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.
Education
M.D., University of Michigan, 1968
A.B., Marquette University, 1964
Current
Duke School of Medicine Professor of Neurosciences
Departments of Neurobiology and Neurology
Director, Center for Translational Neuroscience
Duke University School of Medicine
www.dibs.duke.edu/research/profiles/39-james-mcnamara
Work in Dr. McNamara’s laboratory seeks to elucidate the mechanisms of epileptogenesis, the process by which a normal brain becomes epileptic. Understanding the mechanisms of epileptogenesis in molecular terms may provide novel targets for pharmacologic interventions for prevention of epilepsy.
Earlier this year, CURE announced a partnership with the Howard Hughes Medical Institute’s Research Fellows Program to provide support for up to three medical students to conduct mentored research on epilepsy. One of the Fellows CURE is supporting is Ethan Ludmir, a second year medical student at Duke University School of Medicine. He will be working in Dr. McNamara’s lab, studying cellular and molecular mechanisms underlying development of temporal lobe epilepsy. In 2007, CURE awarded Dr. McNamara a Traumatic Brain Injury (TBI) grant. He eventually shifted his focus to temporal lobe epilepsy, and recently had a major breakthrough.
After completing his residency training in neurology, postdoctoral training in biochemistry, and two years of military service practicing neurology, Dr. James McNamara was offered a faculty position combining clinical work in epilepsy with a preclinical research program in epilepsy. Ever since, he’s been dedicated to researching the molecular mechanisms underlying development of temporal lobe epilepsy. This work culminated in an exciting recent discovery, the identification of a molecular mechanism by which an episode of prolonged seizures in a mouse results in temporal lobe epilepsy and associated anxiety-like behavior.
Dr. McNamara was kind enough to speak with CURE about this exciting discovery.
How did you become interested in epileptogenesis?
I’m a neurologist and interested in developing novel treatments for neurological diseases by understanding mechanisms of the diseases. I wanted to align my research program with my clinical interests and was offered a position at Duke to run an epilepsy program in 1975.This led me to focus my research interests on epilepsy and, in particular, on a problem aligned with my training in biochemistry. This led me to seek the biochemical or molecular mechanism by which temporal lobe epilepsy develops. This was a dream opportunity for me because I could combine care of patients with the same disorder that I investigated in the laboratory. Insights into the disease at the bedside guided and informed my laboratory studies. Likewise, insights from the laboratory studies helped me better understand and treat patients with epilepsy. I am privileged to have been able to pursue this career.
So it’s a cycle—between the lab and the physicians’ office?
Exactly—it’s a mutually reinforcing cycle. I am blessed to have been able to do this.
How would you describe this discovery to someone unfamiliar with the science behind epilepsy?
This requires a bit of an explanation. First of all, the temporal lobes of the brain are important for memory formation. Temporal lobe seizures disrupt the function of the temporal lobe transiently, so it is not surprising that individuals experiencing such a seizure have no memory of the event and the individual is unaware of her or his surroundings during the seizure. The unpredictable occurrence of temporal lobe seizures limits the patient’s ability to drive and to do many jobs.
Temporal lobe epilepsy is one of the most common forms of epilepsy, accounting for approximately 40% of patients. What causes temporal lobe epilepsy? One cause of the most severe cases appears to be an episode of prolonged seizures early in life, the episode frequently triggered by a fever. Inducing an episode of prolonged seizures in a normal mouse is followed by recovery and the emergence of severe temporal lobe epilepsy days to weeks later. We wanted to understand how the prolonged seizure transformed a mouse brain from normal to epileptic because this would provide a clue to what is going on in humans. We recently discovered that the prolonged seizure triggers excessive activation of a receptor called TrkB and that this excessive activation is required for induction of late onset epilepsy.
We are excited about this discovery for three reasons. Our work demonstrates that it is possible to prevent emergence of epilepsy even if we initiate treatment with an inhibitor of TrkB after the episode of prolonged seizures; this is important because treatments started after the prolonged seizure in a human may also be effective. We also found that inhibiting TrkB for just two weeks was sufficient to prevent the animal from becoming epileptic when studied weeks to months later; this is important because treatment of humans for a relatively period following the prolonged seizures may be effective, the brief period limiting unwanted effects of the drug. Finally, our work identifies a specific receptor, TrkB, that is critical and raises hope that drugs to inhibit TrkB can be developed and tested for preventive treatment.
Your discovery raises the possibility of preventive treatment for the most common form of human epilepsy. Are there preventive treatments for other common diseases of the brain? If not, why not?
This is an excellent question. Apart from treating high blood pressure and elevated lipids for prevention of stroke, there are no preventive treatments for any common disease of the human brain. For example, we have no treatments to prevent development of Alzheimer’s or Parkinson’s disease, schizophrenia, manic-depressive disease, multiple sclerosis, etc. The lack of preventive treatments reflects the complexity of the challenge. Availability of an informative animal model of these common diseases is enormously helpful but, even if available, there are literally hundreds of thousands of possibilities. Enormous advances in basic science in the fields of molecular biology, imaging, chemistry, and many others are paving the way for attacking these difficult problems. I am optimistic that scientists will make great progress with these challenges during the next decade and this progress will greatly reduce the burden of disease of the nervous system and other organs as well.
Are genetics involved? For example, if a parent has one prolonged seizure in their lifetime, does it affect the chances that their child will develop epilepsy? Is this something that will be studied?
Longitudinal studies of children who have prolonged seizures reveals that roughly 40% of them go on to develop epilepsy later in life. Why is it that 40% develop epilepsy and the remaining 60% do not? I suspect that one factor that accounts for these differences is genetic susceptibility.
What are the next steps? What is involved in developing a drug?
The next step is to develop a drug that potently and selectively inhibits TrkB. I think that such a drug may benefit multiple disorders of the nervous system, including epilepsy. Developing such a drug requires substantial expertise, resources, time and energy. We and others are working hard on this important challenge. Success with this effort holds promise for preventing epilepsy that arises after episodes of prolonged seizures.
