Claudia’s trachea

This is the English original of my story for Hipertextual, first published in Spanish on 27.10.2016.

What did we learn from the trachea transplant scandal around the miracle surgeon and stem cell pioneer Paolo Macchiarini, who used to conduct his human experiments in Germany, Spain, Italy, Sweden and Russia? That despite the stem cell fairy magic, all his plastic trachea transplants proved deadly for his patients, except of one or two cases where the transplant was removed early enough. These patients were not saved by Macchiarini though: he quickly lost interest in his human Guinea pigs, especially when his miracle cures started to fail. One such patient, a young woman from Turkey, lost several organs in the process, and was only saved so far due to excellent medical care and organ transplants. Macchiarini meanwhile was busy experimenting on humans in Russia, the saddest case was that of another young woman who was tricked into agreeing to an allegedly life-improving plastic trachea, which caused her death soon after.

But it was not only about the lethal plastic, and there were more young women (and some men) who were killed or mutilated by Macchiarini’s trachea transplants, while other options were available to save their lives and health. What often remains unspoken: the technology which Macchiarini used before, that of a dead donor trachea stripped of cells and allegedly reconstituted with stem cells, failed as well. Without exception, but for some reason the method is still being presented as ground-breaking success and in fact there are currently clinical trials happening in UK and soon in the whole EU. These are led by none other than by Macchiarini’s formerly closest ally, the British surgeon Martin Birchall. What the two of them did to their very first patient whom they operated in 2008 at the Hospital Clinic Barcelona, is nothing less but a bankruptcy of basic medical ethics which almost costed that young woman her life. Other Spanish doctors have been rescuing her life ever since, while Macchiarini and Birchall were busy making their fame and careers by parading this utterly failed transplant of a rotting trachea as an epic success story.

The untold story of Claudia Castillo and her trachea transplant features these key points:

• Patient was neglected by Macchiarini and his Barcelona colleagues prior and after the transplant operation, while her condition deteriorated
• Standard therapies were not considered or rejected in favour of a totally untested, scientifically unfounded and unrealistic method
• “Informed constent” of the patient was obtained through deliberate misinformation
• The transplant was prepared in a British veterinary lab using animal products, in total disregard for elementary safety measures in human medicine. The responsible British authorities were misinformed, the incident soon covered up and all research documentation vanished.

The beginning

Claudia Castillo, a young Colombian living in Barcelona, suffered from constricted airways due to complications of a tuberculosis infection. In 2005, when she was 27, she visited the surgeon Macchiarini at the Hospital Clinic, who then freed her upper airways by removing a piece of constricted trachea and stitching the ends together, a procedure called “resection with primary end-to-end anastomosis”. This operation went well, as the director of the Hospital Clinic of Barcelona, Antoni Castells, informed me. However, I was forwarded some clues that Macchiarini’s surgery was possibly botched-up: his patient was examined in 2013 and diagnosed with a “left vocal cord paralysis” as a side-effect of it.

Claudia also had another constricted airway section, namely in her left bronchus. That Macchiarini treated with an inflatable silicone tube, a so-called Dumon stent, to widen the narrowed passage to her left lung. Unfortunately, that standard procedure did not work out, as Castells commented to me: “This stent was placed in March 3rd, 2005 and removed in April 18th, 2005 because of recurrent episodes of pneumonitis and untreatable cough”.

Despite the failed therapy, Macchiarini and his hospital colleagues in Barcelona did not pursue further surgical attempts to help Claudia for another 3 years. Did Macchiarini once again neglect his patient, as his treatment failed to help? We can only guess, but we do know that meanwhile Claudia’s situation worsened: she was in direct danger to have her left lung amputated due to infection. Unlike later news articles suggested, her life was never at stake, yet the so-called pneumonectomy was a valid therapeutically option to avoid further complications and to restore a sufficient degree of Claudia’s life quality.

Macchiarini and his British colleague Birchall thus proposed to save the patient’s lung, by implanting a “tubular tracheal homograft”: a dead donor organ, stripped of its cells and re-seeded with patient’s own cells, which were supposed to regenerate a living trachea. This was the proposal Macchiarini submitted to the hospital’s institutional review board and to the Catalan regulatory agency for transplants:

“Since it is a pioneering procedure, we cannot establish accurately the chances of success. It must be said, however, that if the transplant did not evolve favourably, it would be possible to indicate the first therapeutic option (left pneumonectomy) as a salvage procedure without jeopardizing the success of the latter”.

Neglected alternatives?

One well-established therapy approach might have been the so-called bronchioplasty, similar to the operation which Macchiarini performed in 2005 on Claudia’s upper trachea. Theoretically, the constricted section (which was exactly 2.75 cm long, as the clinic director Castells informed me) might have been surgically removed and the airway ends stitched together. It is however unclear if Macchiarini and his Barcelona colleagues seriously ever debated this possibility, either in 2005 or in 2008. Castells now insisted in his email to me: “Left pneumonectomy was the only alternative to transplant at that moment” and kept quoting Macchiarini’s publication in the journal The Lancet, which declared that “further main-sleeve resection” was not doable. We will probably never know if it was true. All we have is the word from 8 years ago, from that former star surgeon who is by now accused of being a “pathological liar”.

A patient can live a relatively healthy and active life without one lung, since it is an organ we have two of. It is not the same with trachea, this is the only tube we breathe through. If collapses or suffers damage, we suffocate and die. Trachea transplants are extremely difficult, also due to certain peculiarities of blood flow to this organ. Without blood supply, every biological transplant will die, as Pierre Delaere, trachea surgery specialist and Macchiarini-critic, keeps reiterating.

However, Macchiarini and his team decided to test the method anyway, since they simply postulated that Claudia’s body will somehow just regrow blood vessels and revive the dead organ implanted into her. Indeed, they seemed to have convinced all the necessary health authorities without presenting a shred of evidence for their outlandish theories about basic human biology. Castells confirmed that Macchiarini’s proposal was supported by the Hospital Clinic Barcelona, its ethics committee and the Catalan Organization of Transplantation (OCATT):

“All three committees concluded that the proposal was supported by previous experimental data and that the indication of this procedure was adequate. These committees also evaluated the corresponding informed consent, which specifically pointed out risks derived from the procedure and other therapeutic alternatives, and approved it”.

The false pigs

True, Claudia did give Macchiarini her “informed consent” after the charismatic doctor demonstrated the technology’s alleged safety and efficiency by showing her the happy pigs which he said to have tested it on. Claudia believed her doctor, but she shouldn’t have. All animal experiment papers were published by her surgeon long after he operated Claudia as his first human subject. And the Barcelona authorities still staunchly refuse to share any evidence which might prove if these animal experiments were ever performed at all. Basically: we do not know exactly which pigs Claudia was shown.

However, the doctorate dissertation of Macchiarini’s student Philipp Jungebluth (who participated in the entire process) clearly suggests which pigs these might have been. Those animals were indeed happily breathing: through their own untouched windpipes. What they actually were treated with, was a small piece of a decellurised trachea implanted under the skin of their hindquarters, to see if it causes inflammation (and in fact, it did). Without the availability of documented evidence, we can’t even be sure if any trachea transplant experiments at all were performed on pigs or even rodents, and if they were, what actually came out of them (but we do know Macchiarini rigged the outcomes with plastic tracheas when his rats at Karolinska Institutet all miserably died). All in all, what Claudia signed was not an “informed consent”, but most obviously a misinformed one. It is as such completely invalid and constitutes a gross ethics breach and a heinous crime on a patient.

Human transplant from a pig lab

With the institutional approval and patient’s consent in place, Macchiarini and Birchall proceeded with their regenerative medicine magic. A donor trachea was retrieved in November 2007 from a dead person in Spain and flown to Italy to have all of its living donor tissue removed. Afterward, the decellurised organ was brought to the University of Bristol, where Birchall at that time used to have a lab at the School of Veterinary Sciences in Langford. This was where another ethically highly questionable stage of Claudia’s trachea transplant took place.  Because, according to all available evidence, Birchall, Macchiarini and their team cultured Claudia’s cells from her bone marrow and windpipe and seeded the trachea in a veterinary lab where animal experiments on pigs took place. Basically, Claudia’s trachea was “regenerated” by Jungebluth and Birchall’s team members Tristan Cogan and Louise Rees next to dead pig cadavers. The team also used reagents originating from cows to grow Claudia’s cells in a dish, before seeding them onto the dead donor trachea inside a plastic box called bioreactor. Again, in Birchall’s veterinary lab in Langford.

All this went against all rules of human medical care and brought an major risk of infection to this clueless patient. It is not clear if Birchall would have processed an organ transplant for a British patient in his pig research laboratory. He certainly had no such ethical scruples with a Latin American one in Spain. At the same time, the Spanish doctors were left in the dark about where exactly the Brits were preparing the transplant. Castells declared to me in this regard:

“I checked all documentation and there is no mention to any veterinary lab; we did know it was an experimental, research lab, since there was not any clinical, therapeutic laboratory available at that moment”.

The veterinary lab origin of Claudia’s trachea was even indicated by a press release which the University of Bristol briefly removed once I approached them on this topic. To me, the university declared that no records at all of this process and in which laboratory exactly it was performed exist:

“The University’s Research and Enterprise Development department does not hold records in relation to the laboratories where work was carried out. We can confirm that the work was carried out in University of Bristol laboratories under the governance arrangements of one Faculty. Since then there have been changes in staff members and Faculty structure so we are not able to provide further details”. 

This in itself is the most outrageous breach of basic laboratory practice. Unless you are talking about Macchiarini and his colleagues of course, who removed all documentation of their work after the professor was sacked at Karolinska Institutet in Stockholm. So, either Macchiarini and Birchall illegally removed the Bristol documentation years ago, or it was destroyed as soon as I asked about it, by Cogan and Rees who still work in senior positions at the same School of Veterinary Sciences. So much for those “changes in staff members”.

Cheating the authorities

Birchall apparently misinformed the British watchdogs Medicines and Healthcare products Regulatory Agency (MHRA) and Human Tissue Authority (HTA) on what exactly he and his colleagues were up to. A certain letter he received on June 9^th 2008 from HTA is very revealing (exclusively available here, as well as a FOIA reply from University of Bristol which somewhat misrepresented these communications). Birchall tricked the authorities by presenting Claudia as dying from cancer of the oesophagus (while she neither had any cancer nor was dying). He also apparently performed all the handling and differentiation of Claudia’s cells in his veterinary lab in Langford without a HTA licence, for which he unsuccessfully applied in April 2007.  In the letter from June 9^th 2008, an HTA official wrote to Birchall:

“As far as the HTA is concerned, therefore, Langford is an unlicensed premise. Since July 2 2007 it has been an offence to procure, process, test, store or distribute/import/export such cell lines for Human Application.

Under the Regulations, Langford is ‘storing’ and ‘processing’ cells for Human Application and therefore needs an HTA licence. Although the processing is being carried out ‘on behalf of’ the Clinic Barcelona (which, I understand, is licensed by the Spanish Competent Authority), such third party agreements are not applicable across borders from outside the U.K. Service Level Agreements are applicable, but these can only be set up between two licensed establishments. Thus, licensable activities are being carried out on unlicensed premises. The HTA now requests that all licensable activity at Langford (processing, storage, etc) ceases until the Establishment has received an HTA licence. If tissues or cells are currently being stored on the premises alternative storage arrangements on licensed premises will need to be made until a licence is issued”.

Obviously, Birchall and his team never obtained any permits to process Claudia’s trachea, in fact they never told the authorities what they were really doing. In this way, they broke several laws and regulations on basic medical safety while grossly endangering a patient who trusted them her life. This is may even constitute a criminal offence.

Whatever effect the HTA letter had on Birchall and Macchiarini, the very next day, on June 10^th 2008, the trachea was flown to Barcelona with a private plane (as admitted by the University of Bristol in their FOIA reply). It was transplanted in Claudia two days after on June 12^th (as confirmed by Castells) by Macchiarini and Birchall. The date of the flight was kept secret until now, by all parties involved, I had to force the University of Bristol to release it. This is because a false lead was officially created soon after the operation, to hide all tracks to Birchall’s pig laboratory and the absence of HTA permit. Another press release from the University of Bristol, two years after the operation, declared:

“At a laboratory in Bristol, stem cells taken from Claudia’s bone barrow were grown and matured into cartilage cells.   A medical team in Barcelona then used an incubator to cultivate Claudia’s cells and persuade them to grow on the stripped-down scaffold of the donated trachea. They then fitted the patient with her new trachea”.  

This was nothing but a bold-faced lie by the University of Bristol. Castells declared to me:

“Bristol sent us the trachea and we did not perform any cellular manipulation in our center. The trachea was sent immediately before transplant”.

However, the Hospital Clinic Barcelona apparently never made any formal agreement with the University of Bristol about what exactly they will be receiving. The Spanish doctors seem to have trusted Macchiarini’s and Birchall’s word that the trachea will be generated in a proper and medically safe laboratory, and never asked for evidence or certificates. As Castells now admitted, after speaking to the Hospital Clinic’s Legal Department:

“they do not have these documents. I cannot ensure they have not existed, but at least they are not filed”.

The stem cell breakthrough

It was not really smart in this regard for the Hospital Clinic Barcelona to assume the bulk of responsibility for creating the stem-cell –derived organ which they actually received ready to implant, free of all documentation. Yet the Clinic proudly insisted back tin 2008 that the trachea regeneration in the bioreactor took place on their premises. Which may have been partially correct even, for the last few hours before the operation. Given the dates above and the time frames authors themselves provided in the Macchiarini et al 2008 Lancet paper, the culturing and seeding of Claudia’s airway epithelial cells onto the decellurised trachea carcass took place in Bristol, in Birchall’s unapproved veterinary lab. Same goes for the differentiation of Claudia’s bone marrow cells into the cartilage cells called chondrocytes, which was supervised by its discoverer and then-Bristol professor Anthony Hollander (see deleted University of Bristol press release here). The technology was commercialised by Hollander’s private company Azellon Cell Therapeutics since 2007, but it never really took off. Maybe its scientific aspect was found wanting and what Claudia got seeded onto her trachea transplant was not really a cartilage tissue. In any case, Hollander claimed in a 2010 interview with The BMJ:

“I was responsible for taking Claudia’s bone marrow stem cells and growing chondrocytes. These were then flown out to Barcelona, with epithelial cells grown by Martin Birchall, where they were seeded onto a cadaveric trachea that had been decellularised to leave just a collagen scaffold. The trachea was then implanted into Claudia in June 2008, and the rest is history”.

Apparently, either everyone was suffering from a mass delusion, or they were simply telling untruth. Afterwards, all the cheating and trickery were forgotten anyway, since a human life was miraculously saved by brave stem cell pioneer surgeons Macchiarini and Birchall. Except of course, that this was a lie as well.

What happened after the June 12^th trachea transplant was indeed medical history, but not of a good kind. It soon proved to be a predictable medical disaster: Claudia’s trachea transplant failed, utterly and completely.  In his follow-up publication in The Lancet (Gonfiotti et al 2014, which even Castells investigation found to be wrong) , Macchiarini admitted that one year after the operation Claudia had to be repeatedly saved with a stent in her airways, a method which worked so badly for her before. Macchiarini and his team also claimed in 2014 to have been watching over his patient “every 3 months”. But Castells specifies:

“Four months after transplantation, the patient initiated a follow up in a new institution and, consequently, we had no news of her. On February 2014, the patient was admitted in our Thoracic Surgical Department for an acute respiratory failure and total atelectasis [collapse, -LS] of the left lung. At bronchoscopy, a bronchial collapse of 80% was evident. The patient stated that during the previous five years, she had been treated with multiple bronchial stents, most of them bio-absorbable. In this clinical setting, we decided to place a silicone stent and a lung re-expansion was achieved”.

It was however too late. In July 2016, Claudia underwent a lung amputation. Luckily, she was Macchiarini’s only trachea transplant patient in Barcelona, a second operation was stopped due to technical formalities. What happened to Claudia’s miracle doctors since?

Miracle technology

Macchiarini and Birchall both went on to promote the alleged success of her treatment and push each other into professorships. They both were showered with public funding and celebrated as heroes, while treating more patients with cadaveric trachea transplants, and then with plastic. Macchiarini left Barcelona in 2009 and moved to operate a whole list of trachea transplants patients with stem-cell magic at the Careggi hospital in Florence, Italy; the true fates of most of these people are unknown (some are known to have died).  After his Italian colleagues protested against Macchiarini, he used Birchall’s help with a reference letter to obtain a professorship with Karolinska, the rest is history. Jungebluth followed his master everywhere, until the scandal broke and he had to escape to the University Clinic of Heidelberg, a job he recently abandoned. As for Birchall, his Italian partner was one of the helpful reviewers of his professorship application for UCL in London. From there on, it wasn’t pigs anymore for the British surgeon experimenter, but humans. EU is currently funding his pan-European trial to transplant dozens of patients using a similar method which he so gracefully proved with Claudia. Macchiarini’s cadaver trachea technology is still not being doubted as such, and officially at least, Claudia’s transplant is still being presented as a success. It is Claudia who failed her doctors, with her body not taking to the miracle graft as gratefully as she was supposed to.

This is what the lone critic Pierre Delaere has to say in conclusion:

“The problem with the tracheal regeneration concept, portrayed as successful, is that it is theoretically impossible. There is no scientific foundation whatsoever to assume why stem cells would support airway tissue regeneration in this setting. In addition, even if a windpipe-like organ would be generated, it would irrefutably fail after implantation if adequate blood supply had not been restored. […]

How is it possible that a medical approach, for which any scientific theoretical or experimental foundation is lacking, ends up being recognized as a major clinical breakthrough? The reasons for this may be two-fold. Firstly, the ‘stem cell hype’: stem cells have acquired a status of supernatural clinical therapeutic potential. Secondly, the trachea is hidden from the naked eye, which has been used as an excuse for incomplete clinical evaluation, thus facilitating fraudulent reporting. Short and long-term follow-up reports on the tissue-engineered trachea were able to be published because the patient retained the stent during the full course of her treatment.

Purging the literature from these misleading tracheal regeneration claims is an absolute requirement to reinstate credibility in the stem cell therapy and tissue engineering research fields. In addition, the medical community should reflect on the approaches that can be taken to avoid misleading claims in the future”.

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