For those who follow this blog, you will no doubt know that we are great supporters of the work of Drs. Jim Till and Ernest McCulloch. So, we were thrilled to learn earlier this month that the “fathers of stem cell science” will be honoured today with an induction into the Canadian Science and Engineering Hall of Fame.
Recently, Dr. Ron Worton, an esteemed stem cell researcher in his own right and a former student of Till and McCulloch, provided us with an eloquent summary of that initial discovery. Here is an excerpt:
From the beginning of their collaboration, McCulloch and Till were interested in studying how the cells in bone marrow were capable of dividing and differentiating to form all the various cell types found in blood. At the time, it was known that the failure of bone marrow to produce blood cells was one of the main causes of radiation sickness in people who had received large doses of radiation (e.g. atomic bomb survivors). Animal experiments conducted to that point had determined that fresh (unirradiated) bone marrow cells transplanted into irradiated animals could prevent their radiation sickness. The supposition was that the fresh bone marrow cells allowed a new blood-forming system to regenerate. Till and McCulloch set out to discover how many and what type of cells were required to create this new blood-forming system. They set up initial experiments in which a graded number of mouse bone marrow cells were injected into the tail veins of irradiated mice – the aim was to determine how many transplanted cells were required to ensure the mouse’s survival.
On examination of the irradiated and transplanted mice, Till and McCulloch discovered bumps on the surface of the spleen in numbers that were directly proportional to the number of injected cells (Till and McCulloch, 1961). They were not the first to have seen such nodules, however, the explanation given in past experiments was that the nodules were local areas of regeneration – there had not been much thought as to how such regenerative foci came into being. McCulloch and Till, however, considered two possibilities. The first, simplest explanation was local entrapment in the spleen of many different regenerating cell types and this was supported by the fact that when they studied the cells in the nodules under a microscope, they found red blood cells as well as all types of white blood cells, as though many types of regenerating cells had been sequestered at the site.
They also considered anther more interesting explanation – that the nodules were created by a single cell coming to rest at the site, then diving many times to form a localized colony of cells. What they had in mind was that a nodule might be the result of a single “stem cell” with two properties: (i) cell division to make more copies of itself (i.e. self renewal), and (ii) differentiation into more specialized cells found in the blood stream.
This intrigued both scientists because it was known that mature, fully differentiated blood cells had a finite life span and therefore needed to be constantly renewed. But those fully differentiated cells are not able to divide: they must be renewed by differentiation of a more primitive or precursor blood cell that is still capable of cell division. The idea of a stem cell capable of dividing and differentiating into all the different types of blood cells had been the subject of some speculation, but there was no evidence to support this idea.
Till and McCulloch realized that spleen nodules could be key to proving the existence of stem cells. The first requirement was to prove that a nodule was indeed a colony of cells all derived from a single cell – the putative stem cell. The proof was elegant – they spent months creating bone marrow cells containing unique genetic “markers” (each marked cell had a different marker), and following transplant of these cells they were able to show that in each nodule in the recipient mouse spleen all cells in the nodule carried the same unique marker. This proved that all cells in the nodule were derived from the same precursor cell, and since each nodule contained red blood cells as well as many different forms of white blood cells it was clear that the colony-forming cell could differentiate into all or most blood cell types (Becker et al, 1963).
To test for self renewal – the other property ascribed to stem cells, they tested each spleen colony to see if it contained any cells capable of forming another spleen colony upon further transplantation. This was the unequivocal result and the conclusion was clear – spleen colonies were the result of stem cell proliferation and differentiation, and the spleen colony method was an assay for blood-forming stem cells (Siminovitch et al, 1963). They had proven the existence of stem cells and unleashed a new branch of science.
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