In the mid-1980s, when Daniel Sinnett was starting out a young biochemist doing his master's degree at Université de Montréal, mapping the human genome was still unheard of, and, as a scientist-in-training at UdeM's affiliated children's hospital, CHU Sainte-Justine, Sinnett began exploring genetic childhood illnesses like Lesch-Nyhan disease, Incontinentia pigmenti and Duchenne muscular dystrophy.
For the latter, the team he was part of made history as the first in the world to detect the disease prenatally in twins.
"I was interested in human genetics, and the only laboratory in Montreal at the time that was working on that happened to be at Sainte-Justine, with professor Damian Labuda, so I wound up in childhood diseases by default," recalled Sinnett, today a pediatrics professor in UdeM's Faculty of Medicine. “And I stayed in that groove right through my PhD at UdeM and into my postdoctoral studies at Harvard Medical School, at their children's hospital there, in Boston.”
In the early years at CHU Sainte-Justine, Sinnett was part of an early trend, now the norm, of biomedical students doing "translational research" off-campus, in a hospital setting, so as to better understand what causes disease, now just how the disease manifests itself. When he started having a family of his own – a boy and girl with his wife Pascale Benoist, a veterinarian who also teaches at UdeM – the value of working on childhood diseases really struck him.
"It was inspiring," he recalled. “In the hospital I would see kids sick with cancer who were the same age as mine, and to think I was able to make a difference in understanding and preventing and treating diseases of childhood like those, that really hit home as a father.”
By the 2000s, Sinnett got increasingly interested in what he calls "the trajectory" of childhood leukemia in Canada — that is, its genetic determinants — as well as children's response to treatment and the quality of life of the four in five patients who survive into adulthood. What, Sinnett, wondered, becomes of them? Are there any long-term effects of their treatment, and can the harmful ones be mitigated?
"We began to realize that three-quarters of those who'd survived leukemia had long-term effects from treatments they'd received 20 or 30 years before," Sinnett said. “So as scientists, we wanted to figure out who among the current patients were at risk of going on to develop these conditions – heart problems, obesity, learning disabilities and more – and to intervene before it happened.”
Depending on what selection of medications is used to treat their cancer – whether cytotoxic (to kill cells) or genotoxic (to damage DNA) – the long-term effects vary widely. Some patients wind up years later needing hip surgery. Some develop neurotoxic complications: ADHD that makes it hard from them to hold down a job, for instance, or psychosocial problems. Others, as teens, get osteonecrosis: the tissue in their bone joints dies.
Loss of taste
Another, more insidious after-effect begins during the chemotherapy itself: how it changes the child's taste for food and drink. "Everything tastes metallic," Sinnett said, “so the child doesn't eat, and if they don't eat, the chances of healing are diminished, so the parents feed them what tastes best, anything that salty or sweet. And that fast food becomes a bad habit, and the child goes on to develop a weight problem, and eventually type-2 diabetes.”
At CHU Sainte-Justine, Sinnett and his multidisciplinary team at the Charles-Bruneau haemato-immuno-oncology research unit followed a group of 250 cancer survivors called the PETALE cohort, averaging 26 years of age, bringing them into the laboratory for genomic investigation and repeated tests – blood, bone-density, cardiovascular – to identify, measure, quantify and catalogue symptoms of current or eventual late-effects of their treatment. "It was a shock," he recalled, “to see that not only could we identify which patients were likely to go on to develop after-effects, but also which particular after-effects those would be.”
From that research was born, under the leadership of Dr. Caroline Laverdière, an interdisciplinary clinic, the Clinique suprarégionale de suivi long terme en milieu adulte pour les survivants d’un cancer pédiatrique, that now takes each patient's needs into consideration, streaming them towards the right specialist for their particular after-effect and making sure there's follow-up where there was none before.
An added bonus: the research has also been applied to other, adult cancer patients. Survivors of breast cancer in their 30s, for example, often go on in their 50s to develop after-effects of their treatment. The same is often true for young men who survive testicular cancer.
"What we discovered in pediatrics applies to everything," Sinnett said.
In children, CHU Sainte-Justine's Centre de cancérologie Charles-Bruneau was one of the first in their world to propose therapeutic alternatives to non-responding patients thanks to a precision medicine program based on molecular profiling. "Patient Zero" of this so-called TRICEPS study was a young teenager named Laurent who, in 2017, survived very aggressive liver cancer after treatment targeting a specific mutation in his cancer cells.
Success with an otherwise terminal patient like that led to a new push in research at CHU Sainte-Justine: genomic sequencing right from the get-go, when a patient is initially diagnosed with cancer. Called SIGNATURE, the molecular profiling program has since been extended across Quebec, providing such meaningful data that "the pharmaceutical industry has gotten behind it, too, developing new molecules to treat children's cancer," Sinnett said.
"If you ask me in 20 years if we've changed the trajectory of those who survive cancer, I hope the answer will be yes!" said Sinnett. “I can't know for sure, but I think we can predict the trajectory will be a good one.”
As he contemplates retirement this summer from full-time work as a researcher – to raise goats and chickens at the small farm he and his wife have in Napierville, south of Mointreal near the New York border – Sinnett takes pride in having made a difference in many lives, young and old.
"To say I've been able to contribute to the transformation of how young patients are treated and followed into adulthood," he said, “and to have done so without leaving my university and without leaving Quebec, that's simply a lovely legacy.”
