A Philadelphia-area native, Pleasure moved west to UCSF for a residency in neurology, later took up residence as a clinical researcher in the Medical Sciences Building on Parnassus, then two months ago moved to Mission Bay's Rock Hall. So what has he been studying in all these locales? The genetic controls behind, what else, brain cell migration.

As to what guided him to Mission Bay, the father of two credits a family tradition that jump-started his own curiosity about what goes on inside our heads. "My father is a neurologist. My aunt is a pediatric geneticist. And my grandfather was a psychiatrist. We talked about brain development at dinnertime," says Pleasure.

What started as a conversation has now become an avocation, thanks to his combined MD-PhD degrees from the University of Pennsylvania and a lifetime of excited speculation about the wondrous inner world of neurons and cortices. Still, it was the external world of patients in UCSF's Neurology Clinic that set him wondering about a different kind of brain, the epileptic variety.

A dash of mystery spurred him on, as well. "It struck me that so many otherwise healthy adults, who had suddenly suffered an epileptic seizure for the first time, had no family history of the disorder." What they did possess, it turned out, was what Pleasure calls "a developmental hiccup," a malformation in either the hippocampus or the neocortex, two different areas of the brain.

Pleasure zeroed in on the hippocampal malformation in part because the hippocampus is an ancient part of the brain system responsible for emotion and motivation, and because it also is a key player in learning, memory and spatial orientation. "To get at the patients' problem, I had to go back to the beginning, to how the hippocampus is formed," he explains. That meant following the pathways along which cells, once capable of becoming any cell type in the body, specialize into brain cells and assemble into distinct but interconnected regions. There are numerous regions and countless chemical signals that control this process. So where to start?

As with so much else in science, the best way to start exploring what's normal is to locate what's novel. And within the hippocampus, there is a particular area known as the dentate gyrus that is novel indeed. Moreover, animal studies have confirmed that developmental problems in the dentate gyrus are linked with different forms of epilepsy.

"Neuronal stem cells give birth to new precursor neurons in the dentate gyrus," says Pleasure, "but instead of migrating away, they stay put. We've now learned some of the key molecular players and the chemical signals they use to keep the cells there and happy," Pleasure explains.

If such research seems arcane, dubious or just too difficult to think about, consider this. In trying to identify those molecules that operate selectively within the hippocampus, Pleasure and his colleagues have found one, dubbed Frizzled 9, that is associated with a genetic disease called Williams syndrome. Williams, which occurs in one in 20,000 births, is characterized by learning disorders, particularly poor visual-spatial abilities, distractibility and a narrowing of the blood vessels. Half of Williams patients also suffer from seizures, a fact that caught Pleasure's attention. "I call it the anti-autism," says Pleasure. "Kids with Williams syndrome have preserved verbal and social skills, and they are notably friendly," he adds. They also can also appear clumsy and have difficulty remembering 'in pictures" or being able to think and plan ahead.

Research in mice has confirmed that having just one copy of Frizzled 9 interferes with visual- spatial recall. Such mice also are more prone to seizures. Whether this exactly equates with what is happening in human patients is still unclear, but it does raise an intriguing possibility. Perhaps jamming the signals - thereby short-circuiting the negative command - could block the seizures and give the brain a chance to assemble all the building blocks of its visual vocabulary.

Not one to overpromise, Pleasure clearly takes pleasure in having landed in a Mission Bay scientific community where a larger laboratory staff, continuity of research and proximity to like-minded colleagues create the conditions for research success. He also likes the warmer weather. "I was familiar with this part of the city already, having been a consulting neurologist at SFGH for a while. Has Pleasure, the long-suffering Philadelphia sports fan, finally found a home base? In a manner of speaking. "Mission Bay is great. I can park here for free and walk to the Giants games."

Source: Jeff Miller

First posted October 26, 2005

Last updated October 26, 2005

UCSF Mission Bay

Sam Pleasure, clinical researcher, UCSF Department of Neurology. Photo by Majed.