In life, people can look back on a moment — that fork in the road — that changed the trajectory of their life's work. For William Seeley, MD, it was a month before finishing medical school at the University of California, San Francisco (UCSF). He was heading to a neurology residency at the Massachusetts General/Brigham and Women's Hospitals but he wanted to spend his last elective judiciously.
One thing was certain: he loved the brain. He asked an advisor for the name of a neurologist who studied brain-behavior relationships. He landed on the door of Bruce Miller, MD, a neurologist and researcher who had just moved from UCLA to found the Memory and Aging Center at UCSF. Dr. Miller had spent the previous decade meeting with and describing a generation of dementia patients who seemed to lose control of their social behavior.
During that month-long elective, Dr. Seeley shadowed Dr. Miller in clinic, watching him interact with patients who had undergone shifts in their very essence — the core of their personalities. Together, they looked for brain imaging changes that might begin to explain this conversion of “self.”
This clinical research led to a paper published in Neurology in 2001. Throughout his neurology residency, Dr. Seeley couldn't shake the memory of those patients and suspected that he would return to San Francisco to help unravel the mysteries of the disease that his mentor helped put on the diagnostic map: frontotemporal dementia (FTD).
Today, a dozen years after that fateful elective, Dr. Seeley has made advances in the field, first with the identification of a population of neurons hard hit in FTD and then with detailed anatomical descriptions of FTD-related networks.
For those efforts, Dr. Seeley, 39, was named a 2011 MacArthur Fellow on Sept. 20. The news went public within nine hours of the birth of his first child. He is married to Hilary Seeley, a resident in pediatrics.
“A cause for celebration on many levels,” said the neurologist, who received a call from the John D. and Catherine T. MacArthur Foundation to inform him that he was being named a fellow. He was told that the call would be the last time he heard from the foundation. There was to be no fanfare.
No fancy dinner. A film crew would show up once. Then annual checks totaling $500,000 over five years. “To pair this professional honor with an even greater moment in my family life was unimaginable and so special,” he said.
Some people know the fellowship as the “genius grant,” but according to the MacArthur Foundation, “it is an investment in a person's originality, insight and potential.” This year, there were 22 recipients from all walks of life.
After residency, Dr. Seeley returned to his UCSF roots and to the Memory and Aging Center, where he completed a fellowship in behavioral neurology. He is now an associate professor of neurology at UCSF and director of the UCSF Neurodegenerative Disease Brain Bank.
Since 2004, he has been studying the neuroanatomy of patients who died with FTD and comparing the structural changes in the autopsy tissue to the pathological storm that has been well characterized in the brains of patients with Alzheimer disease.
Analyzing the neuroanatomy of FTD paid off. Dr. Seeley and his colleagues identified a population of cells, known as von Economo neurons — VENs, for short — that are selectively damaged in this form of dementia. The cells are elusive and intriguing — they show up in only two regions of the brain, the anterior cingulate and the anterior insula. So far, the VENs have not been cultured in a lab dish. And studying them in laboratory animals is equally confounding, as VENs are only seen in humans, apes, whales, dolphins, and elephants, species that are off limits for invasive anatomical investigations.
Creativity is the key word in figuring out the “why” and the “how” of this vexing, debilitating condition, Dr. Seeley said. FTD is now recognized among neurologists, even though it was Arnold Pick's meticulous observations beginning in the late 19th century that first captured the focal anterior degenerations that would now be classified as FTD. Two decades ago, thanks to Dr. Miller and others interested in this form of dementia, FTD was dusted off from the archives and given a place in modern neurology.
“This is the most mysterious illness I have ever encountered,” said Dr. Seeley.
Despite the discovery that VENs are depleted in FTD, Dr. Seeley and his colleagues have not yet determined what the neurons do or why they are selectively damaged early on. He was quick to point out that VENs are not the only affected cell type but show disproportionate, early injury in FTD. “If we could understand why the disease starts where it does, we might gain a handle on how to prevent or reverse the process.”
Dr. Seeley's long-term goal is to help discover a treatment for FTD. In the lab, he continues to mine the VENs to understand their normal role and their pathobiology in FTD. The cells make up at most 1-2 percent of the neurons in the anterior cingulate and the anterior insula. He said that by the time patients with FTD show up in the clinic, even if it's soon after the emergence of behavioral symptoms, the cells are already significantly depleted.
Dr. Seeley and his coworkers have identified a network of brain regions associated with the condition. They adapted a way to map signals with an fMRI that shows functional relationships between brain regions. They call it intrinsic connectivity network mapping. The method is helping them understand what brain regions fluctuate together in the healthy brain and become “disconnected” in FTD. These network approaches are also being used broadly to study other neurodegenerative and psychiatric conditions. Dr. Seeley's team has begun to re-scan patients identify network changes over time.
On Sept. 21, the day after the MacArthur announcement, two papers published in Neuron reported a new gene on chromosome 9 (C9orf72) that causes familial FTD-ALS. “We are thrilled by this recent collaborative discovery. This information will open a whole new branch of FTD biology, and we are eager to pursue links between the mutation and the anatomy of the disease.”
The neurologist said that he was always captivated by the clinical examination of FTD patients. He spends a lot of time thinking about the disease and how it alters the self. “I don't think of the social self as any one thing,” he said. “My patients have impairments in different aspects of social processing and self-representation. FTD erodes important aspects of social behavior and emotion, including emotional aspects of morality, self-awareness and empathy. I see my role in the field as someone who can help connect the dots and build more integrated models of the disease. Right now, it is not so obvious how all the emerging dots, such as the genetic, molecular, and anatomical discoveries, are connected.”
He's hoping that the MacArthur money will “allow us to continue to pursue our goal of finding treatments for FTD with increased vigor, flexibility, and boldness,” he said.
COLLEAGUES WEIGH IN
John Q. Trojanowski, MD, PhD, co-director of the Center for Neurodegenerative Disease Research at the University of Pennsylvania, has watched his colleague putting the pieces of a very complicated puzzle together. “Bill is a creative clinician-scientist who is advancing our understanding of FTD through his basic science research. He's implicated von Economo neurons in brain degeneration in FTD patients as well as by elucidating cortical neural networks that are affected specifically in FTD.”
When UCSF's Dr. Miller heard that his protégé won the MacArthur award, he was not surprised. “I couldn't imagine a better choice,” he said. “Bill approaches everything he does with originality and he is a wonderful observer. Together, these traits make for some amazing surprises in our field.”
“He thinks in a big way about things. He may start thinking about a problem at dinner but he will still be mulling over every angle the next morning at breakfast. In fact, he won't stop until he makes a connection and sets out to see if it makes sense.”
For instance, Dr. Miller recalled a meeting where John Allman, PhD, a neuroscientist at California Institute of Technology, was discussing a newly observed cell population, the VENs. Dr. Allman described where the cells were and Dr. Seeley immediately saw that their location was smack in the same regions involved in FTD. Dr. Allman was saying that these neurons were phylogenically new and seemed to develop divergently in species with larger frontal lobes and complex social networks.
In a matter of a few days, Dr. Seeley booked a flight to Washington, DC, and showed up at the Armed Forces Institute of Pathology at Walter Reed Army Medical Center, where the Yakovlev-Haleem Collection is stored. The brain bank was started in 1930 at Harvard University by neuroanatomist Paul Yakovlev, MD, before it moved to the National Museum of Health and Medicine at Walter Reed.
The collection houses whole-brain sections on glass slides and provides microscopes for on-site examination. Dr. Seeley spent a week combing through the stacks and examining FTD brains he found in the collection.
On a hunch, Dr. Seeley analyzed the tissue samples from some of the cases and the VENs were obliterated, Dr. Miller said. “That says it all, doesn't it? That is the way he approaches problems and solves them.”