Ernest McCulloch received his MD in 1948 from the University of Toronto. Upon graduation, he began his education in research at the Lister Institute in London, England.
In 1957 he joined the newly formed Ontario Cancer Institute where the majority of his research focused on normal blood-formation and leukaemia. Together with his colleague, Dr. J.E. Till, McCulloch created the first quantitative, clonal method to identify stem cells and used this technique for pioneering studies on stem cells. His experience in hematology, when combined with Till's experience in biophysics, yielded a novel and productive combination of skills and interests.
In the early 1960s, McCulloch and Till started a series of experiments that involved injecting bone marrow cells into irradiated mice. Visible nodules were observed in the spleens of the mice, in proportion to the number of bone marrow cells injected. Till and McCulloch called the nodules 'spleen colonies', and speculated that each nodule arose from a single marrow cell: perhaps a stem cell.
In later work, Till and McCulloch were joined by graduate student Andy Becker, and demonstrated that each nodule did indeed arise from a single cell. They published their results in Nature in 1963. In the same year, in collaboration with Lou Siminovitch, a trailblazing Canadian molecular biologist, they obtained evidence that these cells were capable of self-renewal, a crucial aspect of the functional definition of stem cells that they had formulated.