GWhile rowing in Colorado, Clinton Cave was fascinated by the mysteries of nature and would often get lost in a particular science book that answered questions like why the sky was blue. Through science, “there was a way of finding out about the world around us and then, in turn, about ourselves, which I found very satisfying,” says Cave, now a neuroscientist at Middlebury College, a liberal arts school in Vermont catering largely for undergraduate students.
When he began his own undergraduate studies in the fall of 2002, Cave was studying psychology at Yale University, where his laboratory work focused on how neural progenitor cells influence neocortical development. Despite his interest in neurodevelopment, Cave says he was unsure about following a traditional academic path after graduating in 2006. Instead, he became a research technician at a microscopy lab at the University of Colorado’s Anschutz Medical campus, where he helped researchers design experiments to view everything from single cells to ant brains. “It was a position that allowed a lot of creativity,” he says.
Amid the financial crisis of 2008, a stable job he enjoyed kept Cave from pursuing his education. But when his colleagues and family argued “that it would be a worthwhile cause, not only for me but also for the people that I might be able to help teach and educate in the future,” Cave was convinced.
He received his PhD from Johns Hopkins University in 2009, where he studied with neuroscientist Shan Sockanathan. Cave focused on glycerophosphodiester phosphodiesterases (GDEs), three of which – GDE2, GDE3, and GDE6 – are transmembrane enzymes that affect intracellular communication during neurodevelopment by cleaving glycosylphosphatidylinositol (GPI) anchors that other proteins bind to the outside of cell membranes.
Cave spent almost two years studying whether GDE2 affects cell regeneration in mice, but found that it didn’t — a disappointing result. Sockanathan, who continues to work with Cave, compares research to boxing: sometimes you get hit, but you always have to get back up. Cave, she says, “was always standing up, and he always did it with grace and generosity.”
Finally, the researchers made a breakthrough. They noted that mice lacking GDE2 showed severe signs of aging, including deterioration in posture and movement, suggesting that the enzyme helps neurons survive postnatally and that its absence may exacerbate neurodegeneration. This research became the basis of Cave’s dissertation, and after his PhD in 2016, he worked as a postdoc in Sockanathan’s lab.
During that time, the team directly linked the absence of GDE2 to neurodegeneration in mice, work that Cave says “really attributes a crucial role to these proteins, not only in the development of the nervous system, but later in preventing degeneration.” He began to suspect that low GDE2 levels might also play a role in human neurodegenerative diseases.
In 2018, Cave left Johns Hopkins to open his own laboratory in Middlebury, where he is currently focusing on various aspects of GDE-GPI signaling, such as how GDE6 affects glial radial differentiation. Cave was also recently named Next Generation Leader to advise the Allen Institute for Brain Science.
That year, Cave and his colleagues succeeded in linking GDE2 to amyotrophic lateral sclerosis (ALS) in humans. Post-mortem tissue samples from people with the disease showed that GDE2 accumulated in cellular inclusions and prevented it from releasing GPI-anchored proteins, which were found at lower levels in the cerebrospinal fluid of people with ALS than in healthy people. One day, Cave says, clinicians could use these protein deficiencies as biomarkers to diagnose the disease earlier.
Jason Arndt, a cognitive psychologist at Middlebury, says Cave sets a great example for his undergraduate students by overcoming obstacles with level-headed logic. Cave’s approach to teaching and training students in the lab is as thoughtful as a research problem, adds Arndt. “He thinks things through a lot better than I do.”
Middlebury’s undergraduate focus, Cave recounts The scientist, is a real strength as it gives students early access to challenging labs and prepares them for successful STEM careers. It’s especially important that he helps first-generation students, students of color and women see a way forward, he says. “And being able to pay for the mentorship I’ve received over the years is very rewarding.”