In the medieval Flemish town, there is a Catholic University (KU) of Leuven, and inside this Belgian university there is a stem cell institute. The queen of this stem cell institute is the zombie scientist Catherine Verfaillie, whose once amazingly groundbreaking stem cells discoveries were long since debunked as phony garbage full of data manipulation.
But this story is not about the zombie queen Verfaillie, but about a Roman troll she hosts in her institute. Maurilio Sampaolesi is full professor at the KU Leuven, and he once cured Duchenne muscular dystrophy, together with his Roman mentor, Giulio Cossu. This story is about these two Italian stem cell magicians.
Just some years ago, stem cells and regenerative medicines were the hope of humanity. All diseases looked curable, organs were being grown in the lab like tomatoes, even the Catholic Church rejoiced when Verfaille discovered in early noughties that cells inside your bone marrow were pluripotent just like the cells in the embryonic blastocyst. These magic bone marrow cells could regenerate and reconstitute every tissue in the body, Verfaille was a star and even celebrated on a Belgian stamp. The surgeon Paolo Macchiarini applied this preclinical discovery into clinical breakthroughs, many lives were claimed to have been saved with his trachea transplants where bone marrow cells were seeded on an artificial scaffold.
Now we know that it all was fake.
These days, nobody is talking about pluripotent cells inside the bone marrow or anywhere else in the human body, except the usual criminally-inclined quack doctors running fraudulent stem cell clinics in former USSR, Latin America, or Germany.
But back then, when Verfaillie claimed in Nature to have found stem cell magic in the bone marrow, Cossu and his trainee Sampaolesi claimed in Nature to have harnessed stem cell magic of adult tissues to cure muscular dystrophy, in dogs. The two Italians and their Golden Retrievers were celebrated by the scientific community and the public alike, as the many sufferers of this incurable muscle-wasting degenerative disease saw hope on the horizon.
In November 2006, The Telegraph wrote:
“A stem-cell treatment for the degenerative and fatal disease muscular dystrophy, which mostly affects boys and young men, could be available for testing on patients within two years, following a remarkable series of experiments reported today. […]
The dramatic results of stem-cell therapy on the animals are reported in the journal Nature by Prof Giulio Cossu, the director of the Stem Cell Research Institute of San Raffaele Scientific Institute of Milan. The work shows that it is possible to halt this devastating disease and possibly even reverse it to a degree. […]
The professor estimated that another year or two will be necessary to get a patient’s own genetically modified stem cells to work. “Even though by itself it may not lead to a complete cure, it would ameliorate the condition, then step by step we could work on this to the point of getting a real cure.
Prof Cossu has already discussed human transplants with an Italian charity and is planning clinical trials. The first attempt is likely to use stem cells from a donor with a similar tissue type, the method that succeeded with the dogs.”
An esteemed Oxford professor, Dame Commander of the British Empire and expert on Duchenne muscular dystrophy (DMD) opined:
“Prof Kay Davies, of Oxford University, commented: “The use of stem cells to treat human disease holds great promise but the actual delivery of such therapy is thought to be many years away.
“The data presented in the paper from Cossu’s group, using a particular type of stem cell, a mesoangioblast stem cell, changes that view. . . this is a major step forward and suggests that this approach may be effective for use in DMD patients.”
Thing is, Davies’ own dystrophy research is full of data manipulations, and she is also extremely welcoming towards research misconduct of others.
And sure enough, also the scientific discoveries by Cossu and Sampaolesi were apparently not the breakthroughs we were told they were. Nobody is talking about these results and their discoverers anymore, and nobody wants to correct or retract their old papers despite the data irregularities therein. The spotlight is now taken by new bullshitters of stem cell research, preferably American.
This was that groundbreaking Nature paper by Sampaolesi and Cossu from 14 years ago:
Maurilio Sampaolesi, Stephane Blot , Giuseppe D’Antona , Nicolas Granger , Rossana Tonlorenzi , Anna Innocenzi , Paolo Mognol , Jean-Lauren Thibaud , Beatriz G. Galvez , Ines Barthélémy , Laura Perani , Sara Mantero , Maria Guttinger , Orietta Pansarasa , Chiara Rinaldi , M. Gabriella Cusella De Angelis , Yvan Torrente , Claudio Bordignon , Roberto Bottinelli , Giulio Cossu Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs Nature (2006) doi: 10.1038/nature05282
The Nature study gave hope to many dystrophy sufferers, but it was trash. And it was debunked right away in a 2007 letter to editor by Allan Bretag:
“My first concern is that control and test dogs were not matched for disease characteristics at the start of treatment to avoid inadvertently biased groupings in small experimental cohorts, where extensive individual variations exist. Also, the authors’ evaluations were not blinded. […]
Second, Fig. 5a of Sampaolesi et al.1 indicates that muscle strength declined, rather than was maintained as they imply, in the treated legs of all dystrophic dogs in which it was assessed. […]
Control dystrophic dogs lived, on average, 129 days longer than six out of ten treated dogs (123 days longer than those treated with autologous mesoangioblasts). Three of the four remaining treated dogs, described as “well” 400 days post natal, “rapidly lost walking ability” when immunosuppression ceased (257 days post natal for two of these).
Altogether, the evidence presented by Sampaolesi et al.1 does not convince me that the dogs benefited from mesoangioblast treatment; a rigorous demonstration correlating muscle function, dystrophin expression and mesoangioblast infusion, with adequate controls, would have been helpful in this regard. It is therefore premature to consider a clinical trial in humans as a justifiable extension of this study.”
The first correction came in 2013:
That same figure was then corrected again in 2014:
“In Fig. 4b of this Article, the gel for the loading control MyHC for the dog Varus was an unintentional duplication of the loading controls for the dog Vampire (which is correct). The correct gel is shown below in Fig. 1. The error does not affect any of our results and a University College London (UCL) committee appointed by the Vice Provost for Research has investigated the data presented in this Article and is satisfied of its authenticity.”
Indeed, there was an investigation at UCL where Cossu was professor at that time. UCL is very good in whitewashing research misconduct. The elite London university proved it twice, bigtime, for example in the Macchiarini affair:
But UCL’s greatest achievement was to overrule and to suppress the findings of their own investigation in order to declare their Birkbeck College master and major donor David Latchman as an innocent victim of some foreigner’s fraud:
Hence, no wonder that in 2013, UCL officially found absolutely nothing wrong with Cossu’s papers, as Times Higher Education reported:
“A University College London investigation has found that the research practice of a senior molecular biologist “did not always meet the standard of good practice expected of UCL researchers”.
Suspicions of image manipulation were raised last November concerning eight papers published between 2006 and 2012 by the laboratory of Giulio Cossu, who joined UCL in May 2011 as professor of human stem cell biology.
The allegations were made by an anonymous whistleblower known as “Clare Francis”. UCL’s formal procedure for investigating misconduct allegations requires a named accuser, but, in a statement, the university says that its “commitment to good practice in research” obliged it to examine the allegations.
The investigating panel, which included an external expert, concluded that no research misconduct had occurred. It cleared Professor Cossu of any “deliberate intention to mislead” and found no substance to the “large majority” of the allegations.
But it found that in a “few” cases “the conduct and presentation of the research in question did not always meet the standard of good practice expected of UCL researchers”.
“Where specific errors were detected, the panel recommended that, where possible, corrections should be made to the published papers,” the statement adds. But the investigation “found no indication that the errors altered the fundamental conclusions of these studies, many of which have been confirmed by independent research groups”.
It says that Professor Cossu “has acknowledged the spirit and details of the report” and “sincerely regrets” the errors.
“He will…implement processes to ensure to the best of his ability that such errors do not occur in the future,” the statement adds.”
Just before that decision, a muscle stem cell paper co-authored by Cossu was retracted:
Addolorata Pisconti , Silvia Brunelli , Monica Di Padova , Clara De Palma , Daniela Deponti , Silvia Baesso , Vittorio Sartorelli , Giulio Cossu , Emilio Clementi Follistatin induction by nitric oxide through cyclic GMP: a tightly regulated signaling pathway that controls myoblast fusion The Journal of Cell Biology (2006) doi: 10.1083/jcb.200507083
The retraction notice from January 2013 stated:
“After concerns were raised by a reader, the Editors of The Journal of Cell Biology detected the following issues with the data in the above article:
(1) The top panel in Fig. 1 F (NOS-1μ) is identical to the top panel in Fig. 2 B (α-sGC).
(2) The bottom panel in Fig. 1 F (NOS-III) is identical to the bottom panel in Fig. 2 B (GAPDH).
(3) Lanes 2 and 3 of the Follistatin panel for satellite cells in Fig. 4 A are identical to lanes 1 and 2 of the Myostatin panel for satellite cells in the same figure.
(4) A band appears to have been erased from lane 4 of the Follistatin panel for satellite cells in Fig. 4 A.
(5) Lane 4 of the Myostatin panel for satellite cells in Fig. 4 A is identical to lane 1 of the Follistatin panel for E12.5/E15.5 in the same figure.
(6) The E9.5 explants and E12.5/E15.5 panels for GAPDH in Fig. 4 A are identical.
Given the above issues with the experimental data in Fig. 4 A, the quantification data in Fig. S1 A cannot be validated.
No issues were detected with the other figures in the paper nor with the other parts of the figures listed above (Fig. 1, A–E, G, and H; Fig. 2, A and C–E; Fig. 4 B; and Fig. S1 B). […]
As a result of this retraction, no data in this paper should be cited in the scientific literature.
The Authors and Editors have informed the University of Milan of this retraction.”
Cossu just joined UCL in 2012 as full professor, having left home country, where he ha da full professorship and led a stem cell centre at the San Raffaele research hospital in Milan. After that 2013 investigation, Cossu left UCL, officially innocent of misconduct. But he didn’t return to Italy, but travelled north to become professor at the University of Manchester.
Cossu’s previous collaboration at the University of Milan with Emilio Clementi‘s lab there has been truly productive:
Clara Sciorati , Beatriz G. Galvez , Silvia Brunelli , Enrico Tagliafico , Stefano Ferrari , Giulio Cossu , Emilio Clementi Ex vivo treatment with nitric oxide increases mesoangioblast therapeutic efficacy in muscular dystrophy Journal of Cell Science (2006) doi: 10.1242/jcs.03300
We can assume it was Clementi’s lab fault because some other copied gel bands derived from a 2006 Clementi paper without Cossu’s contribution:
No correction for that paper, maybe that journal had enough of Cossu.
You would expect someone under research misconduct investigation to be particularly careful which data he submits for a new publication, but…
Ornella Cappellari , Sara Benedetti , Anna Innocenzi , Francesco Saverio Tedesco , Artal Moreno-Fortuny , Gonzalo Ugarte , Maria Grazia Lampugnani , Graziella Messina , Giulio Cossu Dll4 and PDGF-BB convert committed skeletal myoblasts to pericytes without erasing their myogenic memory Developmental Cell (2013) doi: 10.1016/j.devcel.2013.01.022
Cell Press issued in 2014 a correction:
“In the originally published version of this paper, Figures S4A–S4C correctly showed control cells; however, these same cells erroneously also appeared in Figures S4K–S4L. We have now replaced the latter three panels with the correct data….”
But apparently Cell Press has a rule forbidding second corrections, so a duplicated gel band is to remain:
Cossu discovered a lot in his time. In those golden years of regenerative medicine, scientific community accepted it as a proven fact that heart stem cells exist. Only after Piero Anversa was exposed as a mega-fraudster, masses of his papers retracted, did this huge field of cardiac stem cells collapse. But a funny thing is that a number of scientists managed to somehow build on and to extend Anversa’s fraudulent results, which either proves that Anversa was a prophet, or that the field of
degenerative regenerative medicine is full of cheaters perpetuating each other’s fraud. E.g. what to make of the heart stem cell research by David Argyle, head of Veterinary School at the University of Edinburgh?
Also Cossu and Sampaolesi proved in 2008, in Nature no less, that cardiac mesangioblasts were self-renewing and differentiate into beating heart muscle, those being true heart stem cells. Which presumably makes it a science fact, everyone must apologise to Anversa.
Here the follow-up paper by Cossu and Sampaolesi about cardiac stem cells:
Beatriz G Gálvez, Diego Covarello , Rosanna Tolorenzi , Silvia Brunelli , Arianna Dellavalle , Stefania Crippa , Salman Afroze Azmi Mohammed , Ludovica Scialla , Ivan Cuccovillo , Fabiola Molla , Lidia Staszewsky , Francesco Maisano , Maurilio Sampaolesi, Roberto Latini , Giulio Cossu Human cardiac mesoangioblasts isolated from hypertrophic cardiomyopathies are greatly reduced in proliferation and differentiation potency Cardiovascular Research (2009) doi: 10.1093/cvr/cvp159
Small thing, a duplicated flow cytometry histogram, but maybe a clue of how reliable all these stem cell discoveries by Cossu and Sampaolesi really were.
Before dogs, muscular dystrophy was cured by Cossu’s and Sampaolesi’s stem cell therapy in mice:
Maurilio Sampaolesi , Yvan Torrente, Anna Innocenzi , Rossana Tonlorenzi , Giuseppe D’Antona , M. Antonietta Pellegrino , Rita Barresi , Nereo Bresolin , M. Gabriella Cusella De Angelis , Kevin P. Campbell , Roberto Bottinelli , Giulio Cossu Cell therapy of alpha-sarcoglycan null dystrophic mice through intra-arterial delivery of mesoangioblasts Science (2003) doi: 10.1126/science.1082254
This is not just an innocent duplication. First, the red signal is very different between the control and the treated mice. But it also seems, the microscopy image was digitally rearranged by some mysterious fraudulent crook.
Cossu and Sampaolesi know of this problem with their paper for years, but neither they not the editor of Science have found time so far to do anything about it. But then again, Science editors are busy with ignoring many other things.
Soon after that breakthrough cure of mice, and before the breakthrough in dogs, a potential cure for human disease suffers was established. Cossu and Sampaolesi even found the right stem cells in the blood of healthy donors. Just sort these “mesangioblasts” by FACS for the famous surface protein market CD133 (AC133), which, science concurred back then, was definitely established to be THE universal stem cell marker of all stem cells:
Yvan Torrente, Marzia Belicchi , Maurilio Sampaolesi , Federica Pisati , Mirella Meregalli , Giuseppe D’Antona , Rossana Tonlorenzi , Laura Porretti , Manuela Gavina , Kamel Mamchaoui , Maria Antonietta Pellegrino , Denis Furling , Vincent Mouly , Gillian S. Butler-Browne , Roberto Bottinelli , Giulio Cossu , Nereo Bresolin Human circulating AC133(+) stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle Journal of Clinical Investigation (2004) doi: 10.1172/jci20325
Judging form the issues above, this study is obviously fraudulent. But its authors made fine careers in academia, and anyway, nobody cares about those miraculous CD133 claims of the past now. Like heart stem cells, the CD133 claims have all been long forgotten and are never mentioned again, not even by their original discoverers. I personally think all past research worldwide about amazing stem cell successes like these should be checked for fraud.
2006 was a very productive year for Cossu and Sampaolesi. The two men from Rome achieved impressive progress on muscle dystrophy in dogs, and even a “complete repair” of dystrophic muscle in mice!
Beatriz G. Galvez , Maurilio Sampaolesi , Silvia Brunelli , Diego Covarello , Manuela Gavina , Barbara Rossi , Gabriela Constantin , Gabriela Costantin , Yvan Torrente , Giulio Cossu Complete repair of dystrophic skeletal muscle by mesoangioblasts with enhanced migration ability The Journal of Cell Biology (2006) doi: 10.1083/jcb.200512085
The paper was subjected to corrections trice, 2x in 2006 and once in 2013, also in the same year concerns were expressed (and apparently assuaged since). In 2006, Figure 9B was replaced, because “the top left (Control) and top middle (Treated) panels under the “120 days” heading of Fig. 9 B were duplicated.“
The last correction was a biggie and mentioned “a clerical error during figure preparation”
Those are simply forgeries. Elisabeth Bik, going through Sampaolesi’s publications in the wake of the affair of his current superior Verfaille, commented on PubPeer:
- “Correction 1 addressed the duplication in Figure 9B, but I agree with Peer 4 in comment #7 that the new figure 9 “Control” panel appears to be a composite of the “Treated” panel – making this replacement even worse than the original simple duplication.
- Correction 2 addressed a name misspelling.
- Correction 3 addressed duplications in Figures 1, 5, and 6, that are worth visualizing here.“
“These are also not simple duplications, but appear to be duplicated FACS plots with altered numbers.”
But because this paper received all these corrections, you must trust the J Cell Biology editors that all conclusions remain unaffected and the corrected results are 100% reliable and trustworthy.
Cossu and Sampaolesi are really skilled issuers of corrections:
Marco Cassano , Stefano Biressi , Amanda Finan , Laura Benedetti , Claudia Omes , Renata Boratto , Frank Martin , Marcello Allegretti , Vania Broccoli , Gabriella Cusella De Angelis , Paolo M. Comoglio , Cristina Basilico , Yvan Torrente , Paolo Michieli , Giulio Cossu , Maurilio Sampaolesi Magic-factor 1, a partial agonist of Met, induces muscle hypertrophy by protecting myogenic progenitors from apoptosis PLoS ONE (2008) doi: 10.1371/journal.pone.0003223
Also, an immunofluorescence image was misplaced. In 2019, Plos One published a correction:
“The authors have provided the original images used in Figures 2E and 3B. The original images do not contain background irregularities and the source of the image artifact is unclear.”
Sure, the images the authors provided for Figure 3B show no splicing tracks anymore. But those for Figure 2E still do, maybe the authors forgot to fix it? Also, in January 2022 someone alleged on PubPeer a band duplication in this figure:
At some point, nobody was interested in correcting anything anymore:
Y. Torrente , M. Belicchi , C. Marchesi , G. D’antona , F. Cogiamanian , F. Pisati , M. Gavina , R. Giordano , R. Tonlorenzi , G. Fagiolari , C. Lamperti , L. Porretti , R. Lopa , M. Sampaolesi, L. Vicentini , N. Grimoldi , F. Tiberio , V. Songa , P. Baratta , A. Prelle , L. Forzenigo, M. Guglieri, O. Pansarasa, C. Rinaldi, V. Mouly, G. S. Butler-Browne, G. P. Comi, P. Biondetti, M. Moggio, S. M. Gaini, N. Stocchetti, A. Priori, M. G. D’angelo, A. Turconi, R. Bottinelli, G. Cossu, P. Rebulla, N. Bresolin Autologous transplantation of muscle-derived CD133+ stem cells in Duchenne muscle patients Cell Transplantation (2007) doi: 10.3727/000000007783465064
In 2013, Cossu left UCL for the University of Manchester, maybe he didn’t want to return to Milan where he was such a bigwig. In 2008, long before the trouble arrived, Sampaolesi used his impressive publication record of regenerative medicine successes to get a professorship at Verfaillie’s stem cell institute at KU Leuven. He is still there, and even if he is not an international big star of stem cell research who publishes in the big journals anymore, Sampaolesi seems to have grown bigger in other ways.
This is the kind of science Sampaolesi’s lab contributes to:
Riccardo D’Aquino , Virginia Tirino , Vincenzo Desiderio , Michèle Studer , Gabriella Cusella De Angelis , Luigi Laino , Alfredo De Rosa , Diego Di Nucci , Sabata Martino , Francesca Paino , Maurilio Sampaolesi, Gianpaolo Papaccio Human neural crest-derived postnatal cells exhibit remarkable embryonic attributes either in vitro or in vivo European Cells and Materials (2011) doi: 10.22203/ecm.v021a23
Sampaolesi never replied to my email (also Cossu remained silent). Here another paper by the KU Leuven professor:
T. Martinello , I. Bronzini , L. Maccatrozzo , A. Mollo , M. Sampaolesi, F. Mascarello , M. Decaminada , M. Patruno Canine adipose-derived-mesenchymal stem cells do not lose stem features after a long-term cryopreservation Research in Veterinary Science (2011) doi: 10.1016/j.rvsc.2010.07.024
A mistake of oversight? Those are collaborative papers, and maybe the problematic figures were not done at KU Leuven. But there is a saying about your choice of friends showing who you really are. And every author is co-responsible, especially those senior authors in professorship position who knowingly decide to do nothing about the evidence.
Francesco D’Angelo , Ilaria Armentano , Ilaria Cacciotti , Roberto Tiribuzi , Mattia Quattrocelli , Costantino Del Gaudio , Elena Fortunati , Enrica Saino , Auro Caraffa , Giuliano Giorgio Cerulli , Livia Visai , Josè Maria Kenny , Maurilio Sampaolesi , Alessandra Bianco , Sabata Martino, Aldo Orlacchio Tuning multi/pluri-potent stem cell fate by electrospun poly(L-lactic acid)-calcium-deficient hydroxyapatite nanocomposite mats Biomacromolecules (2012) doi: 10.1021/bm3000716
Aldo Orlacchio is a special case, look what this University of Perugia professor published together with Sampaolesi, uncovered by Elisabeth Bik:
Sabata Martino, Roberto Tiribuzi , Elisa Ciraci , Georgia Makrypidi , Francesco D’Angelo , Ilaria Di Girolamo , Angela Gritti , Gabriella M. Cusella De Angelis , Gianpaolo Papaccio , Maurilio Sampaolesi, Anna Concetta Berardi, Alessandro Datti, Aldo Orlacchio Coordinated involvement of cathepsins S, D and cystatin C in the commitment of hematopoietic stem cells to dendritic cells The International Journal of Biochemistry & Cell Biology (2011) doi: 10.1016/j.biocel.2011.02.001
It’s an Elsevier journal, so exactly nothing at all was done. Not much is happening also with this study on “multipotent cells” from horse blood:
Tiziana Martinello , Ilaria Bronzini , Lisa Maccatrozzo , Ilaria Iacopetti , Maurilio Sampaolesi, Francesco Mascarello , Marco Patruno Cryopreservation does not affect the stem characteristics of multipotent cells isolated from equine peripheral blood Tissue Engineering Part C Methods (2010) doi: 10.1089/ten.tec.2009.0512
Academia is full of zombie scientists, fallen stars whom nobody should touch with a barge pole, yet they all are perfectly safe in their cushy well-paid faculty jobs, raising in their labs new generations of cheaters, occasionally angling a big grant or placing a paper in a fancy journal. Their networks hold, and while academia has no jobs for whistleblowers, there is always a warm place for a well-connected cheater.
Sampaolesi’s case is somewhat reminiscent of the story of another former young star of stem cell research, Jens Schwamborn, who is safely occupying a professorship in Luxembourg despite past research misconduct findings in Germany.
Yet Sampaolesi’s past papers with Cossu were whitewashed by UCL, and KU Leuven only investigates the work done on their campus. Thus, there is nothing to investigate, think of these amazing muscular dystrophy breakthroughs as vintage science fiction, or as jokes at the costs of the Duchenne patients.
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