Who discovered stem cells & when? Some fun science history

Who discovered stem cells? It goes back further than you might think.

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

In theory yes. However, after research including this in Cell Stem Cell, I believe that no one group discovered stem cells. Also, if you ask the related question, “when were stem cells discovered?” this gets complicated and interesting too.

The “discovery” of stem cells was an ongoing team effort over many decades and there is much credit to go around. The goal of today’s post is to discuss who discovered stem cells and the most interesting science history here.

Pioneers Till and McCulloch

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. They did pioneering studies in hematopoietic stem cell research. In Canada, Till and McCulloch are the world’s discoverers of stem cells. Period. No ambiguity. That’s the stem cell discovery history.

But is that correct?

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 makes me come to this conclusion that they did not definitively discover stem cells?

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

Clonal assay

In 1963, Till and McCulloch published their high impact paper on hematopoietic stem cells in Nature: Cytological 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.” It was a well-established concept and nomenclature by that time in the hematology field.

OK, so that was 1963.

Earlier on, who discovered stem cells?

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. This was 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. Many 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. In contrast, 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 during the field’s history.

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.

Florence Sabin and stem cells

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. Ancient history?

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

Key Sabin paper

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. So if we ask again, “Who discovered stem cells?” could the answer be Florence Sabin? If we ask, “When were stem cells discovered?” do we now have an answer?

Nope.

Let’s go further back.

Pappenheim and Maximov

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.

As 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.

Who discovered stem cells? August Weismann?

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.

Scientific credit conundrums

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.

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.

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.