Taking it to the people
New neurology chair focuses on linking basic research to better treatments
In the mid-1980s, Michael A. Rogawski had completed his residency in neurology at Johns Hopkins University and was invited to join the research staff at the National Institute of Neurological Disorders and Stroke in Bethesda, Md. He was assigned laboratory space and a postdoctoral fellow, and was ready to get started.
The problem was, says Rogawski, "I had no idea what to study."
The focus of his life's work came shortly thereafter when he one day wandered the long corridors of NIH's famed Clinical Center, the world's largest research hospital. A poster on a hallway bulletin board caught his attention. It described how the dissociative anesthetic PCP – better known as "angel dust"– could block excitatory neurotransmission.
Rogawski, who was interested in the role of neurotransmitters in regulating the firing activity of brain cells, knew that excitatory neurotransmission was important in generating seizures in epilepsy. In fact, other researchers had shown that PCP could stop seizures in laboratory animals. Rogawski also knew that PCP itself could never be useful as an antiepileptic drug in people because it produced severe side effects, such as hallucinations. But could it be altered so it would be safe?
"I wondered if you could chemically modify the PCP molecule in such a way that it maintained its anticonvulsant properties without the toxic effects," recalls Rogawski, a leading epilepsy researcher who recently joined the faculty at UC Davis Health System as chair of the Department of Neurology.
Since PCP worked by blocking nerve cell excitation mediated by activation of NMDA receptors, Rogawski focused his epilepsy research in that direction. Years of work would follow, but his lab produced breakthroughs that led to the development of several antiepileptic drugs that targeted these and other receptors.
His research also contributed to the development of memantine, a medication used in the treatment of moderate to severe dementia in Alzheimer's patients. Memantine blocks NMDA receptors in a very similar way to PCP but, as Rogawski had originally shown, it does not produce hallucinations. It also allows individuals with Alzheimer's disease to perform daily tasks more easily.
More recently, he has delved into neurosteroids – steroids that act to enhance inhibitory neurotransmission and that are synthesized in the body from hormones such as progesterone. Rogawski found that the progesterone-derived neurosteroid plays a role in the regulation of seizure susceptibility during a woman's menstrual cycle.
As a result of his work, a drug that is a close chemical relative of this neurosteroid is being evaluated in the UC Davis Department of Neurology and elsewhere as a new treatment approach for epilepsy.
"It's really exciting to see our laboratory research translate into clinical trials, which if the results pan out, could have a positive impact on patients' lives," Rogawski says.
Rogawski, who holds both a medical degree and a doctorate in pharmacology, was already interested in brain research when, as a medical student at Yale University, he found his mentor, George K. Aghajanian, psychiatry and pharmacology professor.
"While there was a huge interest in characterizing the biochemistry of neurotransmitters like serotonin and norepinephrine, George was one of the few scientists in the world trying to understand what the transmitters actually did to neurons," Rogawski says.
Aghajanian also examined the ways in which drugs modified the actions of the neurotransmitters and influenced the behavior of brain neurons.
"In the lab, we used drugs as a probe to understand the functioning of the nervous system. And even though we were working with laboratory animals, we always asked ourselves, ‘what are the implications for people?'"
Yet, Rogawski's ability to study the effects of neurotransmitters in Aghajanian's lab was hampered by technological limitations. There were only two basic ways of measuring cellular electrical events in the brain – by placing an electrode outside the cell membrane, which provided limited information, or by piercing the cell membrane with an electrode, which still didn't provide sufficiently detailed information and had the drawback of damaging the cell.
"I was frustrated," Rogawski recalls. "I couldn't get the level of understanding I wanted."
Things changed in the late 1970s around the time Rogawski was completing his graduate studies. Two German scientists developed a technique called "patch-clamping," in which an electrode was gently sealed onto the cell membrane, allowing the functioning of ion channels to be studied in more detail than ever possible before.
Ion channels are proteins in cell membranes that open and close in response to cell signals, thereby generating the cell's electrical behavior and making it possible for signals to travel from one cell to the next in the nervous system. Patch-clamping enabled Rogawski to study the basic functioning of ion channels in neurons and the way in which drugs influence these channels.
That may sound like an esoteric field of endeavor, but following Aghajanian's example, Rogawski says he tried to relate his basic research advances to clinical problems and particularly to the development of drug treatments.
"We were interested in understanding the fundamental molecular actions of drugs. At the same time, however, we tried to identify implications of our work for clinical medicine, and especially for the development of new strategies to treat brain disorders like epilepsy."
Collaboration is key
At UC Davis, Rogawski wants to keep the focus on treatments. Toward that end, he is working with Lars Berglund, director of the UC Davis Clinical and Translational Science Center, established last year with a $24.8 million grant from the National Institutes of Health for the purpose of fostering collaborative research.
"His focus on developing treatments that improve patients' lives is really what UC Davis and the center are all about," Berglund says of Rogawski. "I'm really looking forward to working with him." Rogawski, whose wife, Julie Schweitzer, is an associate professor of psychiatry at the UC Davis M.I.N.D. Institute, says he wants to "bring together diverse investigators to assess the potential efficacy and safety of new therapies before they go into clinical trials."
Key to that effort will be increasing UC Davis' testing of potential drugs on laboratory animals, a subject Rogawski feels strongly about. "Animal models are absolutely essential as a bridge to treating human diseases," Rogawski says. "It's impossible to predict how a drug will act unless it is first tested in the complex system of a living organism."
Rogawski has another passion he wants to launch at UC Davis: a research program on traumatic brain injury that will benefit civilians as well as soldiers returning from Iraq and Afghanistan. He's setting up the program in conjunction with the Veterans Affairs Northern California Health Care System and members of UC Davis departments of Neurology, Pediatrics, Neurological Surgery and Psychiatry.
"Traumatic brain injury is one of the most significant medical problems that affect returning vets because body armor is so good now," Rogawski says.
"Veterans may have experienced blast injuries that do not produce obvious brain damage, but the trauma can have long-term neurological and psychiatric implications. Traumatic brain injury can also lead to epilepsy. We need to know much more about the biology of these injuries and how to diagnose and treat them."