Research integrity Research Reproducibility

Lopez-Otin and Kroemer: birds of a feather flock together

Following my reporting, the cancer researcher Carlos López-Otín abandoned his ERC-funded 36-member-strong "Degradome" lab at the University of Oviedo in Spain and moved in with his collaborator in Paris, France, Guido Kroemer. Yet Lopez-Otin's data integrity issues seem as poppycock compared to what Kroemer and his life partner Laurence Zitvogel dished out to the scientific community.

Not many pre-retirement age professors abandon their running laboratories for a sabbatical to start anew as a young investigator in a different country. Yet this is what the 60 year old cancer researcher Carlos López-Otín did. This ERC-funded professor of Biochemistry and Molecular Biology left behind his 36-member-strong “Degradome” lab at the University of Oviedo in Spain and moved in with his collaborator in Paris, France, another degradome (autophagy and apoptosis) researcher Guido Kroemer.

That happened after my reporting uncovered numerous instances of inappropriate research data handling and publication from the Lopez-Otin lab, following his 2017 Mentoring Award issued by Nature. Who is going to mentor his over two dozens of postdocs, PhD and undergraduate students in Oviedo now, is anyone’s guess. But Lopez-Otin is now Professeur des universités-praticien hospitalier (PUPH) at the Centre de Recherche des Cordeliers (CRC), which Kroemer is deputy director of.

The issues with Lopez-Otin’s research publications were mostly about re-used loading controls, retouched images and original data which did not match the published figures. It pales however when compared to what Kroemer himself has published, and this post will present some of that PubPeer evidence of duplicated gel bands. Maybe this is why Lopez-Otin moved in with Kroemer: research integrity is a relative issue, especially in France. Kroemer even signed that notorious CNRS Stalinist letter in defence of data manipulations and against whistleblowing and critical journalism.

carlos-and-guido.png
Original photo: La Nueva Espana

Lopez-Otin departure from Oviedo was reported by the Spanish newspaper La Nueva Espana already in July 2018:

“I do not know when Carlos Lopez Otín will return to the University of Oviedo”, said yesterday the rector, Santiago García Granda, who considers the stay of Professor of Molecular Biology at the University Pierre and Marie Curie in Paris as a natural matter. “Moving is a normal thing”. […]

The temporary departure of Otín, García Granda said,is a part of the normal trajectory of the researchers: “He asked and was granted,” said Rector, who said that the professor “went alone” to work with one of his Gallic colleagues”.

The Gallic host of this refugee from Hispania was not named, but it is most obviously Kroemer. Lopez-Otin’s is associated with Kroemer’s department Apoptose, cancer, immunité at the CRC. I tried to find out what happened with Lopez-Otin’s fresh ERC grant of €2.5 million, awarded for 2017-2022, and whether the money stayed back in Oviedo or travelled with its owner to France to meet Kroemer. But unfortunately ERC does not communicate with me, and these EU funders of elite science do not seem to believe in research integrity anyway. In any case, ERC million-heavy grants are known to open hearts and minds, only the eyes stay closed, strangely.

Screenshot_2018-10-18 L'annuaire - CRC

My first article about Lopez-Otin appeared in December 2017, on the occasion of his Nature Mentoring Award, it described the PubPeer evidence of data manipulations in his papers.  Then, in May 2018, my regular contributor Smut Clyde, discovered a “perennial Northern Blot“, which appeared in no less than 23 different papers from Lopez-Otin lab, over a period of 12 years. When my last article from August 2018 addressed the mismatch between the original research data and the presented results in a Nature Cell Biology paper, Lopez-Otin was already hiding in Paris with Kroemer, appreciating the French culture, cheeses and the country’s special variety of institutionalised research fraud.

That elite journal publication earned on October 4th an editorial note:

“Editor’s Note: We would like to alert readers that the reliability of data presented in this manuscript has been the subject of criticisms, which we are currently considering. We will publish an update once our investigation is complete.”

A key contributor to that study Soria-Valles et al Nature Cell Biology, 2015 was George Q Daley, Dean of Harvard Medical School and one of the most influential people worldwide in the field of stem cell research. After my May 2018 article and the comments it ensued, Daley set up a replication effort to reproduce the results he and Lopez-Otin published. At least two people were assigned to that project. The first author Clara Soria-Valles was not part of it though. She used to be a PhD student of Lopez-Otin’s, delegated to the Daley lab, where she remained as postdoc. In April 2018 however, Soria-Valles left Harvard, just when the post-publication peer review debate of her paper took off on PubPeer and the comment section of my site. Another paper of Soria-Valles’ was about to be submitted for publication to a stem cell society journal, but the study’s future and reliability are not sure, especially since all of its appointed authors left Daley lab by now.

For the Nature Cell Biology paper, Soria-Valles’ special contribution was the cell colony-counting technique, and those were the results which the commenters on my site and on PubPeer could make neither head nor tail of. Here are some examples, annotated by PubPeer users:

According to my source, Soria-Valles

“is not looking for her raw data to correct Nature Cell Biology, even though i) the journal published a comment last week; ii) Freije (another co corresponding of the paper) is contacting with all authors on the paper”

Jose Maria Perez Freije is professor at University of Oviedo, now doing the job of saving that paper without the help of Lopez-Otin or anyone else. Incidentally, Soria-Valles’ second co-author on her Nature Cell Biology paper is her fiancée Fernando Garcia Osorio, who also did PhD with Lopez-Otin and in this regard is responsible for a rather problematic paper of his own,  Osorio et al Genes & Development 2012.

Did Soria-Valles and Osorio meet in a “creative Figure Preparation” course at Lopez-Otin lab? More on PubPeer.

Daley’s lab now published a preprint, Powers et al 2018. Apparently, for Biorxiv one duplicated and one Photoshop-assembled loading control were good enough. Will a “better” version be produced for a proper journal, with impact factor?

biorxiv-daley.png

It is a mess, and probably very stressful for everyone involved, and certainly the last thing Lopez-Otin, a hero of Spanish and international cancer research at the peak of his fame, needed. One fully understands why he left behind his huge lab and all the hassle in Oviedo and went to Paris: who wouldn’t? Kroemer is in this regard an excellent choice of a host. Lopez-Otin’s data integrity issues can seem as poppycock compared to what Kroemer and his life partner Laurence Zitvogel, based at the institute Gustave Roussy, dished out to the scientific community. Le Monde described this couple as an “explosive tandem”, it might just as well apply to their PubPeer record.

This is for example what Zitvogel and Kroemer produced in the highly impactful journal Nature Medicine, Apetoh et al 2007:

The relevant PubPeer thread elucidates that the blank gel fragments highlighted with colour circles look suspiciously similar up to the most minor details, not just in that Figure 3A. It would of course be interesting to know what the real western blots of those samples probed with those antibodies looked like. Or of their loading controls, because apparently also there things got duplicated out of every reasonable context.

Or how about this apparently duplicated set of Western blot bands in a Kroemer & Zitvogel co-production, published in EMBO Journal as Criollo et al 2010?

It just looks like laziness, or trolling. In any case, the lone  PubPeer comment received no follow-up, from anyone. But there are many other papers on PubPeer, and some of those happened apparently before Guido met Laurence. Here is something from Kroemer’s bachelor times, again in EMBO Journal, Castedo et al 2002.

kroemer-embo-j.png

Kroemer is EMBO member, maybe this is why he is allowed to leave such beauties stand. EMBO Press seems to give a special leeway to EMBO members, like Olivier Voinnet or Maria Pia Cosma.

Here is another Kroemer-esque work of Photoshop art, same first author, Castedo et al J Exp Medicine 2001:

image-1570043360648

Enough for now, you got the message. If not, visit this Susin et al J Exp Medicine 1999 paper, showing some vintage western blot art by early Kroemer, or these beautifully corrected artworks Massard et al Oncogene 2006 or  Zermati et al, Molecular Cell, 2007, where you can find some duplicated or even triplicated flow cytometry results for a change.

3wtdlzx

After all that, you probably will not be surprised that Kroemer was one of signatories of a recent Stalinist letter organised by CNRS. This letter defended data manipulations commited by CNRS chief biologist Catherine Jessus and the phony fraud-endorsing investigation by her friend and subordinate, the EMBO and Academie des Sciences member Francis-Andre Wollman, while calling for the heads of  whistleblowers and critical journalists (more on that here).

What a company Lopez-Otin is now.


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76 comments on “Lopez-Otin and Kroemer: birds of a feather flock together

  1. Let’s keep eyes on those PubPeer posts. PubPeer is favor to George Daley’s power and may remove thereads eventually. This is exactly happening to Soria-Valles’ Nature Cell Biology which Daley senior-authored.

    Like

  2. Another PubPeer comment to criticise Daley’s ‘epigenetic’ memory.
    In addition to embarrasing duplicated images in the same paper, others cannot replicate one of key claim.
    He is moving to CRISPed baby from reprogramming. He basically said China did wrong to CRISPR human baby, but if Harvard does it, that is RIGHT. See Hong-kong gene edit summit. http://www.nationalacademies.org/hk/index.html https://twitter.com/antonioregalado

    Epigenetic memory in induced pluripotent stem cells
    Nature (2010) – 2 Comments
    pubmed: 20644535 doi: 10.1038/nature09342 issn: 1476-4687 issn: 0028-0836

    K. Kim , A. Doi , B. Wen , K. Ng , R. Zhao , P. Cahan , J. Kim , M. J. Aryee , H. Ji , L. I. R. Ehrlich , A. Yabuuchi , A. Takeuchi , K. C. Cunniff , H. Hongguang , S. Mckinney-Freeman author has email , O. Naveiras , T. J. Yoon , R. A. Irizarry , N. Jung , J. Seita , J. Hanna , P. Murakami , R. Jaenisch , R. Weissleder , S. H. Orkin , I. L. Weissman , A. P. Feinberg , G. Q. Daley

    https://pubpeer.com/publications/E8874B8B02107526F141197718C646
    “Kim et al. showed that blood-derived iPS cells prone to follow blood lineage. In contrast, follow up study by Kyttala et al. did not observe lineage bias. ”

    https://imgur.com/a/TiawZyF

    Like

  3. I have inquired EMBO long-term fellowship program and manager Inga Strazda about Soria-Valles’ ALTF 1240-2015 fellowship. I asked if the money was properly given and used. And what if the money was still payed after Soria-Valles left Harvard. I mentioned them problems around Soria-Valles’ research, which should be concerning to program’s integrity. I hope the money will be properly used in right science and right people.

    Like

    • I learned that Soria-Valles’ EMBO Fellowship expired in May 2018. She left the Daley lab already months before that and is officially on a paid medical leave ever since her fellowship ended, till present date. All the best for her fragile health.

      Like

      • “(Soria-Valles) is officially on a paid medical leave ever since her fellowship ended”. So both Harvard Medical School and EMBO are damping public money to sustain someone her paper is significantly doubted and investigated. Is this common academia practice?

        Like

      • Actually I was also told medical leaves are unpaid in Harvard, incl in Daley lab. Soria-Valles is special.

        Like

  4. PubPeer readers are doubting reprogramming paper of Daley lab. One of his most highly cited paper, 3,113 times (Dec. 1 2018).
    Every cell line from the paper failed reprogramming.

    Reprogramming of human somatic cells to pluripotency with defined factors
    Nature (2008) – 6 Comments
    pubmed: 18157115 doi: 10.1038/nature06534 issn: 1476-4687 issn: 0028-0836

    In-Hyun Park , Rui Zhao , Jason A. West , Akiko Yabuuchi , Hongguang Huo , Tan A. Ince , Paul H. Lerou , M. William Lensch , George Q. Daley

    https://pubpeer.com/publications/A600E09BABFB5C7A28B86BBA6F8AD9#6

    “Lack of transgene silencing is a feature of failed reprogramming. In this paper, cells remained partial reprogrammed state, rather than iPS cells. Please see Hochedlinger and Plath description here.”

    “Wow. Every cell line transgene on. Evidence of failed reprogramming.”

    Like

  5. PubPeer readers are commenting issues in Daley’s human reprogramming Nature paper.
    The data indicated that they could not achieve iPSCs actually.

    Reprogramming of human somatic cells to pluripotency with defined factors
    Nature (2008) – 8 Comments
    pubmed: 18157115 doi: 10.1038/nature06534 issn: 1476-4687 issn: 0028-0836

    In-Hyun Park , Rui Zhao , Jason A. West , Akiko Yabuuchi , Hongguang Huo , Tan A. Ince , Paul H. Lerou , M. William Lensch , George Q. Daley

    https://pubpeer.com/publications/A600E09BABFB5C7A28B86BBA6F8AD9

    “This study used H1-OGN cell line, endogeneous OCT4-GFP reporter. If reprogramming was complete, they should express GFP. However, I do not see any data about GFP in their reprogrammed cells…”

    “On contrary to this paper, Yamanaka reported fully suppression of transgenes and achievement of complete reprogramming of human somatic cells a year ago. Thomson group also achieved human iPS cells whose transgenes were mostly suppressed.”

    Like

  6. More comment on PubPeer argues against Daley lab’s claim on reprogramming.
    Reprogramming of human somatic cells to pluripotency with defined factors
    Nature (2008) – 9 Comments
    pubmed: 18157115 doi: 10.1038/nature06534 issn: 1476-4687 issn: 0028-0836

    In-Hyun Park , Rui Zhao , Jason A. West , Akiko Yabuuchi , Hongguang Huo , Tan A. Ince , Paul H. Lerou , M. William Lensch , George Q. Daley
    https://pubpeer.com/publications/A600E09BABFB5C7A28B86BBA6F8AD9

    “Actually Kevin Eggan lab demonstrated that you do not need Daley’s 6 factors (Large T Antigen + TERT + Yamanaka 4 factors), only Yamanaka 4 factors are enough. citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.666.169&rep=rep1&type=pdf “Our results with patient-derived cells confirm the initial finding that the exogenous expression of only four factors—KLF4, SOX2, OCT4, and c-MYC—is sufficient to reprogram human fibroblasts to a pluripotent state (6). Previous reports using these four genes to generate human iPS cells have required the overexpression of either a murine viral receptor (6) or additional oncogenes such as Large T Antigen and TERT (21). In contrast, our results using retroviruses pseudotyped to transduce human cells dispel the suggestion by a recent study that these four genes are not sufficient to induce reprogramming (21).”

    Like

  7. Another famous Nature paper from the Daley lab had been disputed.

    Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients
    Nature (2010) – 1 Comment
    pubmed: 20164838 doi: 10.1038/nature08792 issn: 1476-4687 issn: 0028-0836

    Suneet Agarwal , Yuin-Han Loh , Erin M. McLoughlin , Junjiu Huang , In-Hyun Park , Justine D. Miller , Hongguang Huo , Maja Okuka , Rosana Maria Dos Reis , Sabine Loewer , Huck-Hui Ng , David L. Keefe , Frederick D. Goldman , Aloysius J. Klingelhutz , Lin Liu , George Q. Daley

    The Artandi group refuted the main findings of this paper by Daley and colleagues and showed that ” even in the undifferentiated state, iPSCs from dyskeratosis congenita patients harbour the precise biochemical defects characteristic of each form of the disease and that the magnitude of the telomere maintenance defect in iPSCs correlates with clinical severity”.

    https://www.ncbi.nlm.nih.gov/pubmed/21602826

    Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells.

    Nature. 2011 May 22;474(7351):399-402. doi: 10.1038/nature10084.
    Batista LF1, Pech MF, Zhong FL, Nguyen HN, Xie KT, Zaug AJ, Crary SM, Choi J, Sebastiano V, Cherry A, Giri N, Wernig M, Alter BP, Cech TR, Savage SA, Reijo Pera RA, Artandi SE.
    https://pubpeer.com/publications/265A83EC56E557C8588D151FFEBBC0#

    Like

  8. More concerns from readers about Daley’s human reprogramming Nature paper.
    Reprogramming of human somatic cells to pluripotency with defined factors
    Nature (2008) – 10 Comments
    pubmed: 18157115 doi: 10.1038/nature06534 issn: 1476-4687 issn: 0028-0836

    In-Hyun Park , Rui Zhao , Jason A. West , Akiko Yabuuchi , Hongguang Huo , Tan A. Ince , Paul H. Lerou , M. William Lensch , George Q. Daley

    https://pubpeer.com/publications/A600E09BABFB5C7A28B86BBA6F8AD9

    “The absence of RT-PCR data for Large T integration is highly disturbing. Why not show the data? If the “Daley iPS cells” really lacked Large T, the authors should be transparent and show the negative data.
    The presence of Large T in “Daley iPS cells” is very concerning.”

    Like

  9. Question raiser

    One really has to raise questions about the scientific judgment of a PI whose lab has so many “controversial” findings.

    Like

  10. The controversial findings of the Daley lab.
    1. One of the first claim of Human iPS cells.
    Disputed by Eggan lab.
    2. Epigenetic memory of iPS cells.
    Disputed by Hochedlinger lab.
    3. Telomere elongation in iPS cells.
    Disputed by Artandi lab.
    4. Ectogenesis from ES cells.
    Disputed by Saitou lab.

    Like

  11. A line of controversial HMS PIs on stem cell therapeutics. Lee Rubin who is mostly well known for forced mental-exam to his own student
    https://www.sciencemag.org/news/2017/01/how-dispute-harvard-led-grad-student-s-forced-mental-exam-and-extraordinary-restraining
    , had founded a start-up company with George Daley to target neurodegenerative diseases
    https://hsci.harvard.edu/company-startups
    iPierian
    “HSCI Co-director Douglas Melton, PhD, Executive Committee member George Daley, MD, PhD, and Principal Faculty member Lee Rubin, PhD, together co-founded iPierian, which is developing therapies that inhibit the progression of Alzheimer’s and other neurodegenerative diseases. Daley, Rubin, and Principal Faculty member Kevin Eggan, PhD, now act as scientific advisers.”

    Like

  12. More PubPeer comments to Daley’s controversial telomere elongation iPS cell paper (Nature).

    Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients
    Nature (2010) – 3 Comments
    pubmed: 20164838 doi: 10.1038/nature08792 issn: 1476-4687 issn: 0028-0836

    Suneet Agarwal author has email , Yuin-Han Loh , Erin M. McLoughlin , Junjiu Huang , In-Hyun Park author has email , Justine D. Miller , Hongguang Huo , Maja Okuka , Rosana Maria Dos Reis , Sabine Loewer , Huck-Hui Ng , David L. Keefe , Frederick D. Goldman , Aloysius J. Klingelhutz , Lin Liu , George Q. Daley

    “Telomere elongation (Daley) vs. shortening (Artandi) in reprogrammmed dyskeratosis congenita cells.”
    https://pubpeer.com/publications/265A83EC56E557C8588D151FFEBBC0#3

    Like

  13. Daley’s reprogramming cocktail induced abnormal karyotype. Large T iPS cells (Park, 2008) are not used in the field any more.

    Reprogramming of human somatic cells to pluripotency with defined factors
    Nature (2008) – 11 Comments
    pubmed: 18157115 doi: 10.1038/nature06534 issn: 1476-4687 issn: 0028-0836

    In-Hyun Park author has email , Rui Zhao , Jason A. West , Akiko Yabuuchi , Hongguang Huo , Tan A. Ince , Paul H. Lerou author has email , M. William Lensch author has email , George Q. Daley

    “Large T iPS cells carry abnormal karyotype. Johns Hopkins group repeated reprogramming with Thomson 4 factors + large T antigen. After 10 passages, all the cell lines carried abnormal karyotype, consistent with previous reports. Thus large T iPS cells (Park et al) have been dismissed in the field. ”
    https://pubpeer.com/publications/A600E09BABFB5C7A28B86BBA6F8AD9

    Like

  14. Soria-Valles’ another paper was commented on PubPeer. Readers are skeptical to weirdly tiny error bars in blood metabolite measure.
    Numerical data should be provided.

    MMP-25 Metalloprotease Regulates Innate Immune Response through NF-κB Signaling
    The Journal of Immunology (2016) – 1 Comment
    pubmed: 27259858 doi: 10.4049/jimmunol.1600094 issn: 1550-6606 issn: 0022-1767

    Clara Soria-Valles author has email , Ana Gutiérrez-Fernández , Fernando G. Osorio , Dido Carrero , Adolfo A. Ferrando , Enrique Colado , M. Soledad Fernández-García , Elena Bonzon-Kulichenko , Jesús Vázquez , Antonio Fueyo , Carlos López-Otín

    “The error bars of figure 3C, blood metabolites in six mice are too small. Based on physiological variability of these parameters, it is concerning. The authors could show source data of numerics.”

    https://pubpeer.com/publications/46D48D7AB88DC28DD57C0CC1BF8DF9#1

    Like

  15. Soria-Valles’ one more paper (Oncogene, 2014) was commented on PubPeer.
    They have not deposited their own microarray data. Instead, they placed the irrelevant dataset of another lab in different tissue.

    The anti-metastatic activity of collagenase-2 in breast cancer cells is mediated by a signaling pathway involving decorin and miR-21
    Oncogene (2014) – 1 Comment
    pubmed: 23851508 doi: 10.1038/onc.2013.267 issn: 1476-5594 issn: 0950-9232

    C Soria-Valles , A Gutiérrez-Fernández , M Guiu , B Mari , A Fueyo , R R Gomis , C López-Otín

    “I do not find accession number of microarray data of breast cancer cell lines produced in this study… The accession number they listed as GPL4718 in Methods section is actually lung cancer of another lab, not breast cancer lines used in this paper. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GPL4718 “we transfected 4175 (LM2) cells with the murine Mmp8 complementary DNA (cDNA) and isolated several stable transfectant clones that expressed the gene. We decided to use two of these clones (clones 3 and 8) for further studies” The authors did microarray of clone 3 in figure 3a. Are the microarray data deposited?”

    https://pubpeer.com/publications/8D0F4C1D83621DE5F72E92A4C39787#1

    Like

  16. Powers et al. from Daley lab (biorxiv, 2018) fixed copy-paste and splicing issues raised by pubpeer readers. The Daleys appear to retract original article and reposted corrected one as a new submission, so current readers can see no trace of issues raised before.

    https://www.pubpeer.com/publications/5D8FDD6767EE6F2424B5D9B0164CF7#4

    The copy-pasted bands and splicing problems were fixed in newer version of manuscript uploaded on biorxiv Dec. 11, 2018.
    https://www.biorxiv.org/content/early/2018/12/11/372920

    Like

  17. It has past over two months since editor’s note was published about Soria-Valles’ Nature Cell Biology article. I wonder there will be any reaction to this article? Ignored? What ” In any case, with Daley and his postdoc on board, the correction of that paper will become a rather sensitive and political issue.” in your August article means? Can big professors bury journal editor actions?

    Like

  18. Pingback: Lopez-Otin and Daley retract Nature Cell Biology paper – For Better Science

  19. Pingback: Spanish elites rally in support of data manipulation – For Better Science

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