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.”

A detailed STAP cell timeline from this blog & elsewhere

Jan 29
Nature publishes STAP papers online
Jan 29Postpub review of papers on ipscell.com
Jan 30First STAP polling starts: respondents mostly positive
Feb 2Surprising interview w/Vacanti: STAP easy to make, same as spore cells
Feb 4First key Pubpeer comment on splicing in Figure 1i
Feb 6Top 5 reasons for doubts on STAP
Feb 7STAP crowdsourcing experiment starts
Feb 13First Pubpeer comment on STAP placenta issue
Feb 13JuuichiJigen first post on STAP problems
Feb 14RIKEN & Nature begin STAP investigations
Feb 27Wakayama interview
Mar 10Wakayama calls for STAP paper retraction
March 13JuuichiJigen post on Obokata Ph.D. thesis problems
March 14RIKEN alleges that Obokata committed misconduct
Mar 24Nature rejects Ken Lee’s STAP paper showing that STAP doesn’t work
Apr 1Vacanti Harvard STAP talk for this fateful day was cancelled
Apr 1RIKEN announces Obokata guilty of misconduct
Apr 9Obokata admits mistakes, but not misconduct
April 25Head of RIKEN STAP investigation committee, Shunsuke Ishi, resigns amid allegations of his own paper problems
May 8F1000 Publishes Lee Lab Paper showing STAP fails
May 27Call for Nature retraction of STAP papers
May 28Obokata OKs letter, but not article retraction
Jun 3Obokata agrees to retract STAP article too
June 12External committee (chaired by Teruo Kishi) issues report calling for zero-based restructuring of Riken Center for Developmental Biology (CDB), the institute with which Obokata, and co-authors Yoshiki Sasai and Hitoshi Niwa are affiliated, and where co-author Teruhiko Wakayama was formerly affiliated
Jun 16Genetics data suggest STAP cells involved mix or switch
July 2STAP Nature papers retracted

Updated: July 8, 2014

What happened during the STAP cell paper mess and when? What were the main events?

Each event listed has a link to a key webpage either on this blog or elsewhere.

Please let me know if you think I should add any other key events, links, etc.

 

Perspectives on STAP cell Nature paper retractions

rp_STAP-cells-300x300.jpgThe Obokata STAP cell papers in Nature were retracted today. It feels like it’s been a long time coming in one way as for months now it has felt like retraction was inevitable, but it’s been extraordinarily fast in another way as retractions almost never happen this fast. It’s a day of mixed feelings.

This is very sad as it affirms some serious problems, but it is also a day for the stem cell field to move on from this mess. It’s sort of like post-STAP day 1. There will of course be many more STAP developments popping up for months or even years as RIKEN still needs to figure out a plan, they are still trying to replicate STAP, we haven’t heard from Harvard/Brigham Women’s, etc. However, it still feels like the STAP cell paper controversy is at least more than half in the rear view mirror after today. Thank goodness. It seems like the right time for more reflection. You can read the retraction notices here that include the two research papers and a News & Views piece about them:

In the STAP research paper retractions, the authors have listed additional problems and errors.
Nature has published an editorial piece on the STAP situation as well that is notable. I’d be curious what people’s reactions are to it. In general my first take on it is that it is a positive step with some openness and reflections on how things can be improved in the future, but it also feels a bit conservative. That’s understandable. Update: After more thought and discussion, I think Nature should have been more open and taken more responsibility in its editorial. It is disappointing. While no reviewer and no journal can always catch certain kinds of misconduct in papers including the STAP ones, there were things about the STAP cell papers that were big red flags. Call me an inherent skeptic, but within a few minutes of first reading the STAP papers I felt something was seriously wrong.
A big hat tip goes to post-publication review and social media for helping move on from STAP. It wasn’t always a pleasant process and was a real roller coaster ride, but it helped greatly to resolve the situation and increased transparency. Without social media, the STAP papers would in all likelihood remain unretracted through 2015. Why does that matter? Beyond damage to the field’s reputation, there are more practical considerations. Millions of dollars in scarce research funds would have been wasted along with potential damage to many young scientists’ careers who might have been directed to work on STAP in labs around the world potentially for years.
Overall, I think the stem cell field dealt with STAP quickly and in an open manner that reflects a dedication to good science. I don’t see any major lasting harm from this and in part that is the case exactly because it was dealt with so directly.

STAP Cell Chatter From ISSCR Meeting

STAP stem cellsWhat were people saying about STAP cells at the ISSCR 2014 meeting?

It was a tale of two meetings when it came to STAP at ISSCR.

Officially, bigwigs at the podiums only briefly mentioned it and they seemed to collectively argue that STAP was something unfortunate, but that the bigger danger was the overreaction to it.

Thus, remarkably their key concern seemed to be their perception of an overreaction to STAP rather than STAP itself.

Outside the lecture halls in the other halls (between rooms of the convention center) and in the restaurants, etc., it was an entirely different story. Amongst the general population of stem cell researchers, the STAP cell situation itself was considered the big deal. Although there was definitely some serious STAP fatigue and I share that, people still were eager to talk about it.

Below is a list of the top points raised by people at the meeting regarding STAP. I’m not endorsing these notions or saying they are right and indeed some may just be gossip, but they are intriguing to think about nonetheless:

  • 1. If the RIKEN Center for Developmental Biology (CDB) is “disbanded”, it will most likely be reconstituted under a new name with mostly the same people. Just wishful thinking?
  • 2. Most of us stem cell folks are opposed to any kind of punitive action taken against the CDB overall. Why punish the whole CDB?
  • 3. Part of the motivation for the intense misguided push initially for STAP cells was due to the STAP folks wanting to compete and “beat” iPS cells. Wildly misguided by those involved?
  • 4. The whole STAP cell fiasco germinated from lack of fundamental knowledge of cell biology with naive misinterpretation of autofluorescence of dead and dying cells and from ignorance of stem cells.
  • 5. STAP cells used in the mouse studies in the Nature letter were most likely actually a combination of ES cells and trophoblastic stem cells.
  • 6. Nature published the STAP papers despite at least some remaining reviewer concerns.
  • 7. RIKEN is having Obokata “help” with the STAP replication efforts so that if/when they fail that should be the final end OR, alternatively and pretty much the opposite, RIKEN/the government are hoping that Obokata can get some vaguely positive results leaving the STAP issue not entirely dead and that the vagueness will keep things uncertain for years.

What are you hearing?

STAP cell top 10 list of predictions

rp_STAP-stem-cells-hope-or-mirage-201x300.pngNow that it appears that the authors have all consented to eventually have both of their STAP cell Nature papers retracted, what’s next for STAP?

Who knows, but below is my attempt at a top 10 list of STAP predictions looking ahead. I hope I’m wrong about several of them.

  • 10. No insight will come from Nature on the STAP review or editorial process and there will be no indication from them that anything went wrong at their level.  I predict the journal will never open up about the editorial and review process behind the STAP debacle. If the papers are finally retracted (keep in mind that they have not yet been actually retracted) by authors as seems most likely at this point, I figure that for Nature that will be the end of the story. I hope I’m wrong.
  • 9. Obokata does not sue RIKEN. She and the institution make a private agreement/settlement (perhaps already a done deal given how things are shaping up with her rejoining the STAP validation team at RIKEN).
  • 8. STAP patent gets approved. Despite all the problems with the STAP scientific story, the US Patent Office approves the STAP cell patent anyway. Crazy, huh?
  • 7. Someone somewhere claims to get STAP to work, but the data are very weak.
  • 6. No news from Brigham and Women’s or Harvard Medical School regarding any potential institutional reactions related to STAP at least until 2015 and perhaps never.
  • 5. At least one person leaves RIKEN related to STAP. This happens either because of their links to STAP or conversely because they find the whole thing too ugly to bear.
  • 4. More retractions or corrections of other papers from at least one or more of the STAP paper authors.
  • 3. More top tier journal stem cell paper problems unrelated to STAP, despite STAP as a potential learning experience. Few lessons will be learned from STAP at the stem cell publication level. One or more likely more stem cell papers in a high-impact, top tier journal will have serious problems (e.g. be retracted, be on a possible path to retraction, have major data manipulation, etc.) in the next 12 months.
  • 2. No convincing reports published in 2014 that STAP cells, as they were portrayed in the Nature articles, really exist.
  • 1. No imminent Obokata departure. Obokata stay at RIKEN at least through the end of 2014. There may even be rumors that she can help the RIKEN team get STAP to work again.