Who really discovered stem cells? The history you need to know

Who really discovered stem cells?

Is it even possible that one scientific team all by themselves discovered something so ubiquitous as stem cells?

In theory “yes”, but after much historical research including this great historical article in Cell Stem Cell, I would argue that no one group really discovered stem cells.

Instead I believe the “discovery” of stem cells was an ongoing team effort over a period of many decades and there is much credit to go around.

Who gets the credit now according to most people now for “discovering” stem cells?

Canada rightly takes pride in the work of their scientists Drs. James Till and Ernset McCulloch, who did pioneering studies in hematopoietic stem cell research.

In Canada, Till and McCulloch are unambiguously called the world’s discoverers of stem cells. Period. No ambiguity.

But is that correct?

Nope.

Based on the answers that I found, I believe that Till and McCulloch did not discover stem cells.

But what they did do–publish the first clonal colony formation assay indicating multipotency–deserves great credit.

What information in the history of the stem cell research field makes me come to this conclusion that they did not discover stem cells?

Let’s start with the most widely acclaimed “discoverers” as a reference point.

In 1963, Till and McCulloch published their high impact paper on hematopoietic stem cells in NatureCytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells.

You can read the full paper here (pdf). I found it fascinating.

Here is the first paragraph:

IN normal mouse hæmatopoietic tissue, there is a class of cells which, on being transplanted into heavily irradiated mice, can proliferate and form macroscopic colonies. In the spleen, the colonies formed in this manner are discrete and easy to count1,2. Microscopically, each colony appears as a cluster of hæmatopoiotic cells, many of which are dividing; and often, within a given colony, the cells which are observed indicate that differentiation is occurring along three lines, into cells of the erythrocytic, granulocytic and megakaryocytic series, respectively1.

I find it very curiously puzzling that Till and McCulloch did not employ the name “stem cells” since it was a well-established concept and nomenclature by that time in the hematology field.

OK, so that was 1963.

What, if anything, preceded Till and McCulloch’s work?

Importantly, substantial research on stem cells had occurred years and even decades before Till and McCulloch’s paper.

We cannot ignore that.

A simple Pubmed search shows that the first paper with the phrase “stem cell” in the title was published 17 years earlier by MS Arrick in 1946, entitled “Stem cell lymphoma of the newborn”.

In fact there were a large number of publications before Till and McCulloch’s 1963 paper that presented research focused solely on stem cells and even used the phrase “stem cell” in the title. What some might say distinguishes Till and McCulloch’s paper specifically from these others is that it is on normal hematopoietic stem cells, while these other preceding papers were on stem cells from hematopoietic tumors.

But were there other earlier papers focused on normal hematopoietic stem cells?

Yes, in fact, many.

Another simple Pubmed search shows that the first paper with the phrase “stem cell” in the title or abstract was published in 1932, 31 years before Till and McCulloch’s paper.

This 1932 paper, entitled, THE PRODUCTION OF OSTEOGENIC SARCOMATA AND THE EFFECTS ON LYMPH NODES AND BONE MARROW OF INTRAVENOUS INJECTIONS OF RADIUM CHLORIDE AND MESOTHORIUM IN RABBITS, had as first author the great Dr. Florence Sabin. The abstract clearly and unambiguously indicates that their data support the notion that hematopoietic stem cells exist and are damaged by radiation.

Sabin writes in the first part of the abstract (emphasis mine):

The observations in this work suggest that with certain doses of radioactive material, the fundamental damage in the lymphoid tissues is to the stem cell and that the damage is to the chromatin of the nuclei of these cells. The erythroid tissues are apparently less susceptible to radioactive material than the lymphoid tissues but an original anemia of secondary type from peripheral destruction may eventually be changed to one of primary type through decreased maturation of primitive cells in the marrow. The damage of lymph nodes and bone marrow leads to atrophy of these organs….

OK, in normal non-scientific English, what does this mean?

Sabin and company (1) identify normal stem cells in the marrow, (2) indicate that radiation damages the chromatin of the stem cells, and (3) conclude that impaired differentiation of the stem cells contributes to anemia. Bottom line = there are undifferentiated hematopoietic stem cells in the marrow and they are functional.

Keep in mind this is in 1932, 80 years ago.

Ernest McCulloch was a 6 year old at that time and James Till was just a 1 year old.

Interestingly, this entire 1932 paper is available through PMC here as a PDF if you’d like to read it. It is fascinating to see what a 1932 paper is like and this paper is quite compelling. The authors write about stem cells in an authoritative way with no indications that stem cells are theoretical or somehow controversial as to their existence.

Perhaps one could argue that 31 years later Till and McCulloch showed more precisely in a novel way that hematopoietic stem cells have a multi-potent function, but that is not the same thing as discovering them.

A 1936 article, again with the first author Dr. Sabin (you can read it here via PDF), makes the following intriguing statements (again, emphasis is mine):

The second question at issue in hematology concerns the nature of the stem cell. It is accepted that there is a common stem cell for all the white blood cells. The only question at issue is whether this stem cell is identical with the lymphocyte or is a less differentiated type. It is clear that the stem cell is the lymphoidocyte of Pappenheim (22), or the lymphoid hemoblast of Jordan and Johnson (18). We have presented evidence for the theory that this cell, though it looks much like the small lymphocyte, lacks certain signs of differentiation

We’ve got stem cells. However, importantly Sabin also gives major credit to three scientists who came before her,  placing her work in the appropriate scientific context. I really appreciate the fact that she did this. If one looks for the Pappenheim and Jordan & Johnson papers that Sabin cited we find they were published earlier and in fact Pappenheim’s work was published in 1917-1918.

stem cell mapAs early as 1905, again sourced from the Cell Stem Cell article, Pappenheim produced a diagram (above) of stem cell fate (much like we see in text books today) that seems amazingly prescient. In the very middle is the multipotent stem cell.

Thus, more than 100 years ago scientists presented evidence that stem cells existed, were germinal in nature, and were undifferentiated.

Overall, I agree that the earlier work was neither as elegant nor quite as compelling a that of Till and McCulloch. However, isn’t it also true in all fields that the older studies may seem somewhat clunky compared to new studies with newer technology? But I don’t think that should be held against the older studies.

In 1908, a Russian histologist Alexander Maksimov (Maximow), Александр Максимов,  coined the phrase (as indicated in this modern era article that you can read here) “stem cell” as part of his model of hematopoiesis.

Even earlier than 1908 others conceived of the notion of single primitive cells producing tumors or organs including Rudolf Virchow and others.

Going further back, August Weismann discussed stem cells using the term “germ plasm” in 1885.

The historical Cell Stem Cell article says:

“Inspired by Weismann’s theory, Theodor Boveri and Valentin Hacker set out to identify the earliest germ cells in animal embryos”

That article also points out that it is notable that the word “Stammzelle”, in other words “stem cell”, appeared as early as 1868 in work by Ernst Haeckel.

As much as it is crucial not to conflate the concept of stem cells with research supporting or demonstrating their existence, it is abundantly clear that not only the concept of stem cells, but also much research on stem cells happened decades before Tell and McCulloch were on this Earth. 

Further, I find it very puzzling that Till and McCulloch’s key paper that is mentioned as reporting their discovery of stem cells, only cited 10 total papers, 3 of which were their own and they did not cite any of the papers I’ve discussed above. They also did not cite the work of Nobel Laureate E. Donnall Thomas of the Fred Hutchinson Cancer Research Center, who in the 1950s worked on bone marrow transplantation. Thomas’ research strongly supported the existence of hematopoietic stem cells as well. Thomas and his team discovered through work in dogs that there were specific cells in bone marrow that could restore hematopoiesis after lethal irradiation. For example, you can read the full 1957 article by Thomas, et al. in the NEJM here which clearly indicates the existence of special primitive bone marrow cells (aka “stem cells”) that can restore hematopoiesis.

It is notable that now the University of Minnesota claims credit for the discovery of bone marrow transplantation by Robert A. Good in 1968, but that work came a full decade after Thomas’ pioneering work.

There is a temptation in science to attribute the discovery of something on the one hand to groups that came earlier because they predated others. On the other hand there is a temptation to give credit to newer groups because their work may be technically more sophisticated. We see scientists and the media falling into both of these traps.

Just in the last couple weeks, this happened in the transdifferentiation field.

Marius Wernig has been a pioneer in this area and over the last several years has produced a variety of somatic cells from other somatic cells such as neurons as well as neural stem and progenitors from skin cells. However, now we see headlines blaring “Somatic stem cells obtained form skin cells for the first time” based on the work of a team led by Hans Schöler of Germany. No matter how exciting this study is (and it is very exciting) it is incorrect to say “first time”. In fact, in 2011, Wernig published a paper in PNAS showing his lab could make neural stem/progenitor cells from fibroblasts.

Clearly scientists, states, universities, and even whole countries want credit for scientific discoveries.

However, we as a society and particularly those of us who are scientists need to give credit where it is due and not re-write scientific history. We also need to avoid the “discovery” trap.

For example with stem cells, Till and McCulloch deserve great credit for their work even if, arguably, they did not alone discover stem cells because their work was inspired and supported by the work of countless others who came decades before them. Still what they did was extraordinary.

If we ignore scientific history, then we do a serious disservice to scientists who came before us and on whose shoulders we are standing. In the stem cell field there are many pioneers so let’s give credit where credit is due even if it means there was no single team that did all the discovering. Let’s celebrate them all including Till and McCulloch.

8 thoughts on “Who really discovered stem cells? The history you need to know


  1. Along with Sabin’s work, Ray Owen’s 1945 paper in Science “Immunogenetic consequences of vascular anastomoses between cattle twins” was another important step in early HSC research. Using the fact that twin adult cattle shared mixed blood types, Ray Own posited that cells of an embryonic origin upstream of mature erythrocytes must exist and be shared.


  2. I think Jim Till would be the first to point out that he and Ernest McCulloch were building on the work of many others, as you rightly point out in this article, and that their main contribution was to define the properties of stem cells (as having self-renewal capability as well as the capacity to give rise to specialized cells). The term “discovery” is not one they would have chosen to describe their work, yet it has been given to them for the very reasons you mention here – a desire to have scientific heros, to claim “firsts”, and our (and the media’s) preference for absolutes.

    Among Till and McCulloch’s own work, even the 1963 Nature paper can be questioned as the “discovery” paper. In Canada, it is their 1961 Radiation Research paper that is identified as the landmark paper. If anything, this further underlines your point that all work is inspired and supported by that which has come before it. Of course, it doesn’t make it any less important.


  3. I have always thought that the key advance of the Till and McCulloch Radiation Res paper as describing an method to quantify stem cells. That whole concept drove the field forward and provided the rich background for the in vitro clonogenic assays that led to discovery of many growth factors and cytokines.

    The hematopoietic stem cell discoveries were the result of many years of radiation biology following the second world war. Leon Jacobson from the University of Chicago demonstrated that mice given a lethal dose of total body irradiation but with their spleen shielded survived the radiation dose [Jacobson, L. O., E. K. Marks, et al. (1949). “The effect of spleen protection on mortality following X-irradiation.” Journal of Laboratory and Clinical Medicine 34: 1538-1543; Jacobson, L. O., E. K. Marks, et al. (1949). “The role of the spleen in radiation injury.” Proceedings of the Society for Experimental Biology and Medicine 70: 740-742]. The question became is it a cell or a factor. The fact it was a cell that could rescue irradiated mice was demonstrated in 1956 by Barnes and Loutit [Ford, C. E., J. L. Hamerton, et al. (1956). “Cytological identification of radiation-chimaeras.” Nature 177: 452-454].

    The “firsts” question reminds me of something that happened with work I was involved in. The “first” published paper on purification of mouse hematopoietic stem cells was in 1984 [Ford, C. E., J. L. Hamerton, et al. (1956). “Cytological identification of radiation-chimaeras.” Nature 177: 452-454]. This was followed 4 years later by a paper from Weissman’s group claiming to be first [Spangrude, G. J., S. Heimfeld, et al. (1988). “Purification and Characterization of mouse hematopoietic stem cells.” Science 241: 58-62]. This paper did not even cite the previous work causing some well know people, including Norman Iscove to write letters to the editor. The whole story was described in Discover Magazine [http://discovermagazine.com/1995/mar/themotherofallbl477].


  4. This is very insightful discussion. The discovery can happen once whereas there is always room for improvements.


  5. A few years ago I wrote my MA dissertation on Till & McCulloch’s work and how it affected the conceptualisation of ‘the stem cell’.
    My current research is a larger project on a history of embryonic stem cell research (http://www.dur.ac.uk/wolfson.institute/featuredresearchprojects/historicizingstemcells/), which we (myself and Prof A-H Maehle) started immediately after completion of my MA.
    If anyone is interested in our research, feel free to get in touch.

  6. Pingback: Get your germplasm! | Knoepfler Lab Stem Cell Blog

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