As two discredited, and now retracted, stem cell papers have produced an almost unimaginable fallout—a national hero accused of scientific fraud, the revamping of one of Japan’s major research institutes, and the suicide of a respected cell biologist—researchers have privately and publicly asked how Nature could have published work that, in retrospect, seems so obviously flawed.
Another piece of the puzzle has come to light. The Science news team received a copy of e-mail correspondence between a Nature editor and Haruko Obokata, the lead author of the papers, that indicates the work initially received as rocky a reception there as at two other journals, Cell and Science, that had rejected the work previously. The e-mail, dated 4 April 2013, includes detailed separate criticisms of the two papers and suggestions for new data to support the authors’ claims of a simple and novel way to make stem cells that could form the myriad cell types within a body. The Nature editor rejected the papers, but left open a window, writing, “Should further experimental data allow you to address these criticisms, we would be happy to look at a revised manuscript.” The two papers were published 10 months later.
A representative for Nature declined to comment on the e-mail correspondence, or how Obokata and her co-authors revised their manuscripts. But the critiques are similar to those Science reviewers reportedly leveled when considering an earlier report on the work. Yesterday the website Retraction Watch published what it says are the cover letter and reviews for a manuscript on stem cells submitted to Science by Obokata. (Science’s editorial department would not confirm that the reported reviews were genuine, but the news staff has received the identical document from an independent source.)
The Nature reviewers call the manuscripts and the results they describe “very interesting,” “potentially groundbreaking,” “highly provocative,” and “truly remarkable.” In the papers, Obokata, who works at the RIKEN Center for Developmental Biology (CDB) in Kobe, Japan, and her co-authors claimed that bathing blood cells from newborn mice in a mildly acidic solution could prompt them to become powerful stem cells. They dubbed the phenomenon stimulus-triggered acquisition of pluripotency, or STAP.
All three Nature reviewers concluded that the data presented in the submitted manuscripts were not enough to support such radical claims. “I would recommend the authors to be extremely cautious in their claims. … The authors should look into the actual effect that the treatment elicits in the genome and they should assess genomic instability,” one writes. “There are several issues that I consider should be clarified beyond doubt because of the potential revolutionary nature of the observations,” writes another.
Foreshadowing the difficulty the study authors have had in providing a clear protocol for others to replicate their work, one Nature reviewer writes, “Of paramount importance for the legitimacy of this paper is that the authors provide a full step by step account of their method such that the community can rapidly validate the reproducibility of the findings. The present method description is minimal and key elements are not properly defined.” The reviewer notes that the methods mention the use of B27 medium, “but B27 is a medium supplement, not a medium itself.” Nor does the manuscript mention whether any measures were taken to control the final pH, the reviewer writes.
Since the papers were published, labs around the world have tried but failed to produce STAP cells. The papers’ authors have posted several different protocols online, including one as recently as 3 September.
The reviewers all point out significant inconsistencies and holes in the data. One notes that although a chimera was supposedly made with STAP cells from a strain of black mice, the offspring are not black. “Please explain,” the reviewer writes.
One reviewer summed up, “As it stands, and whereas this reviewer does not doubt the data presented, the process can be summarized as a 'magical' approach and none of the conclusions related to the 'next-generation' or amplifications in regenerative medicine is supported experimentally.”
On 1 April 2014, almost a year after the rejection notice, a RIKEN investigating committee concluded the papers were marred by falsification and fabrication and judged Obokata guilty of research misconduct. Other authors were spared the misconduct charge, but the committee said that senior authors who failed to verify the accuracy of the data “bear heavy responsibility for the research misconduct that resulted from this failure on their part.” RIKEN leaders have recently announced the radical restructuring of the RIKEN CDB, cutting the staff by half.
It is still not clear what happened between 4 April 2013 when Nature initially rejected the papers and 20 December 2013 when they were accepted. Teruhiko Wakayama, a co-author formerly at CDB now at the University of Yamanashi in Kofu, says that Obokata shared the reviewers’ comments with him and he made suggestions for revisions pertaining only to the chimeric mice experiments, which were his responsibility. He says he has no idea if the revised papers were again sent to reviewers.
Wakayama says it might be a good idea for journals to send reviewer comments to all co-authors as another safeguard against problematic papers. “However, most co-authors just contribute to one or a few parts of the experiments,” he says. This means that even if all co-authors receive the reviewer comments they might not be in a position to address identified problems.