The good life of Benjamin Bonavida

Welcome to another Smut Clyde–guided tour through another fraud freak-show. The central character here is Benjamin Bonavida, cancer and apoptosis researcher, and recently retired distinguished professor at the David Geffen School of Medicine University of California Los Angeles (UCLA), the university where he studied in 1960ies and spent his entire career since. One special joke about Bonavida is that he managed to portray himself as an actual victim of two of his fraudulent lab members, who were sacked and shamed in public, their papers retracted. Neither Bonavida or his senior collaborators suffered any visible consequences, and there were some serious heavyweights involved, including the then-Vice Chancellor for Research at UCLA, James Economou. Another extra bit of irony is that while publishing fabricated research with Bonavida, that Vice Chancellor was actually in charge of research integrity at their common university. Bonavida’s other prominent coauthor is Demetrios Spandidos, once sacked in US for made-up data in his past life as scientist and reborn in Greece as owner of Spandidos Publications, which later expanded into the even more lucrative business of scamference conference organising.

Smut Clyde presents below a long list of fabricated papers signed by Bonavida, while this UCLA professor’s PubPeer record seems to grow daily, with currently over 30 papers covering the time period from 1999 till 2014. Basically, the Golden Age of molecular biology when Photoshop became the standard tool of data falsification while hardly any journal bothered to check. Yet Bonavida’s publication history goes as far back as 1967, long before myself or most of my readers were born. How did Dr Bonavida manufacture his research results back then? A question for science historians.

In an 2017 article in The Scientist, Bonavida was painted as an innocent victim of a criminal Japanese student. His story was equalled to that of Carlos Moraes from the University of Miami, who hosted the German postdoc Tina Wenz in his lab. Together Moraes and Wenz published six papers, all of which were later proven to be fraudulent and retracted. Wenz deployed lawyers, apparently against everyone including Moraes (even I received a threatening letter back then). At the end she was one of the rare German scientists publicly named and shamed by the DFG, and by her own University of Cologne (where she used to have a DFG-funded lab). It was namely Moraes who reported the data manipulations and demanded retractions of his own papers, against the pushback from Wenz’ elite law firm. Bonavida on the other hand tried to prevent journals from retracting his papers despite official verdicts, while his many other clearly fraudulent works on PubPeer have different co-authors.

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You wait and wait for a bus to throw co-authors under, and then three come along at once. By Smut Clyde

There is a quality of entertaining schadenfreud Greek Tragedy about the spectacle of a UCLA Vice Chancellor for Research, and quondam Officer for Research Integrity, incurring the retraction of two research papers because of shenanigans in the data. And in the manner of Sophocles or Euripides, we enter the story in media res with much of the action having already occurred, to be visited in flashback or recounted by the chorus. There may be hubris, or the other tragic flaws of Greek dramaturgy. There will certainly be some Western blots, and perhaps some Northern blots for the sake of variety.

A flurry of papers from the UCLA cancer-research dynamo were retracted at about the same time; please pay attention, and try to keep them distinct in your minds, as there may be a quiz. Fortunately everything has been closely documented by the people at RetractionWatch, providing coroner’s reports for the demise of the papers after their persecution and assassination by anonymous post-publication commentary at PubPeer.

To begin in 2014, then, questions were raised about a publication from 2007… first in a dedicated blog, then echoed to PubPeer:

[1]. Eriko Suzuki, Kazuo Umezawa  & Benjamin Bonavida

Rituximab inhibits the constitutively activated PI3K-Akt pathway in B-NHL cell lines: involvement in chemosensitization to drug-induced apoptosis

Oncogene 2007, doi: 10.1038/sj.onc.1210448 , PubPeer here).

First author Eriko Suzuki promptly shouldered the blame for defects in data quality which made the paper unsustainable (at the cost of her PhD and professional career), as verified by RetractionWatch. By “defects in data quality” I mean images of protein expression which were recycled for different conditions, and sometimes for different proteins:

That dedicated blog had called into question a second paper. However, Suzuki was emphatic that her responsibility did not extend that far. And she did pointedly skipped the opportunity to apologise for a role in other collaborations from her time at UCLA.

So let’s just number that paper as [0] for the moment, and ignore it:

[0] Eriko Suzuki, Tracy R. Daniels, Gustavo Helguera, Manuel L. Penichet, Kazuo Umezawa, Benjamin Bonavida

Inhibition of NF-kappaB and Akt pathways by an antibody-avidin fusion protein sensitizes malignant B-cells to cisplatin-induced apoptosis

Int. J. Oncol. (Spandidos) 2007. doi: 10.3892/ijo_00000615

Anyway, there was evidently an investigation, as The Scientist reported:

“In UCLA’s ensuing investigation, Bonavida was cleared of wrongdoing; nevertheless, he says, he was left in shock. “It affected me very deeply,” he says. “I have trained over a hundred students through my career. Nobody has done something like that with my work before.”

Investigations did not stop there, and the end of 2016 saw two more retractions. Professor Bonavida was again the victim of a conspiracy of fate. Answering questions from Retraction Watch, he thought the university had acted too hastily:

“He said a committee at UCLA investigated the allegations, and although he was initially informed the committee was going to ask the journal to correct the papers,
“…for some reason, they went ahead with the retractions…without asking our opinion.”

… and that the concerns were misguided or malicious.

“Some of the gels that were represented for the controls, apparently somebody claims they were reproduced from other figures. That was not the case, but it was very hard to prove that…I could not defend it, but I tried very hard”.

Here are the two papers, both from the Journal of Immunology, a society journal which seems to be have acquiesced to being a victim of fraud trolling. Some of the authors are recurring members of the dramatis personae so I have boldfaced their names

[2]. Stavroula Baritaki, Alina Katsman, Devasis Chatterjee, Kam C. Yeung, Demetrios A. Spandidos and Benjamin Bonavida

Regulation of tumor cell sensitivity to TRAIL-induced apoptosis by the metastatic suppressor Raf kinase inhibitor protein via Yin Yang 1 inhibition and death receptor 5 up-regulation”

(Baritaki, Katsman, Chatterjee, Yeung, Spandidos, Bonavida 2007, PubPeer here)

[3]. “Inhibition of Yin Yang 1-dependent repressor activity of DR5 transcription and expression by the novel proteasome inhibitor NPI-0052 contributes to its TRAIL-enhanced apoptosis in cancer cells“

J Immunology (2008) doi: 10.4049/jimmunol.179.8.5441, PubPeer here).

The papers dip into a shared library of blots. It turns out that a single image can be rearranged to illustrate different ways of modulating cell death through the surface protein “Death Receptor 5”. Who knew that molecular biology had such Metal names?

Neither of them redounds to the credit of the journal reviewers who looked at the Figures and thought “Yes, that’s what loading controls should look like” (or else “OK, that’s fake, but it’s only a loading control so who cares?”). Nor to the credit of the various authors who can’t have looked at the Figures at all. [3] in particular stands out by the lack of effort to hide the fabrications and manipulations.

In its quieter way, [2] also warrants attention. One of its “jumping-gene” loading controls with the self-shuffling lanes (Fig 5C, here at bottom) made a later appearance in a further paper also under the aegis of PubPeer.

But I am getting ahead of myself. First we should meet papers

[4] Ali R. Jazirehi, Stavroula Baritaki, Richard C. Koya, Benjamin Bonavida and James S. Economou

Molecular Mechanism of MART-1+/A*0201+ Human Melanoma Resistance to Specific CTL-Killing Despite Functional Tumor–CTL Interaction

Cancer Research (2011), doi: 10.1158/0008-5472.CAN-10-1296, PubPeer here);

and

[5] Ali R. Jazirehi and James S. Economou

Proteasome Inhibition Blocks NF-κB and ERK1/2 Pathways, Restores Antigen Expression, and Sensitizes Resistant Human Melanoma to TCR-Engineered CTLs

Mol Cancer Ther. (2012), doi: 10.1158/1535-7163.MCT-11-0814, PubPeer here).

They joined the flurry of retractions in early 2017, on the request of the senior author. Professor Economou wore many hats at UCLA, being head of his own cancer-research lab there, Chief of Surgical Oncology, Vice Chancellor for Research, and Officer for Research Integrity. He did not respond to overtures from RW. Prof. Bonavida was a co-author on [4], and he was more forthcoming with comments, though his response was to downplay his auctorial role:

“Bonavida told Retraction Watch that his involvement in the Cancer Research paper was only as a “consultant” who looked it over before it was submitted:
“All the work was done in Economou’s lab, not mine. I have no idea what exactly took place.
The original findings, they were all prepared by Ali Jazirehi.”
Bonavida added that he knew Jazirehi well, as Jazirehi had worked in his lab “many years” before.”

Given Bonavida’s confident conviction that there were no more shoes left to drop, readers who are familiar with all literary conventions will be wondering about the size of the iceberg of problematic papers for which these five are the tip. By way of answer, let these performing planaria entertain you with their well-rehearsed wriggling routine, as choreographed and trained by Jim McConnell for a special issue of the Worm Runner’s Digest.

Alternatively, they are part of a Western Blot loading control, appearing in three different contexts in a little triptych of problematic papers:

[6] S Baritaki, K Yeung, M Palladino, J Berenson and B Bonavida

Pivotal roles of snail inhibition and RKIP induction by the proteasome inhibitor NPI-0052 in tumor cell chemoimmunosensitization

Cancer Res. (2009), doi: 10.1158/0008-5472.CAN-09-1069, PubPeer here);

[7] S Baritaki, A Chapman, K Yeung, D A Spandidos, M Palladino & B Bonavida

“Inhibition of epithelial to mesenchymal transition in metastatic prostate cancer cells by the novel proteasome inhibitor, NPI-0052: pivotal roles of Snail repression and RKIP induction“

Oncogene (2009), doi:10.1038/onc.2009.214, PubPeer here); and

[8]  S Baritaki, S Huerta-Yepez, A Sahakyan, I Karagiannides, K Bakirtzi, A Jazirehi & B Bonavida

Mechanisms of nitric oxide-mediated inhibition of EMT in cancer: inhibition of the metastasis-inducer Snail and induction of the metastasis-suppressor RKIP

Cell Cycle (2010), doi: 10.4161/cc.9.24.14229, PubPeer here).

A number of shared and relabelled visual elements interlink the triptych (while as was foreshadowed above, [8] and [2] have an element in common). Most notably, some blots of antibody-labelled protein are versatile in their roles, illustrating the presence of “Snail”, XIAP, Fibronectin or β-actin.

As we strip-mine into deeper strata of the PubPeer archive, eventually we reach another nexus of interlinked papers, though this one is more of a Pentateuch. Two of its members are closely entwined:

[9] A Jazirehi, M Vega, D Chatterjee, L Goodglick & B Bonavida

Inhibition of the Raf–MEK1/2–ERK1/2 Signaling Pathway, Bcl-xLDown-Regulation, and Chemosensitization of Non-Hodgkin’s Lymphoma B Cells by Rituximab“

Cancer Res. (2004), DOI: 10.1158/0008-5472.CAN-03-3500 , PubPeer here), and

[10] A Jazirehi, S Huerta-Yepez, G Cheng & B Bonavida

Rituximab (chimeric anti-CD20 monoclonal antibody) inhibits the constitutive nuclear factor-κB signaling pathway in non-Hodgkin’s lymphoma B-cell lines: role in sensitization to chemotherapeutic drug-induced apoptosis

Cancer Res. 2005, PubPeer here.

Loading controls are recycled to an impressive extent,

So many protein bands are using multiple alias that one’s attempts to keep track of them run quickly out of colors.

One of those protein band, identified with brown boxes above as IκB and ERK1/2 (and, after a 180° flip and some tweaks, as NIK) underwent further vicissitudes. It appeared as IκB again in

[11] M Vega, A Jazirehi, S Huerta-Yepez & B Bonavida

Rituximab-Induced Inhibition of YY1 and Bcl-xL Expression in Ramos Non-Hodgkin’s Lymphoma Cell Line via Inhibition of NF- B Activity: Role of YY1 and Bcl-xL in Fas Resistance and Chemoresistance, Respectively

J Immunol. (2005), doi: 10.4049/jimmunol.175.4.2174 , PubPeer here); and in its rotated manifestation, as ERK1/2 in

[12] A Jazirehi & B Bonavida

Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin’s lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis“

Mol. Cancer Ther. (2004), PubPeer here).

Papers in this series are also linked by their use of protein-expression RNA immunoblots (reverse-transcriptase / PCR), providing us with some relief from the barrage of Western Blots. For close inspection reveals many more images of RNA blots than there are underlying data, with some creative re-use linking [9] and [10]…

…with the lanes further jiggered and poked to integrate [12] into the mesh as well.

The ‘Rituximab’ of the titles is not a Mayan temple complex in the Yucatan Peninsula, but rather a monoclonal antibody designed to destroy unwanted B-lymphocytes; evidently its apoptosis-pathway actions were attracting research interest in the early 2000s. Quite how the results found their way into [12] is an interesting question, as Resveratrol has nothing to do with Rituximab except a shared initial letter (and being another popular research topic of the era). Anyway, this leads us to:

[13] A Jazirehi, XH Gan, S De Vos, C Emmanouilides & B Bonavida

Rituximab (anti-CD20) selectively modifies Bcl-xL and apoptosis protease activating factor-1 (Apaf-1) expression and sensitizes human non-Hodgkin’s lymphoma B cell lines to paclitaxel-induced apoptosis

 Mol Cancer Ther. (2003), PubPeer here)

It was first in this nexus to be published, and its contents were plundered to provide illustrations for [10] and [12]. The latter reuse required a 180° flip of the Actin loading band as well as the confusion between Rituximab and Resveratrol.

From the same epoch we find

[14] M Vega, S Huerta-Yepaz, H Garban, A Jazirehi, C Emmanouilides & B Bonavida

Rituximab inhibits p38 MAPK activity in 2F7 B NHL and decreases IL-10 transcription: pivotal role of p38 MAPK in drug resistance

Oncogene (2004), doi: 10.1038/sj.onc.1207336, PubPeer here).

This was a one-off paper, with no pictorial links to other papers, only internal connections… the proteins P-p38 and Bcl-2 proved to be the same, or at least they provided identical bands of immunohistochem gel. A display of RNA expression for a particular protein was dismantled like a Lego tower and reassembled for a different protein.

And [15] A Jazirehi, M Vega & B Bonavida

Development of rituximab-resistant lymphoma clones with altered cell signaling and cross-resistance to chemotherapy

Cancer Res. (2007),   doi: 10.1158/0008-5472.CAN-06-2184 , PubPeer here).

The duplications are blatant, placed side-by-side as if daring the reviewers to do something about it. Dr. Stavroula Baritaki is thanked “for technical assistance”.

The PubPeer archive reveals a few other free-standing papers. Despite the pressure of space I cannot bring myself to omit

[16] S Baritaki, S Huerta-Yepez, T Sakai, D Spandidos & B Bonavida

Chemotherapeutic drugs sensitize cancer cells to TRAIL-mediated apoptosis: up-regulation of DR5 and inhibition of Yin Yang 1

Mol Cancer Ther. (2007), doi: 10.1158/1535-7163.MCT-06-0521, PubPeer here).

We are accustomed to yeoman service from loading controls, overlapped and recycled as in Figures 3 and 4, but in an innovative step, the substantive protein strips of Fig. 3 were sliced horizontally to become the substantive strips of Fig. 4 – DR5 becoming YY1.

#7 Peer 4 commented 2 years ago

After all this, when Bonavida insists that “Nobody has done something like [Suzuki’s short-cuts] with my work before”, we can only marvel at his capacity for constructive inattention.

One last case-study:

[17] Saad Yousuf, MeiLi Duan, Erika L. Moen, Sam Cross-Knorr, Kate Brilliant, Benjamin Bonavida, Theresa LaValle, Kam C. Yeung, Fahd Al-Mulla, Eugene Chin, Devasis Chatterjee

Raf kinase inhibitor protein (RKIP) blocks signal transducer and activator of transcription 3 (STAT3) activation in breast and prostate cancer

PLoS ONE (2014), doi: 10.1371/journal.pone.0092478, PubPeer here.

With Bonavida as only a minor contributor, that paper is peripheral to my topic here; I cite it more for the third appearance of Devasis Chatterjee, here as senior author [see [2, 9] above]. Now Chatterjee has previously come up on the radar through his collaboration with Paul B Fisher of Virginia Commonwealth University, making the present post a sequel of sorts, or a prequel, or a continuity story to that earlier survey of cancer research at VCU.

Demetrios Spandidos was another co-author whose collaborations were regular enough to be singled out with boldface above [2, 3, 7, 16]. At the time of these papers he was affiliated to the University of Crete at Herakleion, but he is best-known as the publisher / editor of cancer-themed journals including International Journal of Oncology (see [0]), and as the entrepreneur of the inevitable cancer-themed conferences. His backstory is eventful, even chequered, stretching back three decades to his time as a postgrad student in Toronto when he was about to publish groundbreaking Nobel-worthy research into oncogenes until everything ended in expulsion from the Louis Siminovitch laboratory and tears before bedtime. But there is no space for that saga now so I will just refer you to primary sources.

From one perspective, all this is now of academic / historical interest. The people most central in all these questionable papers have left research (or left UCLA, which is the same thing!). Stavroula Baritaki still appears on UCLA staff lists but a recent conference (co-organisers: Baritaki & Bonavida) describes her as affiliated to the University of Crete. Bonavida has retired – from his laboratory, if not from conferencing – while Economou has stepped down from vice-chancelloring, closed his laboratory and returned to clinical work. As for Jazirehi, he is suing Economou and the Regents of UCLA for wrongful dismissal.

Now this does not prove that further inquiries did proceed in private, with data shenanigans identified and blamed on Jazirehi, though it is compatible with such a course of events. One can only be sure that whatever was determined. Jazirehi feels that he was singled out as a scapegoat.

Anyway, with these departures, one could argue that even if some of the results reported in [6] to [17] were just made up (with the forgery more egregious than anything in [1] to [5]), another inquiry and further retractions would achieve nothing except institutional embarrassment. Though they would free the PubPeer commentariat from the compulsion to go on documenting image misbehaviour.

This is supposed to be a happy occasion. Let’s not bicker and argue about who faked what!

There is also the possibility that despite the weakness of the evidence available to the authors, forcing one or several of them to fabricate more compelling and publishable results, the conclusions of those papers were actually correct, so additional retractions would be wrong.

I can only say that policies of drawing a discreet veil over academic malfeasance and sweeping scandals under the bus carpet have always worked so well in the past.