Growing up in Colorado, Clinton Cave was enthralled by the mysteries of the natural world, often getting lost in a particular science book that answered questions such as why the sky was blue. Through science “there was a way that we could figure out something about the world around us, and then in turn something about ourselves, that I found very satisfying,” says Cave, now a neuroscientist at Middlebury College, a liberal arts school in Vermont catering largely to undergraduate students. 

When he began his own undergraduate education in the fall of 2002, Cave studied psychology at Yale University, where his lab 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 route after graduating in 2006. Instead, he became a research technician in a microscopy lab at the University of Colorado 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. 

Amidst the 2008 financial crisis, having a stable job that he enjoyed held Cave back from furthering his education. But when his colleagues and family argued “that it would be a valuable thing, not just for me, but for the people that I might be able to help teach and train in the future,” Cave says he was convinced. 

He started a PhD at Johns Hopkins University in 2009, where he studied under neuroscientist Shan Sockanathan. Cave concentrated on glycerophosphodiester phosphodiesterases (GDEs), three of which—GDE2, GDE3, and GDE6—are transmembrane enzymes that influence intracellular communication during neurodevelopment by cleaving glycosylphosphatidylinositol (GPI) anchors that bind other proteins to the outside of cell membranes. 

Cave spent nearly two years investigating whether GDE2 influences cellular regeneration in mice, but found that it didn’t—a disappointing result. Sockanathan, who continues to collaborate with Cave, likens research to boxing: Sometimes you get hit, but you have to keep getting up. Cave, she says, has “always gotten up, and he’s always done that with grace and generosity.” 

Eventually, the researchers had a breakthrough. They noticed that mice lacking GDE2 showed severe signs of aging, including degradations in posture and movement, suggesting that the enzyme helps neurons persist postnatally and that its absence may exacerbate neurodegeneration. This research became the basis of Cave’s dissertation, and after receiving his PhD in 2016, he continued 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 reframed these proteins as having crucial roles, not just in the development of the nervous system, but later on in preventing degeneration.” He began to suspect that low levels of GDE2 may play a role in human neurodegenerative illnesses as well. 

In 2018, Cave left Johns Hopkins to begin his own lab at Middlebury, where he currently focuses on several aspects of GDE-GPI signaling, such as how GDE6 affects radial glia differentiation. Cave was also recently appointed a Next Generation Leader to advise the Allen Institute for Brain Science. 

This year, Cave and his colleagues were able to link GDE2 to amyotrophic lateral sclerosis (ALS) in humans. Post-mortem tissue samples from people with the disease revealed that GDE2 clustered inside cellular inclusions, preventing it from releasing GPI-anchored proteins, which were found in lower concentrations in the cerebrospinal fluid of people with ALS than in healthy people. One day, Cave says, clinicians may be able to use these protein deficiencies as biomarkers to diagnose the disease earlier. 

Jason Arndt, a cognitive psychologist at Middlebury, says that Cave sets a great example for his undergraduate students by handling obstacles with cool-headed logic. Cave’s approach to teaching and training students in the lab is as well thought-out as a research problem, Arndt adds. “He thinks through everything much better than I do.” 

Middlebury’s undergraduate focus, Cave tells The Scientist, is a real strength because it gives students early access to sophisticated labs, setting them up to succeed in STEM careers. It’s especially important that he help first-generation students, students of color, and women see a path forward, he says. “And it’s very rewarding to be able to pay for the mentorship that I’ve received over the years.”