More about the "discovery" of stem cells

This post isn't specifically about cancer stem cells. It`s a response to a recent tweet and an earlier blog post about stem cells by Paul Knoepfler (@pknoepfler).

Knoepfler, on January 30, 2020, posted an ICYMI (In Case You Missed It) on Twitter. The ICYMI pointed to a blog post of his, dated April 11, 2012, entitled "Who really discovered stem cells? The history you need to know".  In this post he questioned claims made by others that Ernest McCulloch and I discovered stem cells.

I didn't respond to the original 2012 post, and the comments section has now closed. Replies about the ICYMI tweet itself are constrained by Twitter`s limits on character count. Hence this blog-based response.

There were three main reasons why I didn't respond to the original post by Knoepfler in 2012. Firstly, I had no disagreement with most of the historical content of his post (except for some of his comments about our own work). Secondly, Ernest McCulloch wasn't alive (obituary in The Lancet) to contribute to our customary joint response. Thirdly, one major point that I would have made in any response had already been well-expressed by Lisa Willemse (@WillemseLA).

Lisa pointed out, in this excerpt from her comment on the original post by Knoepfler, "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".

Ernest McCulloch was a hematologist. He knew that the concept of stem cells of the blood-forming system had existed in the literature for many years. The concept was so well known that it was included in textbooks for medical students, such as Ham's Histology. A review, in 1954, of the 2nd edition of Arthur Ham's book is available here [click on the PDF icon].

Ernest McCulloch was also aware that many attempts had been made to identify individual stem cells using histological techniques. An example was provided by the work of Clermont and Leblond, such as a paper of theirs published in 1953, "Renewal of spermatogonia in the rat". Ernest believed that such techniques, when applied to the search for stem cells of the blood-forming system, could not yield unequivocal results.

Knoepfer, in his original blog post, noted that he found "it very curiously puzzling that Till and McCulloch did not employ the name “stem cells” ..." in a paper published in Nature [1963(2 Feb); 197(4866): 452-454]. A copy of this paper is openly accessible [click on the PDF icon] via J. Immunol. [2014 Jun 1;192(11):4945-7]. The first author of this paper was the excellent experimentalist Andy Becker (tribute), a medical graduate who had undertaken a Ph.D. program within our research group.

The reason that we didn't use the term "stem cells" in this paper was because we were not yet convinced that the cells we were studying were actually stem cells. It's only after further work, published in a less prominent journal, that we became convinced that we were, indeed, dealing with cells that had the properties expected of stem cells. This paper was entitled The distribution of colony-forming cells among spleen colonies, Journal of Cellular and Comparative Physiology [1963(Dec); 62(3): 327-336], It's openly accessible via the TSpace repository of the University of Toronto Libraries [PDF]. The need for stem cells to be capable of self-renewal as a crucial component of a definition of stem cells was emphasized in this paper.The first author of this paper, and the initiator of the work described in it, was Lou Siminovitch, a valued mentor during the early stages of my research career.

Why has the later (Dec. 1963) paper in the Journal of Cellular and Comparative Physiology received less attention than the earlier (Feb. 1963) paper in Nature? I think it's obvious that Nature's high Journal Impact Factor (JIF) provides a credible basis for the difference.The JIF continues to be used to assess the quality of individual publications, even though it has been questioned whether their use has been good for science. See, for example: The Journal Impact Factor: a brief history, critique, and discussion of adverse effects, arXiv preprint [arXiv:1801.08992, 201, PDF]. It should be noted that Eugene Garfield first mentioned the idea of an impact factor in 1955, but the Science Citation Index was first published in 1961. See: The History and Meaning of the Journal Impact Factor, Garfield E, JAMA, [January 4, 2006—Vol 295, No. 1 (PDF, Reprinted)]. Garfield responded to critics of the JIF in this article. It is noteworthy that our papers were published at a time when the JIF was just beginning to be developed. It didn't have the cachet then that it still does now.

Our early work related to stem cells of the murine blood-forming system was reported in three papers. The first was published in Radiation Research [February 1961, Vol. 14, No. 2, pp. 213-222] and entitled: A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. The full text of this paper is openly accessible [PDF] via the TSpace repository at the University of Toronto Libraries, at: http://hdl.handle.net/1807/2781. The second was the paper in Nature [1963(2 Feb); 197(4866): 452-454] referred to above. The third was the paper in the Journal of Cellular and Comparative Physiology [1963(Dec); 62(3): 327-336] also referred to above. These three papers form a package. As noted above, it was only in the third, in 1963, that we began to use the term "stem cells".

Although I was somewhat taken aback by Paul Knopfler's apparent unawareness of the full package of three papers described above, I laud him for his exemplary accomplishments, especially as a blogger and advocate. In particular, I'd point to his efforts as a voice of caution in relation to unproven stem cell treatments. See, for example: The rise of unproven stem cell therapies turned this obscure scientist into an industry watchdog, by Kelley Servick, Science Aug. 3, 2017.