Are iPS cells really induced by reprogramming from differentiated somatic cells?

by Alexey Bersenev on February 15, 2010 · 1 comment

in under discussion

As a followup from my last post, I got very interesting comment from James Trosko. It was very complex and quite long story about connections between iPS cells, reprogramming, adult stem cells and carcinogenesis. I wanted to make this discussion separate from the post, because so many things touching. Today I have the first guest post on Hematopoiesis.

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this is a guest post by James Trosko

These comments continue to add to the debate on the two hypotheses of the origin of cancers (adult stem cell versus the de-differentiation or “re-programming” of a somatic differentiated cell). Isn’t it interesting that those who claim cancers are the result of the re-programming during the multi-stage, multi-mechanism process of carcinogenesis fail to mention that no one has successfully neoplastically transformed a primary culture of human fibroblasts or epithelial cell, which ,under normal culture conditions, contain few, if any, adult stem cells. However, when “immortalizing viruses” ( SV40 or HPV-e6-e7)are added to early primary cultures, a few “immortalized” , but non-tumorigenic clones, are obtained, which, then, can be subsequently neoplastically transformed.

Might it explained more easily that these viruses entered all cells ( the few adult stem cells; the transit-amplifying and terminally differentiated cells) but only blocked the “mortalization” of the adult stem cells [one does not immortalize an already normal immortal adult stem cell? The fact that only a few such “immortalized” cells are recovered from a primary culture is equivalent to the few rare adult stem cells in the primary culture. Also, the frequency of “iPS” cells is about what one would expect from the number of adult stem cells in a primary culture.

In effect, those who still believe that “iPS” cells are really reprogrammed somatic differentiated fibroblast must believe that carcinogenesis starts with the induction of an “iPS” cell during the single “hit” of the initiation process, such as what happens when the skin is exposed to UV light. Yet those “initiated” skin cells do not form teratomas but, only after chronic exposure to non-mutagenic tumor promoters, such as TPA, does one see papillomas and later , carcinomas.

The real problem is that no one has produced “iPS” cells from differentiated skin keratinocytes or mature hepatocytes, yet our lab has easily produced human breast carcinomas from a normal human breast adult stem cell. Moreover, no one has compared the frequency of “iPS” cells from a primary culture of human cells versus that from a pure culture of human adult stem cells. I find it interesting that almost every day, new ways of producing “reprogramming” cells are reported( i.e., mouse skin cells directly, without the need for vector transmission of embryonic stem cell genes).

Ultimately, while this forum allows for academic freedom of thought in science, the current atmosphere of science, as is evidenced in trying to get grants or papers published, has not allowed easy access to challenge prevailing paradigms. When one views the power of the “iPS” story, via its publications in very influencing scientific journals ( and even the public media), and the absence of any challenge ( not to the reality of the production of the “iPS” but of the interpretation of the origin of these cells), one can see how science and the public are not well served.

In my own case, all my grants have been “trashed” or “triaged” and all of my publication, those that ultimately did get published, were rejected by the same journals that can’t publish the “iPS” stories fast enough.

It seems that science ( peer reviewers of grant proposals and manuscripts), while trying to assure quality, rigorous methodology, and ethical standards, should let the individual with “crazy” ideas or their own unique interpretations of their own data, make a fool” of themselves by allowing them to interpret their own data. In my case, I know I might not be correct…but then again, I’m sitting on my experience (of over 20 years of working with human adult stem cells and 44 years of studying all phases of carcinogenesis). With this experience as my guide to understand the “iPS” interpretation and the “re-programming” of differentiated somatic cells makes no sense to me. It does not help me rationalize all my research experience. If someone can demonstrate to me with new experiments ( not all those published as of yesterday), I will immediately be “converted”. I’m not so stupid as to hold onto a scientific idea that no longer has validity.

If one has not read my ideas , see: Tai, M.H. et. al, “Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis”. Carcinogenesis 20: 495-502, 2005; Trosko, J.E., “Cancer stem cells and cancer nonstem cells: From adult stem cells or reprogramming of differentiated somatic cells”. Vet. Pathol. 46: 176-193, 2009; Trosko, J.E. “Reprogramming or selecting adult stem cells?” Stem Cell Rev.4:81-88, 2008).

{ 1 comment… read it below or add one }

James Peyer February 16, 2010 at 4:24 am

Hi James,

Thanks for the guest post. You make some really good points about the induction of carcinogenesis and the hype about iPS and ESC-like phenotypes of cancer.

You asked if anyone has tried to do iPS from stem cells, so I wanted to point out this paper to you from Nature in October 2009 from Hans Scholer’s group at the Planck Institute [1]. They used NSCs to make iPSCs, and showed that they could get iPSCs with only one or two of the famous 4 factors (just Oct4 or Klf4 or Oct4 alone) and got ES-like cells with all the differentiation potential.

The ease by which adult stem cells can be induced to an immortal pluripotent state supports your hypothesis that cancer arises from progenitor cells, and not fully differentiated somatic cells. For, you could imagine, to achieve an ESC-like state, a differentiated cell might need 4 “hits” and an adult stem cell might only require 2. This difference of 2 hits, looking at it from the perspective of calculating the probability that a population of aspiring tumor cells could achieve the mutations, makes it many orders of magnitude more probable that tumors would arise from adult stem cells, with two fewer evolutionary barriers for the cancer to overcome.

[1]: Direct reprogramming of human neural stem cells by OCT4. Kim JB et al.

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