Cycle of life

The poet William Carlos Williams exalted the ordinary: “So much depends,” he wrote, “upon/a red wheel/barrow.” Seen from the vantage point of Pietro De Camilli, M.D., the seemingly unremarkable fact that cell membranes can bend into different shapes is likewise invested with the greatest importance, for life itself—and every thought, emotion, and memory—depends upon it.

As a child, De Camilli spent each year’s four-month school vacation in his mother’s ancestral village by Lake Maggiore, in northern Italy. There he developed the “passion for understanding nature” that drew him to biology. Because little rigorous advanced training in general biology was available in Italy at that time, De Camilli enrolled in medical school. He had little interest in a career as a physician, but relished the chance to be “exposed to one organism, from molecules to mind.”

His early research was in endocrinology, specifically on how hormones are secreted from cells in a process called exocytosis. This manner of secretion is ubiquitous in biology, but is particularly crucial in the nervous system. In neurons, the membrane is shaped into spherical sacs called vesicles that carry neurotransmitters to synapses. There they fuse with the synaptic membrane and empty their cargo, passing on to other cells the chemical messages that allow the brain to function.

De Camilli soon shifted his focus to neurobiology, and in 1978 he joined the Yale laboratory of Paul Greengard, Ph.D., who went on to win the Nobel Prize for his studies of synaptic transmission. As a cell biologist, De Camilli’s favored tool was the microscope, and he needed time to adjust to Greengard’s biochemistry lab, in which “they studied the nervous system with a Waring blender,” isolating proteins from homogeneous solutions of brain tissue using chromatography.

But in a “magic moment” De Camilli realized that antibodies being developed by his colleagues could be used with light and electron microscopy to localize subcellular proteins. Before long he had characterized synapsin, the first synaptic vesicle protein to be understood in any depth, and after launching his own Yale lab, he continued to build an inventory of such proteins.

De Camilli, now the Eugene Higgins Professor of Cell Biology and professor of neurobiology, gradually became intrigued with the question of how new vesicles form after neurotransmitters are released. In this process, called endocytosis, intracellular proteins bend the now-flat synaptic membrane back into a proper-sized sphere, which pinches off and migrates into the cell. This newly born vesicle is loaded with a neurotransmitter, and the secretory cycle begins anew. “These processes are so fundamental that what you learn can be applied to every cell,” says De Camilli, whose wide-ranging work on every step in this progression has earned him election to the National Academy of Sciences and appointment as a Howard Hughes Medical Institute investigator.

De Camilli’s career seems itself to be unfolding in a cycle. Mouse strains with defective vesicle trafficking that were created in his lab to explore basic biology turned out to have characteristics seen in various human diseases, rekindling De Camilli’s interest in concepts he learned in medical school. In 2006 he joined with Stephen M. Strittmatter, M.D., Ph.D., the Vincent Coates Professor of Neurology and professor of neurobiology, to launch the program in Cellular Neuroscience, Neurodegeneration, and Repair, which aims to rapidly translate lab discoveries into new treatments for neurodegenerative diseases and injuries of the brain and spinal cord.

“Basic science helps us understand medicine,” he says, “but increasingly,” as genomics inspires experiments based directly on human biology and disease, “medicine has become a tool of science.”