Collapse of Biotrachea, or how Macchiarini’s greed saved human lives

The trachea transplant experiments by Paolo Macchiarini left many of his trusting patients dead or mutilated. His €5.5 Million EU-funded research project Biotrachea started in April 2012 and was specifically designed to treat even more human beings with lethal plastic tracheas (and with the slightly less lethal cadaveric ones). The consortium was terminated in 2014 (see some background here), but not because the Biotrachea scientists or EU officials suddenly had second thoughts when the Macchiarini scandal unraveled and when his misconduct, ethics breaches as well as painful deaths and suffering of his plastic trachea recipients became known. Unlike an EU spokesperson previously insisted, there were no ethics concerns at all regarding Biotrachea. In fact, all ethics approvals were in place, human Guinea pigs were supposed to be lured en masse using a highly inappropriate patient consent form towards their likely deaths for the sake of EU-funded mega-science.

In truth, Biotrachea collapsed only because of Macchiarini’s greed for money. His financial conflict about patent revenues with the British university UCL drove the star surgeon to seek another plastic transplant manufacturer and then to destroy the entire multinational research consortium which he was presiding over, after the EU rejected his new plastic provider. Not because that one was also deemed unsafe, but as the EU negotiators mentioned, it was because that new type of plastic trachea lacked novelty. All this only became known after the original Biotrachea documents, which the EU and all consortium participants refused to grant me any insight into, were fully legally obtained by Jonas Malmstedt under Swedish transparency from Macchiarini’s ex-employer, the Karolinska Institutet (KI). Thanks to this brave and decent surgeon, I make all that secret documentation available below.

First-in-Man

Macchiarini and his colleagues planned to run two separate “first-in-man” clinical trials, where cadaveric and plastic trachea transplants would be used respectively. The cadaveric trachea transplant was scheduled to begin in 2013, the one with plastic slightly over one year later.

The idea was to progressively test the method on humans, first on some selected patients, then on larger scale in a clinical trial. How many victims exactly were supposed to be recruited, we don’t know. Also the highly toxic and tissue-damaging method of Intraoperative radiation therapy (IORT) was scheduled for experimental use. Macchiarini’s method of combining his disastrous cadaveric trachea transplants with IORT led to heavy complications and death in his trachea transplant patient Keziah Shorten (who was suffering from a slow-growing and well-manageable form of cancer). In Biotrachea, human beings were scheduled to be sacrificed to satisfy Macchiarini’s research curiosity, and the peer reviewers seemed not to mind that at all.

The plastic material for the trachea transplants was described to be POSS-PCU, to be manufactured at UCL by the nanotechnology specialist Alexander Seifalian, the bioreactor-based tracheal regeneration was scheduled to happen in Italy (later on also in Sweden). The patent on this trachea technology was quasi divided: Macchiarini held the “regeneration” bit, which comprised the magic done by patient’s own bone marrow and epithelial cells, which were supposed to re-create the healthy tracheal tissue. The alleged efficiency of this regeneration technology was well documented by Macchiarini’s own publications in the elite journal The Lancet (e.g, Macchiarini et al, 2008 and Jungebluth et al, 2011), which were meanwhile largely proven as unsupported by the actual medical evidence or as simply fraudulent. Seifalian was the maker of the very first transplanted plastic trachea (described in Jungebluth et al, 2011, see also my report here) which caused the unsuspecting patient Andemariam Beyene a prolonged and very painful death (documented by Bosse Linquist’s film “Experimenten”). The only living tissue growing there was scar tissue and mucus, complemented by bacterial and fungal infection plaques. Macchiarini instead claimed in the Lancet publication that the transplant had “a vascularised neomucosa, and  was partly covered by nearly healthy epithelium”.

Bad plastic

Now, the POSS-PCU plastic was once again to be tested on humans, and not just on one, but on many, funded by the European Union. The rights for the plastic nanocomposite were however with Seifalian’s employer UCL, who then demanded of Macchiarini to surrender his part of the invention to them so the entire trachea technology can be licenced to UCL.  Macchiarini, well known for his greed, naturally wanted this exactly the other way around. The patent conflict was basically about who will financially profit from the use of the plastic trachea, paid by EU funding. Macchiarini wanted to receive his inventor’s dividend into his own private pocket, just like UCL wanted to benefit from the marketing of their plastic composite.

Biotrachea was hardly moving, probably also because the patent conflict could not be resolved. After the initial first kick-off meeting in 2012 in Florence, not much happened. Well, there was one minor event. The project’s coordinating institution, the Florentine research hospital Azienda Ospedaliero-Universitaria Careggi was dethroned in 2013. This coincided with Macchiarini losing his employment there after Italian justice investigated him in September 2012 for patient extortion and fraud (in fact, Careggi did attempt to sack their surgeon, following deaths of his patients). Accordingly, the consortium coordination was transferred from April 2013 on to its king’s new place of residence, the KI (also see updated members’ tasks here).

However, at the next conference which happened over 1 year later at the new hub of Biotrachea at Karolinska, Macchiarini gathered the entire consortium behind him and declared Seifalian’s POSS-PCU material as unsuitable. The new plastic provider was to be the US company Nanofiber Solutions, and the new material was to be PET, commercially known as Dacron. This technology Macchiarini also tested extensively already, on three patients: Christopher Lyles, Yulia Tuulik and Alexander Zozulya. The first patient died right away (the evidence for Macchiarini’s misrepresentation of Lyle’s state was documented by a KI whistleblower report). Yulia Tuulik’s prolonged suffering and death are also narrated in Bosse Linquist’s  “Experimenten”. The last patient, Zozulya, died according to Macchiarini’s Russian surgeon colleague Igor Polyakov in a bicycle accident [correction: an earlier version of this article confused that patient with the survivor Dmitry Onagda, whose transplant was removed in time].

For Macchiarini however, all this raised no doubts about Dacron trachea suitability for further human experimenting. Interestingly, Macchiarini later on dropped Nanofiber Solutions as well (possibly they didn’t want to share their trachea patent either). The Karolinska star surgeon then made a much more lucrative deal with Harvard Apparatus (now called BioStage), with whom he patented the trachea technology in a way which apparently finally satisfied him. Harvard Apparatus then paid off Nanofiber Solutions to retain the PET/Dacron technology of trachea transplants. Macchiarini could finally earn his inventor’s share from the plastic trachea transplants he was transplanting.

POSS-PCU or bust

At the KI meeting in July 2013, the entire Biotrachea consortium turned against Seifalian and his POSS-PCU material (see meeting minutes here, page 17). The UCL nanotechnologist pleaded that he could adapt the technology to produce constructs of any desirable softness or flexibility (not that it would have helped either, since plastic tracheas soon proved simply lethal in any form). To no avail, the EU was notified that his and UCL’s POSS-PCU tracheas are all faulty and that new source from Nanofiber Solutions was to be employed. The problem however was that unlike POSS-PCU, PET/Dacron was not a novel material, as the EU negotiator mentioned in one of the emails.

The 3^rd meeting at KI in October 2013 was where the consortium was trying to save itself and its funding. The EU insisted on POSS-PCU or bust. On August 22^nd 2014, the funding for Biotrachea was suspended for “poor performance”, and after a prolonged email exchange (available here) it was finally and officially terminated on February 20^th 2015. The sole argument repeatedly debated back and forth was the switch from POSS-PCU to PET/Dacron: the former was declared as dangerous and unsuitable for patients, the latter was rejected by the EU as not novel. These arguments were indicated to me already before by the former consortium participant Graziella Pellegrini (see my earlier report here), but now the original email communications confirm them as exclusive reasons. No other main issues were raised in the entire communication between the Biotrachea consortium and EU.

This is somewhat in contrast with the official EU statement on the grounds of Biotrachea termination which I was given in March 2016 by a responsible EU representative (quoted in full here):

“The Grant agreement for Biotrachia stipulated a separate ethical assessment through the establishment of an ethics committee leading to binding obligations that could later on be checked during ethics checks, reviews and audits. However, the project failed to establish the required ethics committee by the time stipulated in the milestones, which was one of the reasons for the early termination of the project”.

EU Commission not going on-record

Did Biotrachea really fail to establish an ethics approval? Well, there is a very positive ethics review commissioned by none other than EU themselves from August 30^th 2011. Macchiarini and his partners were solely advised to recruit a philosopher to ponder on the broader ethical dimension of their work and asked to make the patient consent form more reader friendly. Well, if they meant the same patient consent form which was part of the Biotrachea work package, then this ethics committee must have been drunk, crooked or simply incompetent. The form is actually a kind of a bizarre private contract between doctor and patient, where the patient is the obviously duped and misinformed party.  The prospective victims are asked to admit that the cadaveric trachea transplant is their “only possible curative option” and are left utterly in the dark about any risks or previous disastrous failures.

I faced the EU spokesperson with these documents and the EU’s previous statement. What I was offered then, was a phone call with the Director of the Health Directorate at the Research DG of the European Commission, who would answer my questions about Biotrachea termination (as well as about ongoing funding for another cadaveric trachea transplant trial, TETRA). However, shortly before that phone conversation I was instructed:

“It will be a conversation on background (no quotes) about the questions you listed below, and that we would like to ask you to refrain from contacting other officials bilaterally thereafter”.

I declined this kind offer and asked to be given publishable quotes instead. The phone call never happened, and neither did I ever receive any communications afterwards. Meanwhile, TETRA, the phase II trachea transplant trial of Macchiarini’s former partner Martin Birchall (see background here) has already been positively evaluated and is moving towards receiving its ethical approval, in order to start transplanting patients with cadaveric tracheas from July 2018 on.  It seems Birchall came out on top after all, given that the warm friendship and mutual support between the two surgeons turned to animosity, possibly over Biotrachea where Birchall was excluded.

No sick ones and no rules, please

Which patients did Macchiarini have in mind for his human experimenting? As we learned from the documentary Experimenten, the star surgeon didn’t like to operate on terminally ill patients, whose morbidity he blamed for the failure of his transplants. The trachea graft recipients had to be as young and as strong as possible. In Biotrachea, young patients with perfectly manageable and not immediately life threatening form of cancer, but also those with non-malignant tracheal constrictions were envisioned for human experimenting.

Interestingly, one large part of Biotrachea was the development of a bioreactor technology, which was then patented by the German consortium partner Hugo Sachs Elektronik, which in turn belongs to Macchiarini’s then-business partner Harvard Apparatus. At the same time, Macchiarini was keen on moving away from the bioreactor method already from the first time he used it for his very first trachea transplant patient, Claudia Castillo. That time, a cadaveric trachea transplant was “regenerated” in Birchall’s veterinary lab in Bristol, without the knowledge of health authorities (see my report here). Since this is not really “good manufacturing practice” (GMP) or even legal, Macchiarini and Birchall transplanted their next patient, a 10 year old boy Ciaran Finn Lynch, without any use of the bioreactor. The magic stem cells were seeded straight into his throat when the cadaveric trachea was implanted. The child survived, but with a permanent stent he is not doing excessively well, as Birchall himself even admitted (Hamilton et al 2015).

Thus annoyed by the restrictive GMP and other patient safety regulations around the bioreactor technology, Macchiarini and his team proposed to skip it once again and use the patient as “a very sophisticated bioreactor”. They planned to achieve this also by pumping their patients full of growth factors, which well-known side effects include potentially lethal blood clotting (see Karolinska investigation for details).

Who was doing what?

Biotrachea was terminated before Macchiarini and his team could proceed to transplanting patients with cadaveric or plastic tracheas. I tried to establish where these transplants were supposed to be manufactured, if the trial had continued.  All trachea transplant surgeries and the bulk of donor organ preparation process were supposed to take place at Careggi (see detailed protocol here, p10 on). After Macchiarini broke with Careggi, only the task of donor organ decellurisation remained there, the rest was transferred to his new Swedish home, the KI. But of course the plastic or cadaveric scaffold needed the stem cell magic, and that was supposed to come from two sources. The laboratories of the University of Modena in Italy and their spin-off company Holostem were supposed to prepare the inside coating of the tracheal transplants with patients’ own epithelial cells.  Inside the patient, these cells were then supposed to somehow grow into a healthy mucosal epithelium, fed by a miraculously growing vasculature, as instructed by Macchiarini’s high-impact publications in The Lancet. This role of the Modena labs was confirmed to me by the German stem cell professor Augustinus Bader, who was one of Biotrachea partners (more about Bader and his strange miracle cures here). The Biotrachea documentation suggests that it was also Bader’s task to cover the second part of the trachea regeneration process: turning patients’ bone marrow cells into trachea cartilage on the outside of the plastic or cadaveric graft. Bader intended to use “conventional and bionic cell technologies”, the bionic bit is his own invention and only he knows what it is supposed to be. His lab’s work package (WP)6 was supposed to run the full 5 years of Biotrachea and therefore potentially include the first-in-man clinical trials.  Also Bader’s own institutional website insinuates the bioreactor-based clinical application of his cell differentiation technology for Biotrachea. However, his laboratories at the University of Leipzig are not GMP-certified to prepare material for patient transplants. In this regard, Bader declared to me:

“I have been careful in submitting my application, also at the explicit request of Mr Macchiarini, that I was not to be involved in clinical preparations, GMP or manufacturing work with my lab”.

Bader then insisted that he was only supposed to test “new materials with cytokines and cells” using a “2D multiwall bioreactor” from Hugo Sachs Elektronik, and not a 3D one used for trachea regeneration. According to the Leipzig professor, the bone marrow cell preparation for in-patient use was exclusively covered by Macchiarini’s own WP1 and assigned to Careggi and KI. In fact, it was the Careggi-associated WP4 where the seeding of bone marrow cells on trachea contracts was mentioned (see Part B objectives section, page 14). It then moved together with the master himself to KI. However, WP4 was supposed to run only for the first 4 years, but Bader’s WP6 was scheduled to run until the very end of the five years. The preparation of human transplants was supposed to start at the 40^th month of funding and the first-in-man trial during the last year. Where exactly was the bone marrow cell magic for patient transplants supposed to take place, if Bader denies his involvement and couldn’t offer a GMP laboratory anyway?

However, the project never came that far. Biotrachea would have been become an EU-funded bloodbath, had not its lead scientist Paolo Macchiarini become greedy about patents and their revenues. Luckily, the plastic he offered as replacement lacked novelty, and without novelty, no research can be excellent enough to get EU funding. Phew.

The entire Biotrachea documentation is available here, thanks to Jonas Malmstedt. As usual, also thanks to Elizabeth Woeckner for her constant help with this investigation.