How UCL throat surgeon Martin Birchall misleads patients and tricks public funders

How UCL throat surgeon Martin Birchall misleads patients and tricks public funders

This is a new instalment of my investigation into UK and EU funded clinical trials on trachea replacement by the throat surgeon Martin Birchall at UCL. The method of using bone marrow cells to regenerate a dead decellurised donor trachea was developed by Birchall together with Paolo Macchiarini, and tested since 2008 on several human patients, with catastrophic results. Macchiarini by now is a pariah sacked by his formerly proud employer, the Karolinska Institute in Sweden, but Birchall was given further millions in British and EU money for his human trachea transplant experiments.

I finally obtained the patient information brochure for such phase 1 clinical trial INSPIRE, which was consistently denied to me by all participants. The information therein, or rather the strategic lack of it and the consequential wilful misleading of prospective patients, is truly scandalous. There is no mention whatsoever of any of the previous trachea transplant experiments Birchall performed and the clinical outcome of which he likely misrepresented in order to obtain this very funding and even his current full professorship at UCL (with the help of Macchiarini, see page 43 of his CV). His described strategy of transplant preparation and implantation seems scientifically nonsensical, while suggestive of medical obfuscation and even deceit. Now that I finally received the INSPIRE patient information sheet, I understand why the consortium partners preferred in to be hidden from public scrutiny.

For the scientific and medical ethics background of this complicated case, please refer to my earlier reporting (in chronological order):

Selective amnesia

My Freedom of Information Act 2000 (FOIA) request to Birchall’s employers and trial sites UCL and UCL Hospital (UCLH) in London, as well as to various funding and regulatory agencies, failed to turn up any documentation, due to confidential nature of this industrially-led clinical trial. David Hill, director of digital services at UCLH, initially chose not to act on my inquiry about the patient information brochure and consent form. He and UCLH simply pretended I never asked for INSPIRE documentation and left it as such. After I brought my complaint to the UK overarching authority, the Information Commissioner’s Office, UCLH was instructed to reply to my FOIA request within a certain deadline. Which Hill now did, with apologies and with blaming a “member of the team”. This is the document he finally shared with me, with a caveat that “the Participation Information Sheet (PIS) is currently under review” and that an updated version might be forthcoming.

Indeed it looks like the document needs some updating. Birchall somehow completely forgot all the earlier patients which were left dead or in permanent emergency care after his and Macchiarini’s trachea replacement surgeries. Back then, all their trachea transplant recipients were allegedly in grave conditions in the immediate threat of death, the interventions were presented by Macchiarini and his colleagues as compassionate case care. Macchiarini and Birchall transplanted their first “regenerated” trachea in 2008, according to all available evidence before any animal experiments took place. The operation on Claudia Castillo was hailed worldwide as a huge success and led to two publications in The Lancet (though the medical reality was different, details of the patient’s true state see here). Two more trachea transplant recipients of Birchall’s died, one lives with a permanent stent. Macchiarini’s trachea transplant technology has been declared “a failure” by the Italian National Transplant Center.

1
Diagram courtesy of Pierre Delaere, full presentation here

Nevertheless, these operational “successes” were most certainly used by Birchall as argument to procure GBP €2Mio for the INSPIRE phase 1 trial and its follow-up. Even before INSPIRE received its ethics vote, Birchall and his collaborators saw even more cash rolling from the EU, namely the €7 Mio funding for the advance-approved Europe-wide phase 2 clinical trial, TETRA. Meanwhile, INSPIRE is far from even beginning to recruit their four scheduled trial participants. Both INSPIRE and TETRA are officially run by the Liverpool-based company Videregen, who were also assigned a major chunk of this public funding.

Magic bone marrow cells

According to the information brochure I now procured, INSPIRE intends to recruit patients with tracheal stenosis in stable condition who receive standard medical care and whose lives are not in any immediate danger. These patients are supposed to be tricked into believing the technology was never trialled in humans:

“This is a first in human study, being done to investigate the safety and potential benefit of this novel type of tracheal replacement in patients with tracheal stenosis or malacia”.

Interestingly, the prospective INSPIRE patients will read no direct mention of the “mesenchymal stem cells” and their magic, unlike pompously listed at the NHS site. Even Birchall and his team seem to have understood that the stem cell capacities of these bone marrow cells are rather limited. Yet he wants anyway to give it another try (or four, or several hundred). Apparently to placate the patients who are distrustful towards the stem cell hype, the patient information brochure cautiously refers to “cells from your bone marrow” only:

“This trial involves a new experimental technique which uses a combination of a human trachea donated after death that has been stripped of any cells from the original donor (known as the trachea scaffold) and to which your own cells will be added. To make this new treatment, we will take cells from your bone marrow and grow and multiply them in a special laboratory. These cells will then be transferred onto the donor trachea scaffold. During a surgical procedure your own damaged trachea will be removed and the new trachea scaffold (that has been seeded with your own cells previously harvested and grown in the laboratory) will act as the replacement. As this new trachea has your own cells seeded within it, it is thought this new section will become part of your tissue”.

Thought by whom? None of Birchall’s transplanted dead tracheas ever became part of patients’ own tissue, he and Macchiarini failed to produce any trustworthy scientific or clinical evidence. In fact, in some cases the rotting transplants had to be removed, and the first patient Castillo must by now have lost her entire left lung as well, due to complications (details here). The scientific aspect of this tracheal regeneration by bone marrow cells is nil and void. Not only does it lack any experimental evidence, all the existing data, including numerous human experiments by Birchall and Macchiarini show exactly the opposite. There is no regeneration, the dead trachea carcass does not become part of patient’s tissue, the magic mesenchymal stem cells from bone marrow do not help to regenerate mucosal epithelium or blood vessels which are absolutely needed to make a trachea transplant functional.

Trust me, I’m a doctor!

To top things off, also the surgical aspect of the INSPIRE trial is questionable and misleading to the very least. This is what the professor of laryngology and throat surgeon Birchall intends to perform on patients:

“The section of damaged or diseased trachea will be removed using the rigid bronchoscopy technique you would have had at the first screening visit and the new trachea will be grafted in place. During the same operation, the trial doctor will do a surgical technique called a laparoscopy which is a surgical procedure that allows a surgeon to access the inside of the abdomen (tummy) without having to make large incisions in the skin. The trial doctor will perform a laparoscopy to take some omentum (which is fatty tissue around your intestines) and then use this to wrap the tracheal implant with what is known as an omentum wrap; this will act to support the tracheal implant. If however, you do not have enough omentum then the doctor may use as an alternative, a local muscle to wrap and support the new graft. To further support the tracheal implant a removable stent (small tube to prop open the trachea) will also be added”.

It is clear as mud what exactly Birchall announces to do to his four INSPIRE patients, even to a specialist I asked for opinion (note that the target audience of this information sheet are not surgeon colleagues, but medically naïve and desperate patients). Will a part of their trachea be removed and replaced with a “regenerated” cadaveric one, like with the previous patients? Aside of being potentially lethal, such trachea removal is “totally impossible from a technical viewpoint” by the method of rigid bronchoscopy, as explained by Pierre Delaere, professor for respiratory surgery at KU Leuven, Belgium. Delaere has been for years one of the staunchest critics of Birchall and Macchiarini (see his exclusive open letter on my site). To Delaere, it sounds that Birchall instead intends

“to endoscopically remove the stenotic mucosa and preserve the outer part of the native trachea (in an attempt to lower the morbidity and mortality). Then put dead trachea with stem cells inside and then insert the stent to keep the airway lumen open”.

2
Diagram courtesy of Pierre Delaere, full presentation here

Basically, a dead decellurised donor organ sprinkled with magic cells will be stuffed inside the patient’s own. If you have difficulties understanding why, you are not alone. Obviously Britain and EU are willing to pay millions to see Birchall do this. He himself certainly does not bother to explain this charade to his patients. The carefully disguised fact is: the only medically active ingredient here will be the traditional airway-widening stent, as explained by Delaere:

 “A well-known palliative treatment for a tracheal stenosis is the removal of the stenotic mucosal layer by rigid bronchoscopy and introduction of a stent to keep the airway open. The stent will give rise to several complications and therefore it will only be placed for palliation. The INSPIRE proposal uses a similar approach, but they will bring the scaffold in-between the tracheal remnant and the stent. From a theoretical viewpoint this makes no sense. The same result would be obtained with a sheet of paper in between. Both the scaffold and the paper will only make the procedure more complicated without any benefit for the patient. The stent is placed to hamper direct visualization and to make this fraudulent replacement acceptable.

Wrapping the stented trachea with a piece of non-vascularized fat (omentum) or muscle will only bring more damage to the patient. Usually, omentum is used with preservation of its blood supply and this cannot be done through a laparascopic approach”.

However, the use of the fat or muscle tissue omentum for wrapping the carcass would indicate that Birchall does plan to cut out a section of patients’ trachea after all and replace it with a transplant. Again, whether or not the patients will have their windpipe cut out or not, should not be a subject to their guessing, but clearly stated in the information brochure.

In fact, Birchall and his team do not even mention to their prospective patients any possibility that the stent implant would ever be removed for good. The removable stents will only be exchanged from time to time. Once again forgetting all their previous trachea transplant patients, the doctors declare:

“We cannot promise the trial will help you but the information we get from this trial may help improve the treatment of people with tracheal malacia or stenosis in the future. We are hoping that this trial proves that the method of using a donor trachea along with a patient’s own cells could offer patients an alternative, potentially curative treatment which could eliminate the need for repeated surgeries that have limited success. Even if this new technique is not completely curative you could still benefit from an improvement in your quality of life”.

Don’t scare off patients!

Implanting pieces of dead tissue into patients’ unsterile airway environment bears an immense risk of bacterial infection. Another source of danger is immune rejection of the transplant, because it is very difficult, if not impossible, to remove all immune-reactive foreign tissue residues even with most thorough decellurisation. The resulting inflammation can quickly kill or mutilate the trachea recipient. Birchall must know all of this very well. With alternative of either not to implant his beloved decellurised tracheas at all or simply riding it out, he apparently chose to forward the responsibility to the manufacturers of stent and trachea. The way Birchall’s team formulated their risk warnings, a rather predictable medical emergency or even death would be entirely the patients’ own fault, for agreeing to this allegedly “relatively new technique”:

“The risks associated with implanting the trachea scaffold are as follows:

  • Potential for contamination of the scaffold or ability for it to develop a harmful immune response in your body. However, the donor trachea is supplied by the NHS Blood & Transplant service who provide robust compliant tissue sourcing and processing capability and it undergoes sterilisation by irradiation to make sure it is free from any germs. The donor trachea goes through a process known as “decellularisation” which means to remove all the cells from the donor trachea so that afterwards only the scaffold remains which has a low risk of developing an immune response in your body.
  • The new tracheal scaffold graft will be supported by a stent that will keep the tracheal scaffold open. The stent is CE marked [self-approved by manufacturer, and not “approved as safe by the EU or by another authority”, – LS] and suitable for this use although any stent has a risk of infection and tissue damage.
  • […]
  • Whilst the tracheal scaffold graft integrates and fuses with the surrounding tissue [trial operators have yet to present any reliable scientific evidence for this claim,- -LS], it will remain vulnerable to infection.
  • During the time taken for the tracheal scaffold to integrate with the surrounding tissue, there is the possibility you may suffer from obstruction (blockage) of your airways and as a result develop difficulty in breathing.
  • There is a risk of graft failure due to infection and breakdown of its tissue. Tracheal infections will be treated with antibiotics. If the trachea graft breaks down then some of it will have to be removed and a new stent put in place and a tracheostomy (artificial opening into the trachea so that air goes in and out through a tracheostomy tube) may be required. Please discuss this point with your doctor to better understand the potential complications.

There are side effects that you may have that are not listed here and we do not know about”.

The clear and present danger of death is not mentioned anywhere in the information brochure.

Elizabeth Woeckner, head of the Philadelphia-based non-profit organisation Citizens For Responsible Care and Research Incorporated (CIRCARE), lists some past “side effects” which Birchall et al should still be able to recall:

“The consent form says the experimental intervention “is fairly new” yet this seems to sidestep the fact that the approach, if not the specific methods of decellularization and “reseeding” of the donor tracheal graft, has been used (allegedly in compassionate use cases) since 2008, and with uneven if not catastrophic outcomes. As you point out in a previous report, Claudia Castillo is hardly a success.

Mr. Birchall has first-hand evidence of catastrophic outcome in UK patient Keziah Shorten, as he discussed in an interview with Bo Lindquivst in the Swedish Television documentary Experimenten [this patient died after receiving a plastic trachea carcass, see min 36 in documentary, -LS]

UK patient Ciaran Finn-Lynch lives with a stent, which is what got him into trouble and required the transplant in the first place, and so is hard to call a success [this “success” patient received a cadaver transplant, but without any “stem cell” treatment, -LS].

In 2012 UK patient Shauna Davison received a transplant and died a few weeks later, apparently of a hemorrhage [this patient died from a “regenerated” cadaver trachea, -LS].

If the investigational intervention in INSPIRE is so different from previous efforts, Birchall et al. need to explain precisely how it’s different and why the catastrophic adverse effects and deaths are unlikely to be at issue in this trial”.

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Diagram courtesy of Pierre Delaere, full presentation here

The secretive bureaucrats

The patient information sheet version I received is dated at January 5th 2016. Which means, it was made after the funding for the phase 2 trial TETRA already started flowing from the EU and just two days before INSPIRE received ethics approval from South Central – Oxford A Research Ethics Committee. Mark Ryan-Daly, Research Ethics Service Manager at NHS, confirmed to me that an ethics approval as indeed given as published on January 7th 2016.

Even more peculiarly, the British Medicines and Healthcare products Regulatory Agency (MHRA) wrote to me on June 23rd 2016 that they approved the INSPIRE trial months before that patient information sheet draft was prepared, on October 2nd 2015.

Another INSPIRE partner told me something contrary to the MHRA information, once they deigned to reply to my FOI inquiry more than two months after I placed it. This was what Alison Macdonald, Board Secretary at Royal Free London, wrote me on August 1st:

“Whilst the Royal Free London NHS Foundation Trust is mentioned in the research study information the trust’s role in this study is that the Centre for Cell, Gene and Tissue Therapy, based at the Royal Free Hospital, is contracted by Videregen to manufacture the final product in its state-of-the-art facilities.

In line with EU governance of clinical trials, the Centre for Cell, Gene & Tissue Therapy will provide all of the relevant documents for Good Clinical Practice (GCP) and GMP [Good Manufacturing Practice, -LS] compliance to the Medicine & Healthcare Products Regulatory Agency (MHRA) when the formal clinical trial authorisation application is submitted by the trial sponsor Cell & Gene Therapy Catapult”.

When I asked Macdonald at Royal Free to explain whether she meant that an MHRA approval hasn’t yet even been applied for, she simply answered: “we have nothing to add to our previous responses to you”. Why does Royal Free pretend the MHRA approval is yet to be applied for? Is their GMP lab functional at all? Or maybe it is the Videregen’s trachea-regeneration technology which doesn’t work out as instructed? MHRA, which originally even refused to confirm to me the existence of their approval from October 2015, now reiterated in this regard:

“The MHRA can confirm that the information we provided on 23 June 2016 was correct.  The sponsor for the Phase I trial was the Cell Therapy Catapult as part of the INSPIRE consortium.  The INSPIRE consortium includes Videregen, Cell Therapy Catapult, University College London (UCL), NHS Blood and Transplant in Speke and the Royal Free London NHS Foundation Trust (this information is public). Further, the plan for the Phase II study is also in the public domain, a link to this has been provided”.

Videregen’s obscure function

Thus, INSPIRE was granted both the manufactural approval from MHRA and the NHS ethical approval for transplantations before the deceitful patient information sheet was even prepared at UCLH as a preliminary version. The two million British pounds the governmental funder Innovate UK invested into INSPIRE in 2014 might have just as well been flushed down the toilet. At the same time, EU millions from the phase 2 TETRA trial continue rolling. The official industrial sponsor there is Videregen, which is receiving over €1 Million in funding for contributing actually nothing except of “expertise”, since the tracheas are meant to be manufactured by the Royal Free Hospital and NHS Blood and Transplant. This is how Wayne Lawley, Head of External Affairs at the latter insitution clarified to me on July 13th their role:

“NHSBT Tissue & Eye Services are partners in the consortium, however our part of the trial is to seek donor consent and retrieve trachea. We then decellularise the trachea following Videregen’s processes and issue this to Videregen for further preparation for the clinical trial. This is the limit of our involvement in the clinical trial”.

A second GMP lab to use Videregen’s trachea regeneration technology is being funded with €900,000 by EU’s TETRA project at the Technical University Munich in Germany. Videregen therefore either has no own GMP laboratory to “grow” windpipes with magic bone marrow cells or is possibly simply afraid of being made legally accountable should future abused patients or even their bereaved families go to court for damages. In the latter case, it would be fully understandable to delegate the entire responsibility to the public-owned GMP laboratories such as the NHS Blood and Transplant and the Munich clinical centre.

Officially, Videregen is also in charge of INSPIRE, or used to be. The above presented information shows that it is the London-based Cell Therapy Catapult which somehow became the INSPIRE sponsor now. For the follow-up TETRA, Catapult might become sponsor as well. I could not find out more, Videregen’s boss Steve Bloor has been ignoring my emails since long. But if his company manufactures or manages nothing, what for does it need over one million Euro from the EU then? Some of it will surely go into Birchall’s private pocket. He is member of the advisory board to Videregen and is paid for “3 x remunerated meetings per year”. Another million Euro was assigned to a biotech service provider, TMC Pharma, whose task is to manage this currently non-existent phase 2 clinical trial. Not much to spend therefore for anyone on anything really, while the EU money continues flowing down the drain.

Making money 

As it stands now, INSPIRE, TETRA as well as Birchall’s larynx-replacement trial RegenVox work solely as efficient money-milking setups, with a total of around €13 Million in British and European tax-payers’ funding money invested in them. The only good side to it: no patients will likely be ever treated with “regenerated” windpipe or voicebox transplants (unless Britain really proceeds to abolish the cumbersome patient protection regulation imposed by EU, as cheerfully announced by the new cabinet minister).

Delaere wondered aloud:

“How is it possible that well-respected doctors in the field write this kind of proposals? The only explanation is that they, for their own benefit (research money), continue to mislead both patients and the scientific community”.

The INSPIRE patient information sheet and consent form are available exclusively here.

Maria Fousteri, the ERC-funded western blot cheater

Maria Fousteri, the ERC-funded western blot cheater

Maria Fousteri is a highly successful Greek molecular cell biologist who studies the molecular mechanisms of DNA damage repair in human cells and their protective roles “against mental dysfunction or cancer”. Her works in the field of nucleotide exchange repair and epigenetic chromatin remodelling, done at the Leiden University Medical Center (LUMC) in the Netherlands in the department led by the LUMC professor Leon Mullenders, appeared in elite journals such as Molecular Cell.  These publications, described to me by a leading DNA repair researcher as “definitely major papers in the field” consequently helped Fousteri to an ERC starting grant of €1.5 Million for her research project “TransArrest” in 2012. Her young ERC-funded lab is located at the Biomedical Sciences Research Center “Alexander Fleming”in Greece, 20 km south of Athens.

The economic crisis-struck Greek science community should surely be rejoicing about such success of their returning top-scientist, with the most prestigious EU funding award from the ERC in tow. Instead, Fousteri’s colleagues at Alexander Fleming recently learned that a LUMC investigation found her guilty of data manipulations and research misconduct in 5 publications. Once again, it is about western blots. Images were re-used in unrelated context, lanes spliced and occasionally even bands duplicated inside a continuous gel image. The DNA nucleotide exchange repair specialist Fousteri seems to be just as professional in exchanging of western blot bands. These are the five papers, the first four (all in Molecular Cell) were recommended for retraction:

  1. Maria Fousteri, Wim Vermeulen, Albert A. van Zeeland, Leon H.F. Mullenders

Cockayne Syndrome A and B Proteins Differentially Regulate Recruitment of Chromatin Remodeling and Repair Factors to Stalled RNA Polymerase II In Vivo

Molecular Cell 2006, DOI: http://dx.doi.org/10.1016/j.molcel.2006.06.029

2. Jill Moser, Hanneke Kool, Ioannis Giakzidis, Keith Caldecott, Leon H.F. Mullenders, Maria Fousteri

Sealing of Chromosomal DNA Nicks during Nucleotide Excision Repair Requires XRCC1 and DNA Ligase IIIα in a Cell-Cycle-Specific Manner

Molecular Cell 2007 DOI: http://dx.doi.org/10.1016/j.molcel.2007.06.014

3. Roy Anindya, Pierre-Olivier Mari, Ulrik Kristensen, Hanneke Kool, Giuseppina Giglia-Mari, Leon H. Mullenders, Maria Fousteri, Wim Vermeulen, Jean-Marc Egly, Jesper Q. Svejstrup

A Ubiquitin-Binding Domain in Cockayne Syndrome B Required for Transcription-Coupled Nucleotide Excision Repair

Molecular Cell 2010 DOI: http://dx.doi.org/10.1016/j.molcel.2010.04.017

4. Tomoo Ogi, Siripan Limsirichaikul, René M. Overmeer, Marcel Volker, Katsuya Takenaka, Ross Cloney, Yuka Nakazawa, Atsuko Niimi, Yoshio Miki, Nicolaas G. Jaspers, Leon H.F. Mullenders, Shunichi Yamashita9, Maria I. Fousteri, Alan R. Lehmann

Three DNA Polymerases, Recruited by Different Mechanisms, Carry Out NER Repair Synthesis in Human Cells

Molecular Cell 2010 DOI: http://dx.doi.org/10.1016/j.molcel.2010.02.009

5. Therina Theron, Maria I. Fousteri, Marcel Volker, Lorna W. Harries, Elena Botta, Miria Stefanini, Mitsuo Fujimoto, Jaan-Olle Andressoo, Jay Mitchell, Nicolaas G. J. Jaspers, Lisa D. McDaniel, Leon H. Mullenders and Alan R. Lehmann

Transcription-Associated Breaks in Xeroderma Pigmentosum Group D Cells from Patients with Combined Features of Xeroderma Pigmentosum and Cockayne Syndrome

Mol. Cell. Biol. 2005 DOI: 10.1128/MCB.25.18.8368-8378.2005

LUMC published the results of the investigation on their website on June 16th 2016. Especially the first paper, Fousteri et al 2006, proved to contain many instances of deliberate data manipulation (see details below). But also the other papers offered enough evidence of misconduct to warrant retractions.

DNA damage001

Fouseri’s name and her publications were blackened out in the publicly available report version, a decision by the Netherlands Board on Research Integrity (LOWI) made sure the unblackened version will only be distributed to a small circle of recipients, including Fousteri’s coauthors, the editors of Molecular Cell who were asked to retract the Fousteri et al 2006 and Moser et al 2007 papers, and also her current host institute in Greece 

Babis Savakis, president and scientific director of the “Alexander Fleming”, replied to my inquiry about Fousteri misconduct investigation at LUMC as follows:

“Fleming is aware of this case and is currently looking into it. We will arrive to a decision after a careful and thorough review has been completed. Until then, as a matter of policy, we cannot make any comments”.

Fousteri was reported for suspicions of misconduct by her former LUMC colleagues already in 2011, according to the published report. The evidence was overwhelming, the only questions remaining were as to who exactly had faked the figures. Soon Fousteri herself admitted having manipulated data in one of her publications, yet instead of retracting that paper, she retracted her admission of fraud. As the result, an internal investigation by the LUMC department concluded in January 2014 that “there was no definite proof of a breach of scientific integrity by the defendant, given the complexity of the research”. The decision was appealed, and this new external investigation by LUMC came to a different conclusions:

“The Committee concludes that serious breaches of scientific integrity have been committed by Dr. Fousteri while employed at the Leiden University Medical Center. Following the listing of scientific misconduct as given in 1.2, this falls under a. falsification of data and h. acting unacceptably inaccurate in performing research. With reference to the LUMC Code of Conduct for Scientific Integrity (Regeling Wetenschappelijke Integriteit LUMC) it is considered scientific misconduct to wilfully manipulate research results to make them look better. Given the large number of instances in which figures were manipulated, which took place in several publications over a period of several years, and which have grievously misled readers, the Committee concludes that this constitutes a serious breach of scientific integrity. The Committee concludes that several publications need to be retracted. […]

It should be noted that the Committee has only been able to investigate a minority of the data that were presented in the publications, since in many instances primary data were lacking or not properly archived. The Committee did also not investigate unpublished data that were used in scientific presentations. Multiple instances of data manipulation have been found in all five publications that the Committee has investigated. These are clearly most numerous in two publications  (1,2) [Fousteri et al 2006 and Moser et al 2007, -LS], which originated from the LUMC, that will need to be retracted. In two other publications the manipulations were less numerous (3,4), [Anindya et al 2010 and Ogi et al 2010, -LS] but still of a nature that the Committee believes retraction is in order. However, since these publications did not originate from the LUMC, which only provided part of the experiment, the Committee advises further action to be taken by the institutes in the United Kingdom, where the main responsibility for these publications lies. Finally, although not the result of acceptable practice, the irregularities in the fifth paper (5) [Theron et al 2005, -LS], for which the main responsibility also resided at another institution, led the Committee to suggest a correction to be sent to the journal in which the manuscript was published”.   

Alan Lehmann, professor for molecular genetics at the University of Sussex in UK and last author of the Ogi et al 2010 and Theron et al 2005 papers with Fousteri-manipulated data, commented to me as follows:

“The University of Sussex is conducting its own independent investigation. When this is concluded I will discuss with Molecular Cell the appropriate action to be taken with regard to the Ogi et al paper”.

Fousteri’s former head of department Mullenders did not reply to my emails. According to the LUMC report, he told the investigators that “due to this autonomous activity of the defendant, he did not see the original experimental results, and therefore did not oversee the construction of figures from these for publications and presentations”.

Though Fousteri was found to be alone responsible for all data manipulations, Mullenders was anything but a hapless victim of her crimes. In fact, he was assigned part of the blame for his leadership style, and consequently retired as head of department (as indicated by the LUMC report). His name is not listed on the department website anymore, though he remains associated with LUMC, according to phone directory.  This is what the investigators decreed about Mullenders:

“The section in which Dr. Fousteri worked had no uniform way of guaranteeing the integrity of research, and there was no protocol in which standards and procedures were described. Generally accepted archiving processes, such as keeping a laboratory journal, were not always followed, although some individuals did so meticulously. The head of the section could have been aware of this, and professed a belief in adequate archiving to the Committee, but has not enforced it. There was no policy with regard to experimental validation of results, no critical discussion of the selection of primary data for inclusion in manuscripts. Generally, it seems the concept of falsification did not exist: Hypotheses became biological truths, and experiments were considered successful when they confirmed the hypotheses. The Committee concludes that the lack of adequate procedures, and the lack of enforcing of generally accepted procedures, as well as a general uncritical attitude have contributed to the breaches of scientific integrity. […]

Several PhD students who worked in the Department’s section suffered by Prof. Mullenders and Dr. Fousteri did not complete their PhD, which in one case was directly related to the scientific misconduct reported here, as well as in unpublished experiments that have not been investigated by this Committee, and in one case was likely to be related to the way in which the leadership of the section operated”.

The previous history of Fousteri’s Dutch PhD students makes it a matter of serious concern for the future of her current lab members. Presently, the misconduct -tainted group leader supervises five PhD students in her Flaming lab, plus four postdocs.

What about Fousteri’s ERC funding? According to their report, the investigators notified also the funding agencies associated with the manipulated papers. This mean that the European Commission, which supported Fousteri-Mullenders work though the FP6 funding programme, was informed about Fousteri’s misconduct. The ERC however, though directly associated with the European Commission,  denied any knowledge in their communication to me:

“The ERC Executive Agency was not aware of the information mentioned in your email and we will assess it”.

Also the Fleming director Savakis declared in this regard:

“We are aware of ERC policy regarding scientific misconduct and we will notify the ERC when we arrive to a decision”.

With such schedule, ERC is unlikely to even consider terminating Fousteri’s undeservedly obtained funding. With their other misconduct cases, ERC was not necessarily in any hurry to block the money waste. Especially since Fousteri’s EU support is scheduled to end in October 2017 anyway, little can be expected also here. Another elite research project will be concluded and become just another EU statistic.

There can be however another interesting twist to this story, since all four papers to be retracted appeared in Molecular Cell at Cell Press. Their editorial offices are ultimately controlled by the Cell Editor-in-Chief Emilie Marcus, who displayed in many instances a mind-bogglingly tolerant (if not welcoming) attitude to research misconduct (for details, see my report here). It would therefore be hardly surprising if the retractions requested by the Dutch investigation and possibly also its Greek and British counterparts would not be forthcoming, at least as long as Fousteri opposes them.


This is what the LOWI-adviced LUMC investigation found in Fousteri et al 2006 alone, accompanied by my own illustrations (copyright, naturally, with Cell Press/Elsevier):

fousteri1

“0. Duplication of Fig. 1C CSA, right two lanes (normal) and Fig. 1B CSB, soluble fraction, right two lanes.

  1. Duplication of Fig. 1D RNAPIIo, pellet blot and Fig. S2C RNAPIIo blot.
  2. Duplications of part of Fig. 1D and Fig. S2D
  3. Duplications of part of Fig. 1B and Fig. 2SA.
  4. Duplications of part of Fig. 1D and Fig. S2A.
  5. Duplications of Part of Fig. 2A and Fig. 4A.
  6. Reuse of part of Fig. 3D top panel in Fig. 3E top panel.
  7. Possible duplication of images in Fig. 3A top panel and Fig. 5A, top panel.
  8. Duplications of part of Fig. 3D and Fig. 5C.
  9. Fig. 4D. CSB Panel Appears put together in an unusual way.
  10. Fig. 5C. P300 panel, tied in untreated normal and untreated CSA cell appear to be identical (mirror image).
  11. Fig. S2C and S2D, CSB panels are the same, albeit with different exposure.
  12. Fig. S2C and S2D, RPA panels are the same, albeit with different exposure.
  13. Fig. S2C and S2D, XPF panels are the same, albeit with different exposure.
  14. Fig. S2A and S2B, CSB panels appear the same. 15. Fig. S2C and S2D, RPA panels are the same, albeit with different exposure.
  15. Fig. S2A, lanes 1 and 4 are duplicated.
  16. Fig. S2A and Fig. S2B top panels are duplicated.
  17. Fig. S2D, duplication of two adjacent bands.
  18. Duplication of Fig. 5C (Fousteri et al, 2006) into Fig. 4A (Moser et al., 2007)”fousteri2

Growing hearts in Hannover: a job opening

The Medical University of Hannover (MHH) in the German Lower Saxony is searching to recruit a professor who can grow human heart tissue from stem cells (see official call here). If you think you are the right kind of miracle doctor, you must hurry to apply: the deadline is August 26th 2016.

The recruiting MHH department is the clinic for heart, thorax, transplant and vascular surgery and its subdivision of the Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO). LEBAO was established by the heart surgeon and clinic head Axel Haverich, whose goals included creating stem cell-derived organs such as tracheas (hence the transient recruitment of the now disgraced thorax surgeon Paolo Macchiarini to his MHH department at the beginning of the century). Both Macchiarini’s and Haverich’s main objective was to grow a living human heart in a plastic box inside tissue culture incubator (the contraption is also known under the more fancy term “bioreactor”). In fact, Haverich repeatedly predicted to be able to achieve this even before his upcoming retirement (see my report here). The method was originally supposed to be that of stripping dead donor hearts of living tissue and seeding these carcasses with “magic” bone marrow stem cells. Later on, Haverich imagined it more high-tech: 3D laser printers would shoot cells of various types into a shape of a heart, and voila, it would come alive and start beating, ready to save another human life.

The trachea regeneration attempts were dropped by the Haverich team in 2006, as the MHH press spokesman Stefan Zorn told me in May 2016. The heart regeneration research however continues even now, though according to Zorn “in no connection to the work by Prof Macchiarini”. Nevertheless, no hearts, neither whole nor in pieces, were ever grown in Hannover (certainly not due to any lack of funding). Haverich thus focused on manufacturing heart valves with the help of his company Corlife (whether these heart valves are really regenerated and growing together with their juvenile recipients, as he insisted, is yet another issue).

screenshot-www.mh-hannover.de 2016-08-12 23-53-23

The new professorial recruitment to Haverich’s LEBAO is probably expected to make the founder’s dream of a bioreactor-grown heart come true.  These are the rather restrictive scientific requirements of the MHH tenure-track professorship call, which for some reason was placed in German only:

“The candidate should present a proven expertise in the subject area of cardiac tissue engineering and have acquired an international reputation in the field of stem cell biology, biomaterials and / or bioreactor technology”.

There are a number of scientists worldwide who work on differentiating in vitro heart cells from human induced pluripotent stem cells. Not all of them will be able to read this regionally placed German-language job posting though. In any case, I cannot think of any researcher who truly succeeded in growing transplantable heart tissue in a “bioreactor” from stem cells, unless of course Macchiarini is not a pathological liar after all. The Italian surgeon also speaks very good German, with a Swiss accent (since he grew up in Switzerland), and is in urgent need of a job, being sacked from his professorship by the Karolinska Institutet in Stockholm. Finally, Macchiarini conveniently holds since 2001 an adjunct professorship at the MHH.

Even if Macchiarini should fail to make this spectacular comeback to Hannover, a bit of warning to all the hopeful regenerative medicine artists out there, readying themselves to grow hearts with Haverich. It is possible that this open tenure-track position at MHH is not really open. The unrealistic restrictions may simply be meant to discourage and to disqualify any competing candidates. This would also explain why the job posting was issued in German only, running for only 4 weeks during the vacation month August. The MHH published the call (which closes on August 26th 2016) on July 27th 2016. German academic job portals featured the advertisement even later. So sorry everyone, this professorship was most likely already taken before it was even posted.

Whoever the lucky person is, one can only hope that MHH will not be in too much a hurry to test what they grew inside some human patients. Haverich’s “regenerated” heart valves were (according to the publicly available evidence) first trialled in 2002 on at least two Moldavian children, years before sheep were considered as an alternative test model (see my report here). To me, MHH refused to deny, comment or share any documentation on that human-first conundrum; their speaker Zorn also remained silent as to which scientific goals exactly MHH was pursuing with the advertised recruitment. The question is therefore: did MHH learn anything from the quackery and patient abuse by Macchiarini and his colleagues, which began in the Hannover laboratories? Will there be further ethically questionable human experiments because of someone’s dream of regenerative medicine fame?

Frontiers reviewer told: don’t be strict, endorse paper, reports Giulia Liberati

Journal peer review is a mysterious black box all scientists fear. The task of the reviewers is to help authors to improve their manuscripts scientifically and to help journal editors to weed out scientifically substandard and inappropriate works. That’s the theory anyway, in practice there are good reasons why the peer review process is traditionally something to be hidden by all means from the readers of published papers. Probably to avoid occasional shock, disgust  and repulsion, similar to how the supermarket customers should by no means be made aware of the true origins of industrially raised meat. In a kind of a vicious circle, this peer review secrecy is a direct invitation to rig it even more. Editors tend to assign friendly reviewers according to authors’ eminence, while peer reviewer conflicts of interests are routinely disregarded, since no one will ever find out anyway. In the same vein, scientists who made themselves some powerful enemies will see their manuscripts destroyed by unreasonable and aggressive peer review. They often naively hope the editor was decent enough not to invite those same adversaries whom the authors specifically asked to be excluded.

There is even good money to be made from gaming the peer review process. The subscription publisher Taylor & Francis offers manuscript authors premium peer review services: 300€ per page for rapid peer review, with 5-6 weeks “submission to acceptance” and €635 per page for “fast track”, which basically guarantees you to publish your paper in only 3 weeks latest. Now imagine if you paid Taylor & Francis €2000 for a 3-page manuscript, only to get rejected in fast track process- would this make any sense at all? The system can obviously only work to everyone’s satisfaction if all pay-per-peer-review papers are accepted without any hustle or demand for extra experiments in the prepaid time.

This is why so many journals prefer to keep their peer review process “confidential”. Even progressive open access publishers like PLOS leave their readers in the dark about how any given questionable paper got to be published there. Some journals switched to publishing peer review reports, though mostly depending on authors’ approval (see my article here), and some like the Swiss open access publisher Frontiers only list the names of reviewers and editor. Which may help readers to uncover occasional lack of academic or research field qualifications, certain conflicts of interest or to learn that the handling editor was also reviewing the paper instead of recruiting independent reviewers, but this is where the buck stops. The important part, namely the peer reviewer reports, remains secret with Frontiers. As we will see below, some of those consist only of a box-ticked approval.

Frontiers editors recruit reviewers from the vast pool of review editors of a given Frontiers journal. Precisely, these reviewers are largely postdoctoral scientists, but also PhD students and even non-academics, who are led to believe they are members of the “editorial board”. Which they are most obviously not, these review “editors” have zero influence over the editorial processes at their Frontiers journal. However: although they can be reviewing for many respectable journals, where else but with Frontiers can junior scientists receive the merits of membership to a journal editorial board? The cheap trick with these phony “editorial board” credentials works therefore surprisingly well.

Until recently, these “review editors” were not allowed by Frontiers rules even to advise a rejection of a manuscript, however abysmal it was. All they could do was to withdraw, only to be replaced by more cooperative members of the review editor pool, or the editor took over the review job. Now Frontiers reviewers are permitted to recommend rejection, but: as long as at least one of them keeps endorsing publication, rejection is not possible. In fact, also the associate editors, who are charged with managing the peer review process, are not allowed to reject manuscripts after they entered peer review, only chief editors can (see details here). Chief editors are also the only ones who receive a salary from Frontiers, their main task is specified in the contract: to make sure a certain number of papers is published in their Frontiers journal per year. Aside of inviting various research topics and collections to reach that number, Frontiers chief editors have a very limited influence over their own journals. Those who attempt to set editorial and review standards which do not agree with the rules of the publisher, get sacked. This is probably why none of Frontiers chief editors I ever attempted to interact with showed any desire to face responsibility for some rather questionable works which their own journal published.

The Frontiers process is streamlined to publish as much and as quickly as possible. No wonder many reviewers and handling editors abandon all pretence at ethics and integrity to wave almost everything through, or quit. Sometimes they quit officially, like Guillaume Rousselet, sometimes it’s a passive resignation: they remain listed as editorial board members, but refuse to react to editing and review requests from the Frontiers “editorial” office.

CjuriTcWEAAkjt8 twitter

Below a guest post by one such frustrated Frontiers reviewer. Giulia Liberati is post-doctoral researcher at the Institute of Neuroscience of Université Catholique de Louvain in Belgium. She specializes in nociception and tells of her experience of reviewing for the Frontiers flagship founding journal, Frontiers in Neuroscience (where the big boss himself, Henry Markram, used to publish and where he still hold the reins). I contacted twice the responsible associate editor as well as the chief editor and Markram’s closest collaborator Idan Segev and three Neurodegeneration speciality chief editors for a comment. Since there was no reply, I can only offer here Segev’s video as reference, where he makes clear that Frontiers philosophy is about not rejecting papers of paying customers.


By Giulia Liberati, neuroscientist at Université catholique de Louvain.

In July 2014, Prof. Tibor Hortobágyi, editor of Frontiers in Neuroscience, invited me to review a Methods article by Midorikawa, Itoi and Kawamura, entitled “Detection of residual cognitive function through non-spontaneous eye-movement in a patient with advanced dementia”.

Frontiers vs Reviewer: Round 1

From the title, the article seemed to be quite close to some work I had done during my PhD studies, so the invitation made sense. My previous experience with the Frontiers group had been quite good, both as an author and as a reviewer. I personally liked the forum format of the reviews, because I thought it helped both reviewers and authors to be constructive and to the point. I had also appreciated the transparency in publishing the names of the reviewers together with the articles: everyone just had to take responsibility both for the remarks they had made during the review process, and for the manuscripts they accepted. Awesome, wasn’t it?

For these reasons, I decided to accept the invitation to review the paper. As I went through the manuscript, however, I was more and more astonished. Was this some kind of joke? The paper was not written in proper English and was difficult to understand. But what really struck me was that some of my previous work, as well as some studies from my colleagues, were completely misquoted. I knew these works well, and I could see that the authors were using these references in a completely random way. In addition, the article was supposed to be a “Methods” article, but was rather a very weak case study with a limited number of trials (eight) on a single subject, with a very questionable experimental procedure and overstated conclusions.

I listed all these problems in my review, also insisting on the language issue. Furthermore, I requested to remove the incorrect literature citations, and pointed out that the article was not a Methods article, but something closer to a “clinical case” study (though a very weak one). I was very firm, but still polite.

Frontiers vs Reviewer: Round 2

Once I submitted my comments, I could see the other reviewer’s comments in the forum. Incredibly, the other reviewer had endorsed publication of the manuscript, without comment! This was unbelievable! No scientist in good faith could have accepted such rubbish. Even wanting to agree with the manuscript’s content, it was clearly not even written in proper English! How could the other reviewer have no comments at all?

However, some days later, I was notified that some comments had been added to the review forum. To my surprise, the Editor himself had added a remark to my comments. I unfortunately cannot cite the remark verbatim, because I do not have access to the forum anymore. Anyway, the remark was something like:

“I encourage the authors to improve their paper according to the reviewer’s request. However, I would like to ask the reviewer to be less strict. Hopefully, the reviewer will be satisfied after the changes and endorse publication”.

Wow, I couldn’t believe my eyes. This was the first time an editor appeared to interfere with my review, putting pressure on me to accept a paper. My aim was not to be unreasonably strict, my aim was to be objective. Everything I had written could be directly verified. And that paper was very far from being endorsable.

Frontiers vs Reviewer: Round 3

Some weeks later, the authors updated their submission with a new version of the manuscript, this time submitted as a clinical case report. In addition, I received an e-mail from Frontiers, requesting my approval for changing the type of article from Methods to Case Report. The authors had removed some of the wrong citations, but the English was still problematic, and the paper still had major methodological problems.

I wanted to point out these issues in the forum, but I was concerned by the very short time frame I was given to complete the review, i.e., one week. Since I was going to leave for a one-week holiday, I decided to inform the editor that I would have been happy to provide feedback, but one week later. Would that still be ok?

The Editor replied that it would have been more helpful for the authors to have my feedback before I went on holiday. Could I please submit my comments just before leaving? Because there was no way I could write an accurate and helpful review in one (already busy) afternoon, I decided to ignore the editor’s request. I had been honest about my time constraints, so if he really needed an immediate review, he could ask somebody else.

As I came back from my holiday one week later, I added my comments in the forum, once more pointing out the language issue and the methodological limitations of the study. Again, the Editor intervened. This time, he wrote:

“I suggest the authors to write a few more relevant sentences to make the reviewer happy. I ask once more the reviewer not to be too strict and to finally endorse the paper”.

Knock-out

I was enraged! Why was I being asked to review the paper anyway, if my comments did not count at all? I was not simply asking for “a few more relevant sentences”. The English was just too bad, the methodological issues were just too strong. I tried to reply a couple of times to the Editor. At one point, I was sad, frustrated, and exhausted. Having understood that the paper was going to be accepted with or without my endorsement, I decided to resign from the review process.

In resigning as a reviewer, I was asked for an explanation. I still have my reply saved on a word document, so here it is:

“As I feel that I am being put under pressure to accept an article which I do not consider to live up to Frontiers in Neuroscience (neither in its current form, nor with ‘a few more relevant sentences’), it is with regret that I have made the decision to withdraw from the review process, also because I do not want my name to be listed within the reviewers who endorsed the article once it will be published”.

And the winner is: Frontiers!

The paper was eventually published, apparently, as a Methods article in the end [Frontiers charges authors for a “Methods” article more than twice as much as for a “Case Report”, $2490 vs  $1150 -LS]. The Editor is now listed also as reviewer. No third reviewer was asked to give their opinion. The Editor simply replaced me. The English in the published paper appears to be polished, and some of my suggestions were taken into account, but in general, it remains a very low quality article. After exactly two years, it was not even cited once. There is unfortunately no trace of the fact that one reviewer decided not to endorse the paper. I do not even have access to the review forum to “prove” my existence as a former reviewer. So, where is Frontiers’ claimed transparency now?

I later decided to write a complaint to the Frontiers Editorial Office (editorial.office@frontiersin.org), as they encourage researchers to write to them for general comments, suggestions, or queries. I explained the situation in detail. I never got a response. This behavior is apparently absolutely fine for them, and I don’t even deserve a reply.

Was this the best way for me to handle the situation? Probably not. The paper was accepted anyway, probably more easily after I resigned. Maybe I could have just kept on posting the same comments in the forum over and over again, ignoring the Editor’s remarks. But I was really feeling like wasting my time, and getting more and more frustrated. In the end, it was obvious that the paper was going to be accepted.

I did not officially quit the Frontiers editorial board. Although I had had a very bad experience, at that time Frontiers’ reputation was still ok (as much as I was aware of), and I did trust many of the Editors. The last paper I reviewed was for Frontiers in Human Neuroscience in autumn 2014. I don’t think I have been asked to be a reviewer since then.

Does ERC help cheaters pay protection money?

Does ERC help cheaters pay protection money?

Did you ever wonder why certain zombie scientists were still in academic jobs? Despite having been caught on data manipulation or biomedical ethics breach?

It seems the answer is simpler than you thought. They are paying for their protection, by giving pizzo to their crooked research institutions, just as in some unoriginal mafia film. Well, actually YOU are paying their pizzo, through your taxes, which in turn are awarded to these zombie scientists as public research funding, from the national, international and European funding agencies. In fact, the most prestigious and self-important European funding agency ERC is completely unprepared or maybe just unwilling to respond to evidence of research misconduct by their elite grant recipients.  

My understanding is provocative, and I may be utterly wrong. But absent of any reasonable alternative explanations, let us for a moment go with this one. I will provide you with examples where questionable European scientists surprisingly retained their European funding unquestioned (or even received fresh millions of Euros), and coincidently or not,  many institutions did not at all mind to keep them in their jobs.

Got funding

Olivier Voinnet

The plant scientist Olivier Voinnet, whose misconduct affair I have been following since it first popped up on PubPeer in winter 2014/2015, had to retract 7 papers and was allowed to replace manipulated data in a large number of other scientifically problematic publications (please refer for details of his Voinnetting-style corrections and of institutional attitudes to my earlier long-read articles, here and here). Among other calamities, Voinnet lost his research lab at his former CNRS institute in Strasbourg, his research money from the Swiss National Fund (SNF) and even saw his EMBO Gold Medal, awarded to him in 2009, withdrawn. Yet he remained full professor at the ETH Zürich in Switzerland. Why? Maybe this statement to me by the ERC will explain it:

“The 2012 ERC Advanced Grant awarded to Professor Olivier Voinnet for the project ‘Frontiers of RNAi-II’: “High resolution and chemical genetic approaches to RNA silencing mechanisms” is ongoing and hosted by the Swiss Federal Institute of Technology Zürich (ETH Zürich)”.

We are talking about of €2.3 Million, with the funding period of July 2013 till June 2018, nothing to be sniffed at even in the wealthy Switzerland. Can this explain why in July 2015, with 3 more years of ERC funding to go, ETH decided that Voinnet did not commit any research fraud as such, despite his own admission to willful manipulation of figures in his papers (as soon came out, same manipulated figures were also used in his PhD thesis). Can the €2.3 Million from the sympathetic ERC explain why ETH decided to engage with Witold Filipowicz as one of Voinnet’s two external investigators the very scientist who nominated him for the EMBO Gold Medal and who received in April 2014 research funding and €10,000 personal salary for collaborating with Voinnet’s Strasbourg lab? I tried to raise these questions with ETH, but aside of acknowledgment of receipt, no reply was forthcoming.

The Voinnet lab at ETH is now all but defunct; it is very unlikely it spends much of that ERC money on research reagents or even salaries. What is more likely though, is that ETH put that money to good use elsewhere, and ERC doesn’t seem to mind.

Susana Gonzalez

This Spanish stem cell researcher was sacked in early 2016 from her group leader position at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid, after an internal investigation with a secret outcome. Only a few months before she was awarded the ERC Consolidator Grant of €1.9 Million, for her regenerative medicine project “YOUNGatHEART: cardiac rejuvenation by epigenetic remodelling”. ERC was most obviously taken by surprise with Gonzalez’ sudden sacking and suspended the grant pending assessment (see my report here). Importantly, the EU funder decided not to terminate it, although it is reasonable to expect that ERC was privy to that CNIC investigative report, which most likely was not really about extolling Gonzalez’ scientific brilliance and integrity. Soon however, another public research institute in Madrid, the Centro de Biología Molecular Severo Ochoa (CBMSO) offered Gonzalez a new workplace as tenured researcher (see my other report here). To me, the institute’s director Jose de Celis explained that the unsackable Gonzalez was actually forced upon him by the Spanish research council Consejo Superior de Investigaciones Científicas (CSIC). The original whistle-blower told me something different though, therefore one wonders if de Celis personnel decision was instead based on the assumption that Gonzalez’ ERC grant could be reassigned to his institute.  Should this really happen, it will be however unlikely for disgraced Gonzalez to be allowed to use this recovered funding at her own discretion.

Pontus Boström

This Swedish diabetes researcher was caught faking data during his PhD thesis at the University of Gothenburg. He was forced to retract two meeting abstracts (his fraudulent paper manuscript was stopped before publication) and officially found guilty of research misconduct in early 2014 (see my detailed report here). At this time, Boström was already employed by the Karolinska Institutet in Stockholm as group leader and funded by the ERC, all thanks to an irreproducible, artefactual and possibly also manipulated publication in Nature (Boström et al 2012), which boasted the discovery of a magic anti-obesity hormone.  The ERC grant of €2 Million was awarded for the further study of this (most likely non-existent) hormone ‘irisin’ and ran from January 2013 on. However, by December 2015 Karolinska and Boström decided to separate (it is not clear if he was sacked or not), and the once world-famous diabetes researcher became a mere general practitioner in Stockholm. The interesting point is, that despite the results of the Gothenburg investigation being publicly known, ERC made no move to re-evaluate their ongoing funding to Boström for almost 2 years. The funding would have continued happily until end of 2017, fraud notwithstanding.  An insider source told me that it was Boström himself who terminated his ERC grant, “perhaps forced by the department to step down”. When confronted with this information, ERC told me this:

“Karolinska Institute requested the termination of his ERC grant because the principal investigator moved to work in another location. Accordingly the grant was terminated with all the related follow up actions concluded, in accordance with the applicable contractual provisions.

Please note that both the Integrity Standing Committee of the ERC Executive Agency, and the Scientific Council’s Standing Committee on Conflict of Interest, Scientific Misconduct and Ethics address vigorously any case of possible misconduct among ERC projects, according to the established procedures”.

Obviously, in the Boström case ERC saw no reason to investigate anything. The investigation was done for them anyway, by the University of Gothenburg. As the following example shows, what likely counted for ERC was that Boström was caught faking data BEFORE he received his ERC funding, which kind of makes it forgiveable.

Jacob Hanna

This Israeli stem cell researcher is anything but your typical zombie scientist, even if his research is known as not entirely kosher. Hanna is simply indestructible and seems to grow bolder despite data manipulations and reproducibility concerns surrounding his publications. This can only be possible thanks to elite Weizmann Institute in Rehovot, which apparently made it their goal to hide and silence any evidence against their group leader, which in turn can be only “justified” by the enormous amount of international funding Hanna brings to Weizmann (especially considering the tight research budget in Israel). One big chunk of cash is his ERC grant of €2 Million, for epigenetic cell reprogramming, which runs until October this year.

The reliability of Hanna’s research, either from his PhD studies with Ofer Mandelboim at the Hebrew University, from his postdoctoral research with Rudolf Jaenisch at the Whitehead Institute at MIT or from his own lab at Weizmann, has been questioned for years. At the end of 2014, Hanna was accused on PubPeer of heavy data manipulations in a number of his own publications (examples here, here and here). He and Mandelboim had to retract a paper in the Journal of Clinical Investigation (Hanna et al, 2004) due to image duplications. To counter the accusations of misconduct in his paper in Blood (Hanna et al 2005) the Weizmann group leader accused his “medical trainees”.   One would suspect that if a scientist was forced to retract one paper and to issue 10 corrections, an institutional investigation would have been in order. Not so with Hanna. Over Twitter, he refused to tell me if he ever was investigated by any of his employing institutions.

This is what ERC told me:

“According to our initial assessment, there are no serious issues related to the research carried out in his ERC project: the majority of the facts you listed are related to publications published before the start of the ERC grant, or are related to publications where additional information that did not modify the scientific conclusions was added.

Furthermore, we can confirm that for the time being the ERC executive agency is not doing any formal investigation related to the research integrity of Dr Yaqub Hanna and that we are not aware of any investigation being carried out by Weizmann Institute of Science”.

Yet who decided how serious the data integrity issues in Hanna’s papers are if there never was any investigation?

Hanna’s ex-PhD advisor and last author of the retracted paper Mandelboim never replied to my inquiry whether Hanna was ever investigated. Also the two deans of the two biomedical departments of the Weizmann Institute, Elior Peles and Zvi Livneh, remained silent. Most worryingly, the Ombudsman of Weizmann Institute, Doron Yonai, also refused to react to my emails, where I simply asked if Hanna was ever investigated by Weizmann. Yonai is the person whom junior researchers at Weizmann are supposed to contact with their suspicions of research misconduct. If he reacted with silence to my inquiries, how will he react to a hypothetical student of Hanna’s (or any other of several Weizmann’s scientists known for a questionable research integrity track record), if this student were to voice concerns about work practices in that lab? Keep silent and ignore the matter as well? Hand over the name of the little ratfink to his or her principal investigator to take care of?

It is safe to assume therefore Weizmann Institute indeed never investigated Hanna, at least not in any serious way. Also the Whitehead Institute stayed out of it, as Hanna’s ex-boss, the world-leading stem cell researcher Jaenisch told me:

“One paper published from my lab with Hanna had been questioned on PubPeer (CSC 4, 513, 2009) because of duplications of some panels. We corrected this in CSC. There has been no investigation by Whitehead“.

This is the Hanna et al 2009 paper in Cell Stem Cell, here the PubPeer evidence, and here are its two corrections of duplicated images (here and here). A third Erratum addressed Jaenisch’s originally omitted financial conflict of interest.

Omertá, but not always

Normally, a zombie scientist under the pizzo-dependent protection of the host institution must follow the omertá. They are supposed to stay under the radar and not to draw public attention to themselves. Eventually, their misdemeanors become forgotten and funding money resumes to flow. Some of these zombie scientists are in fact even explicitly prohibited from speaking to public. ETH issued and still maintains such a gag order towards Olivier Voinnet, possibly due to worries about the ERC and other funding Voinnet might still have or even gain in the future.  

The notorious immunologist Silvia Bulfone-Paus held onto her second professorship at the University of Manchester after being forced out of her main tenure in Germany following a dozen of retractions (see my report here). After the business-minded University of Manchester exonerated her, Bulfone-Paus regained trust and has recently obtained funding from the British charity Cancer Research UK.

Catherine Verfaillie is a Belgian stem cell researcher who allegedly discovered the pluripotency of bone marrow cells (on this peculiar area of science, including her own work, see my detailed report here). Verfaillie’s claims have long since been refuted and disproved, but are still out zombieing around, infecting research papers and damaging or even killing patients (as the Macchiarini scandal made obvious). The Belgian discoverer of the bone marrow magic had to retract a paper in Blood (Reyes et al 2001), but managed to save her main work in Nature (Jiang et al, 2002) thanks to a heavy correction of manipulated data. Everyone supposed Verfaillie kept quiet afterwards, and she did. She was hardly ever seen at regenerative medicine conferences. It is therefore not widely known that only two years later Verfaillie was awarded almost €10 Million Euro by the European Union for her Consortium project “Hepatic Microfluidic Bioreactor”. The EU funding ran between 2011 and 2015; Verfaillie’s employer Katholieke Universiteit (KU) Leuven was the consortium’s central hub and Verfaillie herself the coordinator. EU Commission magazine Research EU did an interview with Verfaillie on this topic in October 2015 (page 13-14 here). If you think her earlier scandal of irreproducible science and data manipulations was ever mentioned, think again.

Hanna however is different. He never kept the omertá, quite the opposite in fact. Since last year he has been enjoying anonymous PubPeer trolling of his stem cell competitors (predominantly his former colleagues from the Jaenisch lab, see my article here), whom he publicly accused of publishing irreproducible or fraudulent research. Recently, Hanna moved on to a full-out hybrid-warfare against his former mentor Jaenisch. Hybrid warfare, because Hanna now uses both, anonymous trolling on PubPeer and signed criticism on Twitter and PubMed. The details of this “public stem cell skirmish” can be read on Paul Knoepfler’s blog. Is Hanna playing a dangerous game against one of the most powerful researchers in the stem field here, or is there some grander strategy by his Weizmann Institute? All we can gather is: unethical behaviour of Hanna and his colleagues (more on this soon on my site) is tolerated at Weizmann, whatever the reasons.

The smelly compost heap of plant-based nanoparticles

A gang of Indian nanotechnology scientists, allegedly from Annamalai University in India, placed in 2014-2015 several papers in different journals, all of them about nanoparticle synthesis using extracts from various local plants. Most papers went into the journal Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, published by Elsevier. The publications were harshly criticised on PubPeer for their poor science, but also for suspected data manipulations (electron microscopy images, photographs of bacteria dishes and X-ray diffraction measurements were reused across different unrelated papers, see PubPeer examples below).

Five nanotechnology papers at Elsevier are now about to be retracted, at least four of them from Spectrochimica Acta Part A. The concerns about research quality and data integrity may have been however less decisive here. The faculties of the Annamalai University carry no mention of any of these authors as their members, all of the provided corresponding email addresses are from Gmail. A publishing scam, possibly including fraudulent peer review, is the likely reason why these papers are being retracted now.

Regardless of the data manipulations, these papers should have never been published in a serious journal in the first place. The scientific approach the authors used was evident of some miserably poor science.

Metal nanoparticles are being proposed for many different applications, one of them is disinfection. Silver and zinc ions are potent antimicrobial agents, in nanoparticle form they were shown to be even more toxic to bacteria. For the metal nanoparticle synthesis, two key chemical ingredients are needed, which are also present in plant extracts: a reducing agent and a capping agent (which can be a surfactant chemical or any protein). Aharon Gedanken, emeritus professor for chemistry at the Bar-Ilan University in Israel, explained to me briefly:

“All the plants have some carbohydrate and carbonyl groups. These groups are good reducing agents, and as such reduce silver ions to metallic silver. A first year Chemistry student knows it. Over the years I have received a few such Indian papers and recommended to reject these papers and not accept them for publication because of lack of novelty”.

Nevertheless, plant extracts are being proposed for nanoparticle synthesis ad nauseam, regardless of the fact that any plant will do the job. You could even use the filling of your vegetarian kebab to publish a useless paper about lettuce, cabbage, onions and tomato extract-based synthesis of metal nanoparticles and their resulting anti-microbial properties (if you really do this, please acknowledge me for the idea). Authors however prefer to pick some exotic or medicinal plants for this task, insisting that the specific active ingredients therein will make the nanoparticles special as well. Which is scientifically nonsense, there is absolutely no evidence for this supposition. Instead, using chemically undefinable plant extracts actually impedes the efficiency of the metal nanoparticle synthesis process and prevents any control over the process. Finally, there is nothing “green” about wasting expensive food on chemical reactions which could have been done with cheap reagents.

However, this did not stop the editors of Spectrochimica Acta Part A to happily accept in the brief time frame of around one year several papers (six by last count) from same gang of scientists, telling the same story of silver and zinc-oxide nanoparticle synthesis using varying Indian plants. Regardless of data manipulations, the science was always outrageously bad, as PubPeer users documented. Yet it apparently passed editorial vetting and peer review at a respectable Elsevier subscription journal with flying colours.

The only PubPeer critic of these fraudulent Spectrochimica Acta Part A papers, who signed his comments, was Sylvain Bernès, group leader at physics institute of the Benemérita Universidad Autónoma de Puebla in Mexico. Bernès told me:

“I’m glad to see that the editors of Spectrochimica Acta Part A are now taking the bull by the horns. Indeed, the retraction of this bunch of articles seems to be the best way to reduce the damage. Note that my comments posted on PubPeer were not about the weak science included in these papers (after all, we all need weak papers, in order to contrast with good articles). The main issue was the behavior of this team involved in non-ethical practices, and their systematic refusal to address our queries. […]

My (personal) conclusion is that any biomass may be used, instead of a well selected rare plant identified by a distinguished botanist. The other conclusion I reached is that at least 80% of the articles in the field include weak or very weak support for the characterization of the produced nanoparticles (assuming that something is really produced at nanometric scale)”.

For Bernès’ further professional insights into plant-made nanoparticles, please read below a short Q&A wat the end of this article.

I was informed about the upcoming retractions by the research integrity activist Jaime A. Teixeira da Silva. According to the communications between him and Elsevier, these are the five papers to be retracted:

Ashokkumar, Ravi, Kathiravan, Velmurugan. “Synthesis, characterization and catalytic activity of silver nanoparticles using Tribulus terrestris leaf extract” doi: 10.1016/j.saa.2013.10.073 PubPeer debate

History: Received 16 August 2013, Revised 9 October 2013, Accepted 17 October 2013, Available online 26 October 2013.

Elumalai, Velmurugan, Ravi, Kathiravan, Ashokkumar. “Facile, eco-friendly and template free photosynthesis of cauliflower like ZnO nanoparticles using leaf extract of Tamarindus indica (L.) and its biological evolution of antibacterial and antifungal activitiesdoi: 10.1016/j.saa.2014.09.129 PubPeer debate

History: Received 16 May 2014, Revised 26 July 2014, Accepted 30 September 2014, Available online 23 October 2014

Elumalai, Velmurugan, Ravi, Kathiravan, Ashokkumar. “Green synthesis of zinc oxide nanoparticles using Moringa oleifera leaf extract and evaluation of its antimicrobial activity”. doi: 10.1016/j.saa.2015.02.011 PubPeer debate

History: Received 1 October 2014, Revised 10 December 2014, Accepted 4 February 2015, Available online 12 February 2015

Ashokkumar, Ravi, Kathiravan, Velmurugan. “Synthesis of silver nanoparticles using A. indicum leaf extract and their antibacterial activity”. doi:10.1016/j.saa.2014.05.076 PubPeer debate

History: Received 31 March 2014, Revised 15 May 2014, Accepted 28 May 2014, Available online 21 June 2014

 

The fifth paper to be retracted seems to be from a different Elsevier journal, Applied Surface Science:

Elumalai, Velmurugan. “Green synthesis, characterization and antimicrobial activities of zinc oxide nanoparticles from the leaf extract of Azadirachta indica (L.)” doi: 10.1016/j.apsusc.2015.03.176 PubPeer debate

History: Received 21 January 2015, Revised 9 March 2015, Accepted 28 March 2015, Available online 3 April 2015

According to an email Teixeira da Silva forwarded to me, the associate publisher for spectroscopy at Elsevier, Christian Schulz, wrote to him in April 2016:

“I am sure you are happy to hear that we have already radically reworked our editorial board in the last 16 months with several new editors (J. Kim, M. Baranska and S. Canuto, two assistants and a managing editor) replacing former editors. In fact most cases, just like the present one, trace back to the same editor, who is not active anymore.

These changes were triggered after we realized that the journal is steering into the wrong direction. I am confident that our new board will be much better suited to move the journal forward and preventing cases like the one which you flagged in your original mail. I will have a workshop with all editors at the end of the month and will certainly bring up PubPeer in our ongoing discussion about open ethics cases”.

I attempted to contact one of the “old board” editors, Werner Mänthele, who delegated the communication with me to Schulz. Schulz in turn declined to comment, also in regard to the exact identity of the fifth paper. He only referred me to the upcoming retraction notices. The internet archive “Wayback Machine” helped to find to narrow the circle of the Spectrochimica Acta Part A editors who might have been responsible for the publishing of these fraudulent papers. The editors James R. Durig or Bin Ren were board members in 2014, but not anymore. Which one of them was it then? Schulz however remained silent.

It looks like Spectrochimica Acta Part A and other subscription journals participated in a publishing scam and fed their reader rotten science. Not only was it qualitatively abysmal, it was also fraudulent. Given that at last one editor was actively involved, it would be inappropriate to call the journal a victim here. All editors read what was being published and nobody seemed to object (i.e., if they actually read what their own journal published). Even now, the members of the editorial board of Spectrochimica Acta Part A, otherwise proudly aware of their function, seem to be hiding behind the Elsevier manager instead of taking responsibility.


Q&A on “green” nanoparticles with Sylvain Bernès.

Bernès is group leader at physics institute of the Benemérita Universidad Autónoma de Puebla in Mexico and used to work on the field of nanoparticle synthesis with plant extracts between 2006 and 2013. A field professional helped me to formulate the following questions which I now attribute to myself.

LS: Is there any control over the synthesis process and the final properties of the obtained nanoparticles in these “green” nanoparticle synthesis approaches?

SB: In most cases, no control is achieved. Many, many authors claim they have some control on the composition, shape and size distribution for the nanoparticles they produce, however, these studies are never reproduced. On the other hand, the key point (at least for me), is that these particles are almost ever “characterized” by electron microscopy (TEM, SEM, AFM…). Nothing is commented regarding the bulk material, or how the published TEM images are representative of the green process. In the worst cases (like this one, unfortunately from a group of colleagues), I can’t even see a single nanoparticle in these images (the paper is in Spanish, but take a look at Figs. 3-5).

In some cases, however, a real effort is made a posteriori to rationalize the process. For example, by varying the pH, a correlation with the particle size may be observed. Or not.

LS: Are the synthesis mechanisms in these “green” methods actually known and understood by the research field community?

SB: Still controversial. There is a rather strong consensus about the involvement of some plant metabolites in the bioreduction of metal cations: terpenoids, flavonoids, sugars, polyphenols, etc. In contrast, the following steps leading to nanoparticles have been poorly studied so far: nucleation, aggregation and/or coalescence, and eventual stabilization of the nanoparticles.

LS: Does it make any sense to come up with new “green”-nanoparticle-synthesis paper every time a new species of plant or even new plant parts (fruits versus leaves etc.) are tested for this purpose?

SB: In no way. This is pure and blatant salami publication, unless completely unexpected nanoparticle shape and/or size is obtained with a specific part of a given plant (and only with that plant). These salami papers are just worsening the deluge of useless literature.

LS: Is there any evidence that “green”-synthesized nanoparticles versus nanoparticles of the same chemical composition synthesized without usage of plants/plant extract components have any advantage for usage in biomedicine?

SB: I’ve never seen such evidences, however I’m not really familiar with that literature. I’m under the impression that the antibacterial properties of Ag- nanoparticles or the accumulation of colloidal gold in tumors will be the same regardless of the synthesis process.
LS: Is the usage of possibly expensive agricultural products a truly “green” approach?

SB: “Green” does not necessarily means “cheap”. Expensive starting materials have thus their place in “green” processes. Regarding the synthesis of nanoparticles using plants as reducing agents, I think that the green aspect is the substitution of NaBH4 by a safer reagent (biomass). NaBH4 reacts violently with water, and is classified with code 3 for health hazard in the NFPA system: “short exposure could cause serious, temporary or moderate residual injury”. In other words, the green nanoparticle synthesis using plants is in line with principles 3 and 12 of the “12 principles of Green Chemistry”.

With Voinnet and Cosma cover-up, Cell now admits to have no editorial integrity whatsoever

The elite journal Cell issued editorial notices in regard to 3 papers by the Swiss-based French plant scientist Olivier Voinnet (found guilty of research misconduct in many papers) and one by the Spain-based Italian cell biologist Maria Pia Cosma (some information about her papers here). The journal Molecular Cell (which editorial offices are not entirely independent from Cell) issued same note for a different Cosma paper.

Despite obvious data manipulations, the journal decided not to do even as little as a correction. This is in full agreement with a previous declaration by the Cell Editor-in-Chief Emilie Marcus, who announced one year ago to be tolerating data manipulations in her journal, provided the science described is “wow” and “cool” (see details in my satire article here). Indeed, as a branch of the private business Elsevier, Cell is free to publish whatever they wish, even explicit fraud, lies and fakery. It is however the duty of all scientists, funding agencies and the subscription-paying university libraries to decide if what Cell publishes is actually any good science under such policies.  Even if it reads“wow”.

I will simply list the four editorial notices below, accompanied with some corresponding images off PubPeer. Naturally, none of that author-provided evidence (i.e., where it existed in the first place) which Cell found so convincing, is shared with us nosy readers. Make your own judgement, the notices speak for themselves.

Systemic Spread of Sequence-Specific Transgene RNA Degradation in Plants Is Initiated by Localized Introduction of Ectopic Promoterless DNA

Olivier Voinnet, Philippe Vain, Susan Angell, David C. Baulcombe DOI: http://dx.doi.org/10.1016/j.cell.2016.07.014

(Cell 95, 177–187; October 16, 1998)

We the editors of Cell were contacted by the corresponding author, Dr. David Baulcombe, and the first author, Dr. Olivier Voinnet. They informed us that, in Figure 6C, lanes 6 and 7 were intended to show two different negative controls, but one of the lanes was erroneously duplicated. The authors were not able to locate the original data and could not determine how the error arose.

Without access to the original data, a correction of this figure panel is not possible. Our evaluation of the other figures of the paper did not reveal any additional irregularities. Given the age of the paper and that the duplicated lane does not compromise the conclusions of the paper, based on the information available to us at this time, we will take no further action.

A Viral Movement Protein Prevents Spread of the Gene Silencing Signal inNicotiana benthamiana

Olivier Voinnet, Carsten Lederer, David C. Baulcombe

DOI: http://dx.doi.org/10.1016/j.cell.2016.07.015

(Cell 103, 157–167; September 29, 2000)

We, the editors of Cell, were contacted by the corresponding author, David Baulcombe, who informed us that this paper contains an unacknowledged image duplication. The mock control (Mock:M) lane shown in the northern blot experiment in Figure 3D is the same as the mock control lane in Figure 5D. Dr. Baulcombe informed us that these two experiments were carried out at the same time, run on a single gel, and exposed on the same autoradiograph and that they shared a negative (mock) control run in a single lane. Therefore, Figures 3D and 5D present the relevant lanes of each experiment plus the shared mock control. Dr. Baulcombe provided us with a copy of the original autoradiograph for these experiments. We have evaluated the data and confirmed his explanation for this duplication.

According to our current policy (although the paper was published before this stated policy was established), reuse of the negative control should have been mentioned in the figure legend. However, as this issue does not call into question the integrity of data collection and/or presentation overall, and given the age of the paper, we have decided against publishing a Correction of the figure legend. Based on the information available to us at this time, we will take no further action.

LINE-1 Activity in Facultative Heterochromatin Formation during X Chromosome Inactivation

Jennifer C. Chow, Constance Ciaudo, Melissa J. Fazzari, Nathan Mise, Nicolas Servant, Jacob L. Glass, Matthew Attreed, Philip Avner, Anton Wutz, Emmanuel Barillot, John M. Greally, Olivier Voinnet, Edith Heard

DOI: http://dx.doi.org/10.1016/j.cell.2016.07.013

(Cell 141, 956–969; June 11, 2010)

We, the editors of Cell, were contacted by the corresponding author, Dr. Edith Heard, who informed us that this paper contains unacknowledged lane splices in Figures 2C and 4C. In the preparation of these figures, lanes that were not relevant to the experiment presented were removed; however, these splice marks were not indicated in the figure or explained in the legend. Dr. Heard provided us with scans of the original data, which were prepared in her lab. We have confirmed that, in each case, the splice removes irrelevant lanes from a single gel.

Although splicing should have been indicated in the figure and explained in the legend according to our current policies, this issue does not call into question the integrity of data collection and overall presentation; we have therefore decided against publishing a Correction. Based on the information available to us at this time, we will take no further action.

 

Ordered Recruitment of Transcription and Chromatin Remodeling Factors to a Cell Cycle– and Developmentally Regulated Promoter

Maria Pia Cosma, Tomoyuki Tanaka, Kim Nasmyth

DOI: http://dx.doi.org/10.1016/j.cell.2016.07.016

(Cell 97, 299–311; April 30, 1999)

and

Cdk1 Triggers Association of RNA Polymerase to Cell Cycle Promoters Only after Recruitment of the Mediator by SBF

Maria Pia Cosma, Silvia Panizza, and Kim Nasmyth

DOI: http://dx.doi.org/10.1016/j.molcel.2016.07.002

(Molecular Cell 7, 1213–1220; June 2001)

Concerns about duplicated images in Cosma et al. (Cell, 1999) and Cosma et al. (2001, Mol. Cell 7, 1213–1220) were brought to our attention by a reader. We, the editors of Cell and Molecular Cell, have investigated the matter, communicating with the corresponding author, Dr. Kim Nasmyth; the first author, Dr. Pia Cosma; The Research Institute of Molecular Pathology (IMP), where the research in question was conducted; and the Center for Genomic Regulation, Dr. Cosma’s current institute, which conducted its own investigation. The IMP located Dr. Cosma’s notebooks and provided her with high-resolution copies. As part of our investigation, Dr. Cosma brought those copies to the Cell Press office, where we went through them with her, identifying data for the figures in the paper. The notebooks contained original images, alternate exposures, and/or replicate data for most of the figures in the papers, providing support for the reported findings. In a few instances, original data could not be located, making it difficult to assess the concerns raised about those specific data panels.

While we understand the reasons that the figures in the paper were flagged by the community, in our judgment the burden of proof for determining inappropriate data handling or image duplication has not been met. Furthermore, the available original data support the findings of the papers. With these things in mind, based on the information available to us at this time, we have decided not to take any further action. This statement is to notify the community of our investigation and findings.