Tending The Frontier: Pietro De Camilli and the Cell Biology of Neurons

Pietro De Camilli's passion for discovery remains undiminished—a passion that traces back to a childhood in northern Italy. His gray hair frames a face animated by enthusiasm.

"While I lived in Milano, I spent my childhood summers in the countryside near Lake Maggiore,” De Camilli, MD, recalls. “I loved to go out and work with farmers and this is where my curiosity for nature began. Gardening was my favorite hobby." It was an uncommon interest for a young boy. While other children played soccer and basketball, De Camilli tended plants. "I never played with balls," he says. "I realize it was a little bit unusual.”

De Camilli is John Klingenstein Professor of Neuroscience and professor of cell biology at Yale School of Medicine as well as a Howard Hughes Medical Institute Investigator.

He knew his direction early in life: "I always wanted to be a scientist."

De Camilli’s journey from curious observation of nature as a child to understanding the molecular machinery of the brain has consistently been driven by an unwavering commitment to understanding life.

In 1960s Italy, there were no PhD programs in biology. So De Camilli enrolled in medical school, though "from day one, I wanted to be a scientist," he says. “At the time, in Italy, and I would say also more generally in Europe, it was not unusual for scientists interested in biology to go to medical school.”

Medical school offered something unique: the chance to study a single organism across every scale of complexity—”from molecule to mind” as he puts it.

“I like this idea of understanding from the basic element of life to cognition,” says De Camilli.

Medical school, however, nearly derailed his scientific dreams. "At some point, I almost changed my mind because I had not encountered a good scientific environment in labs that I had joined as a student," he recalls. They treated him "like a technician without involving me in the science." Then, in his final year, everything changed.

At an international microscopy meeting in Milano, a professor named Jacopo Meldolesi, MD, gave a talk. Meldolesi had recently returned from The Rockefeller University, where he'd worked with George Palade, MD—the founder of cell biology and co-winner of the 1974 Nobel Prize in Physiology or Medicine. He even got to meet Palade briefly when the cell biologist visited Milano for a seminar. "It was inspiring," De Camilli remembers.

So what made Meldolesi different? "Tremendous enthusiasm," De Camilli says. But more crucially: "He immediately treated me like a colleague. That really was very empowering to me." After being treated as a subordinate elsewhere, this intellectual equality transformed everything. It was a lesson he would never forget, one that would shape how he mentored his own students decades later.

De Camilli wanted to study in the U.S. and in 1978 joined the lab of Paul Greengard, PhD, in YSM’s Department of Pharmacology. Greengard was a neuroscientist and although De Camilli had a strong interest in fundamental cell biology, he thought marrying the two fields would be advantageous to both.

“When I arrived to do neuroscience in Greengard’s lab, I immediately realized there would be a powerful interaction,” he recalls.

At the time, Greengard was pioneering studies of the biochemical reactions that mediate information processing and storage in the brain, a field for which he was co-recipient of the 2000 Nobel Prize in Physiology or Medicine. Researchers purified and analyzed proteins from brain tissue. A key next priority in the field was to understand where these proteins functioned within cells.

“I felt like a kid in a candy store, with all these new biochemical tools to explore the intracellular world of neurons,” De Camilli says.

De Camilli’s main project with Greengard provided an important foundation for the systematic molecular analysis of synaptic vesicles, tiny packages surrounded by lipid-based membranes that store and release neurotransmitters at brain cell junctions called synapses.

While working in Greengard’s lab, he reconnected with Palade (“the mentor of my mentor,” De Camilli calls him) who had just launched the Department of Cell Biology at YSM. “I was in Greengard’s lab doing neuroscience, but I had access to all the resources of the new Department of Cell Biology. And so it was an ideal situation.”

After one year in Greengard’s lab, Palade recruited De Camilli as faculty in the Department of Cell Biology.

De Camilli never intended to stay in the United States. “I felt a commitment to go back to my country,” he says. “I had come to the U.S. to receive some training, but with the intention to return and bring back my expertise to help advance science in Italy.”

And so at the end of 1981, he returned home where the University of Milano had held a position for him.

“I soon realized that it was difficult to do science in Italy at the level I had been doing, as I had already experienced some independence in the U.S.,” he says. “In the United States, you feel like you can really lead in science, be at the frontier.” However, “while in Italy there were fewer opportunities to go in depth into a problem, there was also a silver lining: incentives and occasions to be exposed to a large breadth of topics,” he says.

“Whenever there was a good seminar, I would go,” says De Camilli. “Whenever there was an opportunity to learn something, I would take it”. So, those years in Italy had been enriching in unexpected ways. For example, prompted by ongoing studies on neuroimmunology at his institute, he discovered the autoimmune origin of stiff-person syndrome, a severe neurological condition, and its pathogenic link to autoimmune diabetes. This finding had major diagnostic and therapeutic implications.

This cross-subject exposure was integral to the kind of scientist De Camilli would become.

After five years in Italy, De Camilli returned to YSM. But he remains in touch with colleagues in Italy with whom he continues to share his scientific expertise.

At YSM, De Camilli continued his work at the intersection of cell biology and neuroscience. "Throughout my career, I've been working on fundamental cellular mechanisms and on how they have been adapted to support the specific function of specialized cells of the brain,” he says. “Conversely, by working on specialized features of neurons, I made discoveries about mechanisms of general importance for the life of a cell.

“Cells are very crowded structures,” he says. “There are a lot of organelles inside, and most of these organelles are surrounded by lipid-based membranes. Elucidating the dynamics of these membranes has been a central theme in my work.”

For many years, a main focus of De Camilli’s lab continued to be synaptic vesicles, the processes that mediate their formation, and recycling traffic within the neuronal synapse. These studies led him to discover mechanisms that shape and cut membranes and that define their identity as they move within cells. They also brought the study of membrane lipids and their transport within cells to the center stage in his lab.

“Not surprisingly, some of the proteins that we have identified or characterized turned out to be mutated in genetic diseases,” De Camilli says. “In particular, genetic studies have shown that mutations in two proteins at the core of our lipid studies—Synaptojanin 1 and VPS13C—are responsible for familial forms of Parkinson’s disease. Given my medical training, I embraced the opportunity of building on our work to elucidate disease mechanisms”.

For example, in April 2025, De Camilli's laboratory published a study in Nature Cell Biology on VPS13C that provided insight into how its mutations may result in Parkinson's disease. The work focused on cellular "trash cans" called lysosomes and on the role of VPS13C in helping repair them when they are damaged.

Lysosomes are organelles that accumulate and break down cellular waste. The integrity of their membranes is critical to prevent the leakage of waste components that can be toxic to cells. In normal cells, VPS13C proteins rush to damaged lysosomes within minutes, where they form bridges with the endoplasmic reticulum—where lipids are synthesized. These bridges allow newly synthesized lipids to flow across and seal the holes in lysosomal membranes.

De Camilli and his team then used CRISPR/Cas9 gene editing to create cells lacking VPS13C, mimicking the loss of function associated with Parkinson’s disease, and watched what happened. “The lysosomes became more fragile,” he says. “There is now growing evidence that fragility of lysosomes is an important factor in Parkinson’s disease.”

Timothy Ryan, PhD, a professor at Weill Cornell Medicine, has collaborated with De Camilli for more than 25 years. When asked to describe De Camilli in three words, Ryan doesn't hesitate: "Brilliant, kind, and creative."

Ryan first met him while he was a postdoc at Stanford, and De Camilli visited for a seminar. "He had this reputation of someone who was really rigorous,” Ryan says. “He was sort of a foundational member of the field in some ways. I felt like I didn't know anything, and I wanted to get the opinions of experts, so I sort of sought him out."

That first meeting revealed a "very warm, caring person, extremely scholarly." De Camilli had "deep knowledge of everything that had been done" in the field.

"I consider Pietro really a leading cell biologist of neurons in the world," Ryan says. "He's classically trained in medical school, but then quickly adopted electron microscopy as one of the tools that he became a master at."

Ryan describes how De Camilli sees science: "He has this visual impression. He sees images in electron microscopy, and a story builds in his mind."

What makes their collaboration work is complementary expertise. Ryan, by contrast, comes from a physics background. “I see a trace of a measurement, and my mind goes to trying to interpret the biophysical explanation for why it behaved this way. Our challenge has been to bring those two worlds and perspectives together," he says. "We have very different perspectives, and we sort of try and challenge each other."

The collaboration requires intellectual humility on both sides. "He will tell me in no uncertain terms why he doesn't think the way I'm thinking is correct," Ryan says. "I have great respect for him, so I listen. I also view it as, ‘OK, I've got to convince him.’ That's more important for me than convincing a paper editor or reviewer."

Ryan also appreciates De Camilli's speed and logic. "He's extremely fast. He's an extremely logical thinker, so if there's a flaw somewhere in the logic, he will identify it very quickly."

What drives someone to spend decades studying molecular machinery? For De Camilli, it's the inexhaustible nature of the work and the excitement to be the first to know something about nature. "There is no way to become bored with what we do. There is always something new," he says. "It's a job where you can really express your creativity. Any day, there is something new to discover.”

He also appreciates how the work continuously lets him engage with young scientists. His mentoring reflects the empowerment he felt with Meldolesi. "The direction of my lab has been heavily impacted by people working in the lab,” he says. "I'm not a mentor that likes to tell on a daily basis what they have to do. I like to count on their individual initiative and creativity.

"It's been humbling throughout my career to see how everybody is different,” he reflects. "When I was younger, I would be critical of people who thought in different ways. I was skeptical about their approaches, and then I realized that actually, there are many different ways to do things.”

Outside the lab, De Camilli maintains connections to his roots and passion for nature—gardening, hiking, and fishing. His grandchildren live in Brooklyn—close enough for regular visits—and visiting them, he says, has become a favorite hobby.

De Camilli's contributions extend beyond discoveries to the scientific environment he's helped create. "You cannot do frontier science unless you have a critical mass of people," he insists.

He has been chair of both the cell biology and neuroscience departments and in 2006, he was co-founder of the interdepartmental Program in Cellular Neuroscience, Neurodegeneration, and Repair. “The goal of the program was to bring together cell biologists and neuroscientists towards the elucidation of disease mechanisms and developing new therapeutic approaches for neurodegenerative diseases,” he says. “This field is now thriving at Yale, as exemplified by the newly created Stephen and Denise Adams Center for Parkinson's Disease Research.”

When asked what big mysteries remain, De Camilli's answer comes immediately: "Cognition and consciousness." How do molecular processes create knowledge, generate thoughts, produce self-awareness?

De Camilli brings up artificial intelligence as evidence that the mechanisms behind cognition are discoverable. He says he is impressed with the way artificial intelligence mimics human behavior to produce information. “This tells us that there is not something unique about humans relative to other organisms. The fact that we can reproduce something like human thought with a computer tells us there is nothing magic about how we developed cognition.”

Consciousness, however, is more complicated, he says. “We are just chemistry,” he says. And he wonders aloud how chemical reactions are able to produce something as complex as, say, self-awareness.

“That will be a big challenge for future generations,” De Camilli says. “That is the Holy Grail.”

Asked what he would do if he weren't a scientist, De Camilli laughs. "That's the only job I can imagine." The boy who worked with farmers, who chose science from his love of nature, who wanted to understand life is still—in the end—tending and growing things.