Replicating cells — both normal and cancerous — lie at the heart of discoveries made by four of this year’s seven Canada Gairdner Award winners.vshivkova/iStockPhoto / Getty Images
Canada Gairdner International Awards
Makers, breakers and movers
For life to endure, cells must copy their DNA to pass on to new cells and new generations. It is a basic fact of biology that disguises a Herculean feat.
Consider that in order to maintain a healthy blood supply, the adult human body must produce about 500 million blood cells a minute. Each new cell carries two metres of tightly coiled DNA. Do the math and it works out to one-million kilometres of DNA every 60 seconds – enough to wrap around the equator 25 times over. And that’s just blood. There’s also gut, skin, liver and all the other cells that require regular replacement. In practice, a replicating cell can’t achieve this by starting at one end of a strand of DNA and copying until it gets to the other. Like a medieval monastery where the monks all work together, each reproducing one page of a sacred book, a cell must deploy many thousands of copiers all at once in order to duplicate its entire genome faithfully and swiftly.
As a young scientist, Bruce Stillman long puzzled over how cells manage this trick, especially without some genes being copied twice. “Forty years ago, we really didn’t know how replication occurred,” said Dr. Stillman, who is director and president of Cold Spring Harbor Laboratory, a renowned research centre on Long Island, N.Y.
Bruce Stillman
Born in Melbourne, Australia, he grew up with dreams of becoming a medical doctor. But in university, it was the lab rather than the hospital that captured his imagination. When he first arrived in Cold Spring Harbor in 1979, he had a burning desire to tackle the mystery of DNA replication.
Within a few years, he was joined in his quest by another young researcher, John Diffley, a native of New York and now associate research director at the Francis Crick Institute in London. Working with yeast cells, which share the same form of DNA replication as humans and other animals, the two researchers developed new techniques to study the process. By 1992, they had identified an elegant structure made up of multiple proteins which they dubbed the origin recognition complex – ORC for short. The structure wraps around the DNA double helix at specific sites and serves as a starting point where the rest of the replication machinery is assembled. Key to the find was the discovery of how the protein complex is triggered to begin its work at the appropriate moment in the cell-division cycle.
“It was so beautiful and so clear that it had to be right,” Dr. Diffley said.
John Diffley
Further work has added detail to the picture. In 2015, Dr. Diffley’s team was able to reconstitute the process with purified proteins outside of living cells, making it easier to study. The results shed light on genetic diseases that impair DNA replication and also on how cancer can affect the process so that the DNA of cancer cells increasingly diverges from that of its host.
“It’s really one of the most impressive pieces of molecular biology in recent years,” said Adrian Bird, a professor of genetics at the University of Edinburgh and a previous Gairdner winner.
The mechanics of cell division also come into play in the work of Susan Band Horwitz, a professor of cancer research at the Albert Einstein College of Medicine in New York.
Growing up near Boston in the 1940s, Dr. Horwitz never thought about a career in science but imagined, instead, of becoming a historian. All of that changed when she took a biology course in her first year at college.
“It was wonderful. It opened up a whole new world to me,” she said.
Susan Horwitz
By 1963, she had earned her PhD in biochemistry at Brandeis University. By then, she was married and gave birth to twins five days after defending her thesis. But at a time when few women were working in her field, she was hard-pressed to find a position that would allow her to balance her scientific career with her family life. She eventually found part-time work teaching pharmacology students at Tufts University while pursuing her research on the side. The job had an unexpected benefit because “it introduced me to the idea of small molecules that can do great things."
By the 1970s, she was at the Albert Einstein College, where her husband, a virologist, had accepted a position. She was also working full-time again with a growing track record of studying naturally derived products for cancer treatments. That was when the U.S. National Cancer Institute sought her out to examine a new drug candidate called Taxol, derived from the bark of the Pacific yew tree.
Working with a graduate student, Peter Schiff, Dr. Horwitz discovered that Taxol has an uncanny ability to latch onto tiny fibres inside cells known as microtubules. In normal cells, microtubules are assembled and disassembled continuously and they play a key role during cell division when they are used to pull apart duplicated sets of chromosomes just before a cell splits in two. But when Taxol was present, the microtubules could no longer be disassembled, and instead formed bundles that clogged up dividing cells, including those driving tumour growth.
It would be another 15 years of clinical trials and scientific hurdles before Taxol was approved for use as a cancer drug in 1992, but it was the work done in Dr. Horwitz’s lab that set the wheels in motion. Today Taxol has been administered to millions around the world.
“I never give a lecture when someone doesn’t come over to me afterwards and say thank you,” Dr. Horwitz said.
In addition to roping DNA, microtubules serve as the tracks for an elaborate transportation system found within many cells. Incredibly, those tracks are traversed by a class of proteins called kinesins that amble along like microscopic ants, dragging cargo from production sites near the nucleus and making deliveries to the cell’s outer reaches.
Ronald Vale, a professor of cellular molecular pharmacology at the University of California, San Francisco, has played a key role in uncovering this remarkable system. Born in Los Angeles, Dr. Vale’s childhood fascination with science was sparked by museum and planetarium visits. In graduate school, he studied nerve cells, which require the transportation of neurotransmitters and other chemicals down long extensions, called axons.
Ronald Vale
Working with the cell biologist Michael Sheetz, Dr. Vale turned to the Marine Biological Laboratory at Woods Hole, Mass., where the researcher could work with giant-squid axons that are many times larger than those found in the human nervous system. By squeezing out the contents of the squid axons they were able to painstakingly identify and reassemble the pieces of the cellular transportation system.
“It’s a tribute to human creativity that one can actually probe the natural world at these levels,” Dr. Vale said.
Their initial breakthrough discoveries came in 1983-84, but it would take another 15 years of work before Dr. Vale pinned down precisely how the tiny walkers perform their task and how the transport system, when disrupted, can be linked to certain forms of neurodegenerative disease.
“It’s been my observation that if you make a fundamental discovery there will be practical applications. In this case there’s no question that’s true,” said Randy Schekman, a Nobel Prize-winning researcher at the University of California, Berkeley, who is on the Gairdner Foundation’s medical advisory board.
The same sentiment applies to the work of Timothy Springer, a professor at Harvard University medical school. A gifted researcher, Dr. Springer became disillusioned as an undergraduate in the 1960s because of the use of scientifically developed chemicals such as Agent Orange and napalm during the Vietnam War. But after a period of volunteer work, he decided to return to his studies, earning a PhD and eventually landing at Harvard in 1977.
Tim Springer
It was then that Dr. Springer began making key discoveries about the mechanisms cells deploy to securely latch onto neighbouring cells or to brace themselves against their surroundings so that they can shift location. This ability is particularly important for immune cells, which must leave the blood stream and penetrate into infected tissue in order to do their work. Dr. Springer showed how the molecules involved in the latching operate, and found drugs that can selectively disable them in cases where the immune system is overactive, such as in inflammatory bowel disease.
“Scientists can be like Columbus discovering a new world,” Dr. Springer said. “I very often feel that, if I was born in a different era, I would have wanted to be an explorer. But instead of exploring the Earth I’m exploring the inner workings of cells.”
Each Gairdner Award winner will receive a $100,000 cash prize. In the weeks leading up to the award ceremony this fall, winners will also be sent across Canada to speak to students about their work as a way to inspire the next generation of biomedical researchers. – Ivan Semeniuk
Canada Gairdner Wightman Award
A stem-cell trailblazer and mentor
Connie Eaves
In 1961, when Connie Eaves was one of only 10 female students in a pre-med class of 100 at Queen’s University in Kingston, she knew that being a woman meant having to be better than everyone else simply to be considered for an academic opportunity.
“For me, that wasn’t a big deal," said Dr. Eaves, the daughter of a mathematician and a schoolteacher whose four children all became professors or doctors. “We were brought up to adhere to the principle of always being the best we could, no matter what we did.”
The drive to succeed and to make discoveries led her to England’s University of Manchester, where she found an ideal role model: Alma Howard, a Montreal-born scientist who was known for her work on the biological effects of radiation and who had risen to a position of leadership at one of the most prominent cancer laboratories in the U.K. It was also her entry into an exciting new field in which researchers were striving to understand how blood cells develop from less specialized precursors known as stem cells. After earning her PhD, Dr. Eaves moved to the Ontario Cancer Institute, where she was a postdoctoral researcher with stem-cell pioneers James Till and Ernest McCulloch.
Back in Canada, she found a research community that had not yet learned to accept female researchers as equal the way she had seen in Manchester. “I was just floored," Dr. Eaves said. “It became clear that a future career in science for me in Canada was going to be an extra challenge.”
But the research was exciting, and in 1973 it led to an appointment in Vancouver with the British Columbia Cancer Agency and the University of British Columbia. She was joined there by her husband, physician-scientist Allen Eaves, and together the two collaborated to build a research powerhouse on Canada’s West Coast that would eventually become the Terry Fox Laboratory and also spawn Stemcell Technologies Inc., the largest biotech company in Canada.
Throughout this time, Dr. Eaves’s research led to key discoveries in blood stem cells, including the development of a technique for separating cancerous from normal blood stem cells in patients with chronic myeloid leukemia. She later moved into breast cancer and was among the first, in parallel with an Australian team, to demonstrate the existence of mammary-gland stem cells in mice, before moving on to study the equivalent cells in humans. The finding, published in 2006, set the stage for thinking about how an entire tissue could be generated from a single cell other than in blood. More recently, her team has been perturbing the genes of normal stem cells to reproduce and study the transition to cancerous growth.
Along the way, Dr. Eaves has mentored more than 100 graduate student and postdoctoral researchers, many of them women, creating a growing worldwide network of scientists working in related areas of stem-cell and cancer biology. Her focus on developing a research community and her determined advocacy for women in science are included in her citation for the Canada Gairdner Wightman Award, which recognizes both scientific excellence and extraordinary leadership in Canadian health research.
“Critical mass is essential in science, and Connie created that when she went out to Vancouver,” said Alan Bernstein, president of the Canadian Institute for Advanced Research and a former Wightman Award winner. “She is a true builder.”
Dr. Eaves said that the challenges and rewards of a life in research helped underscore for her the importance of opening doors for all those who have the motivation and the ability to contribute to scientific breakthroughs.
“I was extremely lucky … in the people that I met and the opportunities I was given,” Dr. Eaves said. “That is not true for everyone.” – Ivan Semeniuk
John Dirks Canada Gairdner Global Health Award
Mental health for all
Vikram Patel
When Vikram Patel was a medical student, he says he was drawn to psychiatry “because it was the only field of medicine that was interested in the whole person as opposed to simply where it hurts.”
It is fitting, then, that the groundbreaking research he’s done on mental health has, in a very real way, improved the lives of millions of people in the developing world.
Dr. Patel is the 2019 recipient of the prestigious John Dirks Canada Gairdner Global Health Award, which recognizes “his world-leading research in global mental health, providing greater knowledge on the burden and the determinants of mental disorders in low- and middle-income countries and pioneering approach for the treatment of mental health in low-resource settings.”
Dr. Patel, a professor of global health at Harvard University, said, modestly, that his greatest achievement is “having generated knowledge to change hearts and minds about the importance of mental health everywhere in the world.”
But what he did, over more than two decades, is debunk the commonly held belief that mental illness was a Western phenomenon, and that poor people had more important things to worry about than their mental health, such as poverty, malaria and AIDS.
“It’s a Faustian bargain to say people shouldn’t get mental-health care because they’re in a socially or medically difficult situation. Mental illness can devastate lives as surely as any other condition,” Dr. Patel says.
His research demonstrated not only that mental illness is as common in low- and middle-income countries as in high-income ones, but showed how care could be delivered effectively and cheaply, in even the most challenging circumstances. For example, his research demonstrated the benefits of lay health counsellors being trained to offer brief psychological treatments for depression and anxiety in clinics, and task-sharing to support caregivers of people with dementia, interventions that have been adopted in more than 60 countries.
Dr. Patel said receiving the Gairdner Award, the pre-eminent prize in global health, is flattering and humbling but, more importantly, it sends the message that mental health is being taken seriously in international health circles.
He noted that, early in his career, his research plans were often greeted with mockery and skepticism but he was lucky to have a few mentors and funders who took “enormous gambles” on him, including the Wellcome Trust in the U.K. and Grand Challenges Canada. – André Picard
Illustrations by Murat Yükselir