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: https://www.nature.com/authors/policies/corrections.html.

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: https://www.nature.com/news/protection-priority-1.18354.

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.

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20 thoughts on “Nature cancer paper that raised animal welfare concerns is retracted”

  1. Another study funded by NIH grants has serious data problems. Any accountability? Not likely. Sadly, the NIH will again turn a blind eye, and those responsible for these problems will continue to bask in huge amounts of tax payer dollars. This information is getting out into the public which is fast losing the trust it placed in the NIH.

  2. I don’t think animal welfare concerns should have any bearing on retraction, which should be used as an indicator of the truthfulness and originality of the paper. But in this case, the evidence of image manipulation is enough to sink the paper.

    1. I strongly disagree with the first statement. Animal welfare issues often have a significant and direct impact on the validity of the data obtained. That’s aside from any moral issues of publishing and using data obtained under unethical conditions.

      1. I don’t know why you disagree with me when we both seem to think that the validity of the data is separate from “moral issues”.

        1. When authors doing human research fail to obtain informed consent, their articles are retracted, too. It shouldn’t be different with animal studies and that is a very strong message: if you’re research is unethical and causes unnecessary animal suffering, your articles will get retracted!

        2. The validity of the data is not separate from moral issues.

          When a researcher acts in an immoral fashion, the validity of the data is in question as the researcher has shown that he/she is not capable of performing scientific activity in a rigorous and proper fashion.

          When an animal is treated in an immoral fashion, the response of the animal is likely to be abnormal, so the data arising is likely suspect.

  3. Sam Lee and Toru Ouchi, who share a retraction,
    https://retractionwatch.com/2015/09/04/investigation-leads-to-retraction-of-breast-cancer-paper-second-for-one-author/

    also share this publication.
    http://www.jbc.org/content/281/14/9710.long
    The Journal of Biological Chemistry 281, 9710-9718.
    ATM Activation by Ionizing Radiation Requires BRCA1-associated BAAT1*
    Jason A. Aglipay‡, Sarah A. Martin‡, Hideyuki Tawara‡, Sam W. Lee§ and Toru Ouchi‡,1
    – Author Affiliations

    ‡Department of Oncological Sciences, Mount Sinai School of Medicine, New York University, New York, New York 10029 and the §Harvard Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129.

    Figure 7C.

    https://imgur.com/ibw2QMP

  4. http://emboj.embopress.org/content/22/6/1289.long
    The EMBO Journal (2003) 22, 1289-1301.
    p53 induction and activation of DDR1 kinase counteract p53‐mediated apoptosis and influence p53 regulation through a positive feedback loop
    Pat P. Ongusaha, Jong‐il Kim, Li Fang, Tai W. Wong, George D. Yancopoulos, Stuart A. Aaronson, Sam W. Lee
    Author Affiliations
    Pat P. Ongusaha1, Jong‐il Kim2, Li Fang3, Tai W. Wong4, George D. Yancopoulos5, Stuart A. Aaronson3 and Sam W. Lee*,1
    1 Cancer Biology Program, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine and Harvard Medical School, Boston, MA, 02115, USA
    2 Present address: Department of Biochemistry, College of Medicine, Hallym University, Chunchon, 200‐702, Korea
    3 Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY, 10029, USA
    4 Oncology Drug Discovery Group, Bristol‐Meyer Squibb Pharmaceutical Research Institutes, Princeton, NJ, 08543, USA
    5 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA.

    Figure 1A.

    https://imgur.com/EEazvqM

    https://pubpeer.com/publications/6642F5BE0C95BDE85C019D0D35A5F5

  5. http://mcb.asm.org/content/20/5/1723.long
    Mol. Cell. Biol. March 2000 vol. 20 no. 5 1723-1732
    Overexpression of Kinase-Associated Phosphatase (KAP) in Breast and Prostate Cancer and Inhibition of the Transformed Phenotype by Antisense KAP Expression
    Sam W. Lee1,*, Corinne L. Reimer1, Li Fang2, M. Luisa Iruela-Arispe3, and Stuart A. Aaronson2
    – Author Affiliations

    Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Harvard Medical School, Boston, Massachusetts 021151;
    Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 100292; and
    Department of Molecular, Cell and Developmental Biology, Molecular Biology Institute, University of California, Los Angeles, California 900953

    https://pubpeer.com/publications/E182BF54F2EB5B4A748A2494B61AEF

  6. I want my taxpayer money back! All patents should be immediately voided! The company Canthera should be seized by the federal government. All of these people need to be fired and never get anywhere near a lab or federal money. This outrageous garbage coming from so-called ‘elite’ institutions is outrageous and ABSOLUTELY UNACCEPTABLE

  7. http://emboj.embopress.org/content/20/8/1931.long
    The EMBO Journal (2001) 20, 1931-1939.
    p53 induction of heparin‐binding EGF‐like growth factor counteracts p53 growth suppression through activation of MAPK and PI3K/Akt signaling cascades.
    Author Affiliations
    Li Fang1, Guangnan Li2, Guizhong Liu1, Sam W. Lee*,3 and Stuart A. Aaronson*,1
    1 Derald H.Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY, 10029, USA
    2 Department of Pharmacology, Mount Sinai School of Medicine, New York, NY, 10029, USA
    3 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine and Harvard Medical School, Boston, MA, 02115, USA.

    https://pubpeer.com/publications/2AB99B05875815909F063F63C062C7

  8. http://mcb.asm.org/content/20/20/7450.long
    Mol. Cell. Biol. October 2000 vol. 20 no. 20 7450-7459.
    Tumor Suppressor p53 Is Required To Modulate BRCA1 Expression
    Paz Arizti1, Li Fang2, Iha Park1, Yuxin Yin3, Ellen Solomon4, Toru Ouchi2, Stuart A. Aaronson2, and Sam W. Lee1,*
    – Author Affiliations

    Department of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, Massachusetts 021151;
    The Derald H. Ruttenberg Cancer Center, The Mount Sinai Medical School, New York, New York 100292;
    Department of Molecular Biology, Princeton University, Princeton, New Jersey 085443; and
    Division of Medical and Molecular Genetics, UMDS, Guy’s Hospital, London SE1 9RT, United Kingdom4.

    https://pubpeer.com/publications/6AC86E7AFCBB54BAB8E4F4FFACF822

  9. For Nature, the retraction of this paper is the easy way out. It would be much more helpful to the readership of Nature if the editors invited a group of experts to write a critical commentary/perspective that would clarify which findings have been independently replicated, and are likely valid, and which are false or in doubt. After all, it has been 7 years since the article was published!

    In a similar case of extensive image manipulation involving multiple papers, Cell Metabolism allowed us to write such a review but this seems to be a rare exception not the rule (Cell Metabolism Volume 22, Issue 5, 3 November 2015, Pages 777-787).

  10. https://www.nature.com/articles/1207057
    Original Paper | Published: 03 December 2003
    Oncogene volume 22, pages 8931–8938 (04 December 2003)
    A member of the Pyrin family, IFI16, is a novel BRCA1-associated protein involved in the p53-mediated apoptosis pathway
    Jason A Aglipay, Sam W Lee, Shinya Okada, Nobuko Fujiuchi, Takao Ohtsuka, Jennifer C Kwak, Yi Wang, Ricky W Johnstone, Chuxia Deng, Jun Qin & Toru Ouchi.

    Jason A Aglipay 1 , Sam W Lee 2 , Shinya Okada 1 , Nobuko Fujiuchi 1 , Takao Ohtsuka 2 , Jennifer C Kwak 2 , Yi Wang 3,4, Ricky W Johnstone 5 , Chuxia Deng 6 , Jun Qin 3,4 and Toru Ouchi*,1
    1 The Derald H. Ruttenberg Cancer Center, The Mount Sinai School of Medicine, New York University, New York, NY, USA;
    2 Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA; 3
    Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA; 4 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA; 5 Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Victoria, Australia; 6
    Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases,
    National Institutes of Health, Bethesda, MD, USA.

    https://pubpeer.com/publications/983D28C77FA06F2B9A7149984E91F7

  11. Future assured.
    https://connects.catalyst.harvard.edu/Profiles/display/Person/87338

    1. R01CA210560 (LEE, SAM W) Dec 1, 2016 – Nov 30, 2021
    NIH/NCI
    Tumor suppressor p53 and its targets in checkpoint regulation
    Role: Principal Investigator

    2. R01CA203552 (LEE, SAM W) Jul 1, 2016 – Jun 30, 2021
    NIH/NCI
    p53-mediated dead cell clearance in response to DNA damage and tumorigenesis
    Role: Principal Investigator

    3. R01CA195534 (LEE, SAM W) Mar 1, 2015 – Feb 29, 2020
    NIH/NCI
    P53 survival target DDR1 kinase in DNA damage response and carcinogenesis
    Role: Principal Investigator

  12. Exactly. ORI is a toothless tiger. They “rely on and trust” the institution to investigate. But when the institution benefits with huge amounts of indirect costs from grants, such as in this case, what incentive is there to investigate? It’s a completely broken and perverse system of policing.

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