Mass investigation of 9 senior scientists at Karolinska Institutet

The scandal-shaken Swedish Karolinska Institutet (KI) invited nine of their research group leaders and professors to explain themselves about data integrity concerns raised in regard to their publications. They have time until November 24^th 2016 to address of the suspicions of image duplications which were posted on PubPeer by anonymous watchdogs and subsequently reported to Karolinska by a whistleblower. This was the email the 9 scientists received on November 10^th from Lisen Samuelsson of KI’s legal department:

“Karolinska Institutet (KI) has been notified about inaccuracies in one or more scientific articles according to comments on the website PubPeer. You are named as the main author of the article (s) in question.

KI therefore requests that you provide a statement regarding whether the alleged inaccuracies are correct or not. If there are inaccuracies in the article (s), KI requests that you specify whether they have been corrected, or if they will be corrected, and if so, how. Please submit your statement to KI at registrator@ki.se regarding this matter by November 24, 2016”.

The email was complemented by a list of these scientists’ respective PubPeer-flagged publications. Most of these 9 addressees are very senior KI researchers, like Ulla Stenius and Boris Zhivotovsky. Here is the list, with some background information:

Boris Zhivotovsky, senior professor at the Institute of Environmental Medicine (IMM). He specializes in “molecular mechanisms of cell death and implication in disease” and is the former PhD advisor and mentor of another problematic KI researcher, Helin Vakifahmetoglu-Norberg. The latter was initially acquitted and now apparently again investigated by KI, after new evidence surfaced on my site (and then on PubPeer) about hers and Zhivotovsky’s common earlier publications. Here however, Zhivotovsky is getting his own private investigation. He was now invited to take a stand on the following publication which does not feature Vakifahmetoglu-Norberg as co-author:

Bertrand Joseph, Philippe Marchetti, Pierre Formstecher, Guido Kroemer, Rolf Lewensohn, Boris Zhivotovsky, Oncogene, 21 (2002). “Mitochondrial dysfunction is an essential step for killing of non-small cell lung carcinomas resistant to conventional treatment”. PubPeer evidence.

According to my sources, Zhivotovsky has previously agreed to the editor-in-chief of the journal Cell Death Differentiation to retract his heavily manipulated paper Vakifahmetoglu et al 2008.  Yet as soon as the investigation against himself and his protégée re-opened, Zhivitovsky withdrew his approval, which now makes a retraction much more difficult.

 

Ulla Stenius, prefect of Zhivotovsky’s department IMM, re-installed in June 2016 by the decision of the KI Rector Karin Dahlman-Wright, despite the PubPeer criticisms of Stenius’ research, which focuses on “chemical carcinogensis, prevention and risk assessment”. According to Stenius, the re-election was based on the “faculty board recommendation”. A long list of 12 publications under suspicion has been forwarded to KI, for which Stenius now got 2 weeks to assemble her defense.

This is one paper from the list:

Lauy Al-Anati, Sandeep Kadekar, Johan Högberg, Ulla Stenius, Chem. Biol. Interact., 219 (2014). “PCB153, TCDD and estradiol compromise the benzo[a]pyrene-induced p53-response via FoxO3a”. PubPeer evidence.

An unsigned PubPeer comment which can be safely attributed to Stenius declared:

“Until recently splicing gels together without spacers were considered acceptable practice. However, all the bands presented in the figures from the manuscripts are from the same film and same exposure time”.

I contacted Stenius about these PubPeer concerns, specifically about the image above and its irregular gel splicing. There, loading controls did not seem to correspond to the main western blot analysis, which compared expression of several regulatory proteins under different experimental conditions. Without a proper loading control, such a comparative protein expression analysis becomes pointless, if not deceptive. Stenius replied:

“In this case all the panels were not derived from the same gel. This is shown by the fact that both total FoxO3a as well as its phosphorylated form (pFoxO3a Thr32) is shown. The phosphorylated form of the protein has almost identical molecular weight as the nonphosphorylated form and are not separated. Theoretically it is possible to use a technique called “stripping” in a case like this. However, according to our experience it often gives false results and we use different gels. In the published figure only one loading control is included. This is common practice in many laboratories and accepted by journals”.

This however stands in stark contrast to this paper’s published description of experimental methods, which clearly suggested b-actin was the sole loading control. In any case, the KI prefect chose not to address my question what was exactly the loading control for the sliced p53 western blot supposed to be.

The academic Editor-in-Chief of this journal, Daniel Dietrich, announced to me to investigate this case, after pointing out to be “at the moment overloaded with similar issues, all to be taken very seriously”.

Here is another example of data integrity concerns about Stenius publications:

Aram Ghalali, Zhi-Wei Ye, Johan Högberg, Ulla Stenius, J. Biol. Chem., 289 (2014). “Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and PH domain and leucine-rich repeat phosphatase cross-talk (PHLPP) in cancer cells and in transforming growth factor β-activated stem cells”. PubPeer evidence.

The first author Ghalali uploaded to PubPeer this original gel scan, which proves the suspected splicing and moreover evidences that the loading control Cdk2 does not fit. The journal’s data integrity manager Kaoru Sakabe promised me: “We will certainly look into it”. Update 15.01.2017: This paper has been retracted on January 13th, for gel splicing and image duplications, see reader comment below.

There is also another twist to faculty politics. I received a hint that Stenius was accused already in 2015 of unfair treatment and possibly also research misconduct by none other than Vakifahmetoglu-Norberg, the one who is now being investigated for some blatant data manipulations herself.  Vakifahmetoglu-Norberg brought her charges against her then-faculty boss Stenius to the then-Rector Anders Hamsten. It is unclear therefore if any investigation had followed, since Hamsten as we well know had to resign for his outrageous cover-up of the Paolo Macchiarini scandal of lethal trachea transplants.

More recently, the tables have turned. Stenius reported Zhivotovsky’s highly successful protégée to the KI Rector Dahlman-Wright, according to this email from April 2016 I was forwarded:

“Hi Karin,

I have been notified about info on pubpeer that I want to share with you. It is about the Helin Vakifahmehtoglu-Norberg’s publications. Helin was assistant professor at our Dept. but is since 1 Jan assigned elsewhere. I will inform Per and Henrik more details when they are visiting me after Easter, but yet wanted to inform you already now.

Kind regards, Ulla“

Such bold stand against other people’s research misconduct might have strengthened Stenius’ chance at being re-appointed as the faculty’s prefect. And indeed, she was. Now one has only to clear the issues with her own publications.

These are other scientists who received the KI invitation to explain the PubPeer concerns until November 24^th:

Rolf Lewensohn, professor and senior physician at the Department of Oncology-Pathology. He aims to “develop new oncological treatments in the form of novel drug candidates and precision radiotherapy”. Lewensohn is invited to comment on apparent image duplications in the above mentioned Joseph et al 2002 paper which he co-authored with Zhivotovsky as well as another publication from his own research group, which features as last author Lewensohn’s senior lab member, Kristina Viktorsson (who in turn received her own invitation to take a stand from KI):

L Lundholm, P Hååg, D Zong, T Juntti, B Mörk, R Lewensohn, K Viktorsson, Cell Death Dis, 4 (2013). “Resistance to DNA-damaging treatment in non-small cell lung cancer tumor-initiating cells involves reduced DNA-PK/ATM activation and diminished cell cycle arrest”. PubPeer evidence.

Bertrand Joseph, professor at the same oncology department as Lewensohn. Joseph is like Zhivotovsky an apoptosis researcher, his lab focuses on “life and death decisions at the cellular level”. He is invited to explain suspected image duplications in six publications, one of which is the above mentioned Zhivotovsky lab paper, another four are listed below. The sixth flagged paper which Joseph contributed to is the notorious Nature Communications opus on esophagus transplantation by KI’s former dream and now the nightmare surgeon, Paolo Macchiarini. That publication was found fraudulent by the Swedish central ethics committee CEPN and received therefore an Expression of Concern (but for some unfathomable reason, no retraction, yet). These are other Joseph papers, now placed under KI scrutiny:

Ulrika Nyman, Pinelopi Vlachos, Anna Cascante, Ola Hermanson, Boris Zhivotovsky, Bertrand Joseph, Mol. Cell. Biol., 29 (2009). “Protein kinase C-dependent phosphorylation regulates the cell cycle-inhibitory function of the p73 carboxy terminus transactivation domain”. PubPeer evidence.

Ulrika Nyman, Naveen Reddy Muppani, Boris Zhivotovsky, Bertrand Joseph, J. Cell. Mol. Med., 15 (2011). “Hsp72 mediates TAp73α anti-apoptotic effects in small cell lung carcinoma cells”. PubPeer evidence.

Emma Lindahl, Ulrika Nyman, Farasat Zaman, Carina Palmberg, Anna Cascante, Jawed Shafqat, Masaharu Takigawa, Lars Sävendahl, Hans Jörnvall, Bertrand Joseph, J. Biol. Chem., 285 (2010). “Proinsulin C-peptide regulates ribosomal RNA expression”. PubPeer evidence.

Miguel-Angel Gallego, Bertrand Joseph, Therese H Hemström, Susan Tamiji, Laurent Mortier, Guido Kroemer, Pierre Formstecher, Boris Zhivotovsky, Philippe Marchetti, Oncogene, 23 (2004). “Apoptosis-inducing factor determines the chemoresistance of non-small-cell lung carcinomas”. PubPeer evidence.

 

Cecilia Götherström, senior researcher at the Department of Clinical Science, Intervention and Technology (CLINTEC, which will probably remain most famous for its former star scientist Macchiarini). Götherström declares her overall aim as “to evaluate the clinical potential and significance of stem and progenitor cells obtained from perinatal tissues”. She was now invited to comment on apparent image duplications in three papers. One image somehow seems to have wondered from one of her papers into another (PubPeer evidence here and here):

Shahla Hamza Al-Saqi, Mohammed Saliem, Suvi Asikainen, Hernan Concha Quezada, Asa Ekblad, Outi Hovatta, Katarina Le Blanc, Aino Fianu Jonasson, Cecilia Götherström, Cytotherapy, 16 (2014). “Defined serum-free media for in vitro expansion of adipose-derived mesenchymal stem cells”

Shahla Hamza Al-Saqi, Mohammed Saliem, Hernan Concha Quezada, Åsa Ekblad, Aino Fianu Jonasson, Outi Hovatta, Cecilia Götherström, Cell Tissue Bank, 16 (2015). “Defined serum- and xeno-free cryopreservation of mesenchymal stem cells”

Pascale V Guillot, Cecilia Gotherstrom, Jerry Chan, Hiroshi Kurata, Nicholas M Fisk, Stem Cells, 25 (2007). “Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC”. PubPeer evidence.

 

Thomas Helleday, professor at the Department of Medical Biochemistry and Biophysics, whose overall aim is “to improve the treatment of cancer by exploiting cancer defects in order to tailor specific drugs”. Helleday already publicly commented on the evidence of image duplications against his publication in Cell Reports. He wrote on Pubpeer:

“Going through this in detail, we can reach the conclusion that there has not being any scientific misconduct in this case. However, there has been a couple of serious errors made in the presentation of the data, which will be corrected by the authors in Cell Reports”.

Helleday then discussed the details; here is the paper in question :

Kumar Sanjiv, Anna Hagenkort, José Manuel Calderón-Montaño, Tobias Koolmeister, Philip M Reaper, Oliver Mortusewicz, Sylvain A Jacques, Raoul V Kuiper, Niklas Schultz, Martin Scobie, Peter A Charlton, John R Pollard, Ulrika Warpman Berglund, Mikael Altun, Thomas Helleday, Cell Rep, 14 (2016). “Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities”. PubPeer evidence.

Galina Selivanova, professor at the Department of Microbiology, Tumor and Cell Biology, who studies the tumour suppressor protein p53, was invited to answer to concerns raised against these publications of hers:

Roza Zandi, Galina Selivanova, Camilla Laulund Christensen, Thomas Alexander Gerds, Berthe Marie Willumsen, Hans Skovgaard Poulsen, Clin. Cancer Res., 17 (2011). “PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53”. PubPeer evidence

Carolyn Ying Zhao, Laszlo Szekely, Wenjie Bao, Galina Selivanova, Cancer Res., 70 (2010). “Rescue of p53 function by small-molecule RITA in cervical carcinoma by blocking E6-mediated degradation”. PubPeer evidence

Vera V Grinkevich, Fedor Nikulenkov, Yao Shi, Martin Enge, Wenjie Bao, Alena Maljukova, Angela Gluch, Alexander Kel, Olle Sangfelt, Galina Selivanova, Cancer Cell, 15 (2009). “Ablation of key oncogenic pathways by RITA-reactivated p53 is required for efficient apoptosis”. PubPeer evidence.

Vladimir J N Bykov, Natalia Issaeva, Nicole Zache, Alexandre Shilov, Monica Hultcrantz, Jan Bergman, Galina Selivanova, Klas G Wiman, J. Biol. Chem., 280 (2005). “Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs”

Klas Wiman, professor at the Department of Oncology-Pathology and p53 researcher, was also invited to comment on the PubPeer evidence of alleged data duplication against the latter above Bykov et al paper, co-authored by Selivanova and originating from his own lab. The validity of those concerns is however less certain, in fact Wiman constructively engaged with his critics on PubPeer.