While growing up in Buffalo, New York, in the 1950s and 1960s, Joshua Sanes was surrounded by books. His father, who owned an automobile parts supply store, and his mother, a homemaker who later returned to college to become a speech pathologist, were avid readers. Sanes, too, became a voracious reader, and when he entered his teen years, developed a particular interest in books on psychology, which were popular at that time. “It got me interested in the subject of mental illness, even though there was no one in my family with such an illness,” he recalls.
During high school, Sanes worked on weekends and during summer vacation in the lab of microbiologist Robert Guthrie, who had a mentally disabled son and who was developing what would become the first successful screening blood test for phenylketonuria. “It was the kind of repetitive work that high school kids could do,” says Sanes. “It wasn’t super high-tech or super expensive equipment, but you were still making a contribution.” Sanes remembers his time with Guthrie with fondness. “I really came to love working in labs,” he says.
After high school, Sanes went to Yale University where he “bounced around” among majors. “I was still interested in psychology, but I wanted to find a way of studying those problems from a more reductionist, scientific point of view,” he recalls. Eventually, Sanes found his way to the neurobiology lab of Paul Greengard, with whom he did his senior thesis. “Greengard was a terrific mentor,” says Sanes. “Working with him was my introduction to big-time, high-class neurobiology.”
Sanes went from Yale to graduate school at Harvard University. He remained interested in studying the biological underpinnings of mental illness, but the technologies available at the time for such research were limited. So he joined the neurobiology lab of John Hildebrand, where he studied the development of moth neurons. “Before molecular biology, people tended to work with larger insects, like crickets and moths,” says Sanes. “Their biochemistry was easier to study.”
While working in Hildebrand’s lab, Sanes often listened to the Senate Watergate Hearings on the radio. “It was the best drama ever,” he recalls. “I just got fascinated with what was going on in Washington.” So, when Sanes finished his doctorate in 1976, he took a year off to work on Capitol Hill with the Office of Technology Assessment, whose purpose was to advise members of Congress on scientific and technical issues. “I had a wonderful year,” he says, “but it also convinced me that I really preferred experimental science.”
At the end of his year in Washington, Sanes began his postdoctoral research, first at Harvard with neurobiologist U. J. “Jack” McMahan and then with neuroscientist Zach Hall, who had recently moved from Harvard to the University of California, San Francisco. It was during these fellowships that Sanes started his research on the mechanisms and molecules that drive the formation of neural connections within the neuromuscular junction, the synapse at which motor neurons transmit signals to muscle fiber. In McMahan’s lab, Sanes demonstrated for the first time that some of the signals used to organize the synapse were contained in the extracellular matrix that surrounds the muscle fiber. “That was completely unexpected,” he says. “There was a time when people thought it didn’t do anything.” In Hall’s lab, Sanes began to describe the biochemical composition of a thin layer of that matrix known as the basal lamina.
In 1980, Sanes accepted a faculty position in the Department of Physiology at the Washington University School of Medicine in St. Louis. He soon began to identify and characterize molecular factors within the extracellular matrix that help direct the formation of the neuromuscular junction, including laminin beta-2, agrin and fibroblast growth factors (FGFs). To confirm the significance of these molecules, Sanes worked with the late John Merlie, a colleague at Washington University, to engineer knockout mice that lacked the genes for laminin beta-2 and agrin genes. Together, they found that mice without those genes had devastating defects at the neuromuscular junction. Later, working with another Washington University colleague, Jeff Lichtman, Sanes began generating — with the aid of fluorescent proteins — a technique for tagging mice with color-coded neurons. The resulting images from these “Brainbrow” lines have been used in labs around the world to identify specific neural pathways within the brain’s complex tangle of neurons.
In 2004, Sanes returned to Harvard University, where he became the founding director of the Center for Brain Science. There, his research transitioned to analysis of synaptic specificity – how neurons choose partners with which to form synapses. For this work, he has focused on the synapses formed between neurons in the retina. As part of the central nervous system, the retina offers much greater opportunity than the neuromuscular junction for investigating synaptic specificity — how individual neurons form synapses with specific subsets of presynaptic and postsynaptic partners. Sanes’ lab has identified and described many of the molecules that promote specificity within the retina, such as Sidekicks and Cadherins. These findings have transformed how scientists understand the functional architecture of the central nervous system.
Sanes has received many professional honors throughout his career, including memberships in the National Academy of Sciences (NAS) and the American Academy of Arts and Sciences. He is also renowned for his work as a mentor, teacher, and leader in the scientific community, and has served on numerous advisory panels, including ones for the NAS, the Max-Planck Institute, the Wellcome Trust, the Howard Hughes Medical Institute, and the National Institutes of Health. Sanes lives in the Boston area with his wife, Susan Corcoran, a public interest lawyer, whom he met during the year he worked on Capitol Hill. They have two children, a son, Jesse, and a daughter, Milla.