Michael HotTiger of Zurich, patron of biomedical ethics

The University of Zurich (UZH) in Switzerland and its Unispital clinic are cleaning up the stables. Bad doctors made the news, not just one, but several of them, the accusations are of research misconduct, financial embezzlement, patient abuse and who knows what else. UZH and Unispital tried their best to hush everything up, they even sacked a whistleblower, but eventually the Swiss university clinic lost control of the media, which means a lot in Switzerland. It is most unfortunate.

I want to help, as I did before with the cases of the dark chocolate cardiologist Thomas Lüscher, the creative diabetes healers Marc Donath and his PhD student Kathrin Maedler, and more recently, in the Adriano Aguzzi case, a bully and a drama queen who threatened to have me sentenced and jailed for writing about his imaginary PhD degree and the questionable figures in his papers. Here, I proffer to UZH the case of the veterinary medicine professor Michael Hottiger, who also happens to be a close associate of Aguzzi’s. Someone put naughty things in Hottiger’s papers, and I hope the UZH will find and punish the real culprit.

Unispital travails

But first, a brief overview of the current media scandal and unsavoury mess for which UZH and Unispital can only blame themselves. In the centre of the affair is the head of Unispital heart surgery clinic, Francesco Maisano.

Mitralklappeninsuffizienz und die Behandlung mit dem Mitraclip. «Praxis Gsundheit» mit Prof. Dr. Francesco Maisano. https://t.co/atMeC3fHF5 pic.twitter.com/xhfT4vLPvp

— Unispital_USZ (@Unispital_USZ) May 30, 2017

The affair is best summed up in this paywalled article in Tagesanzeiger, a free-to-read copy was published here. In brief, the whistleblower got sacked, Maisano received unconditional support, and only media reporting forced the Unispital to reconsider their practice.

In late 2019, the heart surgeon Caspar K turned whistleblower and lodged a 42 page report about suspected misconduct by his boss Maisano. 12 heart operations by Maisano and his team were officially reported as success, while the reality was the exact opposite. Incidentally, the media reported already in 2018 about the suspiciously high mortality rates in Maisano’s heart surgery clinic.

In particular, a case of a 74-year-old woman who in 2016 received the heart implant “Cardioband” he developed. It is manufactured by the company Valtech Cardio, which Maisano co-founded, co-owned, used to be Chief Medical Officer with (and still has stakes in), and which was in 2017 sold for $700mn to Edwards Biosciences. Maisano personally received a part of the first tranche of $390 million, a gigantic conflict of interests he omitted, even patients had no clue he was implanting Cardionband while simultaneously receiving gigantic cashflows from his company Valtech. Unispital refuses to say how many millions exactly Maisano received and insist the money didn’t matter to their professor anyway. Only in 2018, after Edwards took over Valtech, was Cardioband revoked. Unispital lawyers saw absolutely no corruption there.

What was worse: the implant failed already during the operation, but Maisano simply edited the video and published the story as success in peer reviewed journals, for example in Maisano et al Eur Heart J 2016. The complications the patient suffered from the torn Cardioband were left out in favour of a fake success story. UZH issued ecstatic press releases, proud to be the only hospital in Switzerland to offer Cardioband implantation. Everyone was happy until Caspar K spoiled the party in Zurich.

The Unispital reacted immediately to the 42 page misconduct dossier. A law firm was tasked with dealing with the matter. Caspar K was offered to immediately depart on sabbatical leave and to sign a non-disclosure agreement. In March 2020, Maisano baselessly accused Caspar K of medical malpractice, several colleagues (incidentally coauthors on the Cardioband papers) supported the accusations. Unispital responded by stripping the whistleblower of operating room access.

Das Universitätsspital Zürich stellt sich hinter seinen Leiter der Herzchirurgie, trotz schwerer Vorwürfe. Patienten seien nicht zu Schaden gekommen, heisst es. Doch es gibt Fragezeichen. (Abo) https://t.co/z4M7MkOD6b

— SonntagsZeitung (@sonntagszeitung) May 24, 2020

In April 2020, the law firm delivered its verdict: Maisano did misrepresent and beautify his data, but no patients were ever endangered. Right after, Caspar K was sacked by Unispital on the spot. On 20 May, Unispital expressed its unconditional support for Maisano. But then, newspaper coverage broke because someone leaked the investigative report. Unispital admitted to journalists that what Maisano did was indeed “research misconduct”, despite the report having determined none whatsoever.

Maisano was suddenly sent on a paid leave for 3 weeks, to organise his defence. Even now, Unispital president Martin Waser commends Maisano for have used his faulty Cardioband implants “sparingly“. UZH and Unispital insist there is no reason at all to involve state prosecutor. In fact, despite there having even been deaths, they insist Maisano did nothing wrong, because, according to Unispital, “the dead patient did not complain”. But the Zurich state prosecutor seems to see it differently.

Two other Unispital doctors also make news. The head of maxillofacial surgery Martin Rücker was ordered to stop re-routing private patients to his private praxis while Unispital pays for the therapies. The head of gynaecology clinic Daniel Fink was also accused of financial misconduct (he managed to get paid for operating 3 patients simultaneously). Whatever he did must have been so bad that Fink was asked to resign “on health reasons”, the investigations continue.

On top of everything, UZH is now part of what may be a gigantic coronavirus-related scientific fraud case: the cardiologist head of Unispital heart clinic Frank Ruschitzka is coauthor on the infamous chloroquine paper Mehra et al Lancet 2020 (read more here), which created a huge impact and is likely steering towards retraction now retracted, with Ruschitzka playing the hapless victim.

Today, three of the authors have retracted "Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis" Read the Retraction notice and statement from The Lancet https://t.co/pPNCJ3nO8n pic.twitter.com/pB0FBj6EXr

— The Lancet (@TheLancet) June 4, 2020

With so much going on, Unispital even announced to open an Ombudsman office for whistleblowers, instead of sacking them on the spot.

Update 19.06.2020. Rücker has resigned, officially utterly voluntarily, Maisano is suspended indefinitely while under investigation (including by state prosecutor), with new clinic head already appointed, both of them plus the previously dismissed Fink now became subject to investigation by regional parliament (Kanton). Ruschitzka is now also under a misconduct investigation by UZH, over the Lancet affair.

Now, my humble contribution. No clinical issues here, just some faulty western blots. The victim: UZH and Unispital Professor Dr vet med Michael HotTiger.

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“basic principles for dealing with the ethical issues“

Hottiger’s research is about molecular signalling in DNA replication, repair and inflammation, his academic career happened almost exclusively in Zurich, where he was born, and then studied, graduated, and became professor at UZH after a brief pro-forma stint in USA (the trip abroad qualified him as external candidate for the faculty position, a popular practice in many European universities).

In 2017, one Swiss politician wanted to ban painful experiments on primates. The protest campaign was led by Hottiger, his second signatory was Aguzzi (backup of protest letter here). These scientists eventually succeeded in preventing the ban. Hottiger is also president of the Swiss Research for Life foundation (Aguzzi is board member there). This is how they describe the foundation’s purpose (highlight theirs):

“We aim to keep the public informed about the objectives, the importance and the latest results of biomedical research.

We establish the basic principles for dealing with the ethical issues of advances in biomedicine.”

Thus, Professor Hottiger must be the topmost biomedical ethics expert in Switzerland. Let us then look at the papers he published and learn some biomedical ethics, people.

There are in total 10 HotTiger papers on PubPeer, most of the evidence is already 3 years old and as it turned out (see update at the end), it was already investigated by UZH with some, but not much, research misconduct found. Most evidence was flagged by Clare Francis. We shall start with a Nature paper, almost 20 years old.

S Hasan, PO. Hassa, R Imhof, MO. Hottiger Transcription coactivator p300 binds PCNA and may have a role in DNA repair synthesis Nature (2001) doi: 10.1038/35066610

Something strange happened here. The yellow labelled bands are strangely similar, but the rest of the gel is not. As if someone was copy-pasting them in an old Photoshop version. Maybe something was wrong with the original experimental results, which were not convincing enough for Nature.

S Hasan , N El-Andaloussi , U Hardeland, PO. Hassa, C Bürki, R Imhof, P Schär, MO. Hottiger Acetylation regulates the DNA end-trimming activity of DNA polymerase beta Molecular Cell (2002) doi: 10.1016/s1097-2765(02)00745-1 

Molecular Cell is also an elite journal, one where data manipulation is explicitly approved of. Hence, back in 2002 there must have been small print in instructions for authors allowing to recycle and digitally stitch gel images in such creative fashion. Even stranger things happened in the next paper.

CM Simbulan-Rosenthal, DS Rosenthal, R Luo , R Samara , LA Espinoza , PO Hassa , MO Hottiger, ME Smulson PARP-1 binds E2F-1 independently of its DNA binding and catalytic domains, and acts as a novel coactivator of E2F-1-mediated transcription during re-entry of quiescent cells into S phase Oncogene (2003) doi: 10.1038/sj.onc.1206897

The title of this publication is so long, it even stretched one protein band into three. Maybe the authors disagreed with what that cMyc gel really showed? While Oncogene might show leniency for data irregularities, the following JBC paper will sure get at least corrected, given the publisher’s policies.

PO. Hassa, SS. Haenni, C Buerki, NI. Meier, WS. Lane, H Owen, M Gersbach, R Imhof, MO. Hottiger Acetylation of poly(ADP-ribose) polymerase-1 by p300/CREB-binding protein regulates coactivation of NF-kappaB-dependent transcription Journal of Biological Chemistry (2005) doi: 10.1074/jbc.m507553200

Also this EMBO Journal paper might need a correction. Even if it is 15 years old:

M Covic, PO Hassa, S Saccani, C Buerki, NI Meier, C Lombardi, R Imhof, MT Bedford, G Natoli, MO Hottiger Arginine methyltransferase CARM1 is a promoter-specific regulator of NF-kappaB-dependent gene expression The EMBO Journal (2005) doi: 10.1038/sj.emboj.7600500

Again, duplicated gel. How can this keep happening to same UZH authors by mistake?

The next case was tricky, because some PubPeer commenter disagreed the Coomassie loading controls were identical. But the analysis in the PubPeer thread does suggest it.

M Altmeyer , S Messner , PO. Hassa , M Fey , MO. Hottiger Molecular mechanism of poly(ADP-ribosyl)ation by PARP1 and identification of lysine residues as ADP-ribose acceptor sites Nucleic Acids Research (2009)  doi: 10.1093/nar/gkp229

The whole point of the Coomassie loading control is to do it for that very same gel you analyse (here, by a radioactive assay). The journal NAR recently discovered research ethics, so maybe they should have a look.

Here is a double feature:

KM Rothgiesser , M Fey , MO Hottiger Acetylation of p65 at lysine 314 is important for late NF-kappaB-dependent gene expression BMC Genomics (2010) doi: 10.1186/1471-2164-11-22

and

KM Rothgiesser , S Erener , S Waibel , B Lüscher , MO Hottiger SIRT2 regulates NF-κB dependent gene expression through deacetylation of p65 Lys310 Journal of Cell Science (2010) doi: 10.1242/jcs.073783

BMC ignored the issue completely, but they sure were aware of the problem. Because a correction was published by J Cell Science in April 2019:

“The authors explained that the data in the two figures validate the specificity of antibodies generated against different acetylated lysines of p65 and originate from the same experiment, meaning that use of the same controls is justified.”

Well, that is OK then. Lazy salami-publishing at best to boost someone’s publication output.

To conclude, a paper coauthored by Hottiger with the infamous Gad Asher as first author, back then in the lab of Ueli Schibler in Geneva. The Israeli biologist Asher has 11 papers on PubPeer flagged for blatant data fakery, it is yet another question if his Weizmann Institute cares about it either way. Or for that matter the elite journal Cell, who are prepared to defend research fraud even against demands from universities. Including in fact even from Weizmann Institute.

G Asher , H Reinke , M Altmeyer , M Gutierrez-Arcelus , MO. Hottiger , U Schibler Poly(ADP-ribose) polymerase 1 participates in the phase entrainment of circadian clocks to feeding Cell (2010) doi: 10.1016/j.cell.2010.08.016

Asher commented on PubPeer:

“There is a slight possibility that the original autoradiographs with these negative results (i.e. empty lanes) were kept in Geneva after Ueli’s retirement at the end of 2015. In case we find them, we will look into it. Figure S3 was contributed by our collaborators in Zürich [Hottiger? -LS], and we have contacted them for clarifications. We will provide an in-depth report with the original data in the near future and plan to prepare a correction note for Cell. We sincerely apologize for our negligence in preparing the concerned figures. Best, Gad Asher and Ueli Schibler“

If Weizmann is OK with Asher investigating himself, so be it. But what will UZH do now to help Professor Hottiger fix his old papers?

Prof. Michael Hottiger talking about the Swiss transparency agreement, STAAR, 'such transparency is a commitment to rigorous and responsible research, and to want people to find out about animal research' @FENSorg @SfNtweets #animalresearch pic.twitter.com/eHLkuFgGdA

— EARA (@The_EARA) November 6, 2019

Update 14.06.2020

UZH’s Vice President Faculty Affairs and Scientific Information, Christian Schwarzenegger, wrote to me:

“The accusations on pubpeer against Mr. Hottiger were definitively investigated by the University of Zurich in October / November 2017.

This investigation led to the result that scientific misconduct was excluded in 8 out of 10 publications. For one of the 8 publications, a statement was published in 2019 after consultation with the editor. For two old publications, the raw data could only be partially reconstructed. The scientific evidence of these two publications has since been confirmed by other experiments. As a result of the investigation, Mr. Hottiger was obliged to take the greatest possible care in handling scientific data, which he also confirmed.

There is therefore no reason for the University of Zurich to examine these publications again. We would also like to ask you to remain factual in your comments.“

There are indeed 10 Hottiger papers on PubPeer. Obviously, the corrected one is Rothgiesser et al JCS 2010. If scientific misconduct was excluded in 8 out of 10 papers, it means it was included in the remaining two, with no desire whatsoever for the correction of the published scientific record. I asked Schwarzenegger if anyone checked for raw data with the 8 “non-misconduct” papers, and will update when he replies.

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