This is an open letter to the academic community by Pierre Delaere, professor for respiratory surgery at KU Leuven, Belgium, and one of the earliest and fiercest critics of Paolo Macchiarini. Delaere recently published a paper explaining that “the engineered trachea is an example of blatant scientific deception” (Delaere and Van Raemdonck, J Thorac Dis. 2016). For the background of Macchiarini’s misconduct and patient deaths after his trachea transplants, as well as Delaere’s attempts to prevent those, please refer to my articles here, here and here. An earlier open letter by Bo Risberg, emeritus professor of surgery at the University of Gothenburg, is also available exclusively on my site. 

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The Tracheal Regeneration Story

by Pierre Delaere

I have written this overview as a trachea surgeon working at KU Leuven and privileged witness of the “Tracheal regeneration scandal” from the very start.

Because of its immense scale, the scandal is difficult to grasp and explain. Fortunately, we have recently been provided with an excellent overview in the 3 x 1-hour documentary by Bosse Lindquist on Swedish national TV. Due to Paolo Macchiarini’s appetite for the spotlights and thanks to the professional standards of the Swedish top producer this is probably the very first case of a medical crime played out in the media. Anyone who has seen this brilliant investigative documentary cannot help but wonder why there are still people who doubt that this is a case of gross medical misconduct.

The story began in Barcelona in 2008 with the publication in The Lancet of a report on a regenerated windpipe, featuring Paolo Macchiarini (PM) as its first author (Macchiarini et al. Lancet 2008). This ground-breaking achievement consisted of bringing to life a dead windpipe from a donor, by putting it in a plastic box, a so-called ‘bioreactor’ together with bone marrow fluid (stem cells). A few weeks later, I wrote a letter to The Lancet, pointing out:

“The main drawback of the proposed reconstruction is the lack of an intrinsic blood supply to the trachea. We know that a good blood supply is the first requirement in all other tissue and organ transplantations. Therefore, the reported success of this technique is questionable” (correspondence by Delaere and Hermans, Lancet 2009).

Following this ‘breakthrough’ in regenerative medicine, which generated a great amount of international attention, the already controversial thorax surgeon PM was recruited by the Karolinska Institute (KI) to boost their regeneration programme. PM also received permission from KI to work at the Kuban State University in Krasnodar (Russia). Shortly after PM’s appointment, the world was told about the first synthetic organ engineered with stem cells (Jungebluth et al. Lancet 2011). [this paper now received an Expression of Concern; -LS]

What had happened? PM had mounted bone marrow extract (‘stem cells’) on a plastic tube (‘bioartificial trachea’) in a plastic box (‘bioreactor’). After a day or two this creation was ‘successfully’ transplanted in a patient with a trachea defect. This occurred in the Karolinska hospital in July 2011 and was reported on in The Lancet shortly afterwards . Biologically speaking, the procedure is absolutely implausible.

In reality an important part of the windpipe had been replaced by a synthetic tube, and the presence of stem cells made no difference to this whatsoever.

For those not in the field, this procedure may still seem acceptable. A blood vessel can also be replaced by synthetic material because the material can grow into the sterile environment of the blood stream. However, this is completely impossible if the synthetic material is exposed to an environment of inhaled air full of bacteria. The laws of biology allow us to predict accurately what will happen after part of the windpipe has been replaced by a synthetic tube. After some time, the suturing between the synthetic tube and the surrounding tissue will come loose, leading to a number of serious complications. These complications inevitably lead to death in the short (months) or in the mid-long term (a few years). How long the patient will survive also depends on the options still left to treat complications. In most cases so far, a metal stent had to be implanted to keep the airway open in the sutured area.It is entirely predictable that additional complications after placement of the metal stent will ultimately lead to the patient’s death, usually by asphyxiation or by bleeding out after complete rupture of the sutures. This gruesome fate awaiting patients was clearly shown in the documentary. Replacing a part of the trachea by a synthetic tube can therefore be compared to death by medical torture. The amount of suffering it induces is directly proportional to the duration between implantation and the patient’s death.

From the documentary and from literature it has become clear that these experiments on human beings had not been preceded by experimental research on animals. However, also in animals the outcome after implanting a synthetic trachea would have been biologically predictable. Moreover, studying how an animal suffers and eventually dies after implantation of a synthetic airway is ethically entirely unacceptable. Another ethically unacceptable and scandalous debate is the current one in Sweden on whether the three patients treated in KI had been ill enough to be supplied with a synthetic airway. Furthermore, whether this crime committed within the walls of Karolinska was part of research rather than clinical care is entirely irrelevant.

Following the reports on ‘successes’ with this repair technique, several other patients were treated in the UK, US and in Russia, both with a windpipe from a dead donor (exact number unknown; at least 10) and with the plastic windpipe (3 in Sweden; 5 in the US and in Russia).

The question whether these procedures should be classified as ‘misconduct’ is an understatement.

How could this happen at one of the most reputable medical universities? A number of factors have contributed. The most important ones are KI representatives’ unbridled ambition in combination with their total ignorance in the field of trachea regeneration and transplantation. In addition, PM’s bizarre personality has also contributed to the drama, as shown in the documentary and in a remarkable article in Vanity Fair. It describes the love affair between PM and an NBC producer. The producer was working on a documentary about the celebrity surgeon’s greatness when she began a relationship with the charming miracle doctor of her documentary. How this all ended in terrible lies and deceit gives yet another indication of PM’s disturbing personality combining narcissism with pathological lies, a cocktail that led to the terrible events. Moreover, PM managed to publish four papers in The Lancet based on nothing but lies (Macchiarini et al. 2008, Jungebluth et al. 2011, Badylak et al 2012,  Gonfiotti et al. 2014. Dozens of other articles hailing this improbable fairytale were published in other journals based on the prestige of The Lancet publications.

Since 2011, I have contacted both the President of KI and the Editors of The Lancet with well-documented information to clarify that what had happened was completely unacceptable. These alerts were repeated in 2013 and 2014. Since 2014, four doctors from KI, who had seen it all happen, have been collecting evidence to show the extent of misconduct [Matthias Corbascio, Thomas Fux, Karl-Henrik Grinnemo and Oscar Simonsson, their letter to Vice-Chancellor Hamsten from June 22, 2015, and its attachments available here; -LS]. Not only did KI not react to the doctors’ complaint, these doctors were in fact intimidated and threatened with dismissal. KI’s Ethical Commission came to a verdict of ‘no misconduct’ in April 2015 following an inquiry based on a series of complaints filed by myself [verdict available from SVT here, -LS]. The Lancet Editor did not even bother to reply to my complaints.

I also lodged a complaint against staff of University College London involved in the ‘PM project’, who also published very misleading information based in particular on an operation that occurred in 2010 in Great Ormond Street Hospital.This operation was announced as ‘The first child to receive a stem cell trachea’(Elliott et al. Lancet 2012, with correspondence by Delaere 2013; Hamilton et al. Am J Transpl 2015). Moreover, the first synthetic trachea that was implanted in KI was produced by a research lab in University College London (UCL). In a video presentation available on the web the researcher responsible for the creation of the first synthetic airway hilariously shows how this was done. However, UCL too, returned a verdict of no misconduct after its internal investigation [original draft of UCL verdict available here, -LS].

The four KI doctors’ complaints were scrutinized by an external investigator, the Swedish plastic surgeon Bengt Gerdin, appointed by KI representatives. In May 2015, he announced that in all 7 publications he had investigated he found that PM had committed serious fraud. In August 2015 at a KI press conference, Gerdin’s conclusions were overruled by rector Anders Hamsten. The verdict of ‘no misconduct’ was reaffirmed. Instead of proceeding to the immediate dismissal of the doctor responsible for blatant fraud and a retraction of the publications in question, KI representatives dismissed all accusations. Moreover, KI representatives confirmed their trust in PM and in November 2015, his contract was renewed for 1 year.

I’m convinced that the newly appointed Karolinska representatives will now make the necessary steps to establish complete clarity.

The Karolinska Institute might then be able to recover and retake its position as exemplary research centre. How many millions of euros, krones, roubles, dollars and British pounds charities and public funders have donated to make this scandal possible, will only become apparent at a later stage. The complete story will eventually surface in its entirety and a number of very important lessons can then be learned to the benefit of the medical world. Medical literature will then also, finally, be cleaned of these dreadful lies.

Will this suffice to clean out the Augean stables? Most certainly not, because KI is not the only player responsible for this drama. To prove that this transplantation technique is effective, reports about the long-term success of this technique in the first 2 patients in Barcelona and London is still being spread. What the real situation of the two patients is at the moment is very difficult to establish. For some time now, reports about these two cases seem to have disappeared from the face of the earth. After the air has been cleared in Sweden, the same will probably happen in London and Barcelona.

Especially The Lancet editors carry an enormous responsibility in this gruesome story. They can only restore their credibility if they set up a thorough internal inquiry into all of this could have happened.

Moreover, they need to retract the 4 papers as soon as possible, as well as all linked editorials. In addition, they need to recommend the retraction of dozens of articles of the same authors on this subject, often accepted on the basis of The Lancet ’s reputation.

All the articles of other researchers who have published similar nonsense because they have chosen the same path as that of the star surgeon and his immediate partners, will no doubt fade away over time. From the above, it has become clear why it takes so long for this scandal to be uncovered in its entirety.

However, once the full extent of the scandal has been exposed, research centres worldwide will be able to draw lessons from it. Research in the area of regeneration and tissue engineering is the top priority in many university centres attracting large sums of money. The pressure on researchers and competition amongst them is fierce.

Unfortunately, in the context of the current hype on stem cells, it has become clear that the greatest nonsense can find its way into the scientific world. Therefore, it should not be surprising that the greatest scandals of the last few years have occurred in just this domain.

The scientific world will eventually be able to lick its wounds and to come back down to earth.

As a conclusion, many positive effects can be expected for the scientific world and its brilliant researchers who try to further science in good faith.

 

 

Other reading

1. Delaere. Stem-cell “hype” in tracheal transplantation? Transplantation 90; 927-8, 2010.

2. Vogel, Trachea transplants test the limits. Science 340; 266-8, 2013.

3. Delaere, Van Raemdonck. The trachea : The first tissue-engineered organ? Editorial. J Thorac Cardiovasc Surg 147; 1128-32, 2014.

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