Recognizing a leading contribution in brain chemistry
After 25 years as CAMH’s Chief Radiochemist, Dr. Alan Wilson has retired.
In CAMH’s radiochemistry lab, Dr. Wilson and his team have invented chemical dyes that have significantly advanced our understanding of mental illness and addiction. Using these dyes – known as radiotracers – and positron emission tomography (PET) imaging, Dr. Wilson and his fellow CAMH researchers have been able to see chemical changes in the living human brain. His work has had a broad influence that has enabled scientists to identify biological targets to treat addiction and depression, as well as to pinpoint mechanisms underlying mental illness, such as inflammation in depression. Half of all the chemical probes currently used in PET imaging around the world have been developed by CAMH’s radiochemistry team under Dr. Wilson’s leadership.
We spoke with Dr. Wilson about highlights from his remarkable career.
From left: Dr. Sylvain Houle, Director of CAMH’s Research Imaging Centre, and Dr. Alan Wilson
How did you enter this field?
After completing my PhD in physical organic chemistry in Scotland, where I grew up, I worked for a year as a post-doctoral fellow in the chemistry department at Johns Hopkins University in Baltimore, Maryland in the early 1980s. My former PhD supervisor suggested that I stay in the U.S. for another year. But I was very disillusioned with chemistry and academia because my work was very theoretical and had no apparent practical application. I suggested to my wife that we should go back to Scotland.
My wife was working in a different part of the John Hopkins campus, and her boss wanted to keep her on. It turned out that, in the office next to her boss, was this scientist who was setting up the PET centre at Johns Hopkins, Dr. Don Burns. Out of the blue, I got a call from Dr. Burns asking me to come for an interview.
Because I really wasn’t thinking we’d stay in the U.S., I went to the interview very casually dressed – I was wearing sandals, old shorts and a T-shirt. Dr. Burns started talking about positrons. After a while, he could tell he was losing my interest. Then, he said everybody’s trying to make a specific radiotracer – this was a new field – and they’re trying to make it by using a chemical reaction involving triazene compounds. I was probably the world’s expert on the triazene reaction at that time because I had written my PhD on this very specialized area. So my background dovetailed into PET beautifully. I told him it would never work. He offered me the job to prove myself wrong. I never got it to work, and neither did anyone else.
After a year or two in my new role, I started working in the cyclotron and the radiochemistry lab. About a month after I started in the radiochemistry lab, Johns Hopkins researchers conducted the first human PET scan of a neurotransmitter receptor using a radiotracer developed by my colleagues in the lab. Everyone, including me, was very excited. Then, I learned the business of working with high levels of radioactivity. I started creating a better way to do this. This made the process simpler and more reliable – this was my first real contribution.
In contrast to my early disillusionment with chemistry as a post-doctoral fellow, something I’ve really enjoyed throughout my years working in PET radiochemistry is that it is very focused on trying to understand psychiatric disorders and help patients.
How did you end up coming to the Clarke Institute of Psychiatry?
Dr. Vivian Rakoff [former CEO and Psychiatrist-in-Chief of the Clarke Institute] had funding to build the Clarke Institute’s PET Centre, which is now part of CAMH’s Research Imaging Centre. He sent a young physician scientist to Johns Hopkins to learn PET – this was Dr. Trevor Young, who is now the Dean of the Faculty of Medicine at the University of Toronto.
We had a going-away party for Trevor at a Chinese restaurant. Trevor said they were looking for someone to work in the radiochemistry lab and asked me if I’m interested, and I said, yes, I guess I am. A few weeks later, I got a call from Vivian asking me to come for an interview.
The interview was actually quite intense. There was a selection committee, including Dr. Sylvain Houle, Dr. Phil Seeman [scientist in the University of Toronto’s Department of Pharmacology] and Dr. Jerry Warsh. There was a whole series of one-on-one interviews and group interviews. Because I didn’t think I would get the job, I wasn’t intimidated at all during the interview and I spoke my mind, and Vivian offered me the job that same day. And I came here on September 2, 1991.
Dr. Alan Wilson demonstrated the new Vivian M. Rakoff PET Centre’s technology in October 1992. Photo courtesy of CAMH Archives, Collection of the former Clarke Institute of Psychiatry.
What stands out for you in terms of your accomplishments throughout your work at CAMH?
That’s hard to say. One of the most important was developing the [11C] DASB radiotracer for the serotonin transporter. Prozac and other modern anti-depressant medications work on this serotonin transporter, so everyone wanted a way to study them. People had been trying to make a radiotracer for the serotonin transporter since the mid-1980s. About 13 different radiotracers worldwide had been made for this transporter, and I had been involved in developing about five of these. DASB was the first good one. So everybody was very excited by this development. Jeff Meyer used DASB to look at the effects of antidepressant drugs that target the serotonin transporter, and he established a new measure to determine the effective dose of these types of medications.
Developing the 11C-(+)-PHNO radiotracer was also very important. I was not at all convinced that this type of radiotracer for the dopamine system was important and had to be dragged into developing this by Dr. Shitij Kapur [former VP of CAMH Research] and Dr. Nathalie Ginovart [former CAMH neuroscientist] in the PET Centre. Nathalie wore me down. It turned out to be very successful, and several groups are now using it worldwide. One example is PHNO lets us study the dopamine D3 receptor for the first time in people. Using PHNO, Dr. Isabelle Boileau identified D3 as a new potential target for developing anti-craving medications to treat addictions to stimulants such as methamphetamines.
The [18F]-FEPPA radiotracer gave us a tool to study brain inflammation in people. Dr. Jeff Meyer went on to discover brain inflammation as an underlying factor in depression, and Dr. Romina Mizrahi showed brain inflammation in Alzheimer’s disease.
Developing the radiotracer to study endocannabinoids is the chemistry work I’m most proud of. That one was the most fun and most clever, because it was the most challenging, and it was logical – it worked the way I conceived it would. The radiotracer, called [11C]CURB, works on the enzyme fatty acid amide hydrolase (FAAH), which breaks down anandamide. Dr. Pablo Rusjan developed a method to quantify FAAH using [11C]CURB, and Isabelle, Romina, Dr. Junchao Tong and Dr. Stephen Kish are all studying the role of FAAH, including in cannabis use disorders.
How have your radiotracers come to be used worldwide?
I’ve had the philosophy of sharing everything we do with anyone who wants it – not just information, but samples too. I believe that in this way we get the recognition for developing the radiotracers that are now being used by other centres around the world. I actively encourage the discoveries to be used by other groups.
Photographed during the 1990s, CAMH’s professional team for PET scanning, including (left to right): Drs. Jean DaSilva, Shitij Kapur, Alan Wilson and the Director, Dr. Sylvain Houle. Photo courtesy of CAMH Archives, Collection of the former Clarke Institute of Psychiatry.
Are there other memorable moments?
There is a funny story we talk about in the lab. We were working on a method to make radiotracers that involved packing a small steel column with a powder. We’d been doing this for six months, and it was working quite well. We were working on a number of radiotracers using this method. One day, instead of getting 100 millicuries of a radiotracer, we made almost nothing. We discovered that we forgot to put the white powder in the column. Everybody denied they did it, including me and my two technicians. But at least we knew why it had happened.
Then, I thought that we didn’t make nothing – we just made almost nothing; the steel container was enough to give us something. Next, I thought that if we changed to using a long and narrow container, this might work better. There was something in the lab already called an HPLC sample loop. We tried using this, and it worked beautifully – it’s called the loop method. CAMH eventually patented it, and entered into an agreement to commercialize this. The twist in the story is we would never have come across it if we had not made the mistake of forgetting to pack the little steel column.
Did you see yourself working in mental health/psychiatry when you were completing your studies?
No. In my generation in radiochemistry, probably nobody envisioned being in PET radiochemistry because it was a new field. There were no formal training sites for it.
How have mental health and addiction research changed over your career?
PET has made a major contribution in that we’re now much more aware that getting the dose of a medication right is important. Pioneering work by Dr. Shitij Kapur and Dr. Jeff Meyer has been influential in showing that there is a proper dose of medications.
We’re also much more aware that no system in the brain stands in isolation – the interconnectivity of different systems in the brain is paramount to try to understand what’s going on.