Extraordinary results typically attract extraordinary scrutiny, and a pair of blockbuster papers recently published by Nature poses no exception. The papers, which are the work of researchers at RIKEN Center for Developmental Biology and Brigham and Women’s Hospital, astonished scientists and the public by presenting evidence that mature cells could be “shocked” into an embryonic stem cell-like state. Instead of relying on the insertion of genes to create induced pluripotent stem cells, the paper said, scientists could simply apply external stresses, such as an acidic environment or physical pressure on cell membranes.

Initial excitement over the papers is now being tempered by rising skepticism. As indicated by a Nature news story published February 17 (“Acid-bath stem-cell study under investigation”), blogs such as PubPeer have cited inconsistencies with images that appeared in the original papers. In addition, scientists have been reporting difficulty reproducing the results.

Summarizing the potential problems with the papers’ images, the Nature news story said, “In one paper, one of the sections in a genomic analysis in the first figure appears to be spliced in. In the other paper, images of two placentas meant to be from different experiments look strikingly similar.” Also, questions have been raised about images that appeared in a preliminary paper, published back in 2011, in which RIKEN biologist Haruko Obokata served as first author: “A figure showing bars meant to prove the presence of a certain stem-cell marker appears to have been inverted and then used to show the presence of a different stem-cell marker. A part of that same image appears in a different figure indicating yet another stem-cell marker.”

With respect to the image problems in the 2011 paper, corresponding author Charles Vacanti, a Brigham and Women’s Hospital anesthesiologist, contacted Nature to request a correction. Vacanti, like Obokata, is also among the authors of the acid-bath stem-cell papers. In the Nature News article, Vacanti is quoted as saying, “It certainly appears to have been an honest mistake [that] did not affect any of the data, the conclusions or any other component of the paper.”

As indicated in a February 18 Boston Globe story (“Controversial stem cell study being investigated, scrutinized”), Vacanti was informed by a RIKEN-based co-author earlier this week that there was a problem with the paper for which he was a co-author. The Boston Globe also cited an email it received from a RIKEN spokeswoman about the institution’s response to alleged improprieties. “RIKEN believes that the research results are valid but launched an investigation [on February 13],” wrote spokeswoman Juliette Savin. “We have asked specialists both outside and inside RIKEN to conduct this investigation.”

While worrisome, the problems with the scientists’ images may be less serious than the issue of reproducibility, or the lack thereof. Several groups have reported difficulty reproducing the acid-bath results, but at least some of the researchers quoted in the Nature news story seem inclined to adopt a wait-and-see approach: “The protocol might just be complicated—even Wakayama [a former RIKEN researcher] has been having trouble reproducing the results. He and a student in his laboratory did replicate the experiment independently before publication, after being well coached by Obokata. But since he moved to Yamanashi, he has had no luck. ‘It looks like an easy technique—just add acid—but it’s not that easy,’ he says.”

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