A Doctor's Quest to Stop a Child Cancer-Killer

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By Mike Pettapiece

They were both five-year-old boys named Christopher. And both had brain tumours, medulloblastomas. But the chain of coincidence broke there. One died and the other survived.

And the reasons why one responded well to treatment but the other did not have haunted Sheila Singh for more than a decade. They led to a personal odyssey for the pediatric neurosurgeon and cancer investigator that has shaped a good part of her medical career.

“At that point, in my head, it crystallized,” said the mother of two boys. “. . . That child (the Christopher who died) is the one who always stayed with me and what really drives my work today.”

Medulloblastomas are the most fatal of the different subsets of childhood brain tumours, originating in the cerebellum, the zone where stem cells reside. In brain cancers overall, childhood tumours are more primitive than those found in adults They are the most common causes of youthful cancer mortality.

The death in the mid-1990s at the Hospital for Sick Children made Dr. Singh, now an assistant professor in health sciences at McMaster University and a principal investigator in the Stem Cell and Cancer Research Institute, ponder “the molecular events that made one tumour behave badly and the other respond well to therapy.”

Were there almost-invisible cancer cells that somehow outran chemotherapy, radiation and surgery, she wondered? What genetic transformations, which signalling pathways, led to an immortal tumour that could not be tamed?

It was in 2003 that, in a world first, she found one of her answers. Working with Dr. Peter Dirks, a surgeon like her, and other colleagues at the hospital, she discovered an abnormal progenitor cell that many cancer scientists now believe is the irreducible unit that drives formation of tumours.

She clearly recalls the moment “of great discovery” when she “saw these beautiful spheres floating” in a cell culture. The spheres were what the team later called a brain tumour initiating cell (BTIC). It was the first isolation from a solid tumour of what is believed to be a cancer stem cell in the central nervous system.

This cancer stem cell hypothesis argues that the cells, like their normal adult stem cell counterparts, can self-renew and divide indefinitely, giving rise to both more cancer cells and progeny that ultimately differentiate into the many cell types in a tumour. CSCs are the body’s machinery gone rogue.

It is somewhat rare for a surgeon to also be a cancer investigator. It is even more unlikely that a pediatric neurosurgeon walks the two paths. But the duality has its advantages. The clinician knows the patient’s history, the lab scientist can apply that knowledge to uncover why a biological event took place.

Dr. Singh came to neurosurgery almost by family design. Her father was a psychiatrist and, as a child, she would wander through his books on occasion. But she did not much fancy helping patients work through neuroses or emotional traumas as much as she did the hands-on medicine offered by surgery.

“It was like activism because you diagnose something and then you do something to fix it,” said the Dundas, Ontario-born woman.

Pediatrics to her was “the kinder, gentler surgery”. It also presented a fascinating opening: a doctor could work with the very cells present in one of his or her patients.

And so there have been nights when Dr. Singh would tuck her boys into bed and then head to the lab to culture tissue from the tumour cells she had taken earlier that day. She would study both normal neural cells and cancer cells under a microscope.

She could compare the two at epigenetic levels and at the RNA level. Working from the CSC hypothesis, she would look for signalling pathways that might suggest why a cell becomes aberrant and turns cancerous. Thousands of investigators are enjoined in this complex search, piling up discovery after discovery.

“It’s like a tidal wave of data coming at us,” said Dr. Singh, who works with fellow researchers at McMaster, in Canada, California and in other areas. To ride this wave demands not only great collaboration but also calls for approaches to researchers outside the medical environment.

For about a year, Dr. Singh has been engaged in “a new way of looking at this”, working with mathematicians from the University of Waterloo. They are refining statistically relevant ways to study the data, building models in time and spatial dimensions to determine which factors accelerate tumour growth and the velocity of that growth.

It is not enough to commit time and funding to look at a gene disregulation here, a signalling pathway there. Far better, and more rigorous, to apply quantitative models to biological problems, in seeking a unified theory as to which transformation events turn a normal stem cell into a cancer cell.
Dr. Singh’s dual capacities as bedside-operating room clinician and cancer investigator help “inform each other and generate new perspectives on a daily basis,” she said.

“At the intersection of surgery and science is the patient. And while surgery in the short term may save or prolong lives, the long-term solution . . . will emerge from the science. Children with brain tumours and their families inspire me to work even harder in the lab, toward the goal of finding a therapy that provides a lasting cure.”

Mike Pettapiece writes and edits the newsletter for the Golden Horseshoe Biosciences Network, based at McMaster University in Hamilton.