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Is the Lancet complicit in research fraud?

This blog was written jointly by Patricia Murray, Professor of Stem Cell Biology and Regenerative Medicine, University of Liverpool, UK and Peter Wilmshurst.

The editor of a medical journal that charges readers for access to articles whilst knowingly keeping fraudulent articles on its website is as guilty of financial fraud as an art dealer who knowingly sells forged artworks, but there is no moral equivalence. The complicity in fraud by the editor of the medical journal may also cause death and harm to patients.

In 2008, the Lancet published “Clinical transplantation of a tissue-engineered airway” in a patient with post tuberculous stenosis of her left main bronchus (Macchiarini P, Jungebluth P, Go T et al.)1. The Lancet also published the five year follow up results of the same patient (Gonfiotti A, Jaus MO, Barale D et al. The first tissue-engineered airway transplantation: 5-year follow-up results.)2.

We have no reason to believe that when the Lancet published the first paper on-line on 19 November 2008 the editors knew that the paper had been falsified, but there was probably excessive enthusiasm and inadequate scrutiny of the data, which the authors had finished collecting only one month earlier. However, we are concerned that senior editors of the Lancet have known for several years that both the 2008 and 2014 articles were falsified, but they have not retracted either paper.

The co-principal investigators of the 2008 paper were Paolo Macchiarini, who was the surgeon that performed the operation in Barcelona, and Martin Birchall, who directed the preparation of the so-called “tissue engineered airway” in Bristol University.

Macchiarini was the lead author and the corresponding author for both Lancet publications. The Contributors statements of the papers say that Macchiarini was responsible for the entire preoperative and postoperative period. The Methods sections say that the corresponding author (Macchiarini) had full access to all the data in the study and had final responsibility for the decision to submit for publication. It therefore follows that if the two Lancet papers contain falsified statements about events in the postoperative period, Macchiarini must have known that the statements were false and those false statements could only have appeared in the articles with Macchiarini’s knowledge and agreement.

Birchall was not a co-author of the 2014 paper. Other than Macchiarini, the only person listed as an author of both the 2008 and 2014 papers was Philipp Jungebluth. Jungebluth had roles in writing both articles, as described in the “Contributors” statements for each of the papers.

After the 2008 paper was published, Macchiarini and Jungebluth moved from Barcelona first to Italy and then to the Karolinska Institute in Sweden. From 2010 to 2015, Macchiarini was also on the medical register in the United Kingdom and he was honorary professor at University College London, to where Birchall had moved.

In October 2017, the Expert Working Group on Misconduct in Research, a branch of Sweden’s Central Ethical Review Board, reported that Macchiarini, Jungebluth and five co-workers were guilty of research misconduct and asked for retraction of six papers including two in the Lancet. The Expert Working Group was authorised to consider only research performed at the Karolinska. It had no authority to investigate research performed elsewhere and no access to data relating to the 2008 Lancet case report. In addition, Macchiarini subsequently received criminal convictions in Italy and Sweden because of harm to patients in those countries. These facts make the Lancet’s decision not to retract the fraudulent 2008 and 2014 papers even more surprising.

The initial 2008 article described a short follow up of the patient. For any treatment to be worth pursuing, it is important that there is data on long-term follow up. Once there was falsification of the 2008 paper, as described below, Macchiarini was under pressure to continue the lie by falsifying data in the follow up 2014 paper.

The 2008 paper reports that a human cadaveric trachea was decellularised and colonised with “stem cells” from the recipient. The in vitro preparation was performed in Bristol University under Birchall’s direction. The prepared graft was flown to Barcelona, where the graft replaced a left main bronchus that was stenosed as a result of previous tuberculosis. Two sentences in the “Summary” section, sub-heading “Findings” crystallise 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.”

In July 2018, Professor Castells, the newly appointed Medical Director of the Hospital Clinic Barcelona where the operation was performed, wrote to one of us (in response to emails from PM) that in May 2018 he sent an email to inform the Lancet “three weeks after the airway transplantation procedure, it was necessary to stent the transplanted bronchus, due to an homograft collapse”.3 (For the benefit of non-medical readers, a homograft is a graft that comes from an animal of the same species – in this case from one human to another.) Because the graft collapsed after three weeks and required a stent, it could not have had “a normal appearance and mechanical properties at 4 months” as claimed in the 2008 paper. Castells also informed the Lancet that there were discrepancies in the claims made regarding lung function improvement.

To explain in non-medical terms the disparity between the statement in the 2008 Lancet paper and the email from Castells, one needs to understand that the trachea and the main bronchi are airways that are rigid because they have rings of cartilage in their walls. The rigidity of the major airways is important for their function. If a major airway becomes floppy, pressure changes in the lungs can cause the airway to close off during phases of respiration leading to inefficient gas exchange and mucus build up with resulting relapsing or chronic lung infections (pneumonia).

There is no reason to believe that what Castells wrote was incorrect. He said the homograft (i.e. transplanted airway) collapsed at 3 weeks. So, it could not have had normal mechanical properties (i.e. rigidity) at 4 months. If as Castells said the transplanted airway needed a stent, it could not have had a normal appearance at 4 months because the criss-cross appearance of the stent would be visible on bronchoscopy and CT scanning which the papers say were the imaging methods used.

Following complaints from us to the United Kingdom Parliament’s Science and Technology Committee, its chair, Norman Lamb MP repeatedly complained to the Lancet’s editor, Dr Richard Horton. On 7th March 2019 Norman Lamb wrote again saying:

The Director of the Hospital Clinic 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-reporting 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.”4

In March 2019, the Lancet solicited and published a clinical update letter from Dr Molins who treated the patient after Macchiarini left Barcelona.5 The letter says “3 weeks after the transplantation, it was necessary to stent the transplanted bronchus because of a homograft collapse”. This confirms the statements in Castells’s email. Molins’s letter also says subsequently the patient 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 as per hospital records and the data reported in the 2008 Lancet 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 truth are too great to believe they were the result of error. The Lancet’s solicitation of the letter suggests to us that the editors of the Lancet wished to avoid denouncing the fraud to protect the journal’s reputation.

However the emails from Castells and the published letter from Molins prove that claims in the 2008 paper that the graft had “a normal appearance and mechanical properties at 4 months” are complete falsifications. There is no possibility that Macchiarini could have published this in error. He knew that he had stented the graft at three weeks after the transplant because it collapsed, which meant it did not have normal mechanical properties. Once it was stented the graft could not have had a normal appearance.

The 2014 paper by Gonfiotti et al also makes falsified claims that there was no problem with the graft or need for stenting until six months after the operation. For example, table 2 claims that the first stent placement was in December 2008 (i.e. six months after the airway transplantation) and that was for a “cicatricial diaphragm-shaped scar” at the proximal anastomosis, not a collapse of the graft. The table also claims that stenting of the graft body was required first in November 2010. November 2010 was 29 months after the airway transplantation and we now know that the claim is false because the graft required a stent after 3 weeks. In addition the 2014 paper by Gonfiotti falsely states that stenting was because of granulation tissue formation, but the true reason for the first stent was airway collapse.

The fact that the graft collapsed and required a stent at 3 weeks after surgery is not consistent with the following statements in the 2014 paper by Gonfiotti et al:

  1. In the Summary that during follow up “the tissue-engineered trachea itself remained open over its entire length”.
  2. In paragraph 3 of the Results “The graft behaved as expected until 6 months after surgery. Thereafter, the proximal (native to tissue engineered trachea) anastomosis began to show a progressive cicatricial diaphragm-shaped scar. The remaining tissue-engineered trachea and distal anastomosis were patent.”
  3. In paragraph 3 of the Discussion “4-month follow-up showed no complications”.

The 2014 paper provides an “Interpretation” in the “Summary” section, where it says;

These clinical results provide evidence that a tissue-engineering strategy including decellularisation of a human trachea, autologous epithelial and stem-cell culture and differentiation, and cell-scaffold seeding with a bioreactor is safe and promising.”

The false claim of safety and promise was only tenable because the fact that the airway collapsed and required a stent 3 weeks after the operation was concealed. It is important to realise that attempts were made to repeat the operation described in the earlier 2008 Lancet paper and as a result patients, including young people and children, have died when the transplanted airways collapse soon after surgery. Many of the deaths occurred before the 2014 Lancet paper was published and Macchiarini was aware of the deaths because he and his colleagues on the 2008 paper were involved in those fatal operations in Italy and at hospitals associated with University College London. Those deaths make repetition of the false claims by Macchiarini in the 2014 paper even more egregious. The deaths compound the Lancet’s guilt from failure to retract the false publications.

It is worth noting that at the Karolinska, Macchiarini stopped transplanting decellularised cadaveric tracheas that had been seeded with so-called “stem-cells”. Macchiarini switched to inserting plastic tubes that were squirted with a suspension of “stem cells”. This change in techniques meant that the original premise, that “stem-cells” could detect from their location what type of cell they should become and differentiate accordingly, was totally discarded: even if stem-cells had the ability to recognise their surroundings, they would not recognise that a plastic tube was meant to be an airway. Macchiarini’s change of technique was probably because of the recurrent fatal tracheal collapses that occurred with the original airway transplants. It is a sad reflection on the Karolinska Institute that they swallowed the original lies of this scientific fraudster and then allowed him to switch to equally lethal experimental human surgery predicated on a more bizarre hypothesis that was not supported by animal experiments.

We know from the emails from Castells that the lung function test results reported in the 2008 paper are false, but we do not know the correct results. The preoperative and three months postoperative lung function data in the 2008 paper was repeated in the 2014 paper, but the two months postoperative results have not been repeated (see table 1 of the 2014 Lancet paper). Therefore we cannot say with certainty whether the lung function test results in the 2014 paper are false, but we believe that they should be regarded with suspicion in the light of the statement by Castells.

In addition, there are concerns relating to a number of the illustrations used in the 2014 Lancet paper because they were also used elsewhere by Macchiarini and colleagues. As a result, there is no doubt that two illustrations used in the 2014 paper have false claims about their provenance.

The legend to figure 4 on page 242 in the 2014 Lancet paper claims to be “Immunohistochemical staining at 4 years after transplantation”. That claim is false as described below. The legend to figure 5 on page 242 in the 2014 paper claims to be “Transmission electron microscopy of implanted airway at 4 years after transplantation”. That claim is also false.

The patient described in the 2008 and 2014 papers had her airway transplantation in June 2008. Four years after transplantation would have been June 2012. So for figures 4 and 5 in the 2014 paper to be genuine it would have been necessary for the tissue biopsies to have been taken from the patient by bronchoscopy in approximately June 2012.

These histological images have been used in at least two other settings with entirely different claims about their provenance. One of those was well before June 2012 and the Lancet should know because those images were in a Lancet publication before June 2012.

One conflicting claim about the provenance of the images is in two panels of figure 3 of a Lancet paper by Badylak SF, Weiss DJ, Caplan A, Macchiarini P.6 The 2012 paper by Badylak et al was retracted in 2018 because of scientific fraud. Figure 4 in the 2014 paper by Gonfiotti et al corresponds with figure 3K (rotated) in the paper by Badylak et al (see illustration below). Figure 5 in the 2014 paper by Gonfiotti et al corresponds with figure 3L in the same 2012 paper by Badylak et al (see illustration below).

The corresponding author of the paper by Badylak et al is Macchiarini. That paper was published on 10 March 2012. That is earlier than when the tissue biopsy would have been taken (in June 2012) if the 2014 paper by Gonfiotti et al were true. There is good reason to believe that the Babylak paper was submitted to the Lancet on 12 August 2011, which is 10 months earlier than would have been the case if the 2014 paper by Gonfiotti were true.

One reason is that Macchiarini wrote at the top of page 12 of his “Reply to: Statement of opinion on assignment ref. 2-2184/2014 by Bengt Gerdin Professor Emeritus” that the 2012 Lancet article by Badylak et al was submitted on 12 August 2011,7 which is 3 years and 2 months after the patient described in the 2008 and 2014 papers had her airway transplantation. Therefore the claim in the 2014 paper by Gonfiotti et al that the histology was obtained four years after the patient described in the 2008 and 2014 papers had her surgery in June 2008 is a falsification. In addition, the 2012 article by Badylak et al says that the tissue was obtained one year after transplantation from “a patient with a primary recurrent tracheobronchial tumour”. Whereas the patient described in the 2008 and 2014 papers had a post-tuberculosis stricture of her left main bronchus.

We believe that the Lancet has known for some time that the publication of the figures in the paper by Badylak et al prove that the use of the same images in the 2014 paper by Gonfiotti et al was fraudulent.

In a telephone conversation, a Lancet editorial assistant stated that the paper by Badylak et al was submitted on 12 August 2011 – the date stated by Macchiarini. Subsequently, when the Lancet was asked to confirm the date by email, the Lancet refused. We believe that the refusal to provide written confirmation of the date of submission is because the Lancet editors are aware that by confirming the date of submission of the article by Badylak et al they will be confirming that images in the 2014 paper by Gonfiotti et al are false.

We are also aware that Macchiarini has used the same images on at least one other occasion, in a presentation available on the internet, which we have downloaded. In it, Macchiarini claimed that the tissue was obtained two months after airway transplantation from an unspecified patient.

In summary it is claimed that the two images used in figures 4 and 5 in the 2014 paper by Gonfiotti et al were taken four years after airway transplantation from the patient who was described in the 2008 paper by Macchiarini et al. If that were true, the biopsies would have been taken in about June 2012. However, the same images were published earlier than June 2012 in the fraudulent paper by Badylak et al that was published in the Lancet in March 2012 and submitted for publication in August 2011 and in the Badylak et al paper the biopsies are said to have been taken one year after transplantation in a different patient, who had malignant disease. The same images were used by Macchiarini in a lecture when he claimed that the samples were two months post-transplantation in an unspecified patient. As a result we do not know when these biopsy samples were taken or from which patient, but we can say with certainty that the claim that they were taken 4 years after transplantation from the patient described in the 2008 and 2014 Lancet papers is falsification.

Macchiarini had a motive to make fraudulent claims that microscopy suggested that that the graft had characteristics of a normal airway after four years in order to maintain the pretence of the original claims in the 2008 Lancet article.

There are also concerns about figure 6 in the 2014 paper by Gonfiotti et al labelled “Scanning electron microscopy of implanted airway”. It claims to show “external (A, C, E, G) and luminal (B, D, F, H) surfaces”. It says “Showing native (A, B) and decellularised (C, D) airway matrices and of implanted airway at 1 year (E, F), and 4 years (G, H) after transplantation.” Panel C therefore claims to be the external surface of the decellularised airway transplanted into the patient described in the 2008 and 2014 papers. That image also appears as figure 1L in a 2010 paper by Baiguera et al, where it is said to be the luminal surface not the external surface (see illustration below).8

The tracheas reported by Baiguera et al were tested to destruction in biomechanical tests described on page 8932 of that paper. Therefore the image cannot also be from a trachea implanted into the patient described in the 2008 and 2014 papers.

In addition there are concerns about the claims made for panels E and G of figure 6 of the 2014 paper by Gonfiotti et al, because they are claimed to be electron micrographs of tissue from the external (i.e. non-luminal) surface of the graft 1 and 4 years after implantation. Panels F and H are the corresponding luminal surfaces. Tissue can be obtained from luminal surfaces of airways during the bronchoscopy procedures that the patient is reported to have had. The external surface, i.e. non-luminal surface, could not be biopsied using a bronchoscope. Access to the “external surface” of the graft would require a much more invasive procedure, such as a re-operation to obtain those specimens and those procedures are not described in the paper. Performance of re-operation to access the non-luminal surface would risk introducing infection, causing haematoma or damaging any blood supply and hence endanger the patient. Therefore it seems unlikely that ethics committee approval would be obtained to re-operate on the patient to obtain the specimens from the non-luminal surface of the transplant as described in the 2014 paper by Gonfiotti et al.

We believe that there is no doubt that the 2008 and 2014 papers are fraudulent. We also believe that senior editors at the Lancet know that both papers are false but they will not retract the papers. We wonder why.

Following Newsnight programmes on BBC Television, the Lancet informed the UK Parliament’s Science and Technology Committee on 14 March 2019 that “following the Newsnight programmes we asked the UK-based authors of the 2008 paper for a response to the issues raised in the programme and to Dr Wilmshurst’s concerns. Once we have their responses, we will decide what the appropriate next steps are.” The Lancet has not explained why they only asked the UK-based authors, when nine of the fifteen authors were based in Italy (Milan and Padua) and Spain (4 departments in 3 institutions). The Lancet has not revealed what responses they received from the UK-based authors. The Lancet’s inaction suggests the “next steps” were to do nothing and hope that they could get away with it.

Repeated email requests to Sabine Kleinert, a Senior Executive Editor of the Lancet, asking what the Lancet will do to correct the false lung function data in the 2008 paper have gone unanswered.

Birchall is now a professor at University College London and he has received more than £10 million in public funded grants to continue follow up research on “tissue-engineered airways”. Macchiarini had an honorary appointment at University College London for 5 years. Hospitals associated with University College London have been the sites of tracheal transplantation using the techniques described in the false 2008 Lancet paper and young patients have died as a result, despite which the hospitals have claimed that the operations were successful. Some members of the team who performed lethal tracheal transplant surgery, including Birchall, were members of the Lancet commission on stem cells and regenerative medicine. The editor-in-chief of the Lancet, Richard Horton is an honorary professor at University College Hospital.

We believe that with the 2008 and 2014 papers by Macchiarini and colleagues we are seeing a rerun of Richard Horton’s failure to retract the falsified Lancet paper linking autism with MMR vaccine that was produced by his old chum Andrew Wakefield.

References

  1. Macchiarini P et al. Clinical transplantation of a tissue-engineered airway. Lancet 2008;372:2023-2030.
  2. Gonfiotti A et al. The first tissue-engineered airway transplantation: 5-year follow-up results. Lancet 2014;383: 238–244.
  3. Email from Prof Antoni Castells, Medical Director of Hospital Clinic Barcelona to Prof Patricia Murray dated 23 July 2018.
  4. Letter from Rt Hon Norman Lamb MP to Richard Horton on 7 March 2019.
  5. Molins L. Patient follow-up after tissue-engineered airway transplantation. Lancet 2019;393(10176):1099.
  6. Badylak SF et al. Engineered whole organs and complex tissues. Lancet 2012;379:943-952 (Retracted).
  7. Macchiarini P, Reply to: Statement of opinion on assignment ref. 2-2184/2014 by Bengt Gerdin Professor Emeritus
  8. Baiguera S et al. Tissue engineered human tracheas for in vivo implantation. Biomaterials 2010;31:8931-8938.
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4 responses to “Is the Lancet complicit in research fraud?

  1. Raphaël Lévy avatar
    Raphaël Lévy

    Reblogged this on Rapha-z-lab and commented:
    Devastating account of the Lancet complicity in keeping on the record article that they have known for years are fraudulent. And which have caused deaths.

    Like

  2. […] cardiologist and whistleblower Peter Wimshurst blogged about Lancet‘s behaviour again, together with University of Liverpool professor Patricia […]

    Like

  3. […] of literature connected to human health?  From a post by Patricia Murray, who is Professor of Stem Cell Biology and Regenerative Medicine at the […]

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