August 20, 2013

CURE Conversations: Dr. Scott Baraban

Get to know our researchers! CURE Conversations features interviews with our scientists and discusses the focus of their work as well as recent breakthroughs in the field of epilepsy research. These investigators are the people behind the scenes who work diligently in the labs to unravel the mysteries of epilepsy, studying the science that will one day lead to cures for the epilepsies.

BA, Johns Hopkins University, 1987
PhD, University of Virginia, 1994

Professor in Residence of Neurological Surgery
William K. Bowes Jr. Endowed Chair in Neuroscience Research
Faculty Member, PIBS Graduate Program in Neuroscience
Faculty Member, Biomedical Sciences Graduate Program
Faculty Member, Eli & Edythe Broad Center of Regeneration Medicine and Stem Cell Research

Selected Honors and Awards
1995: American Epilepsy Society and Milken Family Foundation, Postdoctoral Research Fellowship
1998: Epilepsy Foundation of America, Junior Investigator Research Award
1999: March of Dimes Foundation, Basil O’Connor Starter Scholar Award
2000: Sandler Family Supporting Foundation, UCSF Innovation in Basic Science Award
2001: Symposium Faculty, 21st Merritt-Putnam Symposium (Epilepsy and Disorders of Brain Development)
2003: Esther and Joseph Klingenstein Fund, Fellowship Award in Neuroscience
Can you share some details about what you do?
My lab is interested in the cellular and molecular basis of epilepsy. While seizures can, in some cases, be controlled with available medications, a large number of epilepsy patients are medically intractable. Disturbances of cortical development (long recognized as a cause of epilepsy in children) are particularly difficult to treat, little understood, and marked by severe cognitive deficits. Other forms of pediatric epilepsy, including Dravet syndrome and Tuberous Sclerosis Complex, are equally devastating. How seizures develop in these childhood epilepsies, and how they can be prevented are of particular interest to our laboratory. We employ a multi-disciplinary experimental approach incorporating electrophysiology, pharmacology, molecular biology, and genetics.

What motivated you to become interested in this area of research?
I am a basic scientist with a long standing interest in translational neuroscience research. My earliest exposure to scientific research, both as an undergraduate at Johns Hopkins University and then as a lab technician at Massachusetts General Hospital and Virginia Commonwealth University, has always been geared toward clinically-relevant problems. As I moved on to graduate school and postdoctoral training I was greatly influenced to pursue this interest with a specific focus on epilepsy. The late Eric Lothman at the University of Virginia, and then Phil Schwartzkroin at the University of Washington, nurtured and encouraged me in this regard. When I started my own laboratory, first at Case Western in 1997 and then at UCSF in 1999, I continued to interact with clinician-scientists who focused on epilepsy. In particular, Dan Lowenstein and Nick Barbaro invited me to attend group lab meetings and clinical discussions of epilepsy patients at UCSF. This furthered my interest in translational epilepsy research, and, with the types of pediatric epilepsies we work on, I have met many of the patient advocate groups who have children with these devastating disorders. Having three children of my own, and knowing how these kids with epilepsy are suffering, and further knowing that treatment options are limited, is a strong motivation for the types of research projects we pursue.

What is your current research focus?
Our primary focus has been pediatric forms of epilepsy for which there are few, or no, treatment options. In recent years, we have focused on two pre-clinical areas of interest that we hope will, someday, translate into new therapies for patients with epilepsy.

Can you share some of the latest findings?
One, highlighted by our recent publication in Nature Neuroscience (Hunt et al. 2013) is based on the concept of transplanting neural progenitor cells (from the embryonic medial ganglionic eminence or MGE) that will migrate and integrate as functional GABAergic inhibitory neurons. These interneurons enhance inhibition in the host brain and, if transplanted into the hippocampus of mice with an acquired form of epilepsy (i.e., pilocarpine model), can very effectively suppress, or even eliminate, the occurrence of spontaneous seizures. In addition, these mice perform better on a number of cognitive and behavioral tasks that they had previously performed poorly on. These pre-clinical proof-of-principle studies suggest that “cell therapy” based on transplantation of inhibitory interneurons could be an effective treatment for intractable forms of epilepsy.

A second project that we are also very excited about involves zebrafish. These are small vertebrates commonly used in developmental neuroscience laboratories. A number of years ago, we developed the first zebrafish models of epilepsy. Initially these mimicked rodent models where a convulsant agent (in this case pentylenetetrazole or PTZ) was placed in the bathing medium, and zebrafish larvae, which are permeable to drugs in the bath, exposed to this drug would then exhibit convulsive-like behaviors. If we placed recording electrodes in the vertebrate brain of these zebrafish larvae, we could observe abnormal electrical discharge events that resemble electrographic seizures seen in mammals. More recently, we started using zebrafish with gene mutations that mimic monogenic epilepsies seen in children. One such fish, a mutant for Scn1a (a gene commonly mutated in a catastrophic form of childhood epilepsy known as Dravet syndrome), has been particularly useful as these mutants have spontaneous seizures in normal bathing medium. Taking advantage of this epileptic phenotype, and seizure assays developed in our lab, we used these fish in a high-throughput drug screen to identify lead compounds that might benefit patients with Dravet syndrome. In a recent publication from our group in Nature Communications (Baraban et al. 2013), we show that these Scn1a mutant zebrafish are pharmaco-resistant to several commonly available antiepileptic drugs but do respond, somewhat, to the ketogenic diet and stiripentol. Screening a commercially available library, with initial grant support from the Dravet Syndrome Foundation and CURE, we identified a lead compound that was effective in suppressing spontaneous seizures in this mutant. This type of approach could be applied to any monogenic epilepsy and offers a rapid, cost-effective alternative to traditional drug screening strategies.

What is the ultimate goal for the research and how will it impact patients with epilepsy?
Like any researcher working in the epilepsy field, I hope to someday identify a new treatment option for patients suffering with epilepsy. In my long-range view, I am optimistic that advances in the stem cell field will someday mean that we can apply our cell transplantation approach, now limited to mice, into a clinical treatment. In the short-term, I am equally optimistic that drug discovery using zebrafish will rapidly lead to the identification of new therapeutic options for pediatric epilepsies. I am particularly encouraged by the possibility that newly identified gene mutations, such as those coming out of the Epi4k initiative, can be easily modeled in zebrafish and that these fish can then be used in a targeted “personalized” drug screening protocol.

What accomplishment—personal or professional—are you most proud of?
That is a very difficult question to answer. At a personal level, leading a successful epilepsy laboratory at UCSF and mentoring some very talented young postdoctoral fellows, graduate students, and technicians who will someday contribute to the epilepsy field is something I am proud of. Pushing the envelope on epilepsy research—namely our forays into stem cells and zebrafish—at a time when national funding is limited and pushes research toward conservative approaches is a professional role in the epilepsy community that I am proud to represent. Finally, it goes without saying that our recent research findings, highlighted by organizations like CURE, represent scientific accomplishments that I am also quite proud of.