Ernest McCulloch

Ernest Armstrong McCulloch, OC, OOnt, FRS, FRSC, scientist, physician, researcher, teacher, administrator (born 27 April 1926 in Toronto, ON; died 20 January 2011 in Toronto, ON). McCulloch and James Till conducted pioneering research into stem cells during the 1960s and 1970s that inspired future developments in bone marrow transplants and other medical advances. (See also Stem Cell Research.)

Early Life and Career

Ernest McCulloch was born into a medical family, as his father and two uncles worked as physicians. During his early childhood, and partially because he was not fond of his first name, McCulloch became known as “Bun,” a nickname that stuck throughout the rest of his life. After receiving his MD from the University of Toronto in 1948, McCulloch went to London, England, for a year of research training at the Lister Institute. Upon his return to Toronto, he received clinical training in hematology at Toronto General Hospital and Sunnybrook Hospital. Though he initially maintained a small clinical practice, he was more enthusiastic about scientific research. (See also Medical Research.)

McCulloch joined the University of Toronto’s Faculty of Medicine in 1954. Three years later, he joined the biology division of the Toronto-based Ontario Cancer Institute (OCI) as the head of hematology. His research focused on leukemia and normal blood formation.

Stem Cell Research

Ernest McCulloch and James Till became acquainted at informal meetings held at the home of OCI biology division head Arthur Ham, who believed in encouraging cross-disciplinary work among the institute’s employees. McCulloch was interested in understanding the effect of radiation therapy on mammalian cells and proposed studying mice who had been subjected to lethal amounts of radiation. OCI physics division head Dr. Harold Elford Johns did not allow anyone to use on-site radiation machines without a physicist present. “He wasn’t going to have any damn biologist ruining his reputation by misusing his machines,” McCulloch later recalled during an interview with Joe Sornberger, author of Dreams and Due Diligence (2011). Till, who had reportedly enjoyed McCulloch’s presentations at Ham’s gatherings, volunteered to operate the machinery. McCulloch credited Harold Elford Johns as having brought the two together, believing that the reserved Till’s practical, methodical research style would provide a good contrast to the extroverted McCulloch’s more conceptual and imaginative approach. The level of trust between Till and McCulloch grew quickly. Till later recalled McCulloch saying that “‘If Jim and I disagree, we know that the correct answer is somewhere else.”

Part of the funding for McCulloch and Till’s research came from the Defence Research Board of Canada, which was interested in finding ways to treat radiation exposure in case a nuclear conflict broke out (see Defence Research). Their experiments were conducted on seven groups of 25 mice aged 8–12 weeks. They discovered that the injection of marrow cells into a host exposed to supralethal total body irradiation led to the formation of “colonies of proliferating cells” in their spleens. In 1960, McCulloch discovered lumps of cells on the spleens of the mice and that for roughly every 10,000 injected marrow cells, a nodule (or colony) was found on the spleen. The tests also showed that the longer the mice lived, the more the spleen cell colonies developed the basis of red blood cells, white blood cells and platelets. Subsequent testing showed that the treated cells would self-renew. They initially described the cells they discovered as “colony-forming units,” though the term “stem cell” had been first published by German scientist Ernst Haeckel in 1868. (See also Stem Cell Research.)

The results were submitted to the journal Radiation Research in July 1960 and published as “A Direct Measurement of the Radiation Sensitivity of Normal Mouse Bone Marrow Cells” in the February 1961 edition. “The paper represented an entirely new way of looking at how the body makes blood, not to mention presenting a raft of potential implications for other biological rethinks,” Joe Sornberger observed in his book, Dreams and Due Diligence (2011).

Further research led to two more journal articles published in 1963: “Cytological Demonstration of the Clonal Nature of Spleen Colonies Derived from Transplanted Mouse Marrow Cells” (Nature, 2 February 1963, in collaboration with research assistant Andrew Becker), and “The Distribution of Colony-forming Cells Among Spleen Colonies” (Journal of Cellular and Comparative Physiology, December 1963, co-credited with geneticist Louis Siminovitch). The findings stemming out of these studies showed that stem cells could help develop new bone marrow cells.

Till and McCulloch worked together for about two decades. Their research also led to the discovery that thymus and lymph node cells could be derived from the same clone as colony-forming cells in the hematopoietic system. Similarly, their work led to improvements in the treatment of anemia, leukemia and immunodeficient conditions (see Cancer; Disease.)

Later Work

In 1968, Ernest McCulloch was a co-founder of the Institute of Medical Science at the University of Toronto, which provided research training for clinical scientists. In 1971, he was involved in the establishment of the Princess Margaret Hospital’s bone marrow transplant program. For the rest of his research career, he focused on leukemia, including defining and manipulating the cellular and molecular mechanisms that affected the growth of malignant blast stem cells (immature white blood vessels) drawn from acute myeloblastic leukemia patients (see Cancer).

McCulloch was known for his passion for looking at science from a broader viewpoint. He never allowed visiting lecturers to give slide presentations during lab seminars, preferring to hear their thoughts over data. He encouraged collaborations so that researchers could develop new points of view and he promoted the practice of relating lab findings to clinical issues. McCulloch is also credited for looking for new ideas and methods in scientific research and always seeking the opposite of the obvious answer.

In 2003, McCulloch wrote a history of the OCI, The Ontario Cancer Institute: Successes and Reverses at Sherbourne Street. His death in 2011 occurred less than a month before the University of Toronto and Princess Margaret Hospital had planned an event to mark the 50th anniversary of the publication of Till and McCulloch’s work in Radiation Research. In 2020, Canada Post honoured Till and McCulloch by issuing a stamp as part of a series depicting physicians and researchers.

Legacy

Dr. James Till (left) and Dr. Ernest McCulloch (right) awarded an Honorary Degree from the University of Toronto, 9 June 2004.

Many observers compared the importance of Ernest McCulloch and James Till’s stem cell work to that of James Watson and Francis Crick on DNA during the early 1950s (see Genetics). Joe Sornberger, author of Dreams and Due Diligence (2011), wrote that McCulloch and Till “formed the most important partnership in Canadian medical research since Frederick Banting and Charles Best pooled their talents in the early 1920s and discovered insulin.” (See also The Discovery on Insulin.) McCulloch and Till’s works from the 1960s would be cited in thousands of future papers.

When McCulloch and Till received the Albert Lasker Award for Basic Medical Research in 2005, Till summed up their achievements. “After 40 years, I think it means our work had stood the test of time reasonably well.” Till, however, has speculated that the controversies surrounding stem cell research, ethics and politics delayed recognition of their work.

The legacy of their work was summarized by Evelyn Strauss of the Lasker Foundation in 2005. “They established the properties of stem cells, which still hold true today. Furthermore, they lay the foundation for the isolation of stem cells and for the detection of proteins that help these precursor cells develop and mature. Till and McCulloch’s discoveries explained the basis of bone marrow transplantation, which prolongs the lives of patients with leukemia and other cancers of the blood. Moreover, the team set a new standard of rigor for the field of hematology, transforming it from an observational science to a quantitative experimental discipline.”