Macchiarini, Birchall, Seifalian and EU-funded human experimenting

The disgraced surgeon Paolo Macchiarini has now been officially sacked from Karolinska Institutet (KI) in Sweden, while also the entire Ethics Council was dismissed by the new KI Vice Chancellor in the process of creating a new supervisory body, with more extended authority.

European Union terminated in 2014 its FP7 funding to Macchiarini and his partners of the Biotrachea Consortium (yet as I show below, the EU’s follow-up programme Horizon2020 has awarded just now almost €7 Mio for a stage II clinical trial with regenerated trachea by the very same Macchiarini partners at UCL) . The original wording of the EU spokesperson in regard to BIotrachea termination referred to “difficulties related to important deliverables” and declared that “at no time did any EU funding for this project involve activities, tests or investigations with human subjects”. Yet the List of Milestones of Biotrachea contained points like:

• MS10 Report on the in vivo immune responses to tissue-engineered airway grafts in men.
• WT14: Outcome of first trial in man tracheal clinical trial
• WT15: Obtaining of clinical trials authorization for tracheal trial
• WT 16: Obtaining of clinical trials authorization for synthetic tracheal trial

After I confronted EU with this and other documents from Biotrachea suggesting an upcoming clinical trial on human patients, the EU spokesperson issued an update to their earlier statement (the entire EU message at the end):

“A chronological sequence of milestones (MS) and work packages (WP) were proposed under the Description of Action. These defined and described all of the technical activities that were to be carried out. The Commission terminated the project before the milestones and work packages referred to in your message were achieved or delivered”.

With a help of my website reader’s, I received also Financial Declarations submitted by KI to the EU (2012/2013 and 2013/2014), the travel expenses therein reveal some interesting information. One post from the 2^nd period is particularly intriguing, described as “Philipp Jungebluth, Hannover 130912, meeting with Dr. Schreiber (lawyer) and Dr. Möller (med. doc and veterinarian) regarding legal issues with tissue engineering (human, animal studies)”. To find out what this was about, I contacted the Medical University Hannover (MHH) where, as I previously reported, Macchiarini is still listed as adjunct professor, and where his acolyte Jungebluth studied medicine. Stefan Zorn, head of MHH press office, explained to me that according to his investigation, “this has nothing to do with MHH but with a Hannover-based company MDSS”. The company provides “high quality service as a competent partner for regulatory affairs”, while its head is called Ludger Möller.  Neither Möller nor MDSS replied to my inquiry if he was the same Dr. Möller whom Jungebluth has visited in 2013/2014 to discuss legal issues of human experiments.

Zorn also explained to me on the phone that their adjunct professor Macchiarini never was employed by or received a salary from MHH (and that as such, Macchiarini also cannot be sacked). The surgeon used to earn his income in Hannover by operating patients on the private basis. In fact, Macchiarini stands accused by Italian authorities of having attempted extortion from his Italian patients in Florence, where he requested €150,000 for them to be operated in Hannover. The related trial for fraud and attempted fraud was previously dismissed by the Italian courts, but has now been re-opened.

Another peculiar travelling entry from 2013/2014 was “Philipp Jungebluth, Gothenburg Schweden to pick up trachea”. Was there possibly any collaboration with the University of Gothenburg and its team of rather controversial trachea regenerators Sumitran-Holgersson and Olausson?

Graziella Pellegrini, professor for regenerative medicine at the University of Modena in Italy, was one of the key members of the Biotrachea Consortium. Pellegrini has been very helpful with my inquiry and described her lab’s contribution, namely that of the epithelial stem cells:

“We started primary tracheal epithelial cell cultures from biopsy, approximately 1,5 years into the Biotrachea project. After the approval for biopsy retrieval from Careggi Hospital, the project was transferred to Karolinska, a new approval was requested […] and finally I got it and I received biopsies: at that time I could start primary cultures but the project was stopped approximately 6 months later”.

The biopsy is documented in the Periodic Report Summary 2 submitted to EU by the Biotrachea Consortium. Since the EU has originally specifically agreed to fund Macchiarini’s synthetic trachea experimentation in humans, Pellegrini shared these insights:

“The project contained a plan for human treatments, at a stage of the project when all requirements would have been in place: material, epithelium, cartilage, full characterization, ethical approval, authorizations etc… but we did not reach that point. The project was good, despite the termination, the main technical problem was related to the biomaterial, which was not good at all, neither for trachea nor for epithelial cells”.

The weird thing is, Macchiarini always seeded bone marrow mesenchymal cells onto the biological and artificial trachea carcasses which he then  transplanted into his patients. It is not clear what he offered EU to use for his Biotrachea funding, but it surely was not (or not only) bone marrow cells.

According to Pellegrini:

“ the exclusive use of  bone marrow derived cells, for trachea transplants  was not written in the project. In the proposal, there were included cells able to give cartilage, recruitment factors and epithelial cells from human airway”.

Retrospectively, Pellegrini has this to say about Macchiarini’s claim of trachea regeneration from  bone marrow cells:

“The unproven but attractive (both for scientists and entrepreneurs) concept that mesenchymal cells can do everything, probably captivated Paolo Macchiarini also; and he proceeded in that direction. The non- scientific idea that a mesenchymal stem cell can become any cell type, without the need for certain extreme experimental conditions, produced much damage in many different fields of medicine:  to patients (some are dead), science, society and its research money and serious scientists.

The artificial trachea material described in the Biotrachea proposal was not working with cells, and Macchiarini suggested a different material already known (so the novelty aspect for this nanomaterial funding call dropped). […] The widespread concept that mesenchymal cells can do everything probably drove Macchiarini to think that his transplants could work anyway”.

Pierre Delaere, professor for respiratory surgery at KU Leuven, Belgium, is one of the earliest and fiercest critics of Macchiarini’s . Yet he sees the potential of clinical stem cell research, even for trachea regeneration:

“In the last decade, miraculous tissue and organ regenerations have been described in humans based on the use of “stem cells”, which are purported to have supernatural therapeutic potential. Medical breakthroughs are and will always occur in small, consecutive steps. In regenerative medicine engineering of corneal implants may be this first step. Corneal epithelial implants can be nourished by diffusion and don’t need blood vessels. Engineering of skin grafts may be a next step. Skin grafts are much more complicated because not only the epithelial layer but also a part of the dermis, with its blood vessels, needs regeneration. Let’s start with these first steps. With our current knowledge, dreaming of whole organ regeneration should be seen as fantasy”.

Delaere has been trying to prevent clinical trachea regeneration trials on human patients whenever he saw those as unscientific and, in his own words, “fraudulent”. Delaere accused of misconduct Macchiarini as well as his close collaborators at UCL Martin Birchall, professor of Laryngology, and Alexander Seifalian, professor of Nanotechnology and Regenerative Medicine. Birchall performed together with Macchiarini tracheal transplant procedures on several patients in between 2008 and 2012, they published their reports subsequently in The Lancet.

Seifalian (his self-portrait at The Guardian here) specialises in the production of artificial tracheas from polyhedral oligomeric silsesquioxane (POSS), which Pellegrini and apparently also EU deemed just as unsuitable as the one produced by Harvard Apparatus together with its inventor Macchiarini. A TED Med talk video shows Seifalian creating an artificial trachea after Macchiarini’s request, apparently without ever having ever seen a trachea previously. Seifalian’s nanotechnology-made organ was then seeded with bone marrow cells and implanted by Macchiarini into a patient at KI in Sweden in 2011.

Some of the evidence Delaere submitted to UCL are available here, here and here.

The UCL internal investigative panel (which consisted of four Birchall’s faculty colleagues) dismissed all accusations and decreed that in case of Birchall and Seifalian “there was no prima facie evidence that any research misconduct had taken place”. Birchall was solely criticised for “a misleading element” in his Lancet paper (Elliot et al,2012), where Seifalian and Augustinus Bader were co-authors. UCL committee decreed:

“Professor Birchall should be urged to give greater consideration to the need for clearer and more representative presentation of information and evidence in his published reports in order to support his assertions”.

As Delaere pointed it out to UCL, while Birchall and his co-authors proclaimed in that Lancet publication “the success of the stem-cell-based tissue engineered tracheal implantation and regeneration procedure that had been employed, they had omitted to clearly identify and acknowledge the stent and surrounding vascularised omentum tissue wrap and the essential role and contribution of these elements”. Simply put, Birchall’s stem cell treatment was at the very best utterly irrelevant to the therapy, which otherwise relied on “traditional” procedures.

It seems that Birchall’s and Seifalian’s UCL colleagues were nevertheless quite convinced by his bone marrow-derived mesenchymal cell approach in tracheal regeneration and recommended:

“That the allegation of research misconduct made by the Complainant [Delaere, -LS] as it pertains to Professor Alexander Seifalian be regarded as having no substance and mistaken, and that no further action therefore be taken”.

 I provide the June 2015 dated draft of the entire 9-page UCL report here.

Both Birchall and Seifalian were possibly Macchiarini’s UCL partners at Biotrachea. The loss of this funding cannot be that grave for Birchall though. Further well-funded clinical trials with stem-cell regenerated trachea and larynx are about to commence, under his leadership.

One is the MRC funded project RegenVOX, set to run from June 2013 till April 2018 and funded with almost GBP 3 Mio.  There, Birchall is currently recruiting ten “clinical trial volunteers” for “autologous stem cell based, tissue engineered partial (non-moving, but anatomically matched) laryngeal replacement grafts”.  According to Delaere, the phase I/II clinical trial RegenVOX uses “stem cell based tissue engineered laryngeal implants based on the same decellularization-recellularization approach” as the tracheal transplants.

And if anyone was thinking that EU has stopped funding human trials on trachea transplants, this is not entirely correct. As announced in December 2015, the EU research funding programme Horizon 2020 awarded €6.8 Million to the TETRA Consortium for the phase II clinical trachea replacement trial.  The Consortium is led by Videregen, a company that was established based on the UCL expertise in tracheal transplants. The announcement goes:

“The Phase II trial, which will recruit patients from five clinical sites across Europe, is to assess the safety and efficacy of the replacement trachea product.[…]The project also involves scale-out of stem cell manufacture from the UCL/Royal Free Hospital London Centre for Cell, Gene and Tissue Therapeutics to establish a second GMP [Good Manufacturing Practice, -LS] manufacturing site in Munich, creating a pan-European supply chain. […]

The principal investigator is Professor Martin Birchall (UCL, UCL Hospital NHS Foundation Trust) with additional trial sites at the University of Manchester/University Hospital of South Manchester NHS Foundation Trust (UK), Università degli studi di Brescia (Italy), Medical University of Vienna (Austria) and Instytut Gruzlicy I Chorob Pluc (Poland). Other parties include the Cell Therapy Catapult (pan-European regulatory processes and lead clinical research activities), TMC Pharma (regulatory affairs and lead clinical research activities), NHS Blood and Transplant (tissue retrieval and trachea scaffold manufacture), Klinikum Rechts der Isar der Technischen Universität München (stem cell processing and final product release) and Euram (project management)”.

Update 30.03.2016: according to this press release, the second trachea-production facility in Munich will be the TUMCells centre, led by Martin Hildebrandt:”first patients should be able to participate in the trial in 2017″, with the goal to obtain European market permit in 2019 and to offer the commercial product in 2020.

As Delaere explained, Birchall will be “using the decellularized tracheal scaffold treated with bone marrow for tracheal and laryngeal defects”. This seems in fact the very stem cell technology Macchiarini has been using. Videregen describes their method as:

“Autologous mesenchymal stromal cells and airway epithelial cells are used to reseed the decellularised tracheal scaffold, which is then used to replace the diseased portion of the patients trachea”.

The only problem which may be standing in the way of the success of this EU-funded clinical phase II trial is possibly the actual biology of stem cells and the trachea. As Delaere wrote in his recent publication with his KU Leuven colleague Dirk Van Raemdonck:

“The engineered trachea is an example of blatant scientific deception. […]There is no scientific foundation whatsoever to assume why stem cells would support airway tissue regeneration in this setting. In addition, even if a trachea-like organ would be generated, it would irrefutably fail after implantation if adequate blood supply had not been restored. As expected, the implantation of de-cellularized and synthetic scaffolds resulted in extremely high morbidity and mortality rates (14). At this point in time, this form of airway regeneration should be regarded as hypothetical and scientifically unfounded (15,16)”.

 

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Entire EU statement to me on Biotrachea termination:

“We would like to reaffirm that the Commission services scrutinised every aspect of the work on BIOTRACHEA until termination, and there has been no suggestion that EU funding was used for any purpose that has been harmful towards citizens. A chronological sequence of milestones (MS) and work packages (WP) were proposed under the Description of Action. These defined and described all of the technical activities that were to be carried out. The Commission terminated the project before the milestones and work packages referred to in your message were achieved or delivered.

 The policy of the EU on research involving human beings is that all applicants’ research projects and proposals must comply with applicable international, EU and national law and ethical principles that govern the area of research that is the subject of their work, including on human beings. 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.

 During Period 1 (from month 1 to month 12), the consortium focussed on developing a number of platform technologies, and a human biopsy sample was obtained. This procedure did not involve the testing in humans of any new technology that the project aimed to create. This can therefore be seen as a normal part of the initial stage of a preclinical development process.

 Regarding funding, we can only reiterate what we said in our reply to your original question:

 “The procedure in the case of project termination is that the Commission requires reimbursement of all or part of the financial contribution made by its services, taking into account the nature and results of the work carried out and its usefulness in the context of the specific programme concerned. The legal basis for requiring reimbursement of all or part of the financial contribution made by its services in the event of termination is underlined in the FP7 Grant Agreement for the project (Article II.39 : “Financial contribution after termination and other termination consequences”, Annex II General Conditions). As part of the procedure, the consortium must prove that any non-recoverable funds constitute “eligible costs incurred and accepted up to the effective date of such termination and of any legitimate commitments taken prior to that date, which cannot be cancelled”.

The Commission is proceeding with this procedure of requiring reimbursement of all or part of the financial contribution made by its services. “