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.

Perspectives: RIKEN itself fails to reproduce STAP & big CDB shake up expected soon

Nikkei is reporting that the RIKEN internal attempt to replicate so-called STAP (acid bath) cells has failed. Update: apparently, although RIKEN calls the efforts preliminary, the team tried to make STAP an amazing 22 times and 22 times it failed.

The rumors for weeks in the stem cell gapevine that RIKEN itself could not get STAP to work, even with the help of Dr. Haruko Obokata, have been confirmed by Nikkei. Obokata was first author on both Nature STAP papers, which were retracted. One of Obokata’s mentors and a STAP paper co-author, Dr. Yoshiki Sasai, recently committed suicide at least in part likely due to issue related to STAP. See a tribute to Dr. Sasai here.

STAP cell embryo

The best that the RIKEN team could get in the replication attempt, according to Nikkei sources, was a “faint” hint of pluripotent markers “nowhere near” to that observed in iPS cells or embryonic stem cells. STAP cells were supposed to be not just pluripotent, but also totipotent, allowing for contribution to an entire embryo (see image at left from the STAP work). Now that claim seems light years from reality. For more background on STAP and a timeline of the events see here.

This may be the final straw that pushes RIKEN to formally declare that STAP cells do not exist, a conclusion that I think the world of science has mostly already come to some time ago.

This latest twist is no surprise and just adds to the continuing STAP sadness, but hopefully is another step toward an end for the STAP disaster.

Unfortunately, however, this could get even worse.

Nikkei also reports that tomorrow RIKEN will announce a major shakeup at the RIKEN Center for Developmental Biology (CDB), where much of the original STAP work took place, that could mean as much as half of the scientists at the CDB moving to other RIKEN units and in a few cases losing their jobs (update: new reports and sources indicate that most RIKEN employees leaving the CDB will be transferred to other RIKEN units and not lose their jobs). That seems grossly unfair as most of the affected people would probably have had nothing to do with STAP. This anticipated personnel cut would be just another level of tragedy to the STAP story.

 

STAP News From Harvard? Vacanti Stepping Down as Chair & Going on Sabbatical

Vacanti and Obokata

Vacanti and Obokata

What’s the deal with Brigham and Women’s Hospital or Harvard Medical School when it comes to the retracted STAP cell papers?

I was just writing yesterday in part about how we haven’t really heard anything (news, statements, etc.) from those places about the whole STAP cell mess.

In contrast, in Japan and at RIKEN there has been a non-stop flood of news and developments involving STAP.

Now today I’ve heard from a source that senior STAP cell paper author, Dr. Charles Vacanti, will be stepping down as Chair of the Department of Anesthesiology in a couple weeks. He indicated this decision in an email to his departmental colleagues.

It is formally possible that this may not linked to the whole STAP cell situation, but there could well be a connection. Vacanti was not only the senior author on the STAP cell Nature article, but was also the key mentor to STAP first author, Haruko Obokata (both pictured above).

According to the email (pasted below) that he recently sent out to his colleagues, Vacanti is also going on a 1-year sabbatical to, in his words, “contemplate my future goals…” If his institution is investigating STAP, one might well expect the conclusion to come during that sabbatical period. Again, there are a lot of ‘ifs’ here.

I would note from Vacanti’s email that he does indeed have a great deal to be proud about for his department as they have done amazing things during his tenure as Chair.

Dear Colleagues:

It is with somewhat mixed emotions that I share with you my decision to step down as Chair of the Department of Anesthesiology, Perioperative and Pain Medicine, effective September 1, 2014.

When I accepted the position in 2002, I anticipated serving as Chair for a period of 10 years, having a vision of what I hoped to accomplish during that time.  I approach the age of 65 next year having served as Chair of two anesthesia departments – UMASS then BWH – over the last two decades.  I have always felt that a leader is most effective during the first decade of service, after which time there can be diminishing returns on the energy invested in the challenges faced. I feel that is certainly true in my case, and that by this measure, I am two years past due in making this decision.

I am very proud of what we have accomplished as a department over the last 12 years.  We have matured, expanded and reorganized to meet the demands of a changing environment. Our department now provides anesthesia services to patients on four campuses, including 850 Boylston, the BWFH and Patriot Place.  We now provide non-operative anesthesia services to almost 10 times as many patients as we did in 2001.  Since 2002, the number of full professors in our department has more than doubled, as have the number of departmental endowments, with external funding of our research almost tripling despite the overall decline in availability of federal research dollars. This has resulted in roughly 100 original peer reviewed scientific publications each year.

Our Residency program continues to be among the most competitive in the country.  Our Pain Management program is a nationally recognized Center of Excellence.  Several of our divisions, including Cardiac Anesthesia and Obstetrical Anesthesia are arguably the most respected in the country, and I believe we have developed the preeminent pre-admission test center for patients scheduled to undergo a procedure involving anesthesia services. We have also tripled the number of CRNAs on our staff, enhancing our ability to efficiently provide the safe, compassionate care to our patients.

I plan to take a one-year sabbatical to contemplate my future goals, redirect my efforts and spend time doing some of the things that I enjoy most.  When I return in September 2015, I hope to focus a significant portion of my academic efforts on Regenerative Medicine and mentoring the next generation of anesthesiologists.

Dr. Nabel intends to convene a search committee for my successor.  In the interim, Bhavani Kodali has graciously agreed to serve as interim Chair.

I am extremely proud of this department, and the quality of our faculty, residents, fellows, CRNAs and staff, not only as professionals, but more importantly, as people.  It has been a pleasure serving in this department and I am grateful to have been part of it.  I would like to thank each and every member of our team for their wonderful contributions.  I sincerely appreciate the support you have given to me as Chair.

With very best wishes for a stellar future,

Charles A. Vacanti, MD