In November 2009, Benjamin Philpot’s research team experienced what all scientists hope for and most never experience: a Eureka moment.
The discovery began many months earlier with a wild idea for finding a treatment for Angelman syndrome, a rare disorder characterized by developmental delay, lack of speech, and seizures.
The syndrome is caused by mutations in a gene called UBE3A. In the neurons of healthy people, the copy of this gene inherited from the father is silenced and the maternal copy expressed. In individuals with Angelman syndrome, mutations or deletions on the maternal copy prevent the UBE3A protein from forming.
Philpot’s team at the University of North Carolina, Chapel Hill, set out to answer a question that had been floating around scientific meetings and review papers for years: What if a drug could un-silence the paternal copy?
Postdoctoral fellow Hsien-Sung Huang began in April 2009 with mice that carry a molecular tag that glows green if the paternal copy of UBE3A is expressed. Arthur Beaudet’s team at the Baylor College of Medicine in Houston created the mice and shared them with Philpot and others.)
Huang first figured out how to grow fragile neurons taken from the outer layers of the mutants’ brains in plastic plates. He then used these 384-well plates for high-throughput drug screening. That November, after screening about 500 compounds, he saw the telltale green glow: A cancer drug called topotecan had turned on the paternal copy of the gene1.
The entire approach was untested and risky, and one most postdocs would have shied away from, especially in these days of shrinking research budgets.
But Philpot, an eternal optimist, urges all of his young advisees to take on two projects: one safe and unsexy, another a high-stakes gamble. “It minimizes their exposure to risk, but gives them an opportunity to achieve a great height,” he says.
This sort of smart risk management has propelled the energetic 42-year-old from one adventure to another, whether it’s attempting new lab techniques, learning to rock climb or taking his family to see Chilean volcanoes. His vigor for science has led to major discoveries for Angelman syndrome and for the wider autism spectrum.
“It’s the hallmark of an agile scientist not just to work on the same old problems for 40 years, but to say, where does the science lead you?” says Michael Ehlers, chief scientific officer of neuroscience at Pfizer and Philpot’s friend and collaborator.
Philpot was inspired to study neuroscience as an undergraduate at Duke University in Durham, North Carolina, thanks in large part to Steve Nowicki, his introductory neurobiology professor. “It was almost like going to watch the Oprah Winfrey show, [Nowicki] was so dynamic,” Philpot recalls.
Philpot did his graduate work in Peter Brunjes’ lab at the University of Virginia in Charlottesville, studying how a young rat’s experience with smells can shape the olfactory circuits of its brain. “This is where I started appreciating how powerful our sensory experiences are in brain development,” Philpot says.