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A singleminded pursuit of science

Medicine@Yale, 2021 - January February


Meticulous preparation leads to investigation of what makes us human

Few pivotal life moments can be traced to a single letter. But Nenad Sestan, MD, PhD, Harvey and Kate Cushing Professor of Neuroscience, and professor of comparative medicine, of genetics, and of psychiatry, vividly remembers flipping the thin pages of a medical encyclopedia set that his mother bought him during grade school. He arrived at the letter ‘M’ for mozak, or brain, in his native Croatian.

Sestan recalls saying to himself, gripped with fascination, “I am going to study the human brain and I will work with this person.” That person was the author of the neuroanatomy entry: Ivica Kostović, professor of anatomy and neuroscience at the University of Zagreb and a future vice president of Croatia, whose research specializes in human developmental neuroanatomy.

Sestan describes an idyllic childhood, growing up in the small village of Zemunik Donji and working on his family farm surrounded by relatives of his father, who served as a sergeant in the Yugoslav navy, and his mother, a postal worker. From that initial spark, Sestan’s perseverance has shaped a career in developmental neurobiology, which he modestly credits partly to luck. “I really feel like I was born at the right time, the right place,” he says.

During his first week of medical school at the University of Zagreb, Sestan walked straight to Kostović’s office, asking to work in his lab. Kostović explained to the eager student that he needed to finish anatomy and neuroscience classes first. Undeterred, Sestan asked a postdoctoral fellow who worked in Kostović’s lab to give him a job. In a few days, Sestan was waking up at odd hours at night to retrieve human brains donated for research from the morgue and prepare them for the lab. One evening Kostović caught Sestan in his lab. “He said, ‘Okay, you are obviously crazy.’ I do remember he used the word ‘crazy,’ ” Sestan says, tears coming to his eyes as he recalls attending his first lab meeting.

In the early 1990s, Croatian researchers requested journal article reprints via handwritten notes. Kostović needed someone to do this. Sestan volunteered. “Everybody thought I was an idiot,” he says. But through that exercise, Sestan learned by heart the names of important neuroscientists around the world, including those he would later meet at Yale.

With his university largely spared from the Yugoslav wars, Sestan continued lab experiments after his mentor became Croatia’s vice president. “The biggest thing at the time was the Nobel Prize discovery of nitric oxide as a signaling molecule,” Sestan says, describing how he examined human brain samples for the enzyme that makes nitric oxide. He found it, but sat on the findings; he wanted to determine if other species expressed this same gene in the cerebral cortex region of their brains. (That question would not be settled until Kenneth Kwan, a graduate student in Sestan’s lab, finally concluded, and the lab published in 2012, that this process is very species-specific, and greatly dependent on when during development the enyzme is expressed.)

In 1994, Sestan applied for a doctoral degree at Yale. “This was the Mecca if you wanted to study the cerebral cortex, the outside part of the brain that processes our senses, commands motor activity, and helps us perform higher-order cognitive functions like language,” he says. He lists his important mentors—whose names he recognized from requesting those reprints—who were, and still are, in Yale’s neuroscience department: Amy Arnsten, PhD, Albert E. Kent Professor of Neuroscience and professor of psychology; Michael Schwartz, PhD, associate professor of neuroscience and associate dean for curriculum; and Gordon Shepherd, MD, professor emeritus of neuroscience. Sestan enlisted Pasko Rakic, MD, PhD, Dorys McConnell Duberg Professor of Neuroscience and professor of neurology, as his PhD adviser. He knew he also needed to understand genetics and molecular biology. Sestan asked Spyros Artavanis-Tsakonas, PhD, now professor emeritus of cell biology at Harvard Medical School, to co-advise him. In 2002, at age 31, Sestan became an assistant professor at Yale.

His research has focused primarily on how certain genes control the ability of neurons to acquire distinct identities and form proper connections—collectively called the connectome—in the developing cerebral cortex. “The connections that connect different parts of the cortex, and the cortex with the rest of the central nervous system, I think are key,” Sestan says. He compares the connectome to the Internet’s ability to revolutionize how information is shared without changing the information itself. Sestan and his lab members focus on pyramidal cells, which make long connections originating in the brain’s cortex area.

While following this path, Sestan and his team also took a bit of a detour to find out if they could trace neuronal connections in postmortem brain tissue. Using a perfusion technology they invented, called BrainEx, and a unique liquid that made it work, they restored circulation and some neuronal function in the brains of pigs that had been dead for several hours. They reported their results in Nature in April 2019. Meantime, Sestan continues his primary work uncovering how connections in the human brain differ from those in other species.

“I want to understand what makes us human. No animal can write poetry,” Sestan says. “If I find out what makes us human, I would die a happy scientist.”

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