Update: Jury out on stem cell 'breakthrough'

Japan's prestigious RIKEN institute has admitted to 'inappropriate' behaviour in research that claims stem cells can be created with an acid shock but the investigation continues. Elizabeth Finkel reports.

Biologist Haruko Obokata in her laboratory at the RIKEN Center for Developmental Biology. Doubts have been raised over her revolutionary claim that stem cells could be made by exposing ordinary cells to a mild acid. – The Asahi Shimbun/Getty

Japan’s prestigious RIKEN Center for Developmental Biology has admitted to two instances of “inappropriate” behaviour over controversial papers that made a revolutionary claim that stem cells could be made by dipping ordinary cells into mild acid.

“The committee concluded that there had been inappropriate handling of data for two of the items under investigation, but the circumstances were not judged to constitute research misconduct,” RIKEN told a press conference in Tokyo on 14 March.

It is clear that some data were tampered with and that other researchers can’t repeat the results. But the committee charged with investigating the research has four more issues to assess and could not yet say whether this was a case of honest mistake, outright fraud or merely sloppy work.

The episode has cast a slur not only on the high-profile authors of the paper, but also on Japan's flagship, the RIKEN, Harvard University and the publishing standards of the journal Nature.

“It is surprising and disappointing that a study of this significance in a leading international journal would be compromised by inappropriate presentation of data, especially since many of the authors are senior figures in the field,” said Martin Pera, program leader of Stem Cells Australia.

Known as STAP (stimulus-triggered acquisition of pluripotency), news of this new method for making stem cells was published on 31 January in two papers in Nature magazine and reported in COSMOS.

RIKEN-based Haruko Obokata was the lead author of both reports. The 30-year-old Japanese researcher, who previously did a stint in Harvard, became an overnight celebrity in Japan.

In her first paper, Obokata showed that simply exposing white blood cells of newborn mice to a mild acid bath (pH 5.6) for 30 minutes was sufficient to convert them to a “pluripotent” state capable of generating any tissue of the body.

Her second paper showed that the cells were even more pluripotent than stem cells derived from embryos or by inserting four genes into a mature cell to create induced pluripotent stem cells.

These existing types of pluripotent stem cells are not capable of generating placental tissue but STAP cells purportedly could - raising the possibility that STAP cells could be used to clone entire embryos.

The scepticism began to grow. At least 10 independent stem cells
experts were unable to replicate the result.

The results were met with cautious optimism. “If it can be applied to human cells, then it’s a huge turn of the dial. Any old lab with vinegar could do it,” Alan Trounson, President of the California Institute of Regenerative Medicine, said at the time.

Researchers in Japan claim this mouse embryo’s tissues came from blood cells that turned into stem cells after an acid shock. A “reporter gene” on board the blood cells makes them glow green when they turn into stem cells. – Haruko Obokata/ RIKEN

But researchers wondered at the plausibility of being able to change the programming of cells so easily. Mild acid conditions exist in the stomach yet pluripotent tissues don’t sprout there. Obokata’s theory was that the low-acid conditions represented a natural stress and that the cells were reprogramming themselves to repair the damage, not unlike the way salamander cells reprogram themselves to regenerate a lost limb.

But as Carl Sagan said “extraordinary claims require extraordinary evidence” and Obokata’s paper was rejected multiple times by Nature, requiring her to provide additional evidence over a five year period.

But within two weeks of publication, the scepticism began to grow. At least 10 independent stem cells experts were unable to replicate the result, according to a survey by Nature News. Meanwhile, reports appeared on the internet that one of the papers’ images had been duplicated, yet purported to represent different things. Another image appeared to be from Obokata’s unrelated PhD thesis, suggesting this was not just a simple mix-up as the RIKEN initially suggested.

Yet two of Obokata’s senior co-authors – Teruhiko Wakayama (the first person to clone mice) and Charles Vacanti of Harvard University – claimed they had repeated the work, endorsing its credibility. Wakayama however admitted he’d failed to repeat the experiment at his lab at Yamanashi University without Obokata’s guidance. Nevertheless both they and the RIKEN pushed the view that the STAP method was “tricky” but true. The RIKEN released a detailed recipe for the technique.

But by 10 March, Wakayama’s suspicions overwhelmed him. He asked for a retraction of the paper. “There is no more credibility when there are such crucial mistakes,” he told the Wall Street Journal, adding and that he could not be sure about the cells he used in his experiments.

An apologetic Obokata, who maintains the mistakes were innocent, nevertheless has agreed to a retraction of the papers, as have two other authors Yoshiki Sasai and Hitoshi Niwa. All four authors are under investigation by the RIKEN committee. But any final retraction of the papers requires agreement of the remaining 10 authors and the decision of Nature.

Not all authors appear to be in favour of retraction.

Charles Vacanti of Harvard told the New York Times he felt the paper should not be retracted until the RIKEN investigation was completed. “I continue to feel that the findings presented in these papers are too significant to disregard based on relatively minor errors or external pressures,” he said.

And so the world must wait for the RIKEN to complete its inquiry.

“Even if the work proves impossible to reproduce, there is a huge gulf between unintended experimental error … and deliberate misrepresentation of fact. We need to know on which side of this gulf the STAP story lies,” Pera said.

  1. http://beta.cosmosmagazine.com/life-sciences/acid-shock-stem-cells
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