Ernest McCulloch Cell Biology

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.

"I learned enough about myself to settle on a career in medicine: I did not like discipline - therefore I wanted to work for myself - to be my own boss."

The Story

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.

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.

After these 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.

 

As A Young Scientist...

 Born in an affluent neighborhood of Toronto, on Warren Road south of St. Clair Avenue, Ernest “Bun” McCulloch was raised well, with a private school education at Upper Canada College and summers at the cottage in the country. Given the nickname “Bun” by his grandmother, the name stuck with him for his entire life. McCulloch was educated as a medical doctor at the University of Toronto, graduating with an MD in 1948, then going on to the Lister Institute in London, England, where he had his first experience with scientific research.

“Bun” returned to Canada in 1949 where he interned at the Toronto General Hospital, specializing in internal medicine. His medical career began at the Sunnybrook Hospital in Toronto where he became an assistant resident and a research fellow in pathology at the Banting Institute. In 1954, McCulloch joined the University of Toronto as a teacher in the Department of Medicine. His next move, taking on the Head of Hematology in the Biology Division at the Ontario Cancer Institute in 1957, would result in his most famous work. He became part of a team of new promising young cancer researchers in the newly founded Department of Medical Biophysics, McCulloch quickly partnered up with James Till to study the effects of radiation on mouse bone marrow cells. The pair 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.

Ernest McCulloch was a man of incredible personality and charm. He was extremely well read and enjoyed discussing a wide variety of poetry, classical literature and theatre with his colleagues. He is known for his long-lasting impact on the Canadian medical research community. A list of the notable scientists mentored by Till and McCulloch is a who’s who of Canadian medical scientists, including (but not limited to): former president of the Canadian Institute for Health Research, Alan Bernstein; the discoverer of the T-cell receptor, Tak Mak, and a world leader in the field of hematopoietic stem cell biology, Connie Eaves. 

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 Jim Till, 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 within 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 in the future.

by Ben Paylor

The Person

Birthdate
April 26, 1926
Birthplace
Toronto, Ontario
Date of Death
January 20, 2011
Family Members
  • Ona McCulloch – Wife
  • Tot Johnston – Sister
  • James McCulloch - Son
  • Michael McCulloch - Son
  • Robert McCulloch - Son
  • Cecilia MacIntyre - Daughter
  • Paul McCulloch – Son
  • Kim McCulloch – Daughter-in-law
  • Nancy McCulloch – Daughter-in-law
  • Douglas MacIntyre – Son-in-law
  • Alex McCulloch – Grand-son
  • Sam McCulloch – Grand-son
  • Kate McCulloch – Grand-daughter
  • Steve McCulloch – Grand-son
  • Beth MacIntyre – Grand-daughter
  • Hugh MacIntyre – Grand-son
Personality
Extroverted, Witty, Charming, Passionate, Dreamer, Bold, Sharp
Other Interests
“Words” - Poetry, Classical literature, Plays, Biographies, Cinema, Film
Title
University Professor Emeritus
Status
Deceased
Degrees
  • Medical Doctorate – University of Toronto 1948
Awards
  • 1969 - Gairdner Foundation International Award
  • 1974 – Fellow of the Royal Society of Canada
  • 1988 – Officer of the Order of Canada
  • 1991 - Thomas W. Eadie Medal, Royal Society of Canada
  • 1999 – Fellow of the Royal Society of London
  • 2004 – Inducted into the Canadian Medical Hall of Fame
  • 2005 - Albert Lasker Award for Basic Medical Research with colleague Dr. James Till
  • 2005 - Centenary Medal, Royal Society of Canada
  • 2006 - Made a member of Order of Ontario
  • 2010 - Inducted into the Canadian Science and Engineering Hall of Fame
Mentor
Arthur Ham Louis Siminovitch, a molecular biologist, about how to be an effective mentor
Last Updated
October 28, 2013
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