Dr. Allen Chan Sought to Unlock the Mysteries of his Grandfather's Alzheimer's Disease; Thus Began a Lifelong Scientific Quest

The rugged nickel mining town of Sudbury, Ont., where Dr. Allen Chan grew up, seems a world away from the hushed

01 May 2018

The rugged nickel mining town of Sudbury, Ont., where Dr. Allen Chan grew up, seems a world away from the hushed hallways of the Neurochemical Research Unit (NRU) in the University of Alberta's Department of Psychiatry.

The long, twisted academic journey that Chan, the Department's newest Assistant Professor, undertook to get to Edmonton was equally unlikely, featuring multi-year stopovers at Hamilton's McMaster University, the University of Toronto and the University of British Columbia.

Nonetheless, the seeds of his lifelong quest to better understand how the human brain works - including his current research using in vivo, optical functional neuroimaging in laboratory mice to study how synaptic dysregulation features in brain pathology - were planted when he was just a young boy.

As Chan describes it, that's when his normally friendly and caring grandfather developed Alzheimer's, transforming him into a scary, volatile stranger almost overnight. "He had an early diagnosis of Alzheimer's and the manifestation of his dementia was really terrifying to me. I didn't understand it then and I still don't it in some ways," Chan admits.

"That greatly impacted me, not just because it was terrifying, but also because I needed to understand why he was not the same person he was before. So that led me to a basic question: How does our biology inform how we are as normal people, and how is it altered in pathology? In essence, that's what led me to study biology and psychology as an undergraduate at McMaster."

Chan found his courses interesting and illuminating, especially in terms of providing descriptions of complex human behaviors and social dynamics. Still, it wasn't enough to satisfy his need for more basic physiological explanations of his grandfather's decline.

"There was no mechanistic information (about brain function) that I found satisfying, so I kind of had a reactionary response and went to the other extreme," he explains. "I became very reductionist in my approach and felt that if we were to understand the brain we'd have to go back to first principles of biology and understand that before we could understand complex social and psychological phenomenon."

Chan pursued a PhD at the University of Toronto, working under the supervision of acclaimed neuroscientist Dr. Elise Stanley, a Professor in the U of T's Department of Physiology, a Canada Research Chair in Molecular Brain Science at the Krembil Research Institute (formerly the Toronto Western Research Institute), and the Tanenbaum Joint Chair in Neuroscience at Toronto General Hospital.

"Synaptic transmission is the fundamental unit of information transfer in the brain so that's what I wanted to study, and my PhD research focused on very basic, fundamental questions. I was looking at ion channel biophysics at the synapse," he explains.

"In retrospect it was a naïve way to think, as if this was going to help me to understand these more complex questions. But that was guiding my thinking then, so I spent my PhD in Dr. Stanley's lab looking at these questions using a technique called patch clamp electrophysiology, in which you use glass electrodes to measure the electrical currents at the cell or the synapse level."

Chan describes Stanley as one of the most talented scientists he has ever met, and praises her rigorous, "old school" approach to lab research. Still, by the time he completed his PhD in 2008, he says he realized once again that he'd have to adopt a different approach if he was going to find the answers he was seeking.

At the time, Chan's thinking was coloured by an influential paper published two or three years earlier in the scientific journal Nature Neuroscience by Dr. Karl Deisseroth, now the D.H. Chen Professor of Bioengineering, Psychiatry and Behavioural Sciences at Stanford University.

"It was the first use of optogenetics in a neuroscience context, whereby scientists used light to change the electrical activity of a neuron. I was doing purely conventional electrophysiology, so when I saw this study it blew my mind," he says. "It had a big influence on me and on the whole field. I don't think it's an overstatement to say that it revolutionized basic neuroscientific research."

Chan also realized his "reductionist" approach was too simplistic. To better understand complex manifestations of behavior, he decided he needed to study intact systems in vivo. That's what led him to Dr. Yu Tian Wang, whose work had won acclaim at the University of Toronto before he moved to the University of British Columbia, where he remains a Professor in the Department of Medicine.

Wang, a specialist in synaptic physiology and synaptic plasticity, oversees a large lab with dozens of scientists. His work is focused on understanding the molecular mechanisms that underlie learning and memory, and how the dysfunction of these mechanisms relates to brain disorders such as epilepsy and stroke.

"I was very intrigued by Dr. Wang's work, and when I was looking for a Post Doctoral Fellowship to continue my training I approached him. He knew I was interested in neurophotonic approaches, and because he was co-director of a new in vivo imaging and electrophysiology group along with Dr. Tim Murphy, an internationally recognized expert, he proposed that they become my co-supervisors," Chan explains.

"I thought that was the best of both worlds. So my wife - who was pursuing a career in speech language pathology and had already been accepted into the program at UBC - and I moved to Vancouver in 2009."

At UBC, Chan was involved in a Brain Canada multi-investigator research initiative led by Dr. Ann Marie Craig, a Professor of Psychiatry and the Canada Research Chair in Neurobiology at UBC. Their research focused on the role of synaptic dysregulation in neurodevelopmental disorders.

Meanwhile, thanks to Murphy's affiliation with a government-funded research body called the Canadian Neurophotonics Platform (CNP), Chan met Dr. Robert Campbell, a renowned research scientist, a Professor in the Department of Chemistry at the U of A, and head of the CNP's Optogenetic Protein Engineering Node. "He's a real superstar, and a former Post Doc of Dr. Roger Tsien, who won the Nobel Prize in Chemistry in 2008," Chan notes.

In retrospect, it was this long, complex but fruitful series of serendipitous events, interactions, inter-relationships and research projects that led Chan to his current post in the Department of Psychiatry's Neurochemical Research Unit, where his office is next door to NRU Director Dr. Ian Winship, another former trainee in Murphy's UBC lab.

"I consider myself very fortunate to be here. After the publication of the major aspects of my Post Doc work at UBC, I started looking for faculty positions and luckily the U of A was looking to fill a position in the Department of Psychiatry tied to a Canada Research Chair position focused on neurodevelopmental pre-clinical research," he says.

"So this position is perfectly aligned with my own research interests. I had never met Ian until I came here but I was aware of his work. Ian does multiphoton microscopy, and it's very beautiful stuff. He employs imaging approaches to assess activity on a more microscopic level, while I'm more interested in a systems level. They are beautifully complementary."

Ultimately, Chan hopes his research will help to identify novel neuroimaging biomarkers in the brain of disease progression and altered neuronal circuit function linked to abnormal behavior. If successful, such discoveries could both inform and aid in the testing of potential therapeutic interventions in human clinical trials.

"One thing I'd like to impart is that the level of assessment or the spatial scale I'm looking at is referred to as mesoscale. It basically means an intermediary spatial scale. In the past basic neuroscientific research was focused on the microscale, looking at the synaptic structure or even the subcellular structure of how the brain works," he explains.

"Thanks to tech innovations from the 1990s like PET (Positron Emission Tomography) imaging or FMRI (Functional Magnetic Resonance Imaging) people can now do whole brain imaging, or macroscale. Mesoscale lies in between, so it's the ability to look at large swaths of cortex to be able to assess region specific activity - both local and remote types of activation. Researchers are finding this very helpful in assessing certain types of behavior or decision making."

By harnessing the power of these research tools, Chan hopes to identify neuroimaging biomarkers in the brain that may signal altered neuronal circuit functions that may trigger abnormal behavior.

"One issue with neuropsychiatric disease is, because there is usually no clearly defined physiological basis or mechanism for dysfunction, diagnosis is typically done by observation of perturbed behaviours, or cognitive performance. So the idea that you can get an objective neuroimaging biomarker, a signature of this disorder, its progression or its manifestation, is very appealing," he says.

After a brief pause, he sits back and smiles broadly. "You know, I've been doing these types of experiments for many years now. To this day when I'm acquiring data or analyzing data I have moments where I just stop and think to myself, 'Wow, this stuff is real science fictiony," he says.

And then he laughs.