Nature cancer paper that raised animal welfare concerns is retracted

When Nature published a paper in 2011 describing a compound extracted from a pepper plant that appeared to kill cancer cells but leave healthy cells unscathed, it got some attention.

Of course, the news caught the media’s eye, but also that of other researchers, who have since jumped on the concept, and continued to study the effects of the compound — piperlongumine — on cancer, as well as other conditions.

But ever since the 2011 letter appeared, researchers have raised concerns about some of the figures — including one that showed mice with massive tumors, suggesting they had experienced an unreasonable amount of distress during the study. Nature has responded by issuing two lengthy correction notices in 2012 and 2015— as well as an editorial that admitted the animals may have “experienced more pain and suffering than originally allowed for,”but did not warrant retracting, as the results remained “valid and useful.”

Today, the journal is retracting the paper, with the following brief notice:

This Letter is being retracted owing to issues with Fig. 1d and Supplementary Fig. 31b, and the unavailability of original data for these figures, which raises concerns regarding the integrity of the figures. Nature published two previous corrections related to this Letter. These issues in aggregate undermine the confidence in the integrity of this study.

The notice explains that four of the 14 authors — including the first and last author — disagree with the retraction.

Selective killing of cancer cells by a small molecule targeting the stress response to ROS” has been cited 577 times, according to Clarivate Analytics’ Web of Science — making it a “highly cited paper,” meaning it was ranked in the top 1 percent of all papers in its field for the year it was published. It’s been cited 257 times since its last correction was published in September 2015.

The last author of the paper, Sam W. Lee, has retracted two other papers in recent years.

There’s a lot to unpack here. For starters, what made the journal change its mind and retract the paper now? In response to our questions, a spokesperson told us:

All retractions are considered on a case-by-case basis, and decisions about whether to retract are made by Nature’s in-house editors, who may seek advice from independent peer-reviewers. Following this process, if the editors deem that a retraction is appropriate, all authors are contacted to seek their assent to the retraction and the retraction statement. Following this, the retraction notice will be published, and any dissenting authors noted in the text of the published version. More information about our retraction policy is available on our website:

We take all issues related to animal welfare very seriously and should we become aware of any breach of our policies in any published paper, we would follow an established process to investigate the issues. More details about Nature’s policies for papers that report experiments with animals are outlined in this editorial:

When we asked for more specifics about what happened with this particular paper, the spokesperson referred us to the retraction notice:

The issues detailed in the retraction notice do not relate to the previous concerns regarding animal welfare, although all these issues in aggregate undermine the confidence in the integrity of this study.

One reader forwarded us correspondence with the journal dating back to June 2016, in which he raised concerns that supplementary figure 31 contained manipulated images.

We’re also trying to find out more information about why the authors were split in their agreement over the retraction. We contacted coauthor Stuart Schreiber to ask why he agreed with the retraction, and whether it has any impact on a patent related to compounds for cancer therapy, which cites the now-retracted paper; he said he was traveling, and forwarded us to David Cameron, spokesperson for the Broad Institute of MIT and Harvard. Cameron told us:

Although the scientific conclusions of the paper appear sound and its key findings have been extended by other investigators in independent publications, in an abundance of caution all authors who contributed experiments at the Broad Institute of MIT and Harvard support the Nature editors’ recommendation to retract the paper. Because the particular figures referenced were not generated at the Broad, we are not in a position to discuss them.

We emailed co-authors Mandinova and Lee, who co-founded a company around the technology described in the paper — and disagreed with the retraction — but have not received a response. Mandinova and Lee have also filed patents together, including one from 2012 that mentions piperlongumine.

Lee — based at Massachusetts General Hospital — has retracted two papers — a Molecular Cell paper in 2013 due to figure duplication and a Journal of Biological Chemistry paper in 2015, citing “manipulated” data in a figure. He’s also issued at least one other mega-correction, and last year received an expression of concern on another 2011 paper, noting “credible concerns” about the data and conclusions.