News at Medicine - March 2019 - The job’s not done

The job’s not done
March 7, 2019
Personal connection pushes researcher to do it ‘for this family’

Dr. Mani Larijani has had one constant relationship throughout his career as a university professor: an enzyme called activation induced deaminase, or AID.

AID is important to the body’s immune system as it helps white blood cells respond more effectively to invasions. However, the enzyme can mistakenly mutate these healthy cells into leukemia/lymphomas. 

Dr. Larijani started studying AID early in his career as a post-doctoral researcher in the laboratory of Professor Alberto Martin at the University of Toronto. There, he characterized the enzyme’s behaviour and began to understand how it causes mutations. He then submitted the project for a post-doctoral fellowship to the Leukemia and Lymphoma Society of Canada (LLSC), and they funded it. That was 14 years ago.

“That was a turning point for me,” said Dr. Larijani, an associate professor of immunology and infectious diseases at the Faculty of Medicine. “I could see myself possibly having a career in cancer research.”  

LLSC later presented Dr. Larijani with the David Rae Memorial Fellowship for his research. David Rae passed away from leukemia at the age of 32 and his family created an endowment fund through the LLSC in his name.    

At the award ceremony, Dr. Larijani sat next to David Rae’s family, including his older brother, politician Bob Rae.

“It was the first event for me that made it personal,” he said. “The next morning I was in my lab at 4 a.m. ready to get to work because I had a job to do for this family. It changed the way I approached my science.”

This same drive has led Dr. Larijani to make major breakthroughs over the last ten years in his research, including a revolutionary way to correctly visualize the structure of AID.  

According to a release by the Canadian Institutes of Health Research (CIHR), another of Dr. Larijani’s funding partners, researchers traditionally use techniques such as x-ray crystallography and nuclear magnetic resonance (NMR) to visualize enzymes and other proteins to determine their molecular structure. 

This didn’t work with AID because it’s a highly insoluble protein. Dr. Larijani and his PhD student, Justin King pioneered a new process to identify AID’s structure. This process combines computer modelling, evolutionary biology and functional biochemical testing of the enzyme in the lab.

The work was described in two publications authored by Mr. King and Dr. Larijani, in the journals Structure, and Frontiers in Immunology. Their first publication on the structure of AID also described another significant first: they discovered that AID exists in two states: its ‘on’ state, which causes cancer, and its ‘off’ state, which doesn’t.  

"Beyond revealing its 3-dimensional structure, we were able to reveal more about the workings of AID in that we also understand how it moves in real time, and how much time it spends in each of those moving states, and we think of this as the fourth dimension, which is time. In addition, we understand the relevance of those moving states to the function of the enzyme in immunity and cancer, and one can consider function as the fifth dimension,” said Dr. Larijani. 

Read more on the discovery here.

Cancer treatments
With a clear picture of the structure, Dr. Larijani and Mr. King used super computers to predict drug-like molecule compounds that could block AID from functioning in its ‘on’ state, and found some that actually work to stop AID.

“Having got my start on this project so many years ago with funding from the LLSC, we decided to apply to them again to fund this latest work. I was so pleased that the LLSC liked this project and saw its potential,” commented Dr. Larijani who plans to use his most of the recent funding from LLSC, $200,000 over the next two years, to further develop the compounds.

“They are good enough for the lab, but they are not good enough to be used as a cancer drug,” he said. “If I were to give you these compounds today as a drug, I’d have to give you a bucket of it for it to work because they work at a very low affinity.”

Dr. Larijani is collaborating with a medicinal chemist at McGill University, Dr. Nicolas Moitessier, to assist with further development of the compounds.

Coming full circle

Dr. Larijani’s research contributions on AID and other cancer-causing enzymes have earned him an international reputation including the highly competitive Canadian Society for Immunology new investigator award in 2015 for “exceptional accomplishments in immunology during the early years of his career.”, as well as a list of other prestigious awards. But, the David Rae Memorial Fellowship tops them all.

Holding the award, which he still displays in his office, Dr. Larijani recalls emailing Bob Rae after discovering the potential of the AID inhibitors.

“Fourteen years later, I wanted to tell him because I figured I owed it to this family to let them know about the major breakthrough that was initially sparked so many years ago by their faith in me, and in this project.”

Photo 1: Dr. Larijani holdings his David Rae Memorial Fellowship award in his office (submitted) 
Photo 2: 
Dr. Larijani with Mr. King (middle) giving a lab tour to LLSC board member, Paul Davis and Area Manager, Leah Wade in January 2019. (Credit: Jennifer Armstrong, HSIMS)