September 26, 2020

The Niche

Knoepfler lab stem cell blog

Clues as to the real STAP cell scoop: a trio of biosci traps

STAP cell mixup
STAP cell mixup.

I don’t really hear from almost anyone who fully believes in the STAP cell thing anymore.

The most common thing I do hear is from people assuming STAP is largely or entirely wrong and asking, “what really happened?”

There’s still a chance that STAP is real, but if I were in Vegas or at the race track I’d put the odds in the single digits at this point. Betting on STAP to be entirely true today would be akin to wagering on a 100-1 shot 3-legged horse in the Kentucky Derby. Of course just about 2 months ago that horse was looking more like legendary horse Secretariat.

What I believe is far more likely than STAP being the real deal is that the STAP papers and the data they reported probably at least in part resulted from some relatively avoidable, but potentially devilish problems in the biosciences.

The first probable STAP problem is autofluorescence. One of the common themes I’ve heard from people trying to replicate STAP is that the process of stressing out cells and indeed killing them leads to spikes of autofluorescence. Unhappy, dying, and even dead cells can glow when hit with light. That emission can be broad spectrum, but if relatively naive researchers only look in say the green channel they may be misled to believe their cells are in fact specifically glowing green (e.g. have turned on an Oct4-GFP reporter). Another more remote possibility is that the Oct4-GFP reporter turns on when cells are acidified, having nothing to do with pluripotency at all.

The second likely STAP problem is a cell mixup/contamination. My first job in science was growing cells in culture at UCSD in 1990. The science stone age, huh? Well, some things don’t change. Back then as is true today, you have to be really careful not to contaminate your cells either with pathogens or with other cells. Especially if you are dealing with a fast growing cell type such as mouse ES cells or iPS cells or cancer cell lines, they’ll in all likelihood happily take over some other culture over time if given the right media. In the STAP case this may have gone to an extreme as at least one researcher involved, Dr. Teru Wakayama, has indicated that he is worried that he was given entirely the wrong cell type. A new article today in Japan suggests that while the STAP paper reported that it used a specific genetic strain of mice/cells called 129 that the cells given by Dr. Obokata to Dr. Wakayama turned out not to be 129 (update: instead it seems to be a mixture of two other strains, most likely B6 and one other, perhaps 129, referenced as “F1” generation in the STAP paper). If correct, this would be an extremely serious blow to the STAP papers. See screenshot from video on that Japanese news site above.

A possible third STAP problem is positive reviewer and editor bias. While we as yet have little in the way of a window into the review process of the STAP papers, there have been hints that suggest some of what might have gone wrong. There are indications that the STAP papers in various incarnations were reviewed on multiple occasions and rejected including previously at Nature. Presumably the authors generated more data over time that may have positively influenced reviewers, but I believe a second phenomenon was probably occurring during the sequential reviews: additional, more famous and respected authors were recruited to be part of the overall STAP research team. The reviewers of the resubmitted papers and in all likelihood journal editors too were positively swayed by the presence of the newly added, highly respected authors’ names on the papers. I’ve even heard someone go so far as to say in a broader context “if Dr. ABC is an author on that paper, I believe the paper is true!” Reviewers and editors too should in fact ideally be reviewing the science and not basing their reviews and decisions (positively or negatively) on who the authors are, but in reality the latter makes an enormous difference in today’s review process.

Overall, I believe the three problems discussed above may well explain how things seem to have gone so wrong with the STAP cell Nature papers.

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