The London university UCL has now completed the investigation into the affair around their past honorary professor and now disgraced thoracic surgeon Paolo Macchiarini and the trachea transplants. Subject of the investigation were: the two plastic tracheas UCL produced (one sent to Karolinska Institutet and implanted in patient Andemariam Beyene in Stockholm, another used by UCL laryngologist Martin Birchall to treat Keziah Shorten, who previously received a cadaveric trachea from Macchiarini as requested by UCL) as well as four more cadaveric trachea transplants, namely the very first such intervention organised by Macchiarini and Birchall in Barcelona in 2008, on patient Claudia Castillo, as well as the three trachea transplants which took place under UCL oversight in London, on paediatric patients Ciaran Lynch, Shauna Davison and a 3-year old child who was transplanted just in May 2017 at the same Great Ormond Street Hospital (GOSH). The offhand revelations about the last transplant in this UCL report came as surprise, since it was otherwise kept secret.
No information is provided by the investigative report on how that child is doing now, in fact it seems no evidence like laboratory books, research data or patients’ medical files was ever requested and the committee relied solely on the opinions provided by the very people they were supposed to investigate: Paolo Macchiarini, Martin Birchall and GOSH paediatric surgeon and past director Martin Elliott. In fact, the report seems to become very nebulous or even creative with its use of alternative facts to avoid implicating Birchall in anything unethical at all. The only guilty party in this medical scandal is incidentally also the only non-clinician and the only non-white character in the entire Macchiarini affair: the nuclear physicist Alexander Seifalian, a Persian-Armenian and dual citizen of Iran and UK, whose lab manufactured two plastic tracheas. He was already sacked by UCL in July 2016, accused of bribery. Seifalian is also bowel cancer survivor, which did not prevent UCL of accusing him of failing to oversee the abroad clinical application of his produce just when he was receiving chemotherapy.
These are the results of UCL investigation in the nutshell:
- All UCL-employed clinicians involved in trachea transplants, in particular UCL’s chief trachea transplanter Martin Birchall, are fully acquitted from any suspicion of misconduct or clinical wrongdoing. Even Macchiarini seems partially exonerated from the gist of the UCL report, because:
- The maker of the two plastic tracheas, Alexander Seifalian, is to take all the UCL-related blame for the failed transplants (as well as other plastics implants in India, Iran and Switzerland). His fault is to have manufactured these products though his UCL lab lacked GMP (Good Manufacturing Practice) certificate. Only this lack of GMP-quality seal was what apparently made plastic tracheas too dangerous to implant in humans.
- All five cadaveric trachea transplants under the scope of investigation were considered ethically, medically and scientifically justified. Deaths of the patients were explained with new discoveries of recurrent cancer, or demands of other patients for the same hospital bed.
- Birchall’s clinical trials with cadaveric tracheas (phase 1/2a INSPIRE, and by extension, also EU-wide phase 2 TETRA) are to go ahead as planned and to recruit patients. Same positive recommendation for Birchall’s related trial RegenVox on cadaveric larynx, decellurised and “regenerated” with same technology as tracheas.
How things began
Stephen Wigmore, Professor of Transplantation Surgery, University of
Alicia El-Haj, Professor of Cell Engineering, Keele University.
David Tosh, Professor of Stem Cell & Regenerative Biology, University of Bath.
Marc Turner, Professor Cellular Therapy, University of Edinburgh and Medical
Director, Scottish National Blood Transfusion Service.
Pankaj Vadgama, Professor and Director of IRC in Biomedical Materials
The reports tells us how UCL came to collaborate with Macchiarini, who then became their guest professor, and then was considered for a proper faculty employment:
“In 2009 Dr Birchall was recruited to UCL from Bristol and he was appointed as Professor of ENT Surgery with laboratory space at the Ear Institute and also at the Royal Free Hospital (RFH). Not long after his arrival in London he recommended to Professor David McAlpine, then Director of the Ear Institute at UCL, that Dr Macchiarini should be offered an honorary professorship. Professor Birchall arranged for Dr Macchiarini to meet Professor McAlpine, though Professor Macchiarini said in his submission to the Inquiry that he did not know that, at the time. This was because UCL were planning to offer him an honorary professorship. The principal reason for suggesting this appointment was to strengthen a research collaboration and major grant application ($20 Million) that was planned to the California Institute of Regenerative Medicine by the Ear Institute. Professor McAlpine requested that the appointment be expedited to meet the timeline of the grant. The term of appointment was 5 years between 1 st August 2009 and 31 st July 2014.
The appointment was approved by UCL and Professor McAlpine notified Professor
Macchiarini of this in a letter dated 25 th August 2009. The appointment of visiting or honorary professor was a research appointment but did not allow clinical practice and was not a remunerated appointment. […]
Also in 2009, a separate attempt was made by UCL to formally recruit Professor Macchiarini on a substantive contract as a member of staff using the Exceptional Talent Recruitment Scheme offered at that time by the Medical Research Council (MRC)”.
Macchiarini never became faculty member and full professor at UCL. Not because there were any concerns about how trachea transplant patients fared, but because he was seen as not good enough to join this elite institution:
“On the basis of the unsuccessful bid to the MRC for financial support for recruitment and the lack of strong support from UCL associated clinicians, the potential substantive appointment of Professor Macchiarini was not progressed though he did continue with his honorary Professorship at UCL”.
In 2010, Macchiarini and Birchall (via his UCL surgeon colleague Paul O’Flynn) collaborated again, which led to a cadaveric trachea transplant on the 19-year old Keziah Shorten (Patient C in the UCL report), who suffered from a slow growing form of cancer. After that transplant failed, Keziah received a plastic trachea transplant from Birchall, which then most likely sped up her death. It was only my reporting which proved this collaboration (her story here), and now UCL committee gave some official insight:
“In early 2010 Professor Macchiarini received direct email contact from the mother of a 19-year old female patient with a slow growing cancer of the trachea. Patient C was being treated at Guy’s Hospital in London under the supervision of Dr Ricardo Simo an ENT Surgeon. The surgical plan devised by Dr Simo and Dr Karen Harrison-Phipps a thoracic surgeon also working at Guy’s and St Thomas’s NHS Trust was to resect the tumour which would also have required removal of the thyroid gland and upper trachea and removal of the laryngeal nerves and oesophagus with the stomach pulled up and the creation of a permanent tracheostomy.
Professor Macchiarini visited the patient and reviewed her records and imaging while he was in London on other business. On 29 th May 2010 Professor Macchiarini received an email from Professor Paul O’Flynn thoracic surgeon at UCLH, copying in Professor Birchall and Professor Paul Stimson (both ENT surgeons at UCLH) asking about possible treatment alternatives to that suggested by Drs Simo and Harrison-Phipps and mentioning the possibility of tracheal transplantation.
Professor Macchiarini provided evidence that he reviewed new imaging of Patient C and wrote that the only curative solution that he could see would be to undertake tracheal transplantation. He further informed the UCLH airway team that he would not consider operating on her at UCLH because he did not have operating privileges but could perform the surgery in Florence at the Careggi Hospital where he held a position. […]
Mr O’Flynn travelled to Florence to observe the surgery and asked to be scrubbed at the operating table. Professor Macchiarini provided evidence that the Medical Director of Careggi, Dr Valter Giovanni, granted permission for Mr O’Flynn to be
present at the surgery.
The transplant in Florence was funded by the NHS according to Patient C’s mother”.
Interestingly, even Macchiarini saw stenting as necessary (“Professor Macchiarini said that he thought that this was not the best management option for her based on the information that he had and that she might have been better served by a stent“), but UCL doctors decided that Keziah`s graft will work without, as her father narrated on internet. it did not work out at all, the cadeveric trachea started to rot and to collapse, and UCL doctors tore open Keziah’s oesophagus (already damaged by Macchiarini’s radiation therapy) in the process of re-inserting the stent. Keziah died because her airway failed, her chest became heavily infected and her oesophagus was destroyed, Birchall’s plastic trachea sealed her fate. However, though nobody in Keziah’s family ever mentioned any cancer recurrence anywhere, UCL committee declared:
“Her cancer had recurred and was no longer amenable to surgical resection. In September 2011 a decision was made to try to provide a palliative solution by transplanting a synthetic trachea made of POSS-PCU. Professor Macchiarini opposed this decision because he believed that there were other therapeutic alternatives. Professor Macchiarini claimed that he was not involved in the decision making process at this time”.
The decision to use plastic graft on Keziah was made because of the alleged earlier success in June 2011 with the product Seifalian’s lab made for Macchiarini and sent to Stockholm, to be implanted in Andemariam Beyene (Patient B, read about him and all other Macchiarini trachea transplant patients here). There was no GMP-certificate, but UCL approved the export regardless and had been celebrating their achievement throughout all media. Until that patient died in 2014, killed by that plastic trachea. UCL’s new investigation indirectly advised Karolinska to consider blaming the physicist Seifalian for this disaster:
” …UCL should advise the Karolinska Institute that the POSS-PCU construct made for Patient B had not undergone rigorous pre-clinical assessment and was not made to GMP standards under the relevant UK legislation and licensure”.
The investigators even went so far as to partially absolve Macchiarini and his Karolinska colleagues of their responsibility for having used the deadly plastic trachea on Beyene:
“Moreover the Inquiry found the information presented to the Karolinska Institute was misleading in a number of regards. It is not possible for the Inquiry to judge whether the Karolinska would have taken the same or a different view in respect of the clinical intervention in Patient B had they been in possession of a more accurate representation of the facts”.
Also Keziah’s plastic trachea was made in the lab of Seifalian, again by a jointly supervised PhD student of his and Birchall’s, Claire Crawley. Seifalian insists that Crawley made this second graft behind his back, on Birchall’s instructions, who allegedly pretended to Seifalian that the graft was intended to work as a stent. Yet UCL committee now suddenly forgot who Crawley’s other supervisor was, and blamed Seifalian alone:
“The Inquiry found Professor Seifalian’s denial of involvement either implausible or, if true, a dereliction of his responsibilities as the expert responsible for developing the product and head of the laboratory”.
Scapegoating for doctors
Seifalian was accused of delivering two dangerous plastic trachea grafts, because they were not GMP-certified. Would Beyene or even Keziah still be alive if they were? One cannot postulate a more cynical and outrageous question, and indeed UCL report never directly suggests that. Seifalian’s insistence that everyone involved at UCL knew his lab lacked GMP certificate and pushed to use the products for transplants anyway, was disregarded by the investigative committee. Just as the fact that a plastic trachea is nothing but a tool of cruel execution (according to the Belgian trachea surgeon Pierre Delaere, who also gave evidence at UCL the day after me). A plastic trachea will inevitably gruesomely kill any patient regardless if it has been GMP-certified or blessed by the Archbishop of Canterbury. UCL committee seems to see it differently:
“A POSS-PCU graft was manufactured at the RFH [Royal Free Hospital, in the lab of Birchall’s partner Mark Lowdell -LS]under the direction of Professor Seifalian. Again there is no evidence that the POSS-PCU trachea was manufactured to GMP”.
Keziah’s suffering was horrible, just as that of Andermariam Beyene’s was, but to UCL committee the main issue was that their plastic tracheas were not GMP-certified, for which Seifalian was blamed. In fact UCL used to openly approve of plastic tracheas, even those without GMP-seal, until in late 2011
“Relations between Professors Macchiarini and Birchall had deteriorated and they did not work together on any projects after this time”.
The UCL investigators discuss at length the conflict between Macchiarini and UCL regarding the patents on these plastic tracheas and how it was the faulty, uncertified POSS-PCU material made by Seifalian which led to termination of a €5 Million-heavy EU project Biotrachea (see my reporting on this here). The commission apparently fails to see the ridiculous amount of good luck European patients had. Biotrachea, all set to go to start mass-transplanting plastic airway grafts, did not become a bloodbath only because of that patent fight between Macchiarini and UCL.
Seifalian was also blamed for what clinicians abroad did with his other plastic products: a plastic femoral artery implanted in Tehran, Iran, a plastic lacrymal duct implanted in Zurich, Switzerland, and a plastic ear scaffold tested for biosafety in patients in Mumbai, India. Details of that are presented in detail in a recent Guardian article, where the physicist Seifalian is accused of having abused patients as “Guinea pigs”.
On the first case of uncertified material, Seifalian declared:
“A doctor in Tehran who was research fellow at Royal Free Hospital took a bypass graft and said he implanted in the patient, who was drug addict, and send some picture to me, afterwards when I asked him, more details on the operation, it was apparent he did not use the graft and he used PTFE, the commercial graft in the market. This could be confirmed with the doctor itself. Before the operation, I was not aware or I did not plan it”
About the second case, Seifalian said:
“Karla Chaloupka was senior eye surgeon in Zurich and was part-time Ph.D. student I supervised jointly with Professor Hamilton. Her Ph.D. was on the development of tear duct, I had absolutely no idea, but one day coming back from Zurich she told me that, she implanted a tear duct apparently she made in the lab, in the patient with no other option. I did ask if she needs ethical approval etc. She said that hospital was happy with the procedure in Zurich. Then I did tell the UCLB [UCL Business plc, responsible for technology development and commercial transactions at UCL, -LS] who was in charge of my polymer research, and they were happy with it as well. So again I did not know she did the operation until she told me post operation”.
And finally, Seifalian was undergoing chemotherapy treatment for bowel cancer, when the third event in India took place, as he explained:
“Some polymer disk in size of 100 micrometers thick and 10 mm diameter sent to Indian surgeon to see if suitable elastic properties for ear or not, and he implanted into the patient, who need it the ear reconstruction to see if suitable for the ear reconstruction and taken off a few weeks later. Professor Peter Butler at the time was aware of the operation, this was back in 2013 when I was under chemotherapy treatment for cancer and other were supervising students and my work as well […] At the initial UCL inquiries they did realize that at the time I had cancer, and under treatment with chemotherapy I should give help to the head of the department and stayed at home, I had one week off post operation and then not a single day off throughout the six-month chemotherapy”.
Frightening GMP regulations
So the Persian Scapegoat is made responsible for what clinicians did with his materials, including the two plastic tracheas. But was Seifalian really expected to know that he is not supposed to make plastics in a non-GMP lab? After all, he insists that everyone involved at UCL knew his lab lacked GMP certificate, and never minded. In fact, it is the university and the clinicians who are responsible for what goes into patient, much less so a physicist who manufactures plastics in his lab upon doctors’ requests.
Important bit is: GMP certification is usually reserved for “for manufacture and sale of food, drug products, and active pharmaceutical products“, according to Wikipedia. It is not at all clear, even to clinicians, if plastics internal prostheses need such certificate as well, or if they just need sterility: the guidelines by FDA are not clear in this regard (see here and here). It was the task of treating doctors like Macchiarini and Birchall to inform themselves properly and the task of UCL to ascertain the correct certification. A material scientist like Seifalian is by definition far outside his professional expertise to judge that. But it did not stop committee’s chair Wigmore from fingering the Persian Scapegoat and declaring in The Guardian:
“It’s very serious and it’s quite frightening to think that someone could be manufacturing this kind of device without knowing the regulations that govern it”.
It is interesting that Wigmore saw the lack of GMP certificate as frightening, but not the use of plastic tracheas as such, or what UCL did to Keziah Shorten, or Shauna Davison (her story here and below). In fact, when the investigation was still ongoing, I contacted Wigmore with my freshly obtained evidence into the roles of O’Flynn and Birchall in Keziah’s first, cadaveric trachea transplant, which was performed by Macchiarini in Italy. This was how Wigmore replied to me:
“Dear Dr Schneider, can I remind you that you promised the inquiry not to publish any further comments on these matters before the conclusion of the Special Inquiry into Regenerative Medicine Research at UCL. You may not understand but your interference does risk undermining the inquiry and you also risk compromising your own integrity as a journalist if you were to prematurely publish information which later turns out to be either different or erroneous from what you believe. As I told you at the time of your interview the inquiry will address the majority of the areas where you have an interest and also other areas but needs proper time and consideration to reach its conclusion.
Stephen J Wigmore”
I published my article anyway, and this is probably why UCL felt they must now admit the role of O’Flynn (but not so much that of Birchall). In fact one wonders why Wigmore and his team, so concerned about correct biosafety certificates never bothered about this accusation regarding cadaveric tracheas Birchall and Eliott implanted, as declared by Seifalian:
“Other such as decellularized [trachea,- LS] scaffolds made for Great Ormond Street Hospital for children were not manufactured in GMP laboratories, it was not highlighted in the report and no name was mentioned”.
While UCL committee was performing most exquisite contortions to exonerate Birchall (also see below), Seifalian was charged with being guilty for basically everything. The report even proudly announces that two more misconduct investigations are taking place against their Persian Scapegoat. To top it off, UCL denied Seifalian what every single academic under misconduct accusation anywhere in the world has a right to: to contest or to appeal the final verdict in due time before it is published. This was the email which Edward Payne, secretary to the UCL committee, sent Seifalian on September 27th, 2017:
I hope that this finds you well.
Thank you again for providing evidence to the independent Special Inquiry into Regenerative Medicine at UCL which was chaired by Professor Steve Wigmore.
The Inquiry has concluded and UCL has now received its Report which will be released to the public on Friday 29 September at 12pm. Given your significant role in the subject matter of the Inquiry, UCL believes (and has agreed with Professor Wigmore) that it is appropriate to offer you an opportunity to preview the Report shortly in advance of its official release. Subject to your agreeing to keep the Report and its conclusions entirely confidential until such time as it is released to the public by UCL, a copy will be made available for you to read at 10am on Friday 29 September on the 9th floor of 1-19 Torrington Place. If you wish to accept this offer please contact me as soon as reasonably practicable and I will make the necessary arrangements.
With best wishes,
Past UCL investigation and clean-up
That was not the first UCL investigation. In 2015, both Birchall and Seifalian were investigated and acquitted by UCL after Pierre Delaere accused them of misconduct (see Delaere’s guest post and UCL report). Both Seifalian and Birchall were acquitted back then, yet it was Birchall who was reprimanded about having hid crucial information on Ciaran Lynch case. His stem cell magic (which now forms the basis for the three above-mentioned clinical trials) was slammed as unsupported by evidence, as per 2015 investigative report (highlights mine):
“With regard to the allegation of research misconduct on the grounds of scientific fraud made by the Complainant as it pertained to Professor Martin Birchall, the Panel determined that there was no prima facie evidence that any research misconduct on these grounds had taken place, but that there was nevertheless some substance to the Complainant’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 (see footnote 2) – namely with regard to the two figures within the report that had been highlighted by the Complainant in his interview with the Panel (see paragraph 20 above). 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.“
That was the official version. As I learned from a quasi-first-hand source, UCL started its own “night of the long knives” right afterwards, apparently exactly against those who raised concerns over what went on in the UCL regenerative medicine. 13 scientists at the surgery department led by Mark Emberton were forcefully removed from their positions as part of this Macchiarini-related clean-up, some were made redundant, some quit “voluntarily” with a settlement, and all signed a non-disclosure agreement: if any of them says a word of what happened, UCL threatened to sue them for all they had. Seifalian was sacked for what Guardian now presents to have been a personal bribe of “£24,000 from an overseas student” (he however told me that this student initially wanted to pay for his own research work, but UCL did not agree and the money was then sent back to that student).
The new UCL report corrected the previous finding against Birchall’s research and determined the beneficial effect of stem cells (which are actually bone marrow cells) as proven. As evidence served Birchall’s own publications. A fresh paper by Elliott and Birchall (Maughan et al 2017) is mentioned in the report as proof that cadaveric tracheas probably work, at least in rabbits:
“Decellularised grafts demonstrated malacia and collapse but had features suggestive of vascular connection or revascularisation. POSS-PCU grafts were uniformly encapsulated in fibrous tissue with little or no integration into surrounding tissues with concentric anastomotic stenosis from granulation tissue”.
In fact, the Maughan et al paper declares that:
“There are mirror-image benefits and drawbacks to nonrecellularized, decellularized, and synthetic grafts, such that none emerged as the preferred option. Results from prevascularized and/or cell-seeded grafts (as applied clinically) may elucidate clearer advantages of one scaffold type over another”.
Just as the UCL investigation carefully avoided examining the performance of cadaveric “regenerated” tracheas, this new paper by trachea transplanters Birchall and Elliott did exactly the same. Well, one can spare the rabbits for the follow-up paper, because there are now 11 human patients to build the case from (well, Macchiarini tried, see here). And none of these patient histories is anywhere near convincing enough to recommend a cadaver trachea transplant, even if you look at survivors. Four of these cases were subject to UCL’s new investigation, and this is what we learn:
(aka patient A, read more here). Birchall was at that time placed at the veterinary department of the University of Bristol, and right after Claudia’s miraculous rescue with a bronchus (not a trachea) transplant by him and Macchiarini, he was recruited in 2009 to UCL professor of laryngology. All the evidence I gathered makes clear that Birchall received a decellurised trachea from Italy, which he then seeded with patient’s own bone marrow and epithelial cells in his veterinary lab in Bristol, without telling it in such detail to authorities. When he was told by Human Tissue Authority (HTA) that he can’t even store cells there, the cell-coated trachea was flown to Barcelona and implanted into the patient 2 days after. This is even documented by this media report and Bristol University’s own (now deleted) press release. However, the university declared to me that no records would exist of the laboratory work in this regard.
It is therefore completely mind-boggling why UCL commission insists that no trachea was ever present in Birchall’s veterinary lab, unless of course their goal was to protect Birchall of the truly frightening consequences of breaking all safety regulations and of cheating authorities:
“The specific role requested of Dr Birchall and his colleague Dr Anthony Hollander at the University of Bristol was to prepare epithelial cells (Dr Birchall) and chondrocytes (Dr Hollander) to be transferred to Barcelona to enable seeding of a decellularised tracheal graft which had been prepared there”.
“The cadaveric trachea was procured and decellularised in Padua, Italy and autologous bronchial epithelial cells and MSC were sent to Bristol for expansion. This cell preparation took place in a newly built veterinary laboratory that was not a licensed Tissue establishment under the Human Tissue (Quality and Safety for Human Application) Regulations 2007. […] The cells were prepared and shipped to Barcelona and were added to the decellularised cadaveric trachea in Barcelona by Professor Macchiarini and his team”.
There is another strange bit regarding Bristol. The authorities only allowed Birchall to briefly store the cells (they never knew of whole trachea) because they were told patient Castillo was dying of oesophageal cancer. Who told them that? As HTA wrote to me, it was someone from University of Bristol (though not Birchall) who did so over the phone. The UCL commission now suggests that HTA probably made that bit up:
“The specific wording of the letter indicated that the HTA believed that the patient had oesophageal cancer and that the procedure was life saving (she had a benign tuberculous stenosis of her left main bronchus). The Inquiry has ascertained that the HTA received no correspondence from Professor Birchall or any other person involved in the care of Patient A, that indicated that she had life threatening oesophageal cancer. Where this comment in the HTA letter came from is therefore unknown”
Also, UCL commission insists that the cadaveric trachea technology was verified by Macchiarini and Birchall in preclinical experiments on pigs:
“He [Macchiarini, -LS] and Professor Birchall had, at that point, a long-standing research collaboration around animal models of airway transplantation. The animal data which underpinned the use of recellularised tracheas was subsequently published in 2010 and demonstrated that decellularised trachea with chondrocytes and epithelial cells was superior to either alone or neither (Go et al 2010)”.
Only that there is absolutely no evidence that that animal data existed before the transplant happened in 2008. And in any case, it was slammed as scientifically very insufficient on PubPeer. Did the commission actually read that Go et al 2010 paper? They sure never asked for proof on when these pig experiments were performed, in form of lab records or ethics approvals. It seems the peers of the committee simply trusted Birchall that his paper was duly peer reviewed and hence scientifically solid as a rock.
In any case, UCL investigation declared about patient Castillo:
“In short Patient A experienced good early airway function but developed a recurrence of her bronchial stenosis which required multiple stents. She underwent a left pneumonectomy in 2016, but remains alive and is reportedly in reasonable health”.
That is strange. Who was that mysterious person who gave those assessments including that of “reasonable health”? UCL report is totally silent here, and with no Spanish doctors named in the witness list, one wonders if the unnamed expert was either Birchall, or Macchiarini, or both. When did any of them actually last saw Claudia Castillo, to declare her to be presently “in reasonable health”?
The story of this boy (patient D) and his trachea transplant in March 2010 is available on my site. The UCL report now provides some additional details into his disease history. Interestingly, it still maintains the official version that the decellurised graft was prepared by Macchiarini’s team in Italy:
“The tracheal graft was procured in Florence, Italy under the Italian Transplant Authority approval and was decellularised using a protocol that had been used previously with vacuum-assisted decellularisation”.
This stands in contrast with the information Royal Free Hospital, where Lowdell’s trachea regeneration lab is based, provided to me:
“The “Centre for Cell, Gene & Tissue Therapeutics” (CCGTT) was previously “The Paul O’Gorman Laboratory for Cell Therapy” (LCT) and it was as the LCT that it produced/prepared the grafts to which the FOI relates. The LCT and now the CCGTT are wholly owned and operated by the Royal Free London NHS Foundation Trust. […]
As described in the manuscript to which this POI refers, the first graft [Ciaran Lynch,- LS] was a non-substantially modified tissue and was prepared and released by LCT as a product regulated by the Human Tissue (Quality and Safety for Human Application) Regulations 2007. The product was supplied to Great Ormond Street Hospital as described in the manuscript. It was released on 15th March 2010.
This 15-year-old Patient E received a cadaveric trachea in 2012 from Elliott and Birchall, and from a related BBC documentary it does look as if Elliott somewhat misinformed the GOSH ethics commission about the safety record of the trachea graft technology and its alleged promises to cure Shauna’s disease (read the section about Shauna in my Ciaran article). The girl died not even 3 weeks after her operation, she suffocated because her new trachea collapsed, a cause of death both Elliott and Birchall used to deny. Once again, London doctors decided after the operation that their trachea transplant patient needed no stenting to keep the airways open. The UCL report provides in this regard:
“Professor Elliott, described how, because there had been an attempt to epithelialise the graft, he was advised not to place an absorbable stent at the time of tracheal transplant. His preference was to have placed a stent because he had previously observed a phenomenon with Herberhold homografts where the graft became soft and supple in the weeks after transplant before becoming biomechanically more rigid later in its life history”.
Who advised Elliott not to place a stent which would have safeguarded that Shauna can breathe? An angel from God? A burning bush? Why is UCL report so mysteriously silent on who this advisor was? Common sense suggests it was Birchall, who already witnessed how Keziah suffered and died in UCL Hospital because his team decided to remove her stent. On top of this irresponsible decision against stent, London doctors sent Shauna home to Leeds after only 2 weeks stay at GOSH. If you wonder why, UCL report suggests it was because they needed her hospital bed! No, I am not making it up. UCL now seriously decided to blame other patients for Shauna’s death:
“There was pressure on GOSH from further patients with complex long segment tracheal stenosis awaiting admission and as a consequence of this the tracheal team felt pressure to discharge the patient to the care of the local regional airways team who were described as “well able” to deal with airway issues. Patient E was transferred to her local hospital, however within 48 -72 hours of arrival she got into difficulty and her airway was compromised. She underwent urgent bronchoscopy and her airway was found to be significantly narrowed through collapse. The local team thought that she had experienced a mediastinal bleed and that her new trachea had collapsed through extrinsic pressure. The other alternative diagnosis was that her trachea had simply collapsed with no preceding bleed. She experienced a respiratory arrest and suffered irreversible brain damage and sadly died”.
Officially, there were no more cadaveric trachea transplants after Shauna. A naive mind would think that 10 dead and mutilated patients would be a lesson to maybe pause and reconsider. Not at UCL. In May 2017, a child received a trachea transplant, and the UCL report makes no reference whatsoever as to who was responsible (I now learned Birchall and Lowdell were involved, see here) or how the patient is doing now:
Patient F is a 3-year old girl with severe airway malacia secondary to multiple repaired tracheoesophageal fistulation. She had swallowed a lithium battery at the age of one, which had become lodged in her oesophagus and eroded over a 2.5cm length into her trachea. She had been transferred to GOSH and underwent a slide tracheoplasty, oesophageal repair and a laparoscopic gastrostomy. She required multiple oesophageal dilatations and also required tracheal stenting for tracheomalacia. She has had 27 oesophageal or tracheal dilatations and has required 3 endotracheal stents. She had to have a cervical oesophagostomy and resection of her mid oesophagus because of recurrent fistulation into the trachea. She has developed problems with granulation in the lumen of her shortened trachea. Further surgical procedures were felt unlikely to be successful in view of her previous extensive tracheal surgery and tracheal shortening. Homograft was considered but was thought unlikely to be possible. Her case was discussed at multiple MDT meetings and with clinicians in her home town and also with her parents. Application was made to the Clinical Ethics Service team at GOSH who offered no ethical objection to the use of tracheal transplantation.
She underwent a cadaveric tracheal transplant in May 2017. The graft was obtained through the NHS Blood and Transplant under the Royal Free HTA licence and decellularised using a vacuum technique. It was recellularised with autologous bone marrow-derived MSCs and epithelial cells at the Centre for Cell, Gene and Tissue Therapeutics at GMP under their MHRA Specials licence using xeno and allo free reagents. The precise details of the surgery are unknown but it was proposed to deploy an internal biodegradable stent at the time of transplant and to use an omental wrap if this were possible. The patient is under the care of Mr Richard Hewitt Director of the Tracheal Service at GOSH. Early reports were that 2 months after her surgery Patient F was recovering well but no further details of her condition have been reported. The Tracheal Service have undertaken to formally report the outcome of Patient F in the medical literature in due course.
Since Wigmore and his team saw nothing else “frightening” but the lack of GMP seal on the plastic tracheas, it was hardly surprising that they endorsed Birchall’s ongoing clinical trials on trachea and larynx transplants, made from decellurised donor organs and regenerated with bone marrow cell magic. INSPIRE and respectively RegenVox are invited by the UCL investigators to recruit patients for transplants, and by this logic also the phase 2 trachea transplant TETRA (read about it here and here). The rationale: for one, the allegedly very convincing recent preclinical animal experiments (where one doubts if the committee ever bothered to actually read those Birchall papers), and second: those clinical trials already received ethics votes and other approvals of authorities, and noone should question the authorities:
“Finally, the Inquiry believes that whilst occasional compassionate use is unavoidable, the development of the field is contingent upon rigorous scientific evidence, good manufacturing practices, robust non-clinical evaluation and properly structured clinical trials. The Inquiry has seen evidence that both RegenVox and Inspire studies have received Clinical Trials Authorisation from the MHRA and approval from the independent ethics committee. The Inquiry is mindful of the concerns expressed by some witnesses as to the efficacy and safety of these tissue-engineering approaches, but believes that the best way to resolve such genuine differences of opinion is through systematic preclinical and clinical studies, which have been subject to independent scrutiny by Regulatory Authorities and Independent Ethics Committees”.
This is how Patricia Murray, professor of stem cell biology at the University of Liverpool and former nurse at a head and neck unit, commented to me about UCL committee’s decision to continue with cadaveric trachea and voicebox transplants:
“It is both surprising and disappointing to see that nothing has been learned from the events at the Karolinska, and that once again, we have the interests of a University and some of its researchers trumping patient safety. The UCL report suggests that the ‘Inspire’ and ‘RegenVox’ trials are going ahead despite there being no convincing safety and efficacy data from pigs, which are the most appropriate animal model for airway transplantation. For ‘Inspire’, presumably it is the pig study reported in ‘Go et al’ (referenced in the report) that was presented to the MHRA as evidence for safety and efficacy, but the data in this paper are biologically implausible. For ‘RegenVox’, the supporting pig data have recently been published in ‘Ansari et al’ (described in the report but not specifically referenced). On page 49, the report tells us that following implantation into pigs “…the decellularised scaffolds showed mild inflammatory responses and evidence of remodelled cartilage.” The evidence for remodelled cartilage is not very strong, and it seems that the decelullarised implant fragmented, so it is hard to understand how this study convinced the MHRA that the procedure was likely to be safe and effective in human patients. High risk interventions should not be tested in humans without strong evidence for safety and efficacy in an appropriate animal model. If this approach to airway transplantation does not work in pigs, why would it work in humans?”
One wonders whom UCL will eventually blame if their clinical trials predictably end in deaths and misery for a number of new trachea transplant patients.
Update 3.10.2017: please note this response by Chair Stephen Wigmore to my questions.
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