Scientific discovery in unexpected places

By Emily Leighton, MA'13

“I have no special talents. I am only passionately curious.”

Written by Albert Einstein to his biographer, these words capture the often compelling nature of scientific pursuits.

As a scientist, Shawn Li, PhD, is also driven by his curiosity. A Professor in the Departments of Biochemistry, Oncology and Paediatrics at Schulich Medicine & Dentistry, he views research as a life-long learning experience.

“I get excited to explore the unknown, to figure out what’s going on,” he said. “The diversity of my projects reflects the diversity of my interests.”

Li’s curious mind often leads him to unexpected places.

One such experience resulted in a publication for Nature Communications in October 2018. With this study, Li and his collaborators identified an important signalling protein domain, called SH2, in Legionella - the pathogenic group of bacteria responsible for Legionnaires’ disease.

“The SH2 domain comes in abundance in mammals and plays a critical role in regulating the growth and survival of mammalian cells, but it has never been found before in bacteria,” said Li.

The research team showed that Legionella, which may have evolved billions of years ago, stole numerous copies of the SH2 domain from mammalian hosts.

In Legionella, the stolen protein domain displays unusually high affinity and promiscuity. “The SH2 domain in Legionella acts like super glue,” explained Li. “Which is why we call it a superbinder.”

At the onset of infection, these superbinders are then injected back into the host cell, grabbing onto regulatory proteins more effectively than their mammalian counterparts. “It is like using your own weapons to attack you,” said Li.

“It is highly likely that these bacterial super-binding SH2 domains play a critical role in the growth of Legionella inside the host, such as cells in the human lung, by hijacking the signalling pathways in human cells,” he added.

Calling this process “large scale stealing,” he says it demonstrates how bacteria steal information essential for their growth and proliferation.

“Knowing what genetic materials pathogens might have hijacked from mammalian cells gives us insight into how to block them,” he said. “This could lead to therapeutic approaches for various diseases, including cancer.”

With cancer being his primary area of focus, Li investigates the molecular and epigenetic basis of the disease.

He received a Project Grant from the Canadian Institutes of Health Research (CIHR) in the latest competition to study immune evasion in cancer.

Immune evasion is a strategy used by cancer cells to sidestep our body’s immune response. “If our immune systems are working properly, the cancer cells should be eliminated,” explained Li. “But cancer cells are smart and are able to evade immune surveillance.”

One way tumours escape this control system is by activating immune checkpoints that minimize the body’s immune response. To prevent this from happening, immunotherapy treatments work to block the checkpoints, thus ensuring the body’s normal immune response takes place.

But not all cancers respond well to this approach, including breast and prostate cancers, leaving researchers with many unanswered questions.

“No one knows exactly how this checkpoint therapy works, it’s like a big, black box,” said Li. “We want to drill down deeply into how the checkpoints are signalling between the immune cells and cancer cells.”

The new CIHR funding will allow Li to address fundamental questions underlying the basis of immune escape mediated by immune checkpoints. “By understanding the signalling mechanisms and pathways, we can pre-empt immune escape for hard-to-treat cancers, as well as overcome resistance in cancers that initially respond well to immunotherapies.”

With many research questions and projects in the mix, Li strives for clinical impact. “My ultimate goal for my career is to develop a drug or treatment strategy that can actually benefit patients.”