New Message from Wakayama on STAP retraction & origin of STAP-SC

I have been corresponding now and then with Dr. Teru Wakayama about the ongoing STAP situation. He asked me to pass along the following message from him for clarification on the STAP Nature paper retraction and the origin of the STAP stem cells (STAP-SC).

I would like to take this opportunity to explain the reason for certain differences between the retraction statement in the published paper version of Nature Magazine and the online version of the STAP paper retraction, specifically related to reason No. (5) which was slightly different between the two.

Last month, I reported to the media about the apparent strain difference between mice used in our lab and the STAP cells. Our mouse line uniformly carries identical cag-gfp insertions in chromosome 18, however, STAP-SC appeared to have a different GFP insertion site in chromosome 15. After learning this, I asked for a further analysis to obtain more hints as to the original mouse strain corresponding to STAP-SC. My collaborator found that perhaps the GFP insertion site of STAP-SC was in fact not chromosome 15. However, importantly, the GFP insertion site is absolutely different between our mouse line and STAP-SC. We know this to be the case because we demonstrated that one primer (part of chromosome 18 and cag) only gave a PCR band in our mouse line, but not in the STAP-SC. Thus, the retraction reason of no. (5) is absolutely right. Meanwhile, we are now trying to find the true insertion site of GFP in STAP-SC. Unfortunately, for the paper version of Nature, I could not clarify this point because the deadline had passed. Only the online version could be corrected.

We apologize for any confusion, but in the best interests of science and complete transparency, we wish all of this information to be freely available.

Teru Wakayama

Notes from Paul: I did some minor editing of this text for clarity.

Below is the online retraction statement reason no. (5):

“(5) In the Article, one group of STAP stem cells (STAP-SCs) was reported as being derived from STAP cells induced from spleens of F1 hybrids from the cross of mouse lines carrying identical cag-gfp insertions in chromosome 18 in the background of 129/Sv and B6, respectively, and that they were maintained in the Wakayama laboratory. However, further analysis of the eight STAP-SC lines indicates that, while sharing the same 129×B6 F1 genetic background, they have a different GFP insertion site. Furthermore, while the mice used for STAP cell induction are homozygous for the GFP transgene, the STAP-SCs are heterozygous. The GFP transgene insertion site matches that of the mice and ES cells kept in the Wakayama laboratory. Thus, there are inexplicable discrepancies in genetic background and transgene insertion sites between the donor mice and the reported STAP-SCs.”

Interview with Nature on their editorial process in wake of STAP

NatureI asked Nature a half dozen questions about their editorial process. While they declined to answer any direct questions about the STAP cell paper situation, I thank them for answering these questions via a Nature spokesperson. The end result is an intriguing glimpse inside the editorial/review process at Nature.

1. Does Nature have any kind of automated (or human-based) system for checking submitted or accepted manuscripts for plagiarism? If so, when was this system instituted? If not, why not?

Nature uses plagiarism software (the CrossCheck service which uses the iThenticate software and the CrossRef database) to check all our published papers; however, the software did not detect plagiarism in this particular case. The manufacturers of the software are currently looking into this.

2. Does Nature have any kind of automated (or human-based) system for checking submitted or accepted manuscripts for image manipulation or duplication? If so, when was this system instituted? If not, why not?

Nature Publishing Group utilises tools to do randomised spot check analysis of images but we currently do not have the resources to undertake detailed image analysis on all our papers. For duplications, we do not have resources to check large numbers of figure panels against each other.   However, we are actively reviewing our policy on image checking and have decided to increase the number of checks that we undertake on Nature journal papers.  The exact number or proportion of papers that will be checked in the future is still being decided.

3. Does Nature vet potential reviewers for conflicts of interest (COI) before assigning them to manuscripts or does it rely on the reviewers to self-disclose COIs after they have been invited to be reviewers of specific manuscripts? On this page it suggests that Nature does not itself look for COIs (http://www.nature.com/authors/policies/competing.html), but rather relies on reviewers to self-disclose. What if a reviewer fails to disclose a significant COI?

Editors are well connected within the research communities that they serve and use their judgement not to request reviews from people in the same department or those who co-publish regularly.  However we cannot, of course, know if reviewers are on the same grant or who they may be consulting for, so have to rely on a system where a reviewer will make any potential COI known to us.

4. It’s been brought to my attention that while some Nature Publishing Group journals are signatories to the Committee on Publication Ethics (COPE), Nature Magazine is not. Why would Nature not be part of this group that works to make the publication process as ethical as possible? (see link here: http://publicationethics.org/category/publisher/nature-publishing-group).

Nature editors have engaged with COPE on occasion. However, they and the Chief Editors of the Nature journals have a long history of developing policies collectively for our journals – policies that are more attuned to basic research than is COPE, which has a strong clinical flavour.

5. Would a submitted patent application by an author for the technology described in a manuscript be required by Nature to be disclosed as a competing interest? If authors fail to do so, what is Nature’s policy on what happens as a result? This webpage would seem to clearly indicate that patent applications should be disclosed: http://www.nature.com/authors/policies/competing.html.

The Nature journals require authors to declare to the editors any competing financial interests in relation to the work described. As part of this policy, authors are encouraged to declare patents or patent applications whose value may be affected by publication. However, appreciating how much value can represent a competing interest is a subjective matter, and many authors have patent applications that do not amount to material value. In these cases, the editorial office may feel that the value is not substantive enough to justify declaration of competing interest.

6. Does Nature have a bioethics person on staff or on contract to consult with should ethical dilemmas arise during the review process?

A number of members of staff at Nature have responsibility for considering ethical dilemmas and providing advice during the review process.  We also solicit the advice of experts on subjects such as biowarfare, use of human oocytes, etc, when needed.

TGIF top stem cell headlines of the week: Asterias, lasers, immunity, & more

Laser tooth stem cellsIt’s been an important week for stem cells. Although I’ve been busy working on multiple grants and papers, when I take a break I like to read up on what’s been going on with stem cells.

What are the top stem cell stories and headlines of the week?

CIRM awarded Asterias (a subsidiary of BioTime) $14.3 million to continue clinical research into the use of hESC-derived OPCs for spinal cord injury. This is great news as the work formerly started by Geron lives again and provides real hope.

Lasers, stem cells, and teeth came together in a cool new story that has nothing to do with teeth whitening, but provides promise for tooth repair. In a paper (Arany, et al.) in Science Translational Medicine, a Harvard team showed they could activate stem cells to make dentin, which I believe is even harder than bone and gives teeth their strength. In Figure 1E from the paper above you can see histology showing more dentin in the laser-treated tooth.

Bioscience Technology quoted team leader Dr. David J. Mooney, who is a professor of bioengineering at Harvard School of Engineering and Applied Sciences (SEAS):

“Our treatment modality does not introduce anything new to the body, and lasers are routinely used in medicine and dentistry, so the barriers to clinical translation are low”

Pretty cool.

STAP cell retraction OK’d for one, but not the other Nature paper? Author, Dr. Haruko Obokata, reportedly agreed this week to  retract her STAP cell letter, but not the STAP cell article. You can read more on my take on that here and my editorial the day before calling on Nature to retract both papers.

An interesting twist on iPS cells and immunity. For a long time folks have argued that pluripotent stem cells such as ES cells and iPS cells have a special trait of being immunoprivileged because of their early embryonic-like state. However, the opposite case–that ES and iPS cells are in fact more immunoreactive because they express unique antigens not seen by organisms throughout the rest of life–gained more ground with a new report from Stanford. Krista Conger of SCOPE published on an excellent piece on this new work from the great stem cell researcher, Joseph Wu. The Nature Communications paper (Almelda, et al.) argues that differentiation of iPS cells yields cells that are less immunoreactive. It’s intriguing to think about these different perspectives on stem cells and immunity from a human transplant perspective.

Multiple sources say momentum for STAP paper retraction building in Japan & inside RIKEN

I’m hearing from multiple sources that momentum is building in Japan and even inside RIKEN itself for retraction of the STAP cell papers.

This whole situation is a tragedy on so many levels and has become a no-win situation, but is it so bad at this point that retraction could possibly be the least terrible of the entirely bad array of options?

Why would some folks in Japan and even inside RIKEN think that retraction potentially could be the wisest option?

Some RIKEN scientists may be thinking that it would be dramatically worse for RIKEN if Nature were to go first and editorially retract one or both of the STAP papers. Is it also possible that Brigham & Women’s/Harvard could do a retraction first that in some way might make RIKEN look like the main party responsible? Some are worried about that. It seems the two institutions are largely now on different sides on STAP. A potentially bizarre situation could come to be as well if RIKEN retracts the Nature letter, but the Nature article is not retracted for various reasons including disagreement amongst its authors.

Of course it is difficult to know if retractions by Nature or by Harvard/Brigham & Women’s are at all likely and based on history they may indeed remain unlikely at this time, but it’s a high-risk gamble to count on anything for sure about the frenetic STAP situation at this point.

A RIKEN retraction statement, especially if they pull the trigger in the next few weeks or even sooner, could be short and go something like this: “There are multiple complicated issues here that go well beyond the scope of a relatively short investigation and which cannot be addressed by simple corrections to the papers so at this time what is best for science in Japan and for the stem cell field is to retract the papers. At some future point new papers on STAP stem cells may be submitted once the situation is clearer and if the process has been robustly and independently replicated.”

I personally hope that other labs will replicate STAP cells/STAP-SC at some point, but so much else has gone wrong with this situation that unfortunately even independent STAP replication is not close to a full solution any more. Further, even if STAP replication is in the cards for the future, it may not come for months or even close to a year. In the mean time the situation would continue to develop unpredictably in a risky way. Of course retraction has its own risks too.

In fact, no matter what decisions are made, the risks here are high for all of science in Japan, the journal Nature, and the entire stem cell field as well.