Academic Publishing Open Letter University Affairs

Time to retract Lancet paper on tissue engineered trachea transplants

Paolo Macchiarini affair: I reproduce the letter Patricia Murray, Raphael Levy, Peter Wilmshurst and myself published in The BMJ on 2 March 2022. I also publish Wilmshurst's appeal to the UCL leadership.

This is a green OA authors’ version of a letter Patricia Murray, Raphael Levy, Peter Wilmshurst and myself published in The BMJ on 2 March 2022, where we call for the retraction of the Macchiarini et al 2008 paper in The Lancet, which my past reporting exposed as fraudulent, illegal and dangerous, and yet this study remains protected for reasons one cannot fathom. I also publish a letter by Wilmshurst to the UCL leadership, regarding Paolo Macchiarini‘s close collaborator, Martin Birchall.


Time to retract Lancet paper on tissue engineered trachea transplants

BMJ 2022; 376 doi: https://doi.org/10.1136/bmj.o498 (Published 02 March 2022)

Cite this as: BMJ 2022;376:o498

Leonid Schneider, independent science journalist1Patricia Murray, professor of stem cell biology and regenerative medicine2Raphaël Lévy, professor of physics3Peter Wilmshurst, consultant cardiologist4

Author affiliations

  1. For Better Science, 63526 Erlensee, Germany
  2. Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
  3. Université Sorbonne Paris Nord, INSERM, LVTS, F-75018 Paris, France
  4. Royal Stoke University Hospital, Stoke-on-Trent, UK

Corresponding author: peter.wilmshurst@doctors.org.uk

We call for retraction of the 2008 Lancet article on “clinical transplantation of a tissue-engineered airway” by Macchiarini and colleagues.1 The paper received international media coverage as the “world’s first tissue engineered organ transplant,” and one of the authors, Martin Birchall, told the BBC that “in 20 years’ time, virtually any transplant organ could be made in this way.”2 Reality did not match the hype because nearly all subsequent patients who received “tissue engineered airways” died.3 The Lancet was informed in May 2018 that the key findings of the article were false. Despite this, and subsequent demands for retraction of the paper by us and others, the Lancet has refused to retract, without providing any explanation.

The 2008 article reports that a human cadaveric trachea was decellularised and colonised with “stem cells” from the recipient. The graft replaced a stenosed left main bronchus. Two sentences summarised the claims: “The graft immediately provided the recipient with a functional airway, improved her quality of life, and had a normal appearance and mechanical properties at 4 months. The patient had no anti-donor antibodies and was not on immunosuppressive drugs.”1

On 23 July 2018, in response to emails from one of us (PM), Antoni Castells, the newly appointed medical director of the Hospital Clinic Barcelona, where the operation was performed, wrote that in May 2018 he sent an email to inform the Lancet that “three weeks after the airway transplantation procedure, it was necessary to stent the transplanted bronchus, due to an homograft collapse.” Therefore the graft could not have had “a normal appearance and mechanical properties at 4 months.” Castells also informed the Lancet that there were discrepancies in the claims made regarding improvement of lung function.

Castells told us, in a letter dated 4 May 2018, that permission to perform the airway transplantation was granted by the hospital’s ethics committee on 2 April 2008 and by Catalan authorities on 18 April 2008. Bristol University’s response to our freedom of information request (161007) showed that pieces of the patient’s nasal and bronchial epithelium for so called stem cell production were received at Bristol University on 1 April 2008—that is, before ethical approval was granted. The “tissue engineering” in Bristol was organised by Birchall, Macchiarini’s co-principal investigator. It happened in a building that was not licensed under the Human Tissue (Quality and Safety for Human Application) Regulations 2007.4

Following our complaints to the House of Commons Science and Technology Committee, its chair, Norman Lamb MP, repeatedly complained to the Lancet’s editor, Richard Horton. On 7 March 2019 Lamb wrote again saying: “The director of the Hospital Clinic in Barcelona wrote to the Lancet in May 2018 to highlight problems with the 2008 paper . . . Your response does not give me confidence that this issue is being handled appropriately, or with sufficient urgency . . . The risk to human health of mis-reported patient outcomes surely means that there is a need for the Lancet to be proactive on this issue . . . The Lancet has faced criticism in the past about failure to retract unreliable research in a timely manner. Lives are genuinely at risk if inaccurate research is allowed to persist in the published record without at least a ‘statement of concern’ from the publisher.”

On 14 March 2019, Sabine Kleinert, senior executive editor of the Lancet, wrote a letter to Lamb, which we have seen, saying “We have asked the UK-based authors of the 2008 paper for a response to the issues raised in the [Newsnight] programme and to Dr Wilmshurst’s concerns. Once we have their responses, we will decide what the appropriate next steps are.” Despite freedom of information requests, we have been unable to find any subsequent correspondence between the UK authors and the Lancet.

On 4 March 2019, at the invitation of the Lancet editors, the journal published a clinical update letter by Laureano Molins, who treated the patient after Macchiarini left Barcelona.5 The letter says that “3 weeks after the transplantation, it was necessary to stent the transplanted bronchus because of a homograft collapse.” It also says that the patient subsequently needed multiple stent placements and eventually had a left pneumonectomy. It fails to report the discrepancy acknowledged by Castells, between the patient’s lung function noted in hospital records and the data reported in the 2008 paper.

Journals publish letters of correction from authors when inadvertent errors in publications are discovered. That is not the case here. The letter is not from an author, and differences between the claims in the paper and the letter are too great to believe that they were the result of error. We think that the way in which the Lancet and the Hospital Clinic Barcelona handled this situation suggests that they wanted to avoid denouncing the 2008 paper to protect their reputations.

After publication, Macchiarini moved first to the Careggi University Hospital in Florence and, in September 2010, to the Karolinska Institute in Sweden. From 2010 to 2015, Macchiarini was also on the UK medical register and he was honorary professor at University College London (UCL), to where Birchall had moved. In 2011, Macchiarini and members of the UCL team switched from cadaveric to plastic tracheal transplants. A 2014 UCL impact case study said that this was because decellularising the tracheas risked damaging their underlying structure, “leading to their collapse once they are implanted in the patient.”6

The 2008 paper was foundational in the field and has lent support to future clinical care and research. But the collapse of decellularized cadaveric tracheas contributed to the deaths of several patients, including a 19 year old woman who was referred by University College Hospital to Careggi for trachea transplantation with NHS funding and a 15 year old girl who died 15 days after trachea transplantation at Great Ormond Street Hospital.3 UCL’s website claimed that the latter operation was a success.

The Karolinska Institute sacked Macchiarini in 2016. He was found guilty of research misconduct by Sweden’s Central Ethical Review Board, which requested retraction of six papers resulting from Karolinska research. Sweden created a National Board for Assessment of Research Misconduct in the aftermath of the scandal. Macchiarini received a prison sentence from an Italian court in his absence in 2019.7 The Swedish public prosecutor indicted Macchiarini for aggravated assault on patients in 2020, and he is expected to stand trial in 2022.

Since moving to UCL, Birchall has received approximately £10m of UK and EU funding to continue research into airway transplantation. But despite multiple requests to UCL and Birchall to retract the 2008 paper, neither have done so.

The time has come to retract the paper.

References

  1. Macchiarini P, Jungebluth P, Go T, et al. Clinical transplantation of a tissue-engineered airway. Lancet2008;372:2023-30. doi:10.1016/S0140-6736(08)61598-6 pmid:19022496
  2. Roberts M. Windpipe transplant breakthrough. BBC. 19 Nov 2008. http://news.bbc.co.uk/1/hi/health/7735696.stm
  3. Schneider L. Macchiarini’s trachea transplant patients: the full list. For Better Science. 16 Jun 2017. https://forbetterscience.com/2017/06/16/macchiarinis-trachea-transplant-patients-the-full-list/
  4. Wigmore SJ. Special inquiry into regenerative medicine research at UCL. https://www.ucl.ac.uk/drupal/site_news/sites/news/files/Special_Inquiry_Final_Report_605109702_7_.pdf
  5. Molins L. Patient follow-up after tissue-engineered airway transplantation. Lancet2019;393:1099. doi:10.1016/S0140-6736(19)30485-4 pmid:30833040
  6. Research Excellence Framework Impact Case Studies. Development and transplant of human organs using nanocomposite materials. https://impact.ref.ac.uk/casestudies/CaseStudy.aspx?Id=30007.
  7. Day M. Disgraced tracheal transplant surgeon is handed 16 month prison sentence in Italy. BMJ2019;367:l6676.pmid:31767600 

Letter by Peter Wilmshurst to UCL’s President & Provost Michael Spence

[For context, I interrupt Dr Wilmshurst’s text with links to relevant articles. -LS]


Dear Professor Spence                                4 April 2022

On 18 May 2021 I wrote to you “to enquire what University College London (UCL) has done and plans to do about the fact that Professor Martin Birchall is a co-author of an article (Macchiarini P, Jungebluth P, Go T, et al. Clinical transplantation of a tissue-engineered airway. Lancet 2008;372:2023-30.) that has not been retracted despite being fraudulent.” At that time I presumed that you had enough integrity to realise that a fraudulent medical research article that was resulting in harm to patients should be retracted and enough common sense to realise that a cover up would harm the reputation of UCL.

Since then the BMJ has published a letter from colleagues and I calling for retraction of the paper. The BMJ editors and lawyers checked the supporting evidence before publication. I am attaching a copy of the letter.

On 9 July 2021 UCL informed me that Professor Pillay had been appointed to investigate my allegations under UCL’s Research Misconduct Procedure.

On 2 November 2021, UCL informed me that Pillay had decided: “The allegation is to be dismissed on the grounds of the substance of the concerns having been considered previously for the following reasons: As you know UCL has conducted a Special Inquiry into Regenerative Medicine at UCL and the Inquiry report was published in September 2017 which made a number of recommendations. The paper in question has been scrutinised by the Inquiry as well as two internal reviews at UCL, a House of Commons Select Committee as well as reviews by the Lancet itself. After careful consideration, I do not consider that you have submitted any new substantial evidence that alters the substance of the allegations that have already been addressed by all these various reviews.

The new substantial evidence is the correspondence from Professor Castells in early 2018, in which he said the airway collapsed three weeks after the transplantation and it needed to be stented. That means that the main claim of the paper that the graft “had a normal appearance and mechanical properties at 4 months” was false. In addition, Castells said that the claimed improvement in lung function was also untrue.

Therefore Pillay’s claim that I had not submitted any new substantial evidence is spurious, at least as far as UCL is concerned. Before 2018, the integrity of the 2008 Lancet paper had been doubted and the ethical basis had been questioned by distinguished surgeons, who pointed out that it was unethical to subject a patient to high risk experimental surgery without prior research demonstrating efficacy in an animal model, particularly when alternative conventional surgery was eminently feasible. The 2018 correspondence from Castells alters the substance of the allegations because it provides incontrovertible proof that the main claims in the paper are false and, because there is no possibility that this could be the result of inadvertent error, the correspondence is conclusive proof of fraud.

UCL confirmed that the House of Commons Select Committee that Pillay referred to is the Science & Technology Committee. There are a number of things that show that the Science & Technology Committee was very concerned that the 2008 Lancet paper has not been retracted. For example:

  1. Sir Norman Lamb, who was then Chair of the Science & Technology Committee, added signposts in the previous Committee Report on Regenerative Medicine (2017) to alert readers to incorrect information about the 2008 Lancet paper. The subsequent Report on Research Integrity (2018) refers to the 2008 paper and some of the subsequent follow up research by Professor Birchall at UCL (i.e. RegenVOX). It says “misconduct processes have revealed that the research on using stem cells to support artificial trachea transplants is not reliable, and is based on exaggerated patient outcomes (see Box 2). The ‘RegenVOX’ clinical trial of stem cell-based tissue-engineered laryngeal implants referred to above is now listed as ‘withdrawn’ on the Clinicaltrials.gov website. Having explored the issue of correcting the research record with our witnesses, we resolved to find a way of flagging the now contested evidence that the Committee received to readers of its report. We have arranged for a note to be attached at the relevant places in the online report with a forward reference to this inquiry. Our intention is to help readers of that earlier report to find further relevant information, not to alter the formal record of our predecessor’s work.”
  2. After Sir Norman became aware of the email correspondence from Castells in 2018, he sent letters to the Lancet asking the journal to consider retraction of the 2008 paper. Our BMJ letter quotes from Sir Norman’s letter dated 7 March 2019 and UCL has previously been sent a copy of the letter. Sir Norman clearly believed that the emails from Castells were compelling substantial new evidence.
  3. Sir Norman also appeared on BBC Television’s Newsnight programme questioning the Lancet’s failure to retract the paper. The link is https://www.youtube.com/watch?v=CzygeoqvjoM  The first part of the clip deals with Shauna Davison who died the day after her discharge from Great Ormond Street Hospital when her trachea collapsed and she suffered asphyxia. The second part shows Sir Norman being interviewed on the Newsnight programme.
  4. The Medical Research Council has a timeline of “Leading research for better healthcare”. It originally had two major advances for the year 2008. One was “2008 First stem cell-based windpipe transplant conducted”. In early 2019, Sir Norman criticised the MRC for refusing to remove that entry when the Lancet 2008 paper was known to be false. In May 2019, the MRC removed the 2008 paper from the timeline. Below are links to the current timeline  https://www.ukri.org/about-us/mrc/who-we-are/timeline/2000-to-present-day/ and the one that was on the MRC website in early 2019  https://web.archive.org/web/20190527083339/https://mrc.ukri.org/successes/timeline-of-mrc-research-and-discoveries/accessible-version-of-mrc-timeline/ 
  5. Sir Norman is no longer a Member of Parliament, but he has seen our BMJ letter and amongst his other comments, he said that the failure to retract the paper “beggars belief”.

A question remains whether correspondence from Castell was new substantial evidence as far as UCL was concerned. Pillay maintains that the correspondence from Castells does not add to the scrutiny by the Special Inquiry into Regenerative Medicine at UCL and two internal reviews.

The Report of the Special Inquiry was published in September 2017. That was before the date on which the fraud was confirmed by the correspondence in May 2018. So obviously the Report does not mention the correspondence between Castells and the Lancet. However, it does raise other concerns about Birchall. For example, it points out that the cell preparation in Bristol took place in a building not licenced under the Human Tissue (Quality and Safety for Human Application) Regulations 2007.  The Regulator made a decision not to prosecute the Bristol team for the breaches of the regulations. In addition there is evidence that the four day incubation of the donor trachea with so-called “stem cells” started in Bristol, because the trachea was transported to Barcelona on 10th June, only two days before the operations. Accordingly the trachea should have been classed as an Investigative Medicinal Product in the UK, requiring regulatory approval from the MHRA, but no approval was obtained. Birchall’s attitude to regulations designed to protect patients is illustrated by his statement about the 2008 Lancet paper in an interview to Vogel (Science, 19 April 2013, volume 340, pages 266-8) “We ran rough-shod over regulations – with permission.” In fact there was no permission. He also said “It wasn’t done to the highest possible standards.”

UCL has refused my Freedom of Information requests for the reports of the two internal reviews that Pillay referred to. The reason given by UCL is “Whilst recognising that there is a strong public interest in this area of research, there is also a need for a safe space away from external influence in which allegations of research misconduct can be reviewed and decisions taken. If there was an expectation that these discussions would be disclosed to the public this would inhibit free and frank discussion and would lead to poorer decision-making. For this particular process, the need to ensure robust decision making is considered significant to maintain the integrity and effectiveness of the process itself.

While the Information Commissioners Office is considering my appeal against UCL’s decision, I made an FOI request for UCL to answer the following questions:

  1. Was one of the internal reviews that Professor Pillay referred to titled “Allegation of research misconduct against Professor Martin Birchall, Professor Paolo Macchiarini and Professor Alexander Seifalian. Report of the Screening Panel”, which resulted from allegations made by Professor Pierre Delaere in January 2015?
  2. Was one of the internal reviews that Professor Pillay referred to titled “Allegations of research misconduct against Professor Martin Birchall from Professor Patricia Murray. Report of the Screening Panel” with the report dated December 2018?
  3. If one or both of the two reports mentioned in questions 1 and 2 were not the reports of the internal reviews that Professor Pillay was referring to, what were the titles of the reports, when were they completed, who made the complaints that resulted in the internal reviews and when did UCL receive those complaints?

UCL has refused to answer those questions for essentially the same reason that it refused to provide the reports of the internal reviews. UCL said “Whilst recognising that there is a strong public interest in this area of research, there is also a need for a safe space away from external influence in which allegations of research misconduct can be reviewed and decisions taken. UCL relies on individuals coming forward with complaints of academic misconduct, which they may be less likely to do if they thought the fact they had made a complaint might be made public.

The reason given by UCL for being unwilling to provide a “yes / no” response to questions 1 and 2 is incomprehensible, because I already know the names of those internal reviews, I have copies of both reports and one of the reports is available on the internet. If these two internal reviews are the ones that Pillay was relying on, it calls into question his judgement and his integrity, because neither considered the evidence from Castells.

In addition, subsequent events show that the two internal reviews provided false reassurance about the integrity of UCL employees, which raises additional concerns about the rigor of UCL’s internal review processes. Therefore it is worth considering the findings of the two internal reviews that I believe Pillay was referring to.

In his complaint, Professor Delaere alleged misconduct by Birchall and Professor Seifalian, who were at the time employed by UCL, and by Macchiarini, who had left his honorary professorship at UCL by the time the report was produced in late 2015. That was before the proof of fraud from Castells became available in 2018. So the report did not consider that evidence. 

The three UCL professors had been a co-author of a 2011 Lancet paper (Macchiarini P, et al. Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study. Lancet 2011;378(9808):1997-2004). In addition, Birchall was named as senior author and Seifalian was a co-author of a 2012 Lancet paper (Elliot MJ, et al. Stem-cell based, tissue engineered tracheal replacement in a child: a 2-year follow-up study. Lancet 2012;380(9846):994-1000).

In paragraph 17 of the report of the 2015 UCL internal review (screening) panel it was “noted that the published report on the 2011 synthetic tracheal transplant case, which had included Professor Seifalian as a co-author, was one of six published articles that had been reviewed by four surgeons at the Karolinska University Hospital and cited by them in their allegation of scientific misconduct against Professor Macchiarini on the grounds that the results published by him as the lead author did not appear to correlate with the patients’ actual clinical outcomes. However, the Panel noted that no reference had been made to Professor Seifalian in this allegation, and it determined that there was no prima facie evidence to suggest that Professor Seifalian could be held to account for any of the major inconsistencies or inconsistent and omitted clinical information that had been highlighted by the Karolinska surgeons in their report.

The 2011 Lancet paper has now been retracted because it was fraudulent. Professor Seifalian manufactured at Royal Free Hospital / UCL some of the plastic trachea that were supposedly “seeded with the recipients’ stem cells” before they were implanted by Macchiarini when he was working at the Karolinska Institute –  the plastic tracheas were not made to GMP (Good Manufacturing Practice) standards. Professor Seifalian was dismissed from UCL on 15 July 2016 for misconduct during his collaboration with Macchiarini.

The 2015 screening panel “determined that there was no prima facie evidence that any research misconduct . . . . had taken place, but that there was nevertheless some substance to (Delaere’s) claim that there was a misleading element within the 2012 Lancet published report which had included Professor Birchall and Professor Seifalian as co-authors – namely with regard to the two figures within the report  . . . . These figures had in the Panel’s view not given sufficient emphasis to the presence and possible contribution of the stent and omentum tissue wrap in the recovery of the child patient. Furthermore, the Panel felt that none of the evidence presented by Professor Birchall in this published report in fact serve to demonstrate that the addition of stem cells to the transplanted tracheal scaffold used in the patient case concerned played any therapeutic role in the functioning of the trachea and that none of the effects that were demonstrated in these published reports could be directly linked to the beneficial effects of stem cells.

In addition, the 2015 screening panel “felt that Professor Birchall should be urged to give greater consideration to the need for clearer and more representative presentation of information and evidence in his published reports in order to support his assertions, to allow transparent and complete judgement by the scientific community, and to avoid exposure to further allegations of research misconduct, for example the presentation of misleading information, that might jeopardise his future research efforts and subject both himself and UCL to reputational risk. To this end, the Panel felt that Professor Birchall would be well advised to seek to check some of his assertions and the way that these were presented in his published reports with other senior colleagues and collaborators outside the co-authorship of his publications.

If Macchiarini was solely responsible for the false claims about airway transplantation in the 2008 paper and Birchall, Macchiarini’s co-principal investigator, were blameless, how is it that the 2012 paper made misleading claims about tracheal transplantation when Birchall was its senior author and Macchiarini was not even a co-author?

The complaint from Professor Murray raised further concerns about publications by Birchall, but they were unrelated to the 2008 Lancet paper. Murray’s complaint was also before the information from Castell’s was known. Although the internal review screening panel’s report was produced after Castell’s correspondence with the Lancet, the screening panel’s report does not mention either the 2008 Lancet paper or Castell’s correspondence.

Murray alleged use of the same images in two separate publications, which had different methods, and deliberate misuse of research findings to support an application for ethics approval. Birchall admitted six images in one paper should not have been used because they related to animal experiments in a different paper. Birchall blamed this on a mistake by a former UCL PhD student and “the scientist overseeing the publication”. Birchall also admitted inaccuracies in a PhD thesis and errors in a research ethics committee application.

In addition, I understand that UCL refused to investigate more serious allegations and said that University College Hospital and Great Ormond Street Hospital should investigate those. One of the more serious allegations was that Birchall and Professor Lowdell knew from work undertaken by their PhD student that freeze-thawing the trachea significantly weakened the structural integrity, making it more likely to collapse. But this information was omitted from all papers and applications for ethics approval from UCL. Failure to take this into account was the reason that Shauna Davison’s trachea collapsed on the day after she was discharged from Great Ormond Street Hospital and, as a result, this 15 year old child died from asphyxia.

From these documents, I do not gain the impression of an aberrant medical researcher. Rather I see a departmental culture of dishonesty and poor practice that UCL is trying hard to conceal. 

Therefore it is difficult to escape the conclusion that the reason UCL will not provide answers to my FOI questions is that those internal reviews did not consider the 2018 correspondence between Castells and the Lancet. If I am correct, disclosure of the information will confirm that Pillay has fabricated a spurious reason to avoid investigating the research fraud involving Birchall. I believe that if all the facts came to light, UCL would have to explain:

  1. Why it employed Birchall and gave an honorary contract to Macchiarini on the basis of their fraudulent Lancet paper.
  2. How enthusiasm for bogus science was used to justify lethal experimental surgery on young patients at hospitals associated with UCL.
  3. How large amounts of publicly funded grants were taken by UCL for research predicated on fraud.

I would like to know what UCL is going to do about this scandal and about the apparent attempt at cover-up by Pillay.

Yours sincerely

Peter Wilmshurst


1 comment on “Time to retract Lancet paper on tissue engineered trachea transplants

  1. Ana Pedro

    I am really hoping this paper gets retracted soon and opens to way for other retractions of dangerous paper such as the Nature Sars-cov-2 paper.

    Like

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