Perspectives on final RIKEN report on STAP cell scandal & what comes next

STAP cells FigureThe Japanese research institute RIKEN has come full circle in a way on the STAP cell scandal. Note that the STAP papers included not only authors from RIKEN, but also from Brigham and Women’s Hospital/Harvard Medical School.

With its final report released today (also a powerpoint of images were released including the one showing a figure posted here of reportedly made up data published in a STAP paper), RIKEN seems to now have handled this complicated mess in a relatively rigorous, scientific manner that paves the way for moving on from it.

What would you have done in RIKEN’s shoes? It’s not a pleasant thing to contemplate.

As a research institution, what do you do if a potential major scientific scandal is cropping up under your roof? It’s unpredictable and dangerous and couldn’t have come at a worse time for RIKEN. So how do you handle it? What would you have done?

RIKEN was faced with this kind of unpleasant reality early this year. A very high moment for RIKEN with the publication of two seemingly groundbreaking Nature papers including numerous RIKEN authors quickly headed the other direction and began unraveling.

By February, only weeks after the STAP cell papers were published supposedly reporting the creation of power stem cells called “STAP cells”, there were signs that the research was plagued with profound problems including signs of potential misconduct.

At that point in February and March, what should the leaders at RIKEN do/have done? I’m sure they were asking themselves this tough question.

There have been ups and downs as to how RIKEN has handled STAP, but in the new report there are indications of a sober, objective and more thorough approach to STAP. I think this is a positive, constructive step even if the conclusions are negative and sad.

Dennis Normile has a nice summary over at Science News of the RIKEN report:

“The committee determined that 3 supposed STAP stem cell lines were actually likely to be 3 previously existing embryonic stem (ES) cell lines. “It is unlikely that there was accidental contamination by three different ES cells, and it is suspected that the contamination may have occurred artificially…”

This new RIKEN report on STAP has concluded that what were claimed to be STAP cells were almost certainly embryonic stem cells (ESCs) instead. It cannot be sure if the ESCs were intentionally and fraudulently used, but it says that is probable. If it was done on purpose RIKEN also cannot be sure who did it.

The report concludes that STAP first author Haruko Obokata, who RIKEN earlier had determined committed certain STAP-related misconduct, committed additional misconduct over certain data, but the report also lays some of the blame for STAP to lack of proper supervision by senior STAP authors Yoshiki Sasai, Teruhiko Wakayama, and Hitoshi Niwa. One remaining thing we do not know is what this report means for Wakayama or Niwa, the latter still being at RIKEN.

So what does all of this mean and where do things go from here?

While there is still some more to resolve on the Japan side of STAP, my impression is that this report along with Obokata’s resignation allows for RIKEN to really begin to move on from STAP.

Normile’s article concludes pointing towards where the STAP-related focus may turn next:

One of the papers’ co-authors has been beyond the reach of RIKEN investigators: Charles Vacanti, a tissue engineer at Brigham and Women’s Hospital in Boston, an affiliate of Harvard Medical School. Obokata initiated her work on STAP cells while a post-doc in Vacanti’s lab. Mutsuhiro Arinobu, a RIKEN executive director, said that although they have been in contact with Harvard, input from Vacanti “is not included in this investigation.”

Harvard and Brigham and Women’s Hospital may or may not be conducting STAP investigations of their own. However, certainly at this point relatively speaking key unanswered questions remain on the Harvard side of STAP.

Newly Update Comprehensive STAP Cell Timeline with Key Events & Links

Here is an updated timeline for the major events (and links) for the STAP fiasco. If you think absolutely critical events are missing, let me know in the comments and I’ll consider adding them.

Jan 29Nature 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 12Committee calls for restructuring of Riken CDB
Jun 16Genetics data suggest STAP cells involved mix or switch
July 2STAP Nature papers retracted
Aug 5Yoshiki Sasai, commits suicide
Sept 3Vacanti & Kojima reaffirm absolute confidence in STAP but issue new STAP protocol
Dec 19Obokata and Niwa fail in STAP final replication effort
Dec 20Obokata resigns from RIKEN
Sept 23, 2015Nature publishes refutations of STAP
Jan 28, 2016Obokata book claims she was framed for STAP

STAP Voted as the Stem Cell Story of the Year for 2014

Stem Cell Story of 2014When I asked the readers of this blog what they felt was the biggest stem cell story of 2014 in a poll, they overwhelmingly picked the STAP cell scandal.

For background on STAP you can toggle through the many STAP cell pieces on this blog here, see a STAP timeline, and a STAP image gallery.

Basically, STAP was a bogus scientific claim about a supposedly simple reprogramming method to make powerful stem cells induced by cellular stress.

Despite many flaws in this STAP research and the fact that it seemed way too good to be true, STAP was published in two Nature papers that came out toward the end of January 2014 that are now retracted.

The STAP mess was the product of many things going wrong, almost a perfect storm of research missteps and some have said even misconduct as well as arguably puzzling editorial decision making at one of the most prestigious journals in the world, Nature. Discussion of STAP pointed to more specific, serious problems. Image and data reuse. Plagiarism. Hype. Rush to publish. Unhealthy competition. Gift authorship. And more.

At some point we need to move on from STAP and thankfully that is happening, but there is still more to discuss before we can really fully move on and focus more squarely on the positive stuff. For example, a few puzzles remain about STAP such as where the supposed STAP cells really came from and also how Nature ended up publishing the STAP work when the scientific reviewers that Nature itself enlisted to review the submitted manuscripts skewered them.

The younger generations of scientists in the stem cell field are also watching how the field handles STAP and other events that invoke similar problems too. What lessons will they and the public take home from all of this? There are so many very real, wonderfully positive developments ongoing in the stem cell and regenerative medicine fields that I would rather be discussing instead of STAP, but we have to be careful. The risk that STAP-like events pose to our field comes in the form of a possible harmful narrative of the stem cell field fundamentally losing the public trust.

STAP Cell Update: New STAP-like paper, Obokata, Vacanti, Real Origin of STAP cells, & More

The STAP cell mess that began in January of this year has in some ways quieted down.

In a broader sense, I believe that STAP is now and will be in the future viewed as a scandal that revealed some less than ideal aspects to the world of biomedical science and publishing.

Where does STAP stand today?

A New STAP-Like Paper?electric iPSC

The most recent development is the publication of a new paper pointed out by a number of people to me as perhaps STAP-like. It is entitled “Electromagnetic Fields Mediate Efficient Cell Reprogramming into a Pluripotent State”. It was published in the journal ACS Nano.

This Baek, et al. paper suggests that you can dramatically more efficiently create induced pluripotent stem cells (iPSC) by exposing somatic cells to an electromagnetic field (see graphical abstract above). My reaction? Let’s see if another lab can reproduce this, but I’m not terribly optimistic. Derek Lowe weighed in on this paper here. The Pubpeer folks have some concerns too and the authors have responded (which is a good thing) there as well.

STAP stem cellsObokata Thesis in Jeopardy

At this time, first author Haruko Obokata is faced with more immediate issues such as her future at RIKEN and her thesis. She must correct her Waseda University thesis or it may be revoked. The University did an abrupt U-turn on this as earlier they had said that while the Obokata thesis had problems it was not that big a deal. Now they are requiring a correction. Given the apparent massive plagiarism in it and re-used figures, I don’t see how a correction is possible frankly.

Vacanti still believes in STAP, issues new protocol

Obokata’s former mentor at Harvard/Brigham Women’s, Charles Vacanti, recently reaffirmed his belief in STAP and along with his lab member Koji Kojima, published yet another STAP protocol this time detailing that the addition of ATP might help other labs make it work. I’m skeptical. I do find it fascinating that Vacanti still believes in STAP despite all the evidence to the contrary. Otherwise in the STAP news, it’s interesting to speculate that during his sabbatical that he may continue working on STAP.

Nature‘s role in STAP

I still think that Nature has not come to terms with its role in STAP. As has been said many times, no journal, editors, or reviewers can catch all problems in a paper, but given the released STAP reviews of previous versions of the STAP papers including one at Nature that wasn’t initially accepted and received pretty harsh reviews, it sure seems the overall review process at Nature should have done better. All things considered, I kinda doubt we’ll hear anything else from the journal on STAP. If the trend of a surging number of overall retractions at Nature continues, however, there may be more of an impetus for change.

Remaining STAP mystery: where did STAP cells really come from?

If acid and other stressors (now perhaps including electricity) do not really make pluripotent or totipotent stem cells, then where did the alleged STAP cells/STAP stem cells come from that seemed in the mouse assays to have pluripotency or totipotency? There have been some indications that STAP cells have a different genetic make up or transcriptomic profile than they were “supposed to” as the authors reported these features in the retracted STAP papers. Were STAP cells actually a mixture of ES cells and trophoblastic stem cells? Some kind of iPS cells? We still do not know.

“Magical” STAP papers were blistered by Nature’s own reviewers, but then accepted just months later

The reviews of a STAP paper submitted to and rejected by the journal Science in 2012 were posted at Retraction Watch yesterday. They filled in some gaps in the puzzle of the series of events that led to such flawed science being published in Nature in January 2014, but the reviews also raised more questions.

Today, more STAP paper reviews have surfaced.

ScienceInsider posted a piece with additional STAP paper reviews with these coming from Nature reviewers commenting on what would later become accepted and published by Nature only months later in seemingly only moderately revised form.

The Nature reviews (you can read them here on the Science website) are very critical of the STAP papers and raise a host of important, largely still unanswered questions about STAP.

STAP magic

My overall sense is that the three reviewers did a thorough and fair job of reviewing these STAP papers. It sure seems that none of the three reviewers were even remotely close to being comfortable with these papers being published in Nature. In each case it would seem that a major revision would have been necessary prior to even having a remote chance at publication. One of the reviewers summed up a STAP cell article as essentially reporting an unproven, “magical” approach (see screenshot above).

The ball is now firmly in Nature‘s court to facilitate a thorough understanding of the STAP situation. It seems reasonable to expect more from Nature than its one editorial that shrugged off any significant responsibility including this key portion:

“We have concluded that we and the referees could not have detected the problems that fatally undermined the papers. The referees’ rigorous reports quite rightly took on trust what was presented in the papers.”

Nature‘s own reviewers’ comments would seem to directly challenge this statement.

I’m not going to go through all of these criticisms and questions raised in these reviews of the originally submitted Nature STAP papers point-by-point, but the overall consensus was that these papers were seriously flawed. This fits well with the gestalt of the reviewer comments on the rejected STAP/SAC paper at Science.

If you look at the published STAP cell Nature papers and think about the details mentioned in these acidic reviews of the original forms of the same papers, there is a sense that not much fundamentally was improved in the papers during that intervening period of months.

The big question remains then: how did these STAP papers go from being rebuffed based on scathing reviews at Nature on April 4, 2013 to acceptance by the same journal on December 20, 2013 and publication about a month later?