Following the research
“You have to follow where the research takes you,” says Barbara Triggs-Raine, PhD, Professor and Associate Head, Dept. of Biochemistry & Medical Genetics, University of Manitoba (U of M), who is about to pursue a new direction in her career – as a cancer researcher.
Triggs-Raine heads one of two labs worldwide that studies the degradation of a large, polysaccharide molecule possessed by all vertebrates: hyaluronan (HA). It’s a jelly-like substance that acts as a filler both inside and around cells, particularly in soft connective, skin, and neural tissues. It’s been called the “goo” molecule and is widely used in cosmetic injections and wound-healing applications.
Triggs-Raine has studied the role of HA in rare genetic diseases in unique populations. In fact, that’s where her HA story begins.
Educated as a microbiologist at the University of Manitoba, she developed a love for human genetics at graduate school. During her post-doctoral studies at The Hospital for Sick Children, Toronto, and Montreal Children’s Hospital, she researched Tay-Sachs disease – groundbreaking work that she continues to this day.
That research required the use of tissue samples, which she obtained from Dr. Marvin Natowicz, a researcher at the Eunice Kennedy Shriver Center, University of Massachusetts, Boston. The two colleagues soon became collaborators.
Natowicz moved to the Cleveland Clinic, where, in 1996, he came across a patient with a unique, arthritis-like condition. He brought the case to Triggs-Raine’s attention, and she began to work on the problem.
The patient had mucopolysaccharidosis (MPS) IX, a rare lysosomal storage disease in which HA builds up inside cells. With her U of M team, Triggs-Raine discovered that the patient lacked an enzyme called hyaluronidase (HYAL), which breaks down HA.
In her lab, she and her team located three major genes and three related genes that appeared to encode HYAL enzymes that degrade HA. “So we set out to understand how all of these different genes function,” she says. “That was the start of our HA work.”
To take a closer look at HYALs, she stepped into unfamiliar territory.
“When you work in cell cultures, HA doesn’t form all of the structures that you observe in the whole tissue, so we developed mouse models deficient in three different HYAL enzymes,” she explains.
“I had never worked with mouse models before, but I decided that was the way to do it. In order to study a substance that surrounds your cells in a complex environment, you need to study the whole animal.
“If HYAL2 is missing, it appears that you can’t remove the HA outside cells to allow the cells to stop migrating and start transforming into different cell types,” explains Triggs-Raine. During development, HYAL2-deficient mice are unable to form tissues properly, particularly in the heart.
Then, several colleagues sent her a study that had been published in Nature about naked mole rats. These ugly creatures don’t get cancer, and researchers have hypothesized that high levels of HA surrounding cells in adult mole rats might have a preventive effect.
Triggs-Raine’s laboratory is one of the few with the ability to investigate this theory.
“We have, in our mouse, the ability to take the HYAL2 gene out after development,” she explains, “so we won’t have to deal with defects that make the animal sick. We can find out if it makes a difference to cancer susceptibility.”
If it does, HYAL2 could become a target for anticancer drugs that slow the spread or even prevent cancer.
“I’m not a cancer researcher,” Triggs-Raine admits, “but I’ve always believed that you have to keep changing. Working with mouse models really started me on this complex journey. If I hadn’t done that, I would still be studying mutations in rare genetic diseases.”
Work with mouse models confirmed that a HYAL1 deficiency was responsible for MPS IX. That was just the beginning.
“We also discovered that another enzyme, HYAL2, works outside the cell. It sits on the cell surface and degrades the abundance of HA around the cell.”
During development, jelly-like HA helps proliferating cells to slip-slide to their final destinations within the body. Once cells reach that point, HA is removed to stop the migration. Cells begin to differentiate into their final form, e.g., becoming heart or skin cells.
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