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.

“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?

Full Reviews of Rejected STAP Paper Point to Early Signs of Big Trouble

Before the two STAP cell papers were published in Nature in January of 2014, much of the same data was reportedly submitted as single papers to other high-profile journals including Science.

In these cases, the proto-STAP papers as we might call them were rejected.

But why?

Until now we largely could only speculate.

However, the reviews of the 2012 proto-STAP manuscript at Science can now be read at Retraction Watch.

Retraction Watch

As a result of reading the Science reviews, today we know what the reviewers at Science thought in 2012 of this proto-STAP paper and this sheds much light on what went so terribly wrong with STAP overall. There were many big red flags. Keep in mind that the Nature reviewers would not know about the Science reviews unless by chance one or more of the reviewers for Nature had also participated in the review process at Science.

This early generation STAP paper was entitled “Stress altered somatic cells capable of forming an embryo”.

There was no “STAP” acronym at that point. Instead, the stress-produced stem cells were called “SACs”, an acronym presumably standing for “stress-activated somatic cells” or “stress-altered stem cells”. Therefore, let’s call this proto-STAP paper, the SAC paper.

All three Science reviewers had serious doubts about the SAC paper and pointed out numerous specific concerns.

For example, Reviewer 1 right away early in their review pointed out that the SAC phenomenon was probably not real and was instead explainable by two simple experimental problems: stress-associated GFP reporter activation and cell culture cross contamination.

Crucially, this same reviewer noticed the gel splice, later present in the accepted Nature STAP article Figure 1. However, apparently the STAP/SAC team did not take that concern or most of the other reviewer issues to heart.

Reviewer 2 was extremely skeptical of SAC as well, listing twenty-one specific problems/issues to be addressed. Unfortunately, it seems that most of these concerns also remained unaddressed in the later accepted Nature STAP papers. It is fair to say that although 21 issues seems like a lot that these concerns seem reasonable and not overly harsh.

What else did the reviewers say?

Both Reviewers 1 and 2 had the shared concern that pluripotency-related gene expression seemed abnormally high in the SAC cells. Way way too high.

Reviewer 2 wanted much more data before being convinced. For example, they wrote:

Given the novelty of the claims, a thorough characterization of the SACs is warranted, as is some probing of the mechanisms. This would necessitate a more sophisticated genomic analysis of SACs, through microarray or RNA-seq, and genome-wide DNA methylation analysis — analyses that other pluripotent stem cell lines have been routinely subjected to and for which methods for smaller cell numbers have been developed.

Reviewer 3 was not as detailed with their concerns, but more generally identified some areas of concern such as those articulated in this paragraph:

the methods and cell protocols used must be described in far more detail. For example, the section on Oct4 should state how many cells were sorted and describe the appearance of the cells. Is it possible that rare populations of cells pre-exist or are already apparent on day 1 (thus, what are the “dots” of Fig. 1?). The authors will argue that, indeed, under certain circumstances, they were able to reprogram terminally differentiated cells, and that this was attributable to TCR recombination. I think, ideally, that the cells should be experimentally tagged and traced. This would unequivocally clarify the source of the cells and, further, would exclude the possibility that some cells pre-existed in a pluripotent state.

Critically, it is necessary to determine whether SAC cells can propagate stably in culture and whether such cells can be passaged.

 

Experimental tagging and tracing of the cells would have been a major step forward for clarifying whether the SAC/STAP phenomenon was real. STAP/SAC cells should have been made in parallel to iPS cells as well for direct comparison.

One has to wonder how the Nature reviewers and editors could not have picked up on so many problems that were apparent to the Science reviewers. Every review at a different journal of the identical paper will be distinct of course, but this data seemed inherently flawed in a systematic way. This was no ordinary paper either. It was a no-brainer that this kind of paper with revolutionary claims required extraordinary, very meticulous editorial oversight. It is therefore not an unreasonable expectation that the Nature review process of the STAP papers should have picked up on some of these serious problems.

Nobody likes to get a harsh review of a submitted manuscript, but it’s crucial after you calm down in that situation to consider that some of the comments by the reviewers likely raised legitimate, important issues to address before resubmission. This way you can avoid problems and improve your paper. Apparently to a large extent that didn’t happen between the SAC paper and STAP paper stages.

In the end these Science reviews of the rejected SAC paper indicate that the STAP manuscript and data were problematic in fundamental ways back in 2012.