Dr. Huda Y. Zoghbi, a professor in the departments of pediatrics, molecular and human genetics, and neurology at the Baylor College of Medicine, took home the 2011 Gruber Prize for Neuroscience for her pioneering work examining the genetic underpinnings of neuropsychiatric disorders. She speaks with the Dana Foundation about balancing clinical work with basic science, what we can learn from the study of rare disorders and her vision of the future study of genetics and neuropsychiatric disease.
Q: What initially interested you in the genetic components of disease like Rett Syndrome and spinocerebellar ataxia type 1?
Huda Y. Zoghbi: Back when I was training as a neurologist, I was struck by how many disorders we saw in the clinic were genetic. I thought if I were to really make an impact, I’d have to first identify the genes. That would be the starting point—then we could do the additional work to understand what goes on in the brain when these genes are defective.
Q: As both a clinician and a scientist, how do you strike the right balance in your work?
HZ: When you really care about your patients, you want to spare them bad studies. You want to spare them bad clinical trials. You put the patient first and that helps you to become very selective and objective when it comes to the science.
While I would love to be bringing a drug to the clinic today or tomorrow, I need to be able to look at my patients and say, “I would put my child through this trial.” That is the litmus test for me. And when the answer is no, you know there’s a lot more to be learned and it’s time to go back into the lab.
Q: You work with many rare neuropsychiatric disorders. What has drawn you to them?
HZ: While it’s true when I started my research career, these disorders were unknown to most people outside the families affected by them, what we’ve seen in the past 20 years is that many disorders fit into the rare category.
Most diseases, even the most common ones like Parkinson’s or Alzheimer’s disease, are actually a collection of very, very rare disorders. There is not one cause that can explain the whole of these but rather one cause that can maybe explain 100 of patients, another cause that explains another few dozen patients and so on.
I think we’ve been humbled through the past 25 years of genetic research and learned that even common disorders are simply a collection of rare disorders that share similar clinical features. There’s a lot to be learned from these rare disorders—we just may not know it yet.
Q: Some have voiced discouragement by a lack of “smoking gun” genes found in neuropsychiatric research. How do you respond to that?
HZ: I am more optimistic by what we are finding than what maybe others are. I see genes as a starting point to a disease process.
When you really think about neuropsychiatric disorders, the mutated gene by itself is not what is causing someone to have a problem. Rather, it is the result of multiple changes that happen from the beginning of this mutation all the way to its effect in a neural network. As we begin to peel the layers of all the things that are happening from a mutant gene to the abnormal protein coming from that gene to the variety of altered protein interactions, to the effect on the neurons and then the neurons as they interact together in a network, I believe we’re going to begin to find many commonalities.
While it may seem daunting to say there are, say, 400 genes involved in autism, as we implement the studies that can dissect the process every step of the way, we’re going to find those points of integration that will become that “smoking gun”—and that’s where we can focus our treatments. We still have a lot of basic science to do, and we have to accept that, but the answers are out there.
Q: You’ve said that you’ll consider retirement after you make some of your patients better. While you obviously have many good years of research ahead of you, what do you hope your legacy will be?
HZ: I hope that my legacy will involve the wonderful training that comes out of my lab. I am but one person and can only accomplish so much. But by training students and fellows, whatever I might be able to do can be multiplied and a great group of creative people can continue this mission.
My collaborations, particularly my long collaboration with Harry Orr, are also an important part of that. But, mostly, I also hope that my work advances disease research to find real treatments. That why I came into science to begin with—because I know this research is the only way that we can help these patients. And I hope that others will continue my quest to understand the fundamental basis of neuropsychiatric disease so we can eventually develop those treatments.