Nature trapped by flawed and fraud STAP cell papers

Nature trapped by flawed and fraud STAP cell papers

The following is an Open Letter that I sent to Nature on March 20th, 2014.  Its main content still remains valuable because Nature is still trapped by STAP cell papers even though it was forced to make some retractions.  Nature needs to open its review files on the STAP cell papers to clear its responsibility for promoting some pseudo-science.

Getting out of the STAP’s trap: an open letter to Nature

March 20th, 2014

Dear Nature Editor-in-Chief Dr. Campbell,

I am very sad that Nature is now trapped into a big mess formed by its high-profile publication of stimulus-triggered acquisition of pluripotency (STAP) cells.  I knew this so-called great discovery is a huge hype immediately after I scanned the “twin” research papers and the “duel” news articles on it.  Thus I post a blog article on the very same day Nature published these papers.  I also wished to write a Communication Arising to Nature but did not finish it because my frustration with repeated rejections by Nature on my many solid criticisms against Nature’s flawed publications.

However, if Nature was willing to listen to my points of views, my Communication Arising would be look like this at its beginning (copied from an earlier draft):

Earlier this year Nature published twin papers 1 describing a so-called breakthrough in stem cell research: a simple acid bath will create stem cells 2 with unchained potency 3. However, many attempts to replicate this stimulus-triggered acquisition of pluripotency (STAP) have been failed 4 and the twin papers are even under fire 5 with investigation 6 going on for some data problems 7. The provision of some essential technical tips for generating STAP cells 8 may help overcoming some replicating difficulties. But our analysis on the original papers and the subsequent tips suggests that the general claim of obtaining STAP cells with unchained potency from any tissues through a simple acid bath maybe a mere hype in nature.

Certainly Nature would be very unhappy to see my characterization of its cherished discovery as “a mere hype”.  But I am afraid my characterization would be too “mild” this time because the so-called discovery may even be proved as a major fraud.  Thus, I had asked Nature to retract these STAP papers in my another blog article before a coauthor of the papers expressed this desire.

In order for Nature to come out of this STAP mess “clean” I suggest Nature to investigate its publication process of these problematic papers.  Nature should open its reviewing process and all review comments to public so that scientific community as a whole can learn a serious lesson from this tragic incidence.

Many criticisms on the STAP papers have focused on image manipulation and text plagiarism in the publications of the leading author of the STAP papers.  I would direct your attention to some other problems.  These other problems may add more suspicions to the validity of the discoveries made by the leading researcher on the STAP cells.

On February 21st 2014 I performed a Pubmed search for papers containing author “Obokata, H.”.  I found following 9 publications matching the searching criterion:

  1. Obokata H, Sasai Y, Niwa H, Kadota M, Andrabi M, Takata N, et al. Bidirectional developmental potential in reprogrammed cells with acquired pluripotency. Nature. 2014;505(7485):676-80. Epub 2014/01/31.
  2. Obokata H, Wakayama T, Sasai Y, Kojima K, Vacanti MP, Niwa H, et al. Stimulus-triggered fate conversion of somatic cells into pluripotency. Nature. 2014;505(7485):641-7. Epub 2014/01/31.
  3. Wakayama S, Kohda T, Obokata H, Tokoro M, Li C, Terashita Y, et al. Successful serial recloning in the mouse over multiple generations. Cell stem cell. 2013;12(3):293-7. Epub 2013/03/12.
  4. Canseco JA, Kojima K, Penvose AR, Ross JD, Obokata H, Gomoll AH, et al. Effect on ligament marker expression by direct-contact co-culture of mesenchymal stem cells and anterior cruciate ligament cells. Tissue engineering Part A. 2012;18(23-24):2549-58. Epub 2012/07/12.
  5. Obokata H, Yamato M, Tsuneda S, Okano T. Reproducible subcutaneous transplantation of cell sheets into recipient mice. Nature protocols. 2011;6(7):1053-9. Epub 2011/07/02.
  6. Pirraco RP, Obokata H, Iwata T, Marques AP, Tsuneda S, Yamato M, et al. Development of osteogenic cell sheets for bone tissue engineering applications. Tissue engineering Part A. 2011;17(11-12):1507-15. Epub 2011/02/01.
  7. Obokata H, Kojima K, Westerman K, Yamato M, Okano T, Tsuneda S, et al. The potential of stem cells in adult tissues representative of the three germ layers. Tissue engineering Part A. 2011;17(5-6):607-15. Epub 2010/10/05.
  8. Aoi Y, Kinoshita T, Hata T, Ohta H, Obokata H, Tsuneda S. Hollow-fiber membrane chamber as a device for in situ environmental cultivation. Applied and environmental microbiology. 2009;75(11):3826-33. Epub 2009/03/31.
  9. Obokata H, Yamato M, Yang J, Nishida K, Tsuneda S, Okano T. Subcutaneous transplantation of autologous oral mucosal epithelial cell sheets fabricated on temperature-responsive culture dishes. Journal of biomedical materials research Part A. 2008;86(4):1088-96. Epub 2007/12/15.

Among these 9 papers Obokata played a leading role (as the first author) in 5 papers.  Thus, Obokata is indeed an inexperienced researcher and her short research experience is limited to the technical level of cultivating cell sheets.

Reading Obokata’s earlier publications it seems she had a tendency to over-emphasize her “success” and over-look her failure.  For example, she have described her “success” of cultivating and transplanting cell sheets even though these cell sheets were rejected at the end.  If I were Obokata I would not publish several “succesful” cultivation papers on fabricating cell sheets if I knew the transplantations of these cell sheets all ended with complete degeneration.

Another thing that struked me is a total lack of correct understnading to some scientific methodologies she have used.  For example, in a paper published in Applied and Environmental Microbiology (75:3826-33, 2009), it was repeated in many places that inoculations were made to give 0.1 to 0.5 cell per chamber, or 0.1 to 0.3 cell per chamber.  Using the exact words as shown in the paper (p3832 left column), “The microbial cells were inoculated with 0.1 to 0.5 cell per chamber in this experiment”. I had done many years of microbiological research.  I knew I could not grow a microbial culture from 0.1 to 0.5 cell per chamber because I simply could not inoculate a fraction of a cell.

Apparently, Obokata has not been strictly trained and lacks a comprehensive knowledge.  Thus, it is not surprise she could make some “amazing” discovery.  But the problem with the publication of the STAP papers is that the papers should have been strictly peer-reviewed and rigorously edited.  Then how could such as “simple” method not be easiloy replicated?

In my opinion, Nature has been carried away with its “success” of hyping on iPS cells.  But if Nature had accepted my solid criticism on Yamanaka’s unproven claim Nature might have avoid this even more streched claim.

Interestingly, dispite both STAP research papers may be retracted, one statement in the STAP cell article remains valid: “no study so far has proven that such pluripotent cells can arise from differentiated somatic cells”.  Even though Yamanaka was awarded a Nobel Prize for “the discovery that mature cells can be reprogrammed to become pluripotent”, his response to my Communication Arising to Nature (rejected by Nature but published in Logical Biology) should reflect the truth which is (in his words): “We have never claimed that we generated iPS cells from terminally differentiated cells”.

So what about the repeated hyping on reprograming mature somatic cells into embryonic stem cell-like pluripotent stem cells?  It is really a joke because embryonic stem cells are alive even in mature body and adult stem cells exist in many places in various tissues.  These cells can be selected out even without reprogramming.  But these cells can be changed with reprogramming and can even be changed into cancer cells by iPS reprogramming.

It is a high time for Nature to seriously think the risk of continuing a strong belief in cell DIVISION-based biology and the reward of embrasing a solid discovery on cell REPRODUCTION life science.  No cell can be DIVIDED to live and even “self-renew”.  All cells can REPRODUCE and become older.  This fundamental difference in the basic understanding of cell life may explain why CNS have kept publishing many flawed and even fraud papers while Logical Biology has no need to retract any of its publications.

By the way, I knew that you have received my recent two letters asking you to write to the non-responding “corresponding” authors of two other Nature papers to submit their data for my independent analysis.  I wish you could quickly do that so that some other mistakes promoted by Nature should not remain in nature for too long.


Shi V. Liu MD PhD

Eagle Institute of Molecular Medicine

Apex, NC, USA