The Clock is Ticking

(February 14th, 2014) Things don’t look good for the Stimulus-Triggered Acquisition of Pluripotency, short STAP cells. And evidence against Haruko Obokata and her ‘findings’ is piling up and up, as our resident stem cell expert and cartoonist Leonid Schneider reports.

According to Haruko Obokata and colleagues, it takes a week to turn a differentiated CD45-positive leukocyte (or any other cell) into a quasi-totipotent stem cell by dipping it into an acidic solution (or squeezing it in a pipette). While a very similar publication by Obokata and co-author, Charles Vacanti, in Tissue Engineering Part A went largely unnoticed in 2011, the recent double feature in Nature makes their data, for quite a lot of people, automatically a near-absolute truth. Although most serious scientists reacted with perplexed caution, the two peculiar publications were met with euphoric excitement by media, investors, charities and religious groups (always concerned about embryonic stem cell research). In fact, the discoverer of induced pluripotency (iPS), Shinya Yamanaka, was already informed that his dangerous and inefficient iPS cells will not be needed by humanity anymore. So, has the paradigm change really already begun? Until now, no one was able to reproduce the results. Stem cell researcher Paul Knoepfler from the University of California, Davis, has invited other scientists to share their STAP-experiences here:

Even considering that it has not been long since these results where published, with such a short reprogramming time frame (one week!) and such efficiency (30%!) it shouldn’t be so difficult to reproduce the results, should it? Otherwise, the scientific world will be put to shame once again. What’s the evidence against Obokata? First, no one except Haruko Obokata ever noticed that stress can reprogram cells to pluripotency, and up until now it seems no one is capable to follow a simple experimental protocol either. At the same time, co-author Charles Vacanti has already announced to have successfully repeated the experiments with human cells. Still, it is true that high impact publications are often technically and scientifically so complicated that their results cannot be reproduced outside of the original lab. For example, the bacteria which used arsenic instead of phosphate were never observed doing this again. Closer to the subject, the discovery of pluripotent stem cells in adult human testis was very contested. Meanwhile, the whole research on testis-derived pluripotent stem cells from either men or mice has somehow been forgotten, despite earlier publications in Nature, Cell and Cell Stem Cell. I guess the scientists deem it now unethical to pursue such an easy and embryo-free source of pluripotent stem cells, for reasons of gender-equality, both in humans as well as in mice.

The pluripotency research field is full of surprises: alongside a large body of solid and very relevant work, some quite sensational “breakthroughs” are published on a regular basis. To me, pluripotency seems to be the new cancer. While in the past, major publications were achieved by finding the sole responsible gene for cancerous transformation (sadly, cancers outside of immune-compromised mice proved to be much more complicated), pluripotency is nowadays the code word to get published. This happens for the very same reasons: promise of a cure, and the money attached to it, with the additional aspect of religion- and ethics-based avoidance of embryonic stem cell use. Although the existence of so-called VSEL or MUSE cells (phantom pluripotent stem cells present in adult tissues) has already been sufficiently disproven, research on them continues. After receiving a tremendous boost from Obokata and Vacanti, VSEL and MUSE are expected to leave their niche of more or less obscure journals and colonise the “high-impact” environment.

Of course, it would be great if Obokata’s results turn out to be true but for so many practical and clinical reasons, it is still unlikely to be the case. Plainly, it makes little sense, just as unicorns or mermaids do, but that is my opinion. The arguments supporting the results, for example that similar things have been observed before, are not viable at closer inspection. One of the arguments, as mentioned repeatedly, is the publication by Hans Clevers’ lab in Cell. However, this study is about differentiated stomach epithelial cells turning into stomach epithelial stem cells. This phenomenon of differentiated cells reverting to their respective, tissue-specific somatic stem cells is known as de-differentiation and was also described for other tissues, e.g. brain and lung. It’s indeed a very interesting phenomenon but it is biologically perfectly reasonable, under conditions where endogenous somatic stem cells are defective or insufficient to repair damage. Most importantly, it has nothing to do with induced pluripotency or totipotency.

Organisms like newts and especially axolotls are indeed capable of de-differentiation and limb re-growth, but there are still no signs of pluripotency here. Instead, what is thought to happen is that differentiated cells revert to their respective tissue-specific stem cell state and regenerate the lost tissue. Some degree of trans-differentiation among closely related tissues (i.e. of the same germ layer) is also likely, yet it is no proof for Charles Vacanti’s claims. Indeed, all research so far showed that in order to achieve trans-differentiation between germ layers or pluripotent reprogramming, massive changes in enforced gene expression are necessary. And if somatic cells are thus forced to reprogram to pluripotency in vivo, they immediately form teratomas.

The method, by which STAP cells were generated, is even less scientifically comprehensible than the suggestion for them to occur naturally. It very well may be that short-term stresses can temporarily change cell shape and gene expression patterns, yet no one in the history of biology has ever observed anything of a STAP scale. Basically, STAP discovery came out of the blue; defying all logic and understanding, just like a mermaid riding a unicorn, and the scientists are left to make up their minds about it. Of course, nothing is theoretically impossible  and Douglas Adams did suggest running a spaceship on an infinite improbability drive. Therefore, with every passing day without reproducibility, the probability of the existence of STAP cells dwindles towards that of nuclear missiles turning into bowls of petunias and sperm whales. Don’t panic.

Leonid Schneider

Photo: Hodan

Last Changes: 03.25.2014

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