Pier Paolo and Pier Giuseppe, the titans of IFOM-IEO

This post is dedicated to the IFOM-IEO-Campus, a cancer research centre in Milan, Italy, where I used to work as postdoc for over 4.5 years. The campus is small in area, but tightly packed with research labs and people from all over the world, heavily funded by international grants and Italian charity money. It is run by two institutions, IEO (Istituto Europea di Oncologia) and IFOM ( Istituto FIRC di Oncologia Molecolare, FIRC being a cancer research foundation, my affiliation back then was with IFOM). Aside of that separation, everything is fluid there: facilities are shared and people constantly move employment between IFOM and IEO, as in fact even the former IFOM director, Pier-Paolo Di Fiore, did. He is the main character of this article, together with another IEO bigwig, Pier Guiseppe Pelicci. The two men are incredibly influential in Italian science, and publish in the most prestigious research journals. What to make of their research achievements, is another question.

I know many people mentioned below personally, and in fact I am very disappointed at what I discovered on PubPeer. One case I even covered before, in this article. During my time in Milan, I met many great scientists at IFOM-IEO Campus, yet not many of them progressed anywhere beyond eternal postdoc, while their less qualified, less diligent, or even less honest colleagues became group leaders and tenured principal investigators. Also Di Fiore and Pelicci themselves trained new generations of group leaders, and recruited other group leaders to IFOM-IEO based on certain criteria, these people in turn are now training the PIs of the future. It seems, the only thing which counted were papers in Nature, Cell and Science, less so how the results were generated, or if they were reproducible even in your own lab.

Research integrity and diligence seem to be an obscure concept at IFOM-IEO, in fact one wonders if some of these sceintists grasp it at all. My own then-boss, Fabrizio d’Adda di Fagagna, apparently remains staunchly supportive of his long-term collaborator, the misconduct-tainted German zombie scientist Karl Lenhard Rudolph, despite everything. The d’Adda di Fagagna lab recently published a paper Michelini et al Nature Cell Biology 2017 where a dataset was possibly improperly reused:

It is a money scheme, where hot claims are made in order to attract even more charity funding, much of it via direct advertising to convince people to send 5 per mille of their salaries to IEO or IFOM. This is actually why Di Fiore, Pelicci and others were recently reported to Milanese state prosecutor, more on that at the end. In any case, the money scheme needs papers in high impact factor journals, and that sometimes means heavy bullshitting. The cases I present below contain evidence of more than just bullshitting, namely of actual data manipulation, or research fraud if you like. It is up to IFOM-IEO leaders to find the culprits, or scapegoats. Much of the evidence was posted on PubPeer by the pseudonymous Clare Francis, some of it just recently. I present here a selection, please visit PubPeer for more discussion of Di Fiore’s and Pelicci’s papers.

La #ricerca sul #cancro ha finalmente imboccato la strada giusta: parola di Pier Giuseppe Pelicci, direttore scientifico di @AlleConCancro#tumori #oncologia #cancer #oncology #salute #medicina @SanRaffaeleMI @IEOufficiale #genomics @aimac_it #dna #biology @MinisteroSalute pic.twitter.com/g9SaQkYFUf

— Elisa Buson (@Elisa_Buson) October 31, 2018

Let us start with a 17 year old paper in Nature which surely made Di Fiore big, back then.

Simona Polo, Sara Sigismund, Mario Faretta, Monica Guidi, Maria Rosaria Capua, Giovanna Bossi, Hong Chen, Pietro De Camilli, Pier Paolo Di Fiore

A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins

Nature (2002) doi: 10.1038/416451a 

This Nature paper also helped Simona Polo establish herself as group leader in di Fiore’s IFOM. Also the second author Sara Sigismund is presently group leader under Di Fiore at IEO. Another mentee of Di Fiore is IFOM group leader Giorgio Scita, together with his boss, Scita published this in 1999:

Giorgio Scita, Johan Nordstrom, Roberta Carbone, Pierluigi Tenca, Giuseppina Giardina, Silvio Gutkind , Mattias Bjarnegård, Christer Betsholtz, Pier Paolo Di Fiore

EPS8 and E3B1 transduce signals from Ras to Rac

Nature (1999) doi: 10.1038/45822

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Followed by this 2004 paper as last author:

Nina Offenhäuser, Alessandro Borgonovo, Andrea Disanza, Pascale Romano, Isabella Ponzanelli, Gioacchin Iannolo, Pier Paolo Di Fiore, Giorgio Scita

The eps8 family of proteins links growth factor stimulation to actin reorganization generating functional redundancy in the Ras/Rac pathway

Molecular Biology of the Cell (2004) doi: 10.1091/mbc.e03-06-0427 

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Nina Offenhäuser is now senior manager at Cogentech, a biotech spin-off located inside the IFOM-IEO Campus, among which directors is the current IFOM director, Marco Foiani.

This western blot in yet another Di Fiore Nature paper also looks suspicious:

Letizia Lanzetti, Andrea Palamidessi, Liliana Areces, Giorgio Scita, Pier Paolo Di Fiore

Rab5 is a signalling GTPase involved in actin remodelling by receptor tyrosine kinases

Nature (2004) doi: 10.1038/nature02542 

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Scita is also coauthor there, but he did not yet comment on PubPeer about that 2004 Nature paper. He did comment on another, even older paper, and shared what we are told is the original raw data:

Giorgio Scita, Pierluigi Tenca, Liliana B. Areces, Arianna Tocchetti, Emanuela Frittoli, Giuseppina Giardina, Isabella Ponzanelli, Patrizia Sini, Metello Innocenti, Pier Paolo Di Fiore

An effector region in Eps8 is responsible for the activation of the Rac-specific GEF activity of Sos-1 and for the proper localization of the Rac-based actin–polymerizing machine

Journal of Cell Biology (2001) doi: 10.1083/jcb.200103146 

The raw data Scita uploaded on 1 August 2019 is of very low resolution, which might serve as a red flag. Another scientist, Gary Stacey, submitted low-resolution “raw data” images to counter accusations of band duplication. Obviously it makes no sense why original image files only exist in very poor quality, while higher-resolution images of same gels were submitted to journal for publication. But in any case, Scita’s raw data meant to prove that the allegedly duplicated bands are different. The two Sos-1 and HA bands above sure look different in the low-res data files, but: they do not match the corresponding bands published in JCB 2001. Their neighbour bands match nicely, so it does seem Scita found the original image film. How could this have happened? Surely not because someone played with the raw data after being alerted to a suspected band duplication, hence also the low resolution of the provided scans? There must be a different explanation, maybe Scita can provide it.

This raw data dissonance seems to happen also in another case in the same paper, also there Scita submitted ultra-low resolution “raw data”:

Make up your own mind what this means for research integrity at IFOM. As aside, the Milanese star of cancer research Pier Paolo Di Fiore is originally from Naples, which might explain his past collaboration with the local fraud kingpin there, the unsackable Alfredo Fusco. Together, Fusco and Di Fiore published in the 1980ies and 1990ies 15 papers, two of which have been retracted for gross data manipulation.

But now back to the IFOM-IEO-Campus in Milan. The following paper from there features Di Fiore as coauthor, and Pelicci, the grand man of IEO, as last author.

Myriam Alcalay, Natalia Meani, Vania Gelmetti, Anna Fantozzi , Marta Fagioli , Annette Orleth , Daniela Riganelli, Carla Sebastiani, Enrico Cappelli, Cristina Casciari , Maria Teresa Sciurpi, Angela Rosa Mariano, Simone Paolo Minardi, Lucilla Luzi, Heiko Muller , Pier Paolo Di Fiore, Guido Frosina, Pier Giuseppe Pelicci

Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair

Journal of Clinical Investigation (2003) doi: 10.1172/jci17595 

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Myriam Alcalay, presently director of Experimental Haematology Unit at IEO, pretended on PubPeer not to understand the concerns:

“it is difficult to infer what they are pointing to with the boxes and arrows. […] The faint bands indicated by Petrocephalus and Pseudanapaea are clearly non-specific bands, also present in other lanes, that in no way interfere with the specific bands or alter the significance of the experiment. The result was also confirmed with a different technique (comet assay) as shown in figure 4c. “

The following was probably one of Pelicci’s big papers which helped establish his massive power at IEO and its mothership, the Fondazione Umberto Veronesi.

Luciano Di Croce, Veronica A Raker , Massimo Corsaro, Francesco Fazi, Mirco Fanelli , Mario Faretta, Francois Fuks, Francesco Lo Coco, Tony Kouzarides, Clara Nervi, Saverio Minucci , Pier Giuseppe Pelicci

Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor

Science (2002) doi: 10.1126/science.1065173

The penultimate author Saverio Minucci is now director of Chromatin Alteration Unit at IEO, while first author Luciano Di Croce moved on from IEO to become group leader at CRG in Barcelona, a place famous for protecting an Italian Photoshop artist, Maria Pia Cosma.

Pelicci’s family also works at IEO: both his wife, Luisa Lanfrancone and his sister, Guiliana Pelicci, are PIs there. This was published by the brother and sister team:

Giuliana Pelicci , Flavia Troglio, Alessandra Bodini, Rosa Marina Melillo, Valentina Pettirossi, Laura Coda, Antonio De Giuseppe, Massimo Santoro , Pier Giuseppe Pelicci

The neuron-specific Rai (ShcC) adaptor protein inhibits apoptosis by coupling Ret to the phosphatidylinositol 3-kinase/Akt signaling pathway

Molecular and Cellular Biology (2002) doi: 10.1128/mcb.22.20.7351-7363.2002 

Those were some of Pelicci’s own papers, and it seems diligent research takes a back seat in his lab when the goal is to publish high. Here Pelicci’s coauthor and IEO researcher Enrica Migliaccio posted on PubPeer evidence of a loading control library practice, i.e. when the loading control is run on a separate gel (a discussion about western blot loading controls here and here). The paper was Gambino et al Aging Cell 2013, it was then corrected.

.@IFOMresearch PI indirectly admits to run western blot loading controls on separate gels. Why? https://t.co/luph4f4xjU pic.twitter.com/aOEj7hujjL

— Leonid Schneider (@schneiderleonid) March 26, 2019

Pelicci’s collaborative works are also impressive. This was published by Pelicci and Minucci in collaboration with the lab of Nicoletta Landsberger, from the Ospedale San Raffaele in Milan. The first author Simona Segalla is presently postdoc at the same Milanese research hospital.

Simona Segalla , Laura Rinaldi, Charlotte Kilstrup-Nielsen , Gianfranco Badaracco, Saverio Minucci, Pier Giuseppe Pelicci , Nicoletta Landsberger

Retinoic acid receptor alpha fusion to PML affects its transcriptional and chromatin-remodeling properties

Molecular and Cellular Biology (2003) doi: 10.1128/mcb.23.23.8795-8808.2003 

There is much more of cloned gel bands and gel lanes in that train-wreck of a paper, for example this:

The following paper was made at Pelicci’s IEO, the last author being the Belgian researcher Jean-Christophe Marine, then at IEO. The paper shows the PhD research of the first author, Davide Danovi, done at IEO.

Davide Danovi , Erik Meulmeester , Diego Pasini, Domenico Migliorini, Maria Capra, Ruth Frenk , Petra De Graaf , Sarah Francoz, Patrizia Gasparini, Alberto Gobbi , Kristian Helin, Pier Giuseppe Pelicci, Aart G Jochemsen , Jean-Christophe Marine

Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity

Molecular and Cellular Biology (2004) doi: 10.1128/mcb.24.13.5835-5843.2004 

The paper was criticised for undisclosed splicing, where the loading control library gel image was used to support the downregulation of two proteins. Marine explained that ” when this work was published (more than 15 years ago), this journal did not request to explicitly indicate whether the blots were composite neither to provide the uncropped blots”, and ended the debate with:

“The only remaining questions and/or remarks can no longer be addressed and/or are irrelevant. No additional comments needed. Thanks to all for your consideration and time. “

So a reader of my site showed me this image duplication (on the left), and then posted it on PubPeer. One cannot really reuse an image by mistake while rotating, cropping, darkening and resizing it.

Marine and his IEO coauthors had to correct the paper, and they even had to admit gel splicing in Figure 5 which Marine declared irrelevant and none of anyone’s business. The correction also states:

“These results were generated well over 15 years ago from samples at the European Institute of Oncology tissue microarray facility, which has subsequently been restructured and relocated. After numerous attempts, we have failed to identify how these mistakes were created or locate the original underlying data. This does not undermine the work or the conclusions of our study, which have been extensively cited and validated.”

There is of course more to show from IFOM-IEO-Campus, but this article is getting too long. Maybe I should briefly mention Francesco Blasi (who aged 82 still hasn’t thought of retiring), with 17 papers on PubPeer. He published things like this in Mazzieri et al Mol Biol Cell 2006:

Or this, in Bernardi et al PLOS One 2010. What kind of attitude does this suggest, from the people in the lab, and from the PI who seems not to care?

Maybe also the former IEO researcher Kristian Helin should be mentioned here, with 13 papers on Pubpeer. Helin moved back to Denmark 15 years ago to become director of BRIC, the Copenhagen cancer research institute which now hosts another Photoshop artist, Janine Erler. As director, Helin was personally accused of silencing whistleblowers in the Erler scandal, and even being involved in the massive-scale destruction of the whistleblowers’ research material. Some months ago, BRIC decided to appoint a new director, and Helin announced to concentrate on his new job in New York, though he retains his professorship in Copenhagen.

The following example is from Helin’s paper Bracken et al EMBO J 2003, done back at IEO. The first lanes for SUZ12 are most likely duplicated, not that anyone bothered to investigate so far.

Things are starting to move however. As the newspaper Il Fatto Quotidiano reported, the Italian state prosecutor now investigates allegations of charity money embezzlement in connection with research fraud in Milan (free article version here):

“The suspects professors are Pier Paolo Di Fiore (from IFOM […]), Alberto Mantovani (from Humanitas Institute for research and care by the Rocca family), Pier Giuseppe Pelicci (from IEO, the European Institute of Oncology, founded by Umberto Veronesi), Marco Pierotti, Maria Angela Greco, Elena Tamburini and Silvana Pilotti (from the Istituto nazionale dei tumori). They maneuvered millions of funding from the Ministry of Research, the Ministry of Health, from Istituto superiore di sanità, from the CNR (Consiglio nazionale delle ricerche). They received just for the period analysed by the prosecution, between 2005 and 2012, such high figures: €9.37 mn Di Fiore; €3.06 mn Mantovani; €1.48 mn Pelicci; €3.6 mn Pierotti. “From the first analysis of Milan research centers by the judicial police,” writes the prosecutor, “nine freely available publications emerged which contain manipulations, more or less serious and showing images of the alleged experiments.” Other investigations discovered “additional 17 publications containing image manipulations”. Then the two scientific advisors appointed by the Milan prosecutor’s office analysed “159 scientific articles related to authors in discussion and containing images obtained by the technique of gel electrophoresis.” Once you have narrowed the field to a smaller sample, they concluded that “the 32 of the 25 scientific publications analysed were the subject to manipulation.”

Splendido e coraggioso Pier Paolo Di Fiore che usa il test del #PSA #screening #tumore della #prostata come esempio di #bufala #fakenews propagandata da medici e autorità sanitarie @AIRC_it
Ho scelto il tema del prossimo video 😉 pic.twitter.com/Bfnf0haaL0

— Roberta Villa (@RobiVil) May 31, 2018

Alberto Mantovani, who is EMBO member and professor at the private medical school Humanitas University in Milan, has at least 9 papers listed on PubPeer (not to be confused with another Milanese cancer researcher, Roberto Mantovani, who has his own PubPeer record). Mantovani sent in 2016 this statement explaining the concerns in 6 of his papers to his employer Humanitas University, the university was satisfied and “no problem was raised on their side”. The Humanitas professor also contacted the journals. Here is his letter to PNAS:

Marco Pierotti is not just somebody, but actually director of the Istituto Nazionale Tumori, and as such a major heavyweight in Italian cancer research. 26 of his papers are listed on PubPeer, and this PubPeer evidence apparently formed the basis of the report submitted to Milanese state prosecutor, as well as for Mantovani, Pelicci and Di Fiore. Let’s wait how it plays out. This public declaration was issued by Di Fiore and Pelicci in July 2019, quote:

“We feel obliged and in need to reject firmly the allegations of scientific fraud allegations and to assert towards the scientific community and the public our total scientific and moral integrity.
The charges brought against us refer to allegedly fraudulent manipulations of scientific images (mainly alleged duplication of images during the assembly of the later published figures).
We have produced a large dossier of documentary material, including the available original data from which the disputed images were derived, with which we are ready to reaffirm the total absence of a behaviour in any way related to scientific fraud.”

This article has been updated

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