Logical Biology 8 (1):13-15, 2008

OPEN LETTER

http://im1.biz

 

© Truthfinding Cyberpress

FACTS AND DECEPTIONS ON IPS CELLS

 

Can Yamanaka Explain His Contradictory Statements?

 

Shi V. Liu

 

Eagle Institute of Molecular Medicine

Apex, NC 27502, USA

 

Corresponding with SVL@logibio.com

 

(Received 2008-02-04; final revision 2008-02-7; accepted 2008-02-13; published 2008-02-13*)

 

HIGHLIGHT

 

Yamanaka’s iPS cells are now all over the stem cell research communities and even become well known in public societies.  However, how much truth is contained in the high-profile publications on iPS cells in the “top” journals.  Can Yamanaka explain some of the obvious contradictions contained in his publications?

 

ABSTRACT

 

Yamanaka has claimed that he invented a reprogramming protocol which can induce any normal skin cells into pluripotent stem cells which are indistinguishable from embryonic stem cells.  He also claimed that his new-generation iPS cells are now made without causing cancers.  However, how many of these widely accepted claims are true?  Why it is so often to see different things described in the text than in the abstract of Yamanaka’s publications?  Does Yamanaka really do not know what perceived by public from his publications is actually different from what his observations?  Why did Yamanaka change his response to a criticism submitted to Nature? Why did Yamanaka refuse to make any public comments on numerous PUBLISHED scientific criticisms on his flawed publications?

 

KEY WORDS

 

Yamanaka, iPS cells, Stem cell, Induction, Deception, Reprogramming, Distortion, Criticism, Suppression

 

Sir – I am fed up with the continued hype on iPS cells when there is not a single piece of convincing evidence supporting the claim of inducing pluripotent stem cells from normal (differentiated) skin cells and there are plenty of solid evidence to object the claim that iPS cells are indistinguishable from embryonic stem (ES) cells (see many published criticism collectively listed at http://im1.biz/Cloning.htm).

I am also very disappointed with the reluctance of stem cell experts to publicly comment on my published denouncement against iPS cells, especially after being urged by open invitations posted in various popular websites such as Nature News and Scientific American.

In addition, I simply do not understand why, as the corresponding authors, Yamanaka, Jaenisch, Thomson/Yu, and Daley, would totally ignore the request of an open-review scientific journal, Logical Biology (http://im1.biz), to submit their rebuttal against PUBLISHED criticism on their PUBLICATIONS.

It is also amazing that objective scientific criticisms on published iPS cell research were not only rejected by some “top” journals but also totally ignored by them.  Comparing with the lightning fast publication of iPS cell studies, some of my criticisms have been “under consideration” for over two months but still no decision has been made.  Cell even totally ignored my submissions entirely without giving a simple reply, despite my repeated inquiries and even complaints 1.

In frustration with this unscientific and unfair treatment of different views on iPS cells, I have resorted to blogging in various mass media websites.  My publications on misrepresentation in iPS cell reports in my own blog (http://blog.sina.com.cn/im1) have attracted over 316,000 visits and thousands of comments.  Many people have expressed strong anger towards the ignorance of western “scientific” journals over the suspicions and criticisms on the various unbelievable claims made in the high-profile “top” journal publications on iPS cells.

Compared with this allowance of true freedom in expression, Nature has enforced some censorship on my expression by repeatedly “hiding” some of my comments.

In one removed comment, I quoted a reply from Yamanaka which clearly admitted that he did not claim induction of pluripotent stem cells from terminally differentiated cells and showed complete agreement with my suggestion that some control experiments need to be done.  Nature stated that “[T]o quote from a private email to yourself may breach copyright; as such we must remove this post.”

However, I must point out that Yamanaka’s email to me is not any “private” email.  It is a formal response to my scientific criticism and was submitted to me as part of the required component for a Communications Arising to be published in Nature.  Although Nature later declined its publication, that does not change Yamanaka’s reply to my public criticism into any “private” communication.  I have only public scientific dispute but not any personal relationship with him!

Worried about the warning by Nature, I consulted a copyright attorney.  He showed me the following legal regulations on the fair use of even some copyrighted materials:

“A fair use is any copying of copyrighted material done for a limited and "transformative" purpose such as to comment upon, criticize or parody a copyrighted work. Such uses can be done without permission from the copyright owner.”

“The underlying rationale of this rule is that the public benefits from your review, which is enhanced by including some of the copyrighted material.”

With this legal protection on my side, I now wish to quote some of Yamanaka’s direct communications to me as part of the revelation of some contradictory statements made by Yamanaka in his “high-profile” publications on iPS cells.

1.        Yamanaka stated “[W]e have never claimed that we generated iPS cells from terminally differentiated cells” in his initial formal response to my criticism and then stated “the manuscripts have indeed convincingly demonstrated the induction of cellular pluripotency” when he was asked by Nature to re-respond to my same criticism?

2.        Yamanaka stated “[M]ice derived from iPS cells that had not been transduced with the Myc retrovirus showed a significantly reduced incidence of tumorigenicity” in the text but then stated “[M]ice derived from Myc- iPS cells did not develop tumors during the study period” in the abstract of the SAME report in Nature Biotechnol. 2.

3.        Yamanaka stated “iPS cells were not identical to ES cells, as shown by the global gene-expression patterns and DNA methylation status” in his 2006 Cell paper 3.  However, he not only endorsed the view that iPS cells are “indistinguishable” from embryonic stem (ES) cells” 4 but also stated later that “[M]ouse iPS cells are indistinguishable from embryonic stem (ES) cells man many respects” 2.

4.        Yamanaka summarized his “reprogramming” iPS cells as induction of iPS cells from somatic cells requiring transformation by the two tumor-associated gene products, c-Myc and Klf4 and the presence of Oct3/4 and Sox2 directing the cell fate toward ES-like cells rather than tumor cells 5.  He even emphasized that “[T]he balance between c-Myc and KLF4 might be a critical for transformation in iPS cells” and a reason for the low “induction” efficiency 6.  However, his own later study showed that Myc is not required  2.  Others’ recent studies showed that both Myc and KLF4 are not required for “inducing” iPS cells 7 and even Oct4 may not be necessary because it is not required for stem cell “self-renewal” 8.  But did Yamanaka retract his “reprogramming” scheme?

5.        Yamanaka agreed with me on some critical control experiments that I suggested to him as “important to examine this possibility” [of isolating pre-existing stem cells as the “generated” iPS cells].  However, why he still has not done these “important” control experiments?

Yamanaka knew from the very beginning that the summarization of his research as “Takahashi and Yamanaka have successfully reprogrammed terminally differentiated cells to a pluripotent state” 9 is not true.  However, has he done any thing to correct this mischaracterization?  Now, a cloning authority even stated that “Yamanaka and colleagues have recently achieved remarkable success in deriving ES cells directly from adult fibroblasts 10.  Did he offer any correction?

Does Yamanaka really do not know the difference between his observations and his reports and others’ summarizations?  Or is he actually enjoying the benefit of riding on misrepresentation and even distortion?

Due to the high-profile “top” journal publication and mass media hyping, Yamanaka’s iPS cell research has become a national project 11.  Rumors even say that his seismic shift on stem cell research 12 will win a Nobel Prize 13.

But before Yamanaka making further research “progress”, he needs to take a short pause to publicly answer my criticisms on various deceptions buried in many of his “landmark” publications.

 

References

 

1.     Liu, S. V. Induction of pluripotency: Where is the evidence? An open letter to Cell and Yamanaka. Top Watch 2 (2007).

2.    Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnol. 26, 101-106 (2008).

3.    Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-76 (2006).

4.     Wernig, M. et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318-24 (2007).

5.     Yamanaka, S. Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell 1, 39-49 (2007).

6.     Yamanaka, S. Induction of pluripotent stem cells from mouse fibroblasts by four transcription factors. Cell Proliferation 41, 51-56 (2008).

7.     Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920 (2007).

8.     Lengner, C. et al. Oct4 expression is not required for mouse somatic stem cell self-renewal. Cell Stem Cell 1, 403-415 (2007).

9.     Rodolfa, K. T. & Eggan, K. A transcriptional logic for nuclear reprogramming. Cell 126, 652-5 (2006).

10.   Gurdon, J. Primate therapeutic cloninng in practice. Nature Biotechnol. 26, 64-65 (2008).

11.   Cyranoski, D. Stem cells: a national project. Nature 451, 229 (2008).

12.   Holden, C. & Vogel, G. Cell biology. A seismic shift for stem cell research. Science 319, 560-3 (2008).

13.   Normile, D. Shinya Yamanaka: Modest researcher, results to brag about. Science 319, 562 (2008).

 

*      This paper was submitted to Nature on Feb. 5, 2008 and re-submitted with correct style of references on Fb. 7, 2008.  It was rejected by Nature on Feb. 13, 2008 due to “space limitation”.  The publication here is the same as submitted to Nature except for the added highlight, abstract and keywords.

**   This publication is sent to Yamanaka for a public comment.  The editor of Logical Biology promised to publish whatever he will write in his submission.

*** This publication is also sent to Nature as a record.

 

Appendix

 

Cover letter for submission to Nature

 

Dear Nature Editors:

I am submitting a Manuscript entitled "Can Yamanaka explain his contradictory statements?" to be published in Nature as a Correspondence or other suitable format.  I wish that Nature will live up to its scientific responsibility to objectively assess my submission and give it a responsible treatment. 

 

Sincerely,

 

Shi V. Liu MD PhD 

2008-02-05