for my residency.

When I arrived at Baylor, I studied pediatrics and neurology and just loved it, truly enjoying my residency years. For someone who’s been transplanted as an immigrant, not knowing anyone in Houston, the program became my family and Dr. Feigin became like a second father to me. I decided to stay for additional training.

I was trained as a physician, but patient encounters during my pediatric neurology residency inspired me to get research training and led me into science. It was 1985. At the time, the best you could do for a patient with a neurological disease was to meet with the family members, tell them the likely diagnosis, let them know it was probably a genetic disorder that could happen again, and let them know there was unfortunately nothing to be done. It was devastating, to say the least. That’s what compelled me to go into the lab. I wanted to learn what I could about biology and genetics, and how to find disease genes so that we could diagnose more accurately and help families by eventually understanding how to treat these devastating disorders.

Q | Are there any moments from your career that stand out as being your proudest achievements?
A | Making a discovery in an area that I’d been working on for years always stands out—knowing how important it is for us to understand how to solve a neurological problem or better treat a disease. Those moments stand out the most.

I will never forget the day my collaborator, Harry Orr, and I simultaneously sent each other faxes. We were both exchanging the discovery of the spinocerebellar ataxia 1 mutation in our respective labs. We had been collaborating and both discovered the mutation on the very same day. I will never forget that. It’s our special anniversary—April 8, 1993, and we always congratulate each other on that day.

On another occasion, I was returning from a family trip to Lebanon with my children and as I was putting the key in the door, I heard the phone ringing. I picked it up and my postdoctoral fellow, Ruthie Amir, said, ‘We found a change in a gene in Rett syndrome patients. Can I show you the data?’ And I said, ‘Absolutely. Yes!’ I had just traveled for 24 hours, yet I still wanted her to come to the house immediately with all her data. That moment, the excitement of seeing the changes for the very first time, plays over and over again in my head. A few days later we wrote the paper, and two days after that, the paper was accepted.

It was a very exciting time when we found the Rett syndrome gene, because it was a result of a 16-year search. When you wait for something for 16 years and it finally comes, it’s an unbelievable feeling.

Those two discoveries are the moments that truly stand out. There are many others, of course. When students I’ve mentored and grown to love graduate, or when my first fellow received a faculty position, I’m holding back a tear. These are all very special and the moments that I am the most proud of. And then, of course, to be recognized for what I love to do is so meaningful and such a privilege.

Q | Speaking of your discoveries, can you tell us a little bit about what those mean? And what has been the impact of those discoveries?
A | There have been several different discoveries and each has had a different impact.

Our first discovery was a gene that causes neurodegeneration. It’s an inherited disease called spinocerebellar ataxia type 1 (SCA1) that affects balance. Patients experience gradual neurodegeneration and ultimately die from the disease. It’s a rare disease, but is a typical adult neurodegenerative disease, which means that it shares features with diseases such as Alzheimer’s and Parkinson’s. A patient can be healthy for decades and then the symptoms appear. Because we found the gene for this terrible disorder, we can now provide families with the opportunity for early diagnosis. If the family is affected, they can then choose what lifestyle changes they may want to make. Some may choose not to have children, or to adopt children, so that they eliminate the occurrence of the disease in their family. So many patients and their families are grateful for this knowledge.

Once we finally identify a gene, we are able to create an animal model that closely mimics the human disease. This allows us to better understand how, when a particular gene mutates, it wreaks havoc in the neurons. We found out how the mutated gene affects brain cells and what we might be able to do about it.

Beyond SCA1, the work on this disorder has helped us better understand Alzheimer’s and Parkinson’s disease and has provided us insight and new strategies to tackle those more common diseases.

Another discovery, the identification of the gene that causes Rett syndrome, was one of the most important pieces of evidence proving that sporadic (not inherited) autism could be genetically determined. At the time of the Rett gene discovery, in 1999, we had no idea that most autism spectrum disorders were caused by genetic defects. The Rett gene was one of the first genes discovered that can cause autism and other neuropsychiatric problems. Identifying the gene for Rett syndrome also allows us to accurately diagnose children early and thereby intervene sooner and more successfully with physical therapy.

We’ve also learned that the Rett syndrome gene is important for all aspects of brain function. At the time of the discovery, we had no idea how important it was, but now, after a decade of research, we know it impacts all neurological functions. It tells you when to stop eating by controlling the neurons in your brain that signal when you’ve had enough food. It’s essential to remembering a conversation or reacting to stress. It is important when it comes to learning something new or coordinating movement. It controls the activity of so many brains cells and is a critical gene for many of the brain’s functions.

We also discovered that mutations in the same gene not only may cause Rett syndrome, but can also cause other disorders such as juvenile schizophrenia, bipolar disorder (a specific form), as well as classic autism and various intellectual disabilities. The impact of the work is well beyond what we first anticipated when we embarked on the Rett syndrome project. People thought of Rett syndrome as an isolated disorder, but we have learned so much more about other disorders and diseases, including how critical certain molecules are for our brain function, by studying Rett.

And then there’s one more very significant point. We study these disorders top down, meaning that we start with a patient, drill down to the cause, and drill still further to find the mechanism of disease. But we also have a very interesting project that started bottom up. It started not with a patient, but with an extremely obscure, small organism: a fruit fly. People don’t think about how important fruit flies are. In fact, humans and fruit flies share most of the important genes that control development, behavior and physiology.

In 1993, I was discussing interesting genes with my Baylor colleague Dr. Hugo Bellen. I asked, ‘What is an interesting gene in the fruit fly?’ And he replied, ‘Well, there’s this gene called Atonal that’s really important for balance and coordination in the fruit fly, and perhaps it’s important in mammals as well.’ Because of my interest in balance disorders, I decided to find the equivalent gene for Atonal in the mouse and see if it’s relevant. In 1993, no one had really taken genes from fruit flies, mice, and humans to compare them. It was unusual at the time. My colleague, Dr. Bellen, and I wrote a grant together to further pursue this idea. Reviewers told us the idea would never amount to anything.

Despite the naysayers, I went ahead and identified the mouse gene and started studying it. As it turned out, this gene is very important. It is the gene that makes the little hair cells inside the cochlea and vestibular system inside the inner ear (hair cells are the mechanoreceptors for hearing and not actual hairs in the ear). The hair cells inside the cochlea sense sound and transmit that information to the brain. If you move your head, the hair cells sense the movement and transmit that information to the brain to help retain balance. The gene, in fact, is extremely important for many components of balance.

It turns out the gene also appears to be important for certain brain cancers.

In one of the most common child brain tumors, this gene becomes hyper-functional. It’s also critical for special neurons in the brain responsible for breathing. These are the neurons that are vulnerable in sudden infant death syndrome. The gene is also important for making the cells in the intestine that secrete mucus, neuropeptides and antimicrobial peptides. And the gene is important for you to be able to feel things through touch receptors. If you are playing the piano, you can feel the difference between the white keys and the black keys because of the mechano-sensitive cells that depend on this gene. All of this depends on this one particular gene.

We started with a gene from a lowly organism, and by studying it in mammals, we discovered the gene is critically important for numerous functions. Now labs around the world are studying this gene and testing it in cancer, hearing and deafness. Those little hair cells are what become damaged when you hear a loud sound or as you age, causing a loss of hearing and even deafness. If we can find a way to help recreate the hair cells, it may serve as a potential therapy down the line. We also hope to gain a better understanding of neonatal breathing to prevent sudden infant death syndrome through studying this gene.

Q | What inspired you to start the Jan and Dan Duncan Neurological Research Institute?
A | I’ve loved being in the lab working on my research. As you can tell, it took a long time to answer the questions that drew me to research in the first place, but in the end we did succeed. Our hard work paid off in areas we never expected, like the fly gene that turned out to be so important for mankind. When you have this kind of experience, you become very committed to the lab and hooked on the excitement of being a scientific investigator. Any time someone approached me about becoming a department chair, a dean, or other such similar role, I was completely uninterested. I loved being in the lab and didn’t want to leave. This remained the case until Cynthia and Tony Petrello, along with Dr. Feigin, challenged me to think hard about what more we could do for childhood neurological diseases. Why are so few childhood neurological diseases being studied in depth? Why is progress so slow? What can we do to change this?

The Petrellos’ lovely daughter, Carena, has a neurological disability. I initially reviewed her records because her parents thought she might have Rett syndrome. But she does not. We continued to talk and get to know one another. The Petrellos visited academic medical centers around the country, but they could not find any place where there was an integrated approach to neurological disorders. They wanted to better understand how I had made my discoveries. I explained that I attributed my success to the brilliant people working alongside me, as well as to my ongoing collaborations. I had created my own interdisciplinary, integrated program to make things happen in my own lab. But not everyone can do that and it’s not easy.

The Petrellos made a very compelling argument, ‘Look what you’ve done for Rett syndrome. Why can’t you do the same for additional disorders? What can we do to help?’

That’s when I started reflecting about what it would take to address a range of devastating disorders. After careful thought, I told the Petrellos that to be successful at researching a wide range of disorders, we needed a place where all researchers who work on these disorders could work together, a place that could offer access to a diversity of expertise—because there is no way you are going to understand a brain disorder just because you’ve identified a gene. There is no way you are going to get anywhere just by observing behavior or by simply placing neurons in a dish or on a slide and recording from them. It really has to involve connecting all these different approaches with everyone working together from their respective areas of expertise to solve previously intractable problems.

Due to the massive amounts of data that scientists have to understand to solve a problem, an ideal research team would include experts in genetics, biochemistry, physiology, behavior, statistics, mathematics and computer science. We needed to bring together key individuals from various disciplines, ensure they would work collaboratively, and provide an infrastructure of core facilities that offered cutting-edge technology and expertise no individual investigator could afford on his or her own. We quickly realized that we needed a place to bring these different disciplines together under one roof and study disease comprehensively, as a whole, rather than in discrete pieces.

This became the impetus to start the NRI. Mr. Mark Wallace, CEO of Texas Children’s Hospital, was very excited and whole heartedly supported the vision. Jan and Dan Duncan stepped in to provide the substantial naming gift. So together, the Petrellos, Mr. Wallace, and the Duncans were instrumental in making our vision a reality.

If you look at our faculty, we’ve gone well beyond what we first imagined. Of course we planned to have geneticists, neuroscientists, cell biologists and neurologists, but we now also have computational scientists, high-level statisticians and faculty who work at the NRI under dual appointments with Baylor and Rice University. Shortly after we started on this program, we were approached by Dr. Ron DePinho, the newly appointed president of The University of Texas MD Anderson Cancer Center, to combine our strength in disease neurobiology with their program for developing potential discoveries into therapeutics, and collaborate on neurodegeneration. Our exciting neurodegeneration consortium was created and supported by the Robert A. and Renée E. Belfer Family Foundation.

We also were approached by the Telethon Institute of Genetics and Medicine (TIGEM) in Naples, Italy, where beautiful discoveries have been made in genetics for a variety of disorders. In the area of neurodegeneration and neurological diseases, TIGEM felt our infrastructure at the NRI was ideal, so ideal, in fact, that Dr. Andrea Ballabio, TIGEM director, now has a laboratory at the NRI and a joint appointment with Baylor College of Medicine. Ballabio’s NRI lab is performing research that can truly benefit this class of disorders. We are one of only a very few institutes that have this kind of reach, where investigators from labs throughout the Texas Medical Center, across the country, and around the world truly collaborate on solving problems related to devastating neurological disorders and disease.

Because the Texas Medical Center is such a rich environment, we could not have created the NRI anywhere else. The institute works because everyone in the medical center is open, friendly, generous and collaborative. If you draw a map around the Texas Medical Center, you will discover that the NRI is in the very heart of the Texas Medical Center. This was by design and something I absolutely insisted on—we could not go to the periphery, because we needed to be close to as many of the Texas Medical Center institutions as possible to ensure robust collaborations. The work between Baylor, MD Anderson, Rice, UTHealth and others is very fluid precisely because of our location.

Q | What do you hope for the future of the NRI and these rich partnerships?

A | My dream for the NRI is that the work happening here will allow us to better understand how the brain works and result in discoveries that will truly help patients with devastating neurological disorders. This goal is why our brilliant physicians, physician-scientists, and basic scientists have chosen to come to the NRI. If we can better understand the brain, we can better help those suffering from brain disorders.

For our medical center, I have an even bigger dream. I think the Texas Medical Center institutions, along with Rice University, have absolutely some of the best people in the world working in medicine and science. We have the potential to rise up and become the most exciting third coast in America. Yes, the East Coast is steeped in tradition, so much older than Houston and the Texas Medical Center, and the West Coast has unsurpassed natural beauty and the energy of the tech industry. Yet, from an intellectual standpoint, a capability standpoint, and our indefatigable can-do attitude, I think we have so much more to offer than either the East or the West Coasts. The question now is how to harness our energy to elevate the Texas Medical Center to the place it truly deserves, and be recognized for our contributions to science and medicine.




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