by Jamie Talan
Thomas C. Südhof, MD, was one of three Americans awarded the Nobel Prize in Physiology or Medicine yesterday for his work with neurotransmitters. Dr. Südhof has been studying the molecular events that underlie the regulation of the release of neurotransmitters at the synapse first at the University of Texas Southwestern, and then at Stanford since 2008, where he is currently the Avram Goldstein professor of molecular and cellular physiology at Stanford University School of Medicine and a Howard Hughes Medical Institute Investigator.
In September, Dr. Südhof and his colleague Richard H. Scheller, PhD, were awarded the 2013 Albert Lasker Basic Medical Research Award for their work. In an interview with Neurology Today, Dr. Südhof discussed the ideas and events that have inspired and propelled his research.
Dr. Südhof said that he grew up in “an academic household with a strong religious bent.” Early on, he said, he began questioning his parents’ beliefs and “this desire to question what is actually true” is deeply ingrained in his nature. Dr. Südhof was 27 years old when he finished a postdoctoral fellowship at the Max Planck Institute for Biophysical Chemistry in Germany, where he was born and where he would later complete his medical studies.
“My greatest pleasure has always been to discover facts, to figure out how something works, to identify the relationships and connections that explain an observation.”
“After finishing my postdoc, I merged my earlier love of synaptic vesicles with my new knowledge of how to purify and clone membrane proteins, with the ultimate goal of pursuing something entirely new — to identify all the membrane proteins that make up a synaptic vesicle, and to figure out how these vesicle proteins mediate release of neurotransmitters,” he said.
In 1983, with his medical degree in hand, Dr. Südhof settled into another postdoctoral training position at the University of Texas Health Science Center. It was there that he worked for Michael Brown, MD, and Joseph Goldstein, MD, who would share a Nobel Prize in Physiology and Medicine (1985) for their work in unraveling the role of LDL receptors in cholesterol metabolism. Their work would lead to new ways to treat high cholesterol and reduce the risk for heart disease. A year after Drs. Goldstein and Brown accepted their Nobel award, their protégé realized that he was more interested in the molecular underpinnings of tissue in the brain.
At the University of Göttingen, he was doing research on organelles and proteins in the laboratory of Victor Whittaker, PhD. Dr. Whittaker isolated synaptic vesicles in the 1960s. Two decades later, when Dr. Südhof wanted to study the synapse, neuroscientists were working on life on the post-synaptic side of the neuron. Dr. Südhof’s interest was in the events on the pre-synaptic side. He was fascinated by the synapse, a career choice that has kept him busy for three decades.
“It was 1986. At the time, nothing was known about the molecular underpinnings that allow a synapse to operate as precisely and quickly as it does. Bernard Katz’s work 50 years earlier had beautifully illustrated that calcium influx into the presynaptic nerve terminals trigger neurotransmitter release, which then leads to post-synaptic receptor activation. But how calcium triggers that release was unknown,” Dr. Südhof explained.
“We cloned the first synaptic vesicle protein in 1987. Two more followed in our lab and the field took off. But unraveling the whole mechanism took much longer. It took years to understand how precisely the pre-synaptic terminal operates. We figured out how the fusion mechanism works but also how calcium triggering operates and how calcium influx in a pre-synaptic nerve terminal closely localizes to synaptic vesicles and the tight coupling of the action potential.”
His work in the Brown/Goldstein lab gave him the tools to go after the events at the synapse. “We showed how synapses are organized by active zone proteins, and described the first synaptic cell-adhesion molecules that guide synapse formation.”
For more on the research of Dr. Südhof and Dr. Scheller, see the Oct. 17 issue of Neurology Today. Listen to a podcast interview with the two neuroscientists: http://bit.ly/rCBryX.