Conducted a series of experiments that would eventually result in the first proof of the existence of stem cells, a discovery that would revolutionize our understanding of human biology and disease.
"When I started to do research, I was surprised that one could be paid for doing something that I would have been willing to do for nothing, if I had some other way to support myself."
On an ordinary Sunday more than half a century ago, so ordinary a day that its exact date would later be forgotten, a young faculty member at the Ontario Cancer Institute in Toronto went to work to perform a routine check on his experimental animals. Many years later, he only remembered that it was a cold day, perhaps in the autumn. Navigating his way through quiet streets, Dr. Ernest McCulloch arrived at the Institute and entered the building. After donning his lab coat, McCulloch went to the animal quarters and checked his experimental mice. McCulloch followed a routine process for obtaining samples of their blood-forming tissues, a process which he had done many times before. His goal, working with his research partner James Till, was to determine if, by irradiating mouse bone marrow cells before transplanting them into irradiated mice, changes might later be found in the kinds of cells responsible for blood formation. It was a routine collection of samples on an ordinary day, noteworthy only because it was a Sunday.
After the samples were processed McCulloch, ever the sharp-eyed observer, noticed the unexpected presence of several small rounded bumps on the spleens of mice that had received bone marrow cells, and he decided to count them. He found that the number of nodules on each spleen was directly related to the number of bone marrow cells the mouse had received.
Suddenly things got very exciting for this unlikely duo of researchers. McCulloch was short, a medical doctor, raised in affluent downtown Toronto, with a penchant for classical literature, cinema and poetry. Till, on the other hand, was tall and athletic, a straight-shooting biophysicist who grew up on the Canadian Prairies and loved the sport of curling.
After many breakthroughs in the 1960s, the pair continued to work together in the field of experimental hematology for the next two decades. Although they continued to make more discoveries, it was those first findings that caused a huge impact on biology today by demonstrating the presence of stem cells. The field of stem cell biology has expanded dramatically and is now on the verge of a potential revolution in how we understand health and treat disease.
James Till was born on the Saskatchewan side but raised on the Alberta side of the rural and provincial border town of Lloydminster on August 25th, 1931. The life of a farmer was a different one in these times, with combines (giant grain harvesting machines) only coming into common practice during his teenage years. Till has childhood memories of manual labor stretching from five in the morning until nine in the evening, during harvest time. He remembers clearly the introduction of combines on the farm, and the ease they brought with them. Till was offered a small scholarship to enroll in an undergraduate program at the University of Saskatchewan, and he took it, thus starting his scientific career. Staying in Saskatoon to complete a Masters degree in Physics under the supervision of Harold Johns, a scientist who had pioneered the Cobalt bomb radiation treatment, Till’s unwavering attention to detail was only further honed. His analytical and rigorous nature helped him secure a fellowship from the National Cancer Institute of Canada, granting him the ability to pursue further post-graduate studies and embark on a PhD in Biophysics at Yale University, a world famous Ivy League school in the United States.
Having long since been earmarked as a student with incredible potential, Till was offered an assistant professor position to stay on at Yale following the competition of his PhD in 1957. His desire to return to Canada trumped this prestigious offer however, and Till eventually found himself in Toronto with a position in the Physics Division at the newly constructed Ontario Cancer Institute (OCI).
Neither Till nor McCulloch remember their first meeting, but do recall that a mutual interest in each others work grew through a series of informal scientific meetings hosted in the basement of the house of Arthur Ham, then head of the Biological Research Division at the OCI. Their collaboration formally began in 1958 when McCulloch wanted to begin performing experiments on irradiating mice, experiments that required the use of radiation and a physicist with the know how to do so.
Never straying from his rural roots, Till was known to frequently visit his family’s farm in Lloydminster and help with the harvest there each fall. His honest and hardworking upbringing are strongly reflected in his analytical way of thinking, often described as both cautious and highly logical. The places where he lived have had their impact on him, with a lifelong passion for curling acquired during his school years in Lloydminster. This passion even overflowed into his academic life in a 1967 investigation examining the effect of sweeping on the path of a curling stone.
McCulloch and Till’s work resulted in almost every top honor in science, except for the Noble Prize. Widely expected to be a joint winner of this top prize in science with Ernest McCulloch, sadly McCulloch passed away in 2011 preventing him from receiving this distinction. Till and McCulloch’s legacy in Canadian biomedical research cannot be understated, with their foundational work in establishing the presence of stem cells in bone marrow and prolific scientific mentorship. With two recent Nobel prizes, 2007 and 2012, going to stem cell researchers who worked on embryonic stem cells and induced pluripotent stem cells, respectively, it is still expected by many scientists that Till’s seminal experiments on adult stem cells will garner him the Nobel prize some day.
by Ben Paylor
Although it had long been postulated that a single type of cell—a so-called stem cell— could give rise to multiple different cell types, no definitive evidence proved that they existed. The potential of such a “stem cell”, if discovered, would be dramatic, because its ability to regenerate different human body tissues could be used to treat all sorts of diseases. Following this cold, ordinary yet ultimately incredibly exciting day, McCulloch and Till went on to perform a series of seminal experiments in the 1960s that proved, for the first time, the existence of stem cells detected by their “spleen colony formation” assays.
The initial discovery of a direct relationship between the number of colonies and the number of transplanted cells suggested that single rare cells were able to initiate these colonies, but the suggestion required further validation. They knew that they were onto something very interesting, because they found that the colonies contained a variety of precursors of mature blood cell types—red cells, white cells and platelets—the normal cellular components of blood. These foundational observations were published in the specialty journal “Radiation Research” in 1961 under the un-dramatic title “A Direct Measurement of Radiation Sensitivity of Normal Bone Marrow Cells”. The paper did not use the words ”stem cell”, because Till and McCulloch, being rigorous scientists, required stronger evidence before making such a bold interpretation of their findings. Hence, their paper went unnoticed by the general biology community.
Their next paper, published in Nature in 1963, changed this and really brought Till and McCulloch to the forefront of hematological biology —the study of blood. Till’s PhD student Andy Becker found a way to trace the source of the cells in the spleen colonies to demonstrate that they originated from individual cells (not clusters of cells) in the bone marrow and could generate three types of progenitors required to make blood. The paper, titled “Cytological Demonstration of the Clonal Nature of Spleen Colonies Derived from Transplanted Mouse Marrow Cells”, still did not use the word “stem cell” as this was not the nature of these exacting scientists, who demanded that any degree of doubt be extinguished before making such claims.
McCulloch and Till went on to publish a number of subsequent papers, which have now been cited thousands of times, unequivocally demonstrating the presence of special cells within the bone marrow. They, with colleague Louis Siminovitch, offered the first biological definition of stem cells, which included two key characteristics: 1) self renewal – to be a stem cell, a cell must be able to give rise to new copies of itself; 2) differentiation – stem cells are able to divide and generate more mature cells that, following subsequent divisions, are eventually able to generate the highly specialized and functional cells essential for complex multi-cellular organisms work. An example of this can be seen in the hematopoietic (e.g. blood forming) stem cells they described, with a single undifferentiated stem cell being able to eventually form all the different types of cells that comprise our blood.
If you think you're interested in science, get research experience as soon as you can. You'll find out whether you like it or not, and you'll find out whether you're good at it or not. My first mentor in science was Harold Johns, who I had as a first year physics teacher. In those days, students that did well academically got invited to serve as summer students. I got invited to do physics research by a student of Harold's and I thought the science was interesting. It was challenging science that involved a fair amount of math and also related to practical matters that I thought were important. After one good experience, it turned out I wasn't too bad at it either.