UNEXPECTED RESULTS CAN happen at any level of research, says James Till (BA’52, MA’54), and “it’s how they’re dealt with that matters.”
Till knows of what he speaks; it was almost 60 years ago that the renowned University of Saskatchewan graduate, along with a colleague, found something unexpected in research results that simply could not be ignored.
Although they did not know it at the time, the two scientists were on the path to discovering stem cells and the great potential they hold for treating everything from blindness to spinal cord injuries.
The discovery was not a eureka moment, Till says, “but our reactions were the same. We both thought, ‘That’s really interesting.’ ”
Till was a researcher at the Ontario Cancer Institute in 1960 when he and his colleague, Ernest McCulloch, spotted an anomaly during a study they were conducting into the effects of radiation on mice.
The mice were irradiated with enough X-rays to kill them within 30 days if they did not receive a transplant of bone marrow cells. The mice were also injected with a varying number of cells in order for the researchers to determine how many cells it would take to keep the animals alive.
On a Sunday morning, several days after injecting the cells, McCulloch examined samples taken from the mice. The hematologist noticed small lumps on the spleens of the mice, one lump for every 10,000 injected bone marrow cells.
“Dr. McCulloch’s observation that the number of clumps, which we both thought of as colonies, was linearly related to the number of transplanted marrow cells suggested that the colonies might be clones—that they derived from single cells,” says Till.
“We weren’t sure what track we were on, but we quickly agreed on what we would do next. We needed more evidence that the colonies were clones.”
Till and McCulloch published their initial observation in 1961 in the journal Radiation Research to little fanfare, and then dedicated themselves to confirming their suspicion. Their work was also aided by graduate student Andy Becker and senior scientist Lou Siminovitch, with Becker’s experiments demonstrating “quite convincingly that the colonies were clones,” says Till.
Those results were published in Nature in 1963.
At the same time, Siminovitch, a molecular biologist and Till’s mentor for his postdoctoral work, was the lead investigator for studies “that revealed the cells that gave rise to colonies had, among their descendants, cells that could themselves give rise to new colonies. So, colony-forming cells could self-renew.”
Siminovitch’s work, also published in 1963, combined with the previous findings, “convinced us that we had blood-forming stem cells. Before then, we only referred to them as colony-forming units—CFUs—because we weren’t sure what we were dealing with.”
That ability to self-renew, says Till, “seemed to us to be one crucial defining property of stem cells,” and it is the definition of stem cells that is still in use today.
“It took us three years to establish that we were, indeed, dealing with something of considerable significance,” he says.
Till and McCulloch’s work formed the basis for all stem cell research going on today, and paved the way for advances such as bone marrow transplants to treat cancer. It also opened the door to the field of regenerative medicine—in which scientists seek ways to regrow, repair or replace damaged or diseased cells, use therapeutic stem cells and even produce artificial organs.
The discovery was not the first time an unforeseen event had changed the course of Till’s life and career. Raised on a farm near Lloydminster, Till was nearing the end of high school when he found himself wavering between attending the University of Alberta in Edmonton, like a couple of his classmates, or pursuing his post-secondary studies across the border in Saskatchewan. He says it was the unexpected arrival of an entrance scholarship from the U of S that helped him make up his mind.
Turning points and epiphanies
Piya Chattopadhyay (BA’95)—globetrotting reporter and host of CBC Radio’s Out in the Open—remembers the day she decided to become a journalist. The political studies major says she was in Place Riel talking to someone “terribly interesting” when she realized her favourite thing to do was have conversations with fascinating people about their lives and the world we live in. Asking herself, “How do I turn this into a job?” she walked outside to the Bowl and sat down to think. “And then it dawned on me,” she recalls.
One mystery hovered over Department of Geological Sciences Professor Brian Pratt for much of his career. On a hike near the Alberta-Montana border as a young geologist, he came across rock structures patterned with bizarre crumpled veins. He later learned that the origin of these structures had baffled scientists for a century. Pratt brooded over the puzzle for the next 15 years until one evening, during a quiet drive, he says he had a true “eureka moment”: the structures must have formed when water was shaken out of sea floor mud. “Basically, it’s a seismograph,” Pratt says—a record of an ancient earthquake frozen in stone.
During the Arab Spring in 2011, Ahmed Abdelmoamen (PhD’17) was among thousands of protesters shouting slogans and defending Tahrir Square in Cairo, Egypt. “However, it was challenging for me to know what [was] happening at one side of the square when I [was] at another side,” he says. The experience inspired his later PhD work in the Department of Computer Science at the U of S, where he developed a platform to coordinate the sending and receiving of information between smartphones. His research has applications in everything from conducting instant opinion polls to determining wait times at restaurants.
After performing the first-ever complete human heart valve transplant in 1962, Raymond Heimbecker (BA’44, Cert/Med’45) made a pivot that surprised the surgical world. The future of heart valve surgery was not in humans, he said, but pigs. Pig heart valves were readily available, came in a range of sizes and had no rejection issues in the bodies of human patients. Colleagues were skeptical, but were soon convinced by Heimbecker’s high rates of success. Pig heart valves are still commonly used in transplant surgeries today.
A second serendipitous event, also involving the U of S, set Till on course for what would be an illustrious career in biophysics. This time, it was the offer of a summer studentship working with Harold Johns, a medical physicist who was doing pioneering research in the use of cobalt-60 in radiation therapy to treat cancer.
“I hadn’t applied for the position but I accepted, and that’s where I got my first experience in research. I liked it.”
Till went on to do a PhD in biophysics at Yale before taking up a postdoctoral fellowship at the University of Toronto. It was there he was reunited with Johns, who recruited him to the Ontario Cancer Institute in 1957. Till now holds the distinguished title of professor emeritus at the U of T.
In 1993, Till was awarded the Robert L. Nobel Prize by the National Cancer Institute of Canada and, in 1994, was made an officer of the Order of Canada. In 2004, he and McCulloch were inducted into the Canadian Medical Hall of Fame. The following year, the two received the Albert Lasker Award for Basic Medical Research.
Chance favours the prepared mind
During his career, Till dealt with a number of unusual findings, although none as dramatic as the bone marrow-derived colonies.
“I think that quite a few scientists don’t know what to do with unexpected findings, and I think that two issues are involved,” he says.
“One is their willingness or determination to follow up on unexpected findings. Is it worth the time, effort and resources needed to follow up?
“The other issue is the nature of the available research funding. Is there the kind of flexibility that permits an investigator to make a major change in direction?
“If you do try to explore the basis for the unexpected findings, you might be led in a new direction that’s quite different from the one for which the research funds were awarded. In our case, we weren’t looking for stem cells—but there was flexibility built into the funding, so we could do the fundamental research that was required.”
The Till and McCulloch story represents a case study in the value of fundamental research and serendipity in science. Till is a proponent of increased funding for basic science in Canada, understanding from experience that it is the necessary link between discovery and future developments.
Till is also a strong advocate of the open access movement to get primary research literature into the hands of anyone who wants it. The current publication process can create delays of months or even years before research results are widely available, he says, “which means that scientists can’t build as quickly on each other’s findings.”
He also takes issue with the practice of putting new results behind paywalls, systems that prevent access without a paid subscription. “Open access means anyone—other scientists, bright students, young entrepreneurs, medical practitioners—can follow the current scientific literature without unacceptable costs.”
He points to high-energy physicists as the leaders in open access. That group has used a preprint server to quickly disseminate their research results for some 25 years. “It has been hugely popular and, much more recently, preprint servers have been set up for a range of disciplines, at last.”
Asked where he thinks stem cell research might go in the future, Till says he dislikes making predictions “because major breakthroughs in science involve unexpected findings. You can’t expect the unexpected, but I would say to young researchers that I hope they’re lucky enough to get some truly unexpected results—and, if they do, not to immediately assume that what’s happened is an experiment that didn’t work.”