‘A zillion overnights’
For Katalin Kariko, going it alone started early.
Growing up in Hungary during the Cold War, she was in eighth grade when her father put her on a train by herself so that she could travel to Budapest for a national science competition.
“My family was very supportive,” said Dr. Kariko, who is now a researcher and senior vice-president with the German pharmaceutical company BioNTech. But her parents were working and did not own a car, so off she went on the train.
She placed third in the week-long competition. But the real takeaway was a lesson in self-reliance.
“This is what is the important part,” she said. “Realizing that I have to stand up for myself, always.”
It would prove to be an essential skill.
For the next four decades, most of it spent in the United States, Dr. Kariko would labour in obscurity in university labs where she was often short on resources, frequently passed over for promotion and sometimes let go. Her project was one that few believed in and for years seemed to interest no one. But in the end, it would became one of the most consequential and widely used medical interventions in a generation: the development of messenger RNA vaccines against COVID-19.
On Tuesday, Dr. Kariko was named one of this year’s recipients of the Canada Gairdner International Award, among the most prestigious science prizes in the world of biomedicine. She has been recognized alongside her close collaborator Drew Weissman of the University of Pennsylvania, as well as Pieter Cullis, the University of British Columbia scientist whose discoveries with lipid membranes would ultimately provide the delivery mechanism for the vaccines.
Few discoveries singled out by the Gairdner Awards over their 65-year history have directly affected so many Canadians. At this point, most people in the country have received at least one dose of an mRNA vaccine. That fact alone indicates how basic research that begins far from the clinic can lead to world-changing therapies, sometimes in ways that are completely unanticipated.
This holds true for Dr. Kariko, whose career-long interested in messenger RNA – the molecule that carries instructions from DNA to the protein-making parts of the cell – came about first because of an interest in neurological disease rather than viral infections. In short: If a disease was caused because the gene for making an essential protein was missing, perhaps that deficit could be remedied by supplying the instructions in the form of RNA.
The idea faced several practical challenges. The most serious became evident in 1997, when Dr. Kariko began working with Dr. Weissman, who specialized in dendritic cells, which are part of the immune system. The pair found that inserting RNA into the cells provoked a strong immune response in mice, as though the cells were trying to battle foreign invaders, such as bacteria, which also carry RNA.
The roadblock looked like it might kill the dream of RNA as a therapy, but the two researches persisted. In 2005, they realized how to chemically alter the RNA to disarm the immune reaction. Yet, despite the progress, there was little reaction from the research community or its funders.
“I think the big problem was that people just weren’t that interested,” Dr. Weissman said.
At the same, Dr. Cullis was in Vancouver and making progress with the development of lipid nanoparticles – tiny globules that could be made to encapsulate and successfully transport molecules across cell membranes.
It was a potential delivery system for messenger RNA, but when Dr. Weissman called a Vancouver company that Dr. Cullis had helped to start, he was rebuffed. The company was working on a different RNA therapeutic with another partner and Dr. Cullis had already moved on.
“In many ways, it was just as well,” Dr. Cullis said. “We weren’t really ready for prime time at that point, whereas when we did get together, we actually had a much better system.”
In 2013, the pieces finally came to together, including the modified RNA with the lipid nanoparticles. By then, the work had finally spawned interest and given rise to a Massachusetts-based competitor called Moderna.
Meanwhile Dr. Kariko went to BioNtech, determined to see her idea come to fruition. The German company licensed the Canadian-developed nanoparticles and also partnered with the pharmaceutical company Pfizer.
Years of work were still on the horizon, but, by the time COVID-19 arrived, it was possible to move quickly to create an mRNA vaccine that can induce cells to make the coronavirus spike protein, thereby stimulating the body’s defences against the coronavirus.
When the vaccines proved effective, the development was questioned by skeptics who wondered how such a miracle of medicine could have been cooked up seemingly overnight.
Looking back over her 40-year odyssey, Dr. Kariko smiled at the idea and then said, “It took a zillion overnights.”
In the blood
The window sill in John Dick’s office at the Princess Margaret Cancer Centre in Toronto hosts a tidy parade of empty Champagne bottles, each opened to celebrate a notable research paper published by his lab over a 30-year career.
“Research is like shining a light into darkness,” said Dr. Dick, who is also a professor of molecular genetics at the University of Toronto. “You don’t know what you’re finding,” he added, but as the bottles attest, sometimes it turns out to be quite important.
Raised on a farm in southern Manitoba, Dr. Dick came to Toronto in the mid-1980s after receiving his PhD and went to work with Alan Bernstein, a cancer researcher and a fixture of the Canadian research community, who would provide a perfect training ground in the newly developing field of stem cells.
After starting his own lab in 1986, Dr. Dick began a series of investigations with mice that would build on the work of Canadian stem-cell pioneers James Till and Ernest McCulloch. It led, a decade later, to the discovery of cancer stem cells in blood and a demonstration of how the slow-growing stem cells could evade chemotherapy, eventually causing cancer to return.
That work, together with its continuing and world-recognized impact on the understanding, diagnosis and treatment of cancers such as acute myeloid leukemia, has now earned Dr. Dick a Canada Gairdner International Award.
Yet, at 67, he said he still hopes to keep adding more papers, and perhaps a few more Champagne bottles, to his collection. By prioritizing research over administrative roles that often become a career path for senior investigators, he said he has been able to maintain his lab’s formidable output. “I still have a lot of energy for research,” he said. “I’ve never been as productive.”
The same enduring enthusiasm animates Stuart Orkin, a Harvard Medical School scientist who rounds out this year’s complement of International Award winners – also for research focused on blood.
Dr. Orkin is best know for discovering the genetic mechanism by which the body’s ability to receive oxygen shifts from a form of hemoglobin that is found in utero to the form that takes over after birth.
By showing that there are ways to keep the switch open, the discovery has applications for the treatment of diseases such as sickle-cell anemia and beta-thalassemia. The former is especially prevalent in sub-Saharan Africa and among populations with genetic ties to that part of the globe.
Dr. Orkin said the award helps draw attention to diseases that continue to affect large numbers of people but that have historically received less attention and research for reasons of equity.
“I think it validates basic discovery science” he said, adding that the recognition serves as a reminder that the journey from lab to patient is rarely a straight line and potentially life-saving research requires support at every step of the process.
Where the evidence leads
Ultimately, it’s the little things that matter to our health, from ensuring that a mother-to-be has proper nutrition to granting simple wishes to a patient at end-of-life.
That is the common message that emerges from the disparate work of two giants of health research being recognized this year by the Gairdner Awards.
Decades of research by Zulfiqar Bhutta, co-director of the Centre for Global Child Health at Toronto’s Hospital for Sick Children and founding director of the Centre of Excellence in Women and Child Health at the Aga Khan University in Pakistan, have demonstrated the importance on lifelong health outcomes of the 1,000 days from the moment of conception to the toddler stage.
“The bulk of mortality, in mothers and children, happens in those first 1,000 days,” he said in an interview. “We can have a tremendous impact with simple public-health interventions.”
Dr. Bhutta, who is being recognized with the 2022 John Dirks Canada Gairdner Global Health Award, began his career as a neonatologist in his native Pakistan but became increasingly frustrated at the futility of treating individual children for preventable conditions while the environment that was making them sick never changed.
“I got into this because I wanted to influence population health, to have a bigger impact” he said.
In his 40s, Dr. Bhutta returned to school to do a PhD at the famed Karolinska Institute in Stockholm. His research since then, which has focused on nutrition and prevention of deadly conditions such as diarrhea in babies, has been the foundation of multiple public-health guidelines around the world.
By showing which simple, affordable interventions work (and don’t work), and rewriting public-health interventions, Dr. Bhutta has produced research that is credited with saving millions of lives. In 2002, more than 10 million children under the age of 5 died annually, largely from malnutrition; today, that number has dropped to 4.5 million.
“In the past 20 years, we’ve seen the fastest reduction in childhood mortality in the history of mankind,” Dr. Bhutta said. “That’s why this work matters.”
He is also quick to add that, beyond research, scientists have a role to play in advocacy. “I’ve always felt that if you don’t disseminate your findings and push for them to be implemented, it’s a job less than half done.”
Deborah Cook, a distinguished professor of medicine at McMaster University and a critical care physician at St. Joseph’s Healthcare in Hamilton, is also a fierce advocate of bringing research findings to the bedside.
In the process, she has revolutionized how critical care patients – the sickest of the sick – are treated for everything from blood clots to lung infections and gastrointestinal bleeding.
But Dr. Cook, who is being honoured with the 2022 Canada Gairdner Wightman Award, is perhaps best known for developing the 3 Wishes Project, a way of ensuring compassionate care at end-of-life for critical care patients.
“Our patients often can’t speak for themselves, so we have to try and understand them, to make treatment concordant with their wishes,” she said.
“It’s a paradox but, in the end, it’s the simplest things that really matter the most, even in a fast-paced technologically complex setting like the intensive care unit,” Dr. Cook said.
She is a founding member of the Canadian Critical Care Trials Group, which advocates for a multidisciplinary approach to research – an approach that has been copied around the world. And she is known for her precise methodology.
“Rigorous science is essential,” Dr. Cook said. “We have an ethical imperative to find answers that are credible and will provide good return on investment.”