Ernest Armstrong McCulloch (1926–2011)

Ernest Armstrong McCulloch was a medical researcher who studied the biology of blood cells and blood cancer in Toronto, Ontario, in the second half of the twentieth century, and who, with James Till, demonstrated the existence of stem cells in the blood, called hematopoietic stem cells. Stem cells are cells that can develop into more specialized cells in the body. Hematopoietic stem cells, or HSCs, are a type of stem cell that, when present in blood and bone marrow, can develop into specialized blood cells, such as red blood cells, white blood cells, and platelets. Since the start of the twentieth century, researchers hypothesized the existence of something with the self-renewal properties of what were later called stem cells but lacked evidence identifying those stem cells. McCulloch’s work provided the necessary evidence, which laid the foundation for identifying the function of stem cells in other tissues. Through his work leading to the identification of blood stem cells, McCulloch aided the development of treatments for blood cancers, which affect roughly 1.6 million people in the United States.

McCulloch was born on 27 April 1926 in Toronto. McCulloch’s father and uncles were physicians, so he had exposure to the medical field at a young age. His grandfather was a wealthy businessman named James Armstrong. According to an obituary written by Tak Wah Mak, a senior scientist on McCulloch's research team, in Biographical Memoirs of Fellows of the Royal Society, McCulloch’s family was relatively wealthy, and he had a privileged childhood. Throughout his childhood, a chauffeur driver drove McCulloch to school. During McCulloch's early childhood, he received the nickname Bun, partially because he did not like his first name. That nickname stuck with McCulloch throughout his life, and his close friends used that nickname to address him.

McCulloch attended high school at Upper Canada College, or UCC, in Toronto. Mak explains that UCC was a private school where many upper-class individuals sent their children and that McCulloch thrived academically there. McCulloch was also the editor of the UCC school magazine. Outside of the magazine and academics, McCulloch frequently sailed, a skill he learned from spending time as a child at a family estate near Ahmic Lake in Parry Sound District, Ontario. McCulloch did not spend time on other sports besides sailing. In that regard, Mak shares that McCulloch did not relate to his father, who often played sports until he suffered an injury during World War I. McCulloch also frequently spent time walking and thinking in the woods near Ahmic Lake.

After high school, McCulloch attended the University of Toronto in Toronto. According to Mak, McCulloch studied the humanities, especially English literature and poetry. However, despite his interest in the humanities, McCulloch pursued the career of a physician. Mak explains that some of McCulloch’s motivations for pursuing medicine were because his father and uncles were physicians and because McCulloch wanted to be his own boss. McCulloch received his medical degree from the University of Toronto in 1948.

After receiving his medical degree, McCulloch completed a year of research training at the Lister Institute of Preventive Medicine in London, England, where he began his research. There, McCulloch learned how vaccines and antitoxins could treat people. Afterward, McCulloch returned to the University of Toronto to complete clinical training in hematology, which is the study of blood and blood disorders, at Sunnybrook Hospital in Toronto, as well as at Toronto General Hospital in Toronto. While at those hospitals, McCulloch maintained a clinical practice, and he became a teaching faculty member in the Department of Medicine at the University of Toronto. Over the following years, McCulloch concentrated further on his research, and in 1957, he joined the Ontario Cancer Institute, or OCI, in Toronto as the head of hematology. Due to his increasing emphasis on research, McCulloch no longer maintained his clinical practice after joining OCI.

At OCI, McCulloch pursued research on leukemia, specifically using mice to investigate how normal mammalian cells differed from blood cancer cells exposed to radiation. At that time, in the late 1950s, there were heightened global tensions due to the Cold War and growing fear of nuclear war. As a result, many governments were willing to fund research investigating the effects of radiation on humans. McCulloch planned a study that used mice that had received high doses of radiation to gain insight into how human cells might be affected by radiation. Harold Elford Johns, who was the head of the physics division of OCI, did not allow biology researchers to operate the radiation machine without the supervision of a radiation physicist. James Edgar Till, who was a researcher in the physics division of OCI and had trained in radiation physics, offered to help McCulloch with his radiation study using mice. Till and McCulloch had briefly met during OCI meetings, but it was not until that radiation study that the pair got to know each other. According to an article by Jamie Bradburn and Jessica Poulin in The Canadian Encyclopedia, McCulloch believed that his own conceptual approach to research worked well with Till’s practical style of research. The pair received funding from the Defense Research Board of Canada, which sought to find ways to treat the negative consequences of possible radiation exposure due to the Cold War.

One of McCulloch and Till’s first experiments used mice to investigate whether bone marrow cells could regenerate blood cells that radiation had damaged. They transplanted normal mice bone marrow cells into mice that had been exposed to high doses of radiation, to see if those cells were capable of regenerating healthy blood cells. McCulloch and Till found that the survival of the mice depended only on the number of viable cells transplanted into the mice. They concluded that those viable cells were able to regenerate the damaged blood cells. McCulloch and Till next investigated the spleen of the mice that survived the experiment and noticed that small lumps formed on the spleen that consisted of proliferating cells. The spleen is an organ that is sometimes involved in blood cell formation if something damages bone marrow. McCulloch and Till called those lumps spleen colonies and found that the number of colonies that formed on the spleen was directly proportional to the number of bone marrow cells they originally transplanted into the mice.

McCulloch and Till did not yet call those transplanted cells stem cells, although they had the basic concept of what was later called stem cells. According to a profile on McCulloch published in 2006 by Anne Harding in The Lancet, McCulloch and Till believed their experiment might have provided some initial evidence for the existence of stem cells. They still performed additional experiments to further define the properties of those potential stem cells. McCulloch and Till also demonstrated that more spleen colonies formed as the mice survived longer and those spleen cell colonies began to develop other blood cells, such as red blood cells, white blood cells, and platelets.

McCulloch and Till performed further experiments with collaborators to reveal more information about the properties of those spleen colonies. In 1963, in collaboration with Andrew Becker, a graduate student in Till’s laboratory, McCulloch and Till found that one initial cell generated the cells that make up the spleen colony, or one colony-forming unit. That same year, McCulloch and Till collaborated with Louis Siminovitch, a geneticist and senior staff member of OCI, and investigated whether those units possessed the ability to self-renew and differentiate. Self-renewal is the process in which a cell divides to make more copies of itself so the cell can maintain itself over time. Differentiation is a process in which unspecialized cells develop into more specialized ones that perform specific functions. McCulloch, Till, and Siminovitch found that those colony-forming units not only had the ability to proliferate but also self-renew and differentiate into more specialized blood cells, such as red and white blood cells, and platelets. All of those findings led McCulloch and Till to conclude that stem cells played a role in the process of hematopoiesis, or the formation of blood cells.

In 1968, McCulloch, Till, and Siminovitch performed a study focused on the thymus, lymph nodes, and blood cells in the body. The thymus and lymph nodes are structures in the body that are critical for immune function. McCulloch, Till, and Siminovitch found that cells from the thymus, lymph nodes, and normal blood cells formed from hematopoietic stem cells. Later, in 1992, other scientists, such as Irving Weissman, devised methods of isolating those hematopoietic stem cells.

In the 1970s, McCulloch shifted his research to focus on human acute myeloid leukemia, or AML, which is a cancer of the bone marrow and blood. McCulloch and his team proposed a model for the origin of AML. They also investigated how normal cells and blood cancer cells respond to chemotherapy, which is a drug treatment regimen that treats cancer.

Outside his professional and scientific life, McCulloch was married to his wife Ona and had five children. According to Mak, McCulloch’s family frequently spent time at that same family estate on Ahmic Lake that McCulloch went to as a child. McCulloch also taught his children how to swim, sail, canoe, and chop wood for a fire. He frequently took his kids on long walks in the woods, a similar activity to something McCulloch experienced as a child.

McCulloch’s research contributions to stem cells, specifically blood stem cells, laid the groundwork for future research and treatment of blood disorders. McCulloch and Till’s research influenced clinical bone marrow and blood cell transplantation, which are treatments that use blood stem cells to regenerate a harmed blood system in some blood cancer cases.

McCulloch’s work with blood stem cells paved the way for future studies. In 1977, Eugene Goldwasser, a researcher at the University of Chicago in Chicago, Illinois, built on models used in McCulloch and Till’s experiments to isolate erythropoietin, which is a hormone that signals the production of red blood cells. Researchers later developed erythropoietin to use as a treatment in certain cases of anemia. McCulloch and Till’s research also influenced clinical bone marrow and blood cell transplantation. In 1994, John Dick identified the stem cells that initiate cancer in AML. Other studies built off those identified cancer stem cells in other cancers, such as the brain, colon, prostate, and lung cancer. Also, researchers could develop targeted therapy drugs against those stem cells to treat people with cancer since they hypothesize that cancer stem cells drive tumor growth and recurrence.

As a result of his contributions to research, McCulloch received many awards and held multiple roles throughout his career. In 1968, McCulloch co-founded the Institute of Medical Science at the University of Toronto, which provided clinical scientists with opportunities to train in research. Additionally, in 1971, he helped found the bone marrow transplant program at the Princess Margaret Hospital in Toronto. In 1974, McCulloch became a Fellow of the Royal Society of Canada, and in 1999, he became a Fellow of the Royal Society of London. In 2004, McCulloch joined the Canadian Medical Hall of Fame. In 2005, McCulloch, alongside Till, received the Albert Lasker Award for Basic Medical Research (Bradburn & Poulin, 2023 & 2024). Additionally, in 2007, along with John Dick and James Till, McCulloch received the National Cancer Institute of Canada Diamond Jubilee Award. In 2010, McCulloch joined the Canadian Science and Engineering Hall of Fame.

McCulloch died on 20 January 2011 at the age of 84 in Toronto.

Sources

1. Bains, Ajeet, "“Perspectives on the Properties of Stem Cells” (2005), by Ernest McCulloch and James Till". Embryo Project Encyclopedia ( 2020-06-30 ). ISSN: 1940-5030 https://hdl.handle.net/10776/13158 (Accessed May 26, 2025).
2. Bains, Ajeet, "James Edgar Till (1931– )". Embryo Project Encyclopedia ( 2020-11-20 ). ISSN: 1940-5030 https://hdl.handle.net/10776/13189 (Accessed May 26, 2025).
3. Becker, Alexander, Ernest A. McCulloch, and James E. Till, "Cytological Demonstration of the Clonal Nature of Spleen Colonies Derived from Transplanted Mouse Marrow Cells." Nature 197 (1963): 452–4. http://www.jimmunol.org/content/jimmunol/192/11/4945.full.pdf (Accessed May 26, 2025).
4. Bradburn, Jamie, and Jessica Poulin. “Ernest McCulloch” The Canadian Encyclopedia. https://www.thecanadianencyclopedia.ca/en/article/ernest-mcculloch (Accessed May 26, 2025).
5. Canadian Medical Hall of Fame “Ernest McCulloch, MD.” Canadian Medical Hall of Fame. https://www.cdnmedhall.ca/laureates/ernestmcculloch (Accessed May 26, 2025).
6. Harding, Anne. “Ernest McCulloch: Father of Experimental Haematology.” The Lancet 367 (2006): 467. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)68166-X/fulltext (Accessed May 26, 2025).
7. He, Shenghui, Daisuke Nakada, and Sean J. Morrison. “Mechanisms of Stem Cell Self-Renewal.” Annual Review of Cell and Developmental Biology 25 (2009): 377–406 https://web.archive.org/web/20170808220233id_/http://courses.bio.unc.edu/2009Fall/Biol624/Bautchfiles/LectSEVENstem09/pdffiles09/HeMorrisonSTEMrev09.pdf (Accessed May 26, 2025).
8. Ikuta, Koichi, and Irving L. Weissman. “Evidence That Hematopoietic Stem Cells Express Mouse C-Kit but Do Not Depend on Steel Factor for Their Generation.” Proceedings of the National Academy of Sciences of the United States 89 (1992): 1502–6. https://pmc.ncbi.nlm.nih.gov/articles/pmid/1371359/ (Accessed May 26, 2025).
9. Leukemia & Lymphoma Society. “Facts and Statistics Overview.” Leukemia & Lymphoma Society. https://www.lls.org/facts-and-statistics/facts-and-statistics-overview (Accessed May 26, 2025).
10. Mak, Wah Tah. “Ernest Armstrong McCulloch. 21 April 1926—20 January 2011.” Royal Society 64 (2017). https://royalsocietypublishing.org/doi/10.1098/rsbm.2017.0019 (Accessed May 26, 2025).
11. Miyake, Takaji, Charles K. H. Kung, and Eugene Goldwasser. “Purification of Human Erythropoietin.” Journal of Biological Chemistry 252 (1977): 5558–64. https://www.sciencedirect.com/science/article/pii/S0021925819633879 (Accessed May 26, 2025).
12. Steensma, David P., and Robert A. Kyle. “James Till and Ernest McCulloch: Hematopoietic Stem Cell Discoverers.” Stamp Vignette On Medical Science 96 (2021): 830–1. https://www.mayoclinicproceedings.org/article/S0025-6196(21)00063-X/fulltext (Accessed May 26, 2025).
13. Till, James, Ernest A. McCulloch, and Louis Siminovitch "A Stochastic Model of Stem Cell Proliferation, Based on the Growth of Spleen Colony-Forming Cells." Proceedings of the National Academy of Sciences of the United States 54 (1964): 29–36. https://tspace.library.utoronto.ca/bitstream/1807/2777/2/Till_et_al_PNAS_1964_51_29.pdf (Accessed May 26, 2025).
14. Wu, A. M., James E. Till, Louis Siminovitch, and Ernest A. McCulloch. “Cytological Evidence for a Relationship Between Normal Hemotopoietic Colony-Forming Cells and Cells of the Lymphoid System.” Journal of Experimental Medicine 127 (1968): 455–64. https://pmc.ncbi.nlm.nih.gov/articles/pmid/5636553/ (Accessed May 26, 2025).