New Nature papers debunk STAP cells

Today marks nearing the completion of a full circle for one of science’s biggest controversies: the STAP cell fiasco. Today STAP cells are completely refuted with the publication of two new papers in Nature and we know much more–with some notable gaps still–about what went wrong.

In January of last year, an international team of collaborators from RIKEN in Japan and Harvard/Brigham & Women’s Hospital (including the lab of Charles Vacanti where the STAP idea reportedly originated) here in the US published two Nature papers making the extraordinary claim that ordinary cells could be reprogrammed into embryonic stem cell (ESC)-like cells.

And it could be done simply, cheaply, and quickly using various forms of cellular stress including low pH. I was highly skeptical when I read the papers, but tried to keep an open mind. This sounded cool, even if also too good to be true.

I published a review of the papers here on this blog on the day they were published and I included six key open questions that would be required to assess the real impact of these papers. Over the next few weeks I posted an increasingly skeptical series of posts questioning STAP.

Others in the larger community including anonymous scientific sleuth JuuichiJigen and some on PubPeer were skeptical as well. In fact, they started noticing issues with the data and text of the papers.

RIKEN and Nature began investigations. Ultimately the papers were retracted in relatively quick fashion. While a lot of harm was done even so and tragedy would strike later, the rapid refutation of STAP attenuated the overall damage.

For more background on the key STAP events check out this comprehensive STAP history timeline. Ken Lee’s lab took the lead in scientific refutation of STAP and published their work in F1000 here after Nature rejected it under unclear circumstances.

I also started a novel, but admittedly somewhat basic attempt at crowdsourcing global efforts at STAP replication. Very quickly we came to a consensus that autofluorescence was likely a key stumbling point for the STAP papers as the authors probably misinterpreted it as real signal from a GFP pluripotency reporter.

Suspicions grew elsewhere that STAP cells might really be ESCs or some other pluripotent stem cells, possibly mixed with trophoblastic stem cells (TSC). Ultimately, STAP first author Haruko Obokata was found by RIKEN to have committed misconduct and she is no longer working at the institution. RIKEN underwent a big shakeup as a result of STAP as well. STAP co-author and highly respected biologist Yoshiki Sasai committed suicide, which was one of the most tragic and sobering events I’ve seen in science during my career. In Japan there had been a media frenzy on the STAP problems. In the US things on the STAP front were and continue to be quieter. As recently as about a year ago, Vacanti and co-author Koji Kojima publicly expressed complete confidence in STAP and put up a refined protocol on the web.

So what was the real deal with STAP?

Today Nature published two articles thoroughly refuting STAP cells and providing some further insights.

In one of the papers, STAP cells are derived from ES cells, the authors used whole genome sequencing (WGS) to examine archived STAP cell-related samples and other cells present in the laboratories where the STAP work was conducted. Using essentially a form of genomic fingerprinting, the team reports conclusive evidence that STAP cells were in actuality ESCs:

In summary, our investigations based on WGS of STAP-cell related materials reveal that all of these materials are derived from previously established ES cell lines and refute the evidence shown in the two Nature papers that cellular stress can reprogram differentiated cells into pluripotent cells.

You can see Figure 1b from this study showing the WGS comparison that the genomic characteristics of various cell lines.

STAP refutationThe matching patterns between two STAP-derived lines FLS3 and CTS1 and the supposedly unrelated FES1 ESC line are particularly striking. It now seems almost certain that a number of STAP cells are in reality FES1-related ESC lines and that the STAP cells were not created by cellular stress.

The other new paper from another team, Failure to replicate the STAP cell phenomenon, comes to similar conclusions and further clarity arises:

“In summary, our replication attempts and genetic analysis indicate that existing STAP protocols are neither robust nor reproducible. To substantiate future claims of reprogramming and alternative states of potency, we urge a rigorous application of several independent means for validating functional pluripotency and genomic profiling to confirm cell line provenance. Ultimately, the essential standard of robustness and reproducibility must be met for new claims to exert a positive and lasting influence on the research community.”

This second team led by George Daley at Brigham and Women’s spans the globe, but importantly they did some of the work actually in Vacanti’s lab, still finding no evidence that STAP is real. They wrote, “Working within the Vacanti laboratory where the concept of STAP cells originated, and assisted by a co-author of the STAP papers…”

Seven laboratories were involved in this second STAP replication effort: Daley, Deng, Hanna, Hochedlinger, Jaenisch, Pei and Wernig. This is an all-star team of stem cell research labs.

One bottom line from the paper is that this team collectively worked very hard to try to get STAP to work, but it didn’t:

“In summary, 133 replicate attempts failed to document generation of ES-cell-like cells, corroborating and extending a recent report.”

Like the other team, these scientists analyzed the STAP cells including their genomes. They found inconsistencies between their new findings and the claims in the original STAP papers:

“In the original STAP reports, the authors stated that they mixed CD451 cells from male and female mice owing to the small number of CD451 cells retrieved from individual neonatal spleens. However, our analysis indicates that CD451 cells were female, whereas the derived cells (STAP cells, STAP stem cells and FI-SCs) were all male, a clear inconsistency.”

These authors also found indications of trophoblastic stem cells (TSC) being mixed into the STAP samples. TSC may explain the reported totipotency of some derivations of supposed STAP cells.

Nature itself explained why it published these new papers (in the Brief Communications Arising or BCA format):

“Why is Nature publishing these pieces? The main reason is to update the scientific record. The wording of the STAP retraction notices left open the possibility that the phenomenon was genuine. It said: “Multiple errors impair the credibility of the study as a whole and we are unable to say without doubt whether the STAP-SC phenomenon is real.” The two BCAs clearly establish that it is not.”

We are just about, but not quite at the end of the STAP story it seems. In my opinion there is still more to be learned about what went so wrong. How did the ESCs and in some cases TSCs end up in the cell culture mix? Accidental contamination? Intentional attempt to bolster the seductive hypothesis?

We may never know, but today there is a great deal more clarity overall at least.

The publication of these two new papers is a very positive step, but it is important to stress that absent post-publication review, rapid and open team science, and social media efforts, the STAP cell myth may have continued to have been believed by many in the research world until this day when these debunking papers were published. That delay would likely have caused immeasurable damage. Thus, there were important roles both for traditional scientific correction via journals and new, transformative types of rapid post-publication review.

Did NHK, Japan’s PBS, Violate Human Rights of Obokata (小保方 晴子) over STAP?

Obokata press conference

Obokata late press conference

The Japanese public broadcasting system, NHK, has been accused by scientist Haruko Obokata of violating her human rights.

Obokata was the primary researcher involved in the STAP cell fiasco in which two ultimately retracted Nature papers contained duplicated, plagiarized, and manipulated data. She was certainly not the only researcher on those papers, but overall she has been accused of having the most central role in the STAP problems. Obokata left RIKEN late in 2014.

During the height of the STAP cell mess the Japanese media hounded Obokata and other STAP cell authors including Yoshiki Sasai, who ultimately committed suicide. From accounts in Japan, the STAP cell story was on the equivalent of the nightly news and on the front of national newspapers and tabloids almost every day for a time.

For instance, NHK was incredibly persistent with pursing Obokata and now Obokata has said that they violated her human rights in a complaint to the Japanese Broadcasting Ethics & Program Improvement Organization or BPO. Obokata asserts that NHK violated her rights in numerous ways including accusing her of stealing embryonic stem cells and she sustained injuries while being pursued by NHK. BPO will be investigating these and other assertions by Obokata against NHK.

During the STAP cell mess last year, it seems because I was covering the STAP cell claims and science here on this blog, many members of the Japanese media emailed and called me. I can understand that they were looking for information and perspectives, but it went out of control in certain cases. Some, including reporters saying they were from NHK, were very aggressive with me. They some persistently called me at work and even at home in the middle of the night.

I had decided to not talk with them because of their aggressiveness and their tendency to focus on negative, personal stories rather than the science and facts, but they wouldn’t take “no” for an answer. Several pursued me for comment at conferences too. I don’t have direct knowledge of what happened with Obokata and NHK, but my sense is that the media went way out of bounds on STAP and made it personal.

Haruko Obokata 小保方 晴子-like Game Character Conducts ‘Dangerous Research’

I’ve seen many crazy things over the years doing this blog.

There was the Moriguchi IPS cell fraud, the electric stem cell bra, the stem cell supermodel case, the stem cell soup No. 7 aphrodisiac, the STAP cell scandal….and the craziness goes on.

Today there’s a new one that even surprised me.

Haruko Obokata, lead STAP cell author, has now entered the online game world, although it seems not of her own choosing.

The Asahi Shimbun reports that a new character in the video game Star Galaxy, “Haruko Oppenheimer” bears a striking resemblance to Obokata. Presumably this name is a mash up of Haruko Obokata and Robert Oppenheimer of the Manhattan Project that made the first atomic bombs.

Gamers noticed the virtual Obokata. See image here for yourself.

Obokata was known for decorating her lab with cute cartoon-like characters as well (see one on her incubator).

Obokata game

In the Star Galaxy online game, Haruko Oppenheimer was conducting “dangerous research” under the theme “ultimate cell”. Not sure what that means exactly, but it sure seems like a reference to STAP cells.

Wow.

Game maker Square Enix, apologized and changed the character’s name to “Jesca Fred”, but not her appearance.

Obokata is now officially immortalized in pop culture.