Paolo De Coppi, UCL professor and surgeon at the London paediatric clinic Great Ormond Street Hospital (GOSH) has nothing at all in common with another Italian thoracic surgeon of the same first name. It is basically a slanderous accusation to insinuate that De Coppi’s achievements of growing all possible internal organs in his UCL lab have anything to do with Paolo Macchiarini‘s claims of the same. Where Macchiarini was a fraud, De Coppi created truths and hope for patients, and we know it because it is in The Guardian: oesophagi, intestines, livers, bladders, kidneys, lungs, hearts, diaphragms and of course tracheas were all grown under his supervision at UCL. Pity that something somehow prevents De Coppi from human experimenting, outside of occasional “compassionate use” stint that is.
GOSH’s already funded clinical trial with lab-grown oesophagus on 10 babies was shelved, apparently the method proved not even yet ready for proper animal testing. Another project De Coppi runs with UCL on tissue-engineered intestine is not really yet ready to be tested on humans, despite big promises and €7.1 mn in EU funding.
Three trachea transplants
De Coppi rose to his current high standing of fame, money and influence because of one trachea transplant at GOSH. In 2010, he was part of the celebrated trachea transplant team led by GOSH then-medical director Martin Elliott, UCL laryngologist and regenerative medicine enthusiast Martin Birchall and well, Paolo Macchiarini, who was honorary UCL professor at that time. The child patient was Ciaran Lynch, and this boy, by the sole virtue of having survived the intervention, serves till the present day as evidence of success for Birchall and De Coppi on their quests to become even more famous, wealthy and powerful.
What De Coppi will under no circumstances ever talk about, are his other two trachea transplants. In January 2012, he was assisting Martin Elliott with implanting a trachea transplant into Shauna Davison, a 15 year old girl (see my earlier reporting here and here). The intervention was not really justifiable, especially since a number of decellurised trachea transplant recipients were already dead at that time, including UCL’s own patient Keziah Shorten. This is why GOSH only spoke of the survivor Ciaran when talking the GOSH ethics board and Shauna’s mother into agreeing. One doesn’t want to scare off a prospective research participant, you know. Shauna was apparently used by the UCL scientist in charge, Martin Birchall, to field-test his new product: a defrosted and decellurised trachea. Nevertheless, the GOSH surgeons decided against a life-saving stent which would prevent the tracheal graft from collapsing, with the result that Shauna suffocated and died two weeks after the transplant. My information indicates that at that time, animal experiments with airway implants were not performed yet (later on they failed), while Birchall’s team knew that freezing reduces the graft’s stability. On top, the decellurisation process for Shauna’s trachea graft malfunctioned, but the team went ahead anyway. These scandals recently reached UK news, with these article in The Telegraph (here and here), UCL issued afterwards their own statement.
In April 2017, UCL performed another trachea transplant, on a 3year old child whose airways and oesophagus were destroyed after she swallowed a button battery. The operation only became known because it was mentioned somewhere in the back pages of the 2017 UCL investigation of the Macchiarini trachea transplant affair. No information of how the child fared since was ever released by UCL or GOSH, this seems to be a highly guarded secret. However, with this very recent paper Thakkar et al 2018 featuring De Coppi as last author it is now at least clear the GOSH surgeon was key participant in that trachea transplant as well. The little girl is the “F 23” patient in the Table 2. Prior to the transplant at the age of 47 months she suffered horrible complications: thoracotomy for recurrent fistula, excision of mid-oesophagus and oesophagostomy and sternotomy. Last follow-up was allegedly some time in 2018. The little girl might be one of the children mentioned in this BBC article.
Now De Coppi, who likes to talk about all those organs he grows in his UCL lab, is mostly into oesophagus and intestine. He put the trachea behind him, as too simple a challenge.
The little oesophagus trial which could
In April 2017, GOSH announced that De Coppi received fresh funding for a clinical trial and is about to begin transplanting babies with a lab-grown oesophagus carry already next year. According to media reports 10 children were about to be operated in 2018, using a decellurised pig scaffold regenerated with patients’ own cells. De Coppi himself said:
“The focus is on newborns at the moment, but in the next 10 years we hope to apply this to adults with conditions such as cancer of the oesophagus”
In case you wonder why pigs and not deceased human donors, like with decellurised trachea: De Coppi’s intended patients are newborns, and there are no human donor organs of this tiny size available, for obvious reasons. In fact, there are even not enough suitable adult human cadavers available if you ask for a trachea, a larynx or an oesophagus to decellurise. The reasons are simple: first you need the consent, from the donors or their families. But even then, surgeons need to harvest live organs like hearts and lungs really fast, for proper transplantation, not some regmed decell-recell mambo-jumbo. The cadavers such regmed enthusiasts have access to, are in the morgue, their organs already decaying. This of course did not stop Macchiarini, who also stored his bank of tracheas in a fridge in PBS buffer, where they likely just rotted (this is why Birchall went for frozen and defrosted tracheas, despite knowing those lost mechanical stability). At the end every single recipient of such a decellurised cadaveric trachea died. The very first patient of Macchiarini and Birchall, Claudia Castillo received a bronchus, not a trachea replacement, and escaped death by getting that graft removed.
Only Ciaran Lynch is alive. Chiefly because nobody tried to remove the stents, as De Coppi, Elliott and Birchall decided to do with Shauna in 2012, who suffocated and died right after. But also: the 11 year old boy received in 2010 an adult trachea, from a dead Italian female donor, this graft was the only one ever freshly harvested and rapidly delivered. Ciaran’s graft doesn’t have to grow to reach adult size, it was namely already oversized when put into the patient, a trick another regmed visionary, Macchiarini’s former boss in Germany Axel Haverich applied to develop “growing” heart valves.
It is one thing to find a tiny organ to fit a newborn, but what happens if the baby does survive the experimenting and, well, grows? De Coppi expects the tiny piglet oesophagi to grow with the children he transplants those into. He must be a very strong believer. In this regard, it is also not known which size of trachea De Coppi put into the little girl in 2017, under compassionate use. Fact is: none of the regmed tracheas, either from UCL or from Macchiarini ever showed any objective evidence of growth, or for that matter, of vascularisation or actual regeneration, aside of some ingrowth of native tissue at the graft’s ends.
In October 2018, GOSH reported first success with lab-grown oesophagus, it made the news in all the big media as if a human life was saved with a miracle transplant. It wasn’t really the case. De Coppi is actually back in the lab, implanting his regmed oesophagus into mice. No, not as functional replacement of their murine oesophagus. Bits of De Coppi’s lab-grown organs were stuffed into mouse abdominal fat tissue or kidney capsule, and that was it. The last year’s announcement to replace oesophagus in chidren was quietly forgotten. Instead De Coppi was quoted:
“We’re really excited about these promising preclinical findings. However, lots more research lies ahead before we can safely and effectively translate this approach to humans”
It seems the oesophagus clinical trial at GOSH is postponed indefinitely, but it is not due to the lack of trying. As UCL informed me in November 2017 on its status “as of the 21/08/2017”:
“The MHRA (Medicines & Healthcare Products Regulatory Agency) application is in preparation. No patients have been recruited or treated.”
But already back in 2015, despite there being absolutely no objective evidence for Ciaran’s trachea growing, De Coppi was quoted:
“We showed that we could use a donor organ as a “scaffold” to build a new trachea with the child’s own stem cells and grow it in the body”
He also declared to be making all possible organs:
“Although the trachea is a simple organ, we hope that in the future we will be able to engineer more complex organs using stem cells including hearts, intestines, kidneys and livers.
We are continuing to make advances such as our recent discovery that stem cells found in amniotic fluid surrounding the foetus show good potential for tissue engineering. The cells could one day be used to grow more complex organs which are made up of different types of tissue.
‘At the moment this work is bring done on children partly because their organs are smaller but also because they can potentially benefit the most in terms of extra years of life – each stemcell transplant costs round £250,000. In the future, they will be done on adults too.”
From that interview we also learn what that bizarre PhD thesis by Jonathan Fishman was meant for, titled “Characterisation and immunomodulatory effect of a decellularised skeletal muscle scaffold for tissue engineering“. Despite being from 2013, UCL keeps it secret, the thesis is not available on internet. Fishman is award-winning ENT surgeon and presently works with Birchall at UCL Ear Institute. But why on Earth would anyone work on regenerating decellurised skeletal muscle tissue? Apparently De Coppi and Birchall had plans to use the technology to regenerate diaphragm, the huge muscle at the bottom of the rib cage which pulls the lungs so we can breath. It is not a good idea to try replacing it with something which you dragged out of the lab, even with what you call stem cells on it. The patient is unlikely to leave the operating room alive.
This is why trachea and oesophagus or intestines are such a much better plaything for regmed enthusiasts among surgeons. Once the stem cell miracle happened and the surgeons congratulated each other, the patient can basically bugger off home to suffer and die, as GOSH and UCL demonstrated it with 15 year old Shauna.
As aside, from published charity reports from 2014 (here, page 9) it doesn’t look like Fishman achieved much success with regenerating muscular tissues. If he got even a shred or recellurisation, they would have mentioned it, right? Not just talk about how good decellurisation worked?
“Clinical Fellow, Dr Jonathan Fishman, has been carrying out work to tissue-engineer organs and tissues that actively contract (e.g. skeletal muscles, the food-pipe or bowel)by growing immature muscle cells in the laboratory and seeding them on to a scaffold.
His research has shown that it may be possible to transplant tissue-engineered organs/tissues with little or no immunosuppression.”
Success sounds differently, but it was good enough to announce a clinical trial on children 3 years later.
De Coppi’s oesophagus experiments on babies have been scheduled at GOSH since at least 5 years ago. One parent even started a donation campaign for De Coppi and GOSH, hoping that De Coppi can deliver a new oesophagus for his child, while “Paolo and his team continue to push the boundaries of stem cell science“. Maybe it was not really responsible of GOSH to misinform a parent like this, but who can say no to charity money?
In 2014, GOSH announced ” the first step towards a clinical trial of a tissue engineered oesophagus in infants”:
“Building on previous work, the team are set to develop their approach using stem and other cells taken from amniotic fluid in pregnancy, which are then grown on a donor ‘scaffold’ to create a new oesophagus. Development and analysis of this technique is expected to lead to a clinical trial in newborns in 2016.”
The Guardians of Lego science
Interesting is not only that the clinical trial on babies has been meanwhile postponed indefinitely, but also that the stem cell technology was completely overhauled since. The amniotic cells were thrown out of the proverbial window, De Coppi’s new method, celebrated worldwide in Urbani et al Nature Communications 2018 paper names utterly different sources of cells. Less stem cell magic, more of a crazy construction project by an overambitious surgeon who thinks a living organ can be assembled as if from 3 differently coloured Lego bricks.
Like trachea, oesophagus is vascularised in a messy unintelligently-designed manner which makes the transplantation of a live organ very difficult. The food pipe is also coated with a sheet of epithelial tissue, which needs vasculature to survive and to make the organ functional and protected against the germ-ridden outer environment. How the vascularisation will happen is something which is best not to ponder about. Obviously there never was any evidence for trachea recellurisation in Macchiarini’s or UCL patients, but UCL is very positive it will work for oesophagus.
Unlike a trachea, oesophagus is an innervated and moving muscular organ. Now De Coppi intends to use “human mesoangioblasts (hMAB) […] from paediatric skeletal muscle biopsies from patients“, oesophageal epithelial cells (those can be sampled from patients also) and finally, neural crest cells which the authors insist “can be derived directly from the stomach” of newborns and which probably should provide innervation. Please do not laugh, this design passed peer review at Nature Communications.
The first author Luca Urbani comes actually originally from Macchiarini’s former team, as evidenced for example by this Jungebluth et al 2009 paper, where the authors claimed decellurised tracheas were just as good as native ones. This year 2018, Urbani published with De Coppi some of the skeletal muscle decellurisation work Fishman used to work on, in Scientific Reports. Apparently, the plans with diaphragm are not totally abandoned!
It was not that straightforward to obtain from UCL any details on how oesophagus is to be regenerated and vascularised, and why they think it is more feasible than trachea. On 7 November 2017, UCL answered my FOIA inquiry in this manner:
“The transplantation techniques used for the trachea procedures are outlined in the following academic papers:
https://www.ncbi.nlm.nih.gov/pubmed/22841419 – Please see the Methods section [Ciaran’s case, -LS].
http://onlinelibrary.wiley.com/doi/10.1002/sctm.16-0443/full – Please see the Materials and Methods section [Shauna’s case, -LS].
The two trachea processes and the proposed oesophageal process are quite different. The oesophagus is a much more complex organ to engineer than the trachea and it will require multiple different cells.
The product is intended to bridge the 2-4cm gap as needed for those patients with severe long-gap oesophageal atresia, a rare congenital malformation in which it is not possible to overcome the defect by simple anastomosis.
In a future clinical trial, the research team plan to isolate the different cell populations required to produce a complete oesophagus using a biopsy of the patient. The cell populations would be expanded in culture and seeded onto a donor cadaveric scaffold. This would be produced from a donor oesophagus which has been through a process of decellularisation to remove all donor cells. The decellularised scaffold would be seeded with cells and grown in the laboratory under GMP conditions to create a complete functional graft prior to transplantation into the patient.
In this way a graft would be produced which closely resembles the original tissue and is made of the patient’s own cells. This should reduce the chances of rejection and improve long-term graft survival.
Specifically, the plan is to produce the new oesophagus from a decellularised porcine oesophagus construct because of the difficulty to obtain a matched human oesophagus for transplantation. The porcine oesophagus, stripped out of all cells, would be recellularised with autologous human epithelial cells on the luminal surface and autologous human mesangioblasts, differentiated to smooth muscle cells, on the extraluminal surface. The construct would be implanted for vascularisation and cell maturation, then anastomosed to the ends of the existing oesophagus.
As indicated above, further laboratory research will define any refinements needed before human transplantation”.
You might notice that even under FOIA, UCL refused to give any insights as to which kind of cells they intend to use to regenerate oesophagus. When I complained, UCL replied that they were not supposed to answer me in such detail. If you think they wanted to protect the method as proprietary: not really. Because right at around that time when UCL wrote to me to deny revealing any details about the technology, they sat down with a trustworthy Guardian journalist Hannah Devlin, showed and explained her everything. The result came on 5 December 2017, it was a Guardian fairy tale story where Devlin was celebrating De Coppi’s true genius of organ making as a pleasant antidote to that horrid Macchiarini:
“De Coppi takes me on a swift tour of the research department he leads at University College London. At one point, as we zoom down a corridor, he opens what looks like a broom cupboard, revealing instead a small walk-in fridge lined with shelves loaded with tiny organs. “This is a decellurised rat liver,” he says, picking up a jar with what looks like a small, translucent ball of mozzarella floating within. “This one’s an intestine.” Bladder, kidney, cartilage and lung tissue are being grown elsewhere in the building, he says.
He describes the protocol for creating a new oesophagus. The decellurised scaffold is basted in patient stem cells, called mesoangioblasts, that are found around blood vessels. “Normally, when there is an injury these cells can migrate and proliferate to regenerate new muscle fibres,” De Coppi says.
When placed in a bioreactor – a jar that has nutrients pumped in one end and waste products sucked out the other – these cells begin to form a tube of smooth muscle. This is then placed under the skin of the stomach and blood vessels automatically begin to vascularise it.
Meanwhile, outside the body, a second set of stem cells taken from the gullet will be cultured into thin sheets that are wrapped around a dissolvable polymer scaffold to make the organ’s epithelium lining.”
The epithelial polymer sheet? Same method Birchall plans to use for his trachea transplants. Implanting the graft heterotopically, in a different part of the body first to expect vascularisation? Ditto.
The exactly next day after Devlin’s article in The Guardian appeared, on 6 December 2017, UCL finally answered my request for “A statement how exactly the regeneration technology differs from that used by Dr De Coppi for trachea transplant patients Ciaran Lynch and Shauna Davison”. This was what UCL said:
“The 3 processes are quite different. In particular the oesophagus is a much
more complex organ to engineer than the trachea. Moreover, some final steps
necessary before human transplantation will be defined by the next set of
The transplant performed on the first patient receiving the tissue engineered
trachea [Ciaran, -LS] was performed using the following protocol:
• Bone marrow mononuclear cells were taken directly from the patient
and added to the cadaveric donor trachea after decellularization in the
laboratory before transplantation. […]
The transplant performed on the second patient was performed using a
protocol; of which the specific details have not been released in to the public
Also here UCL refused to give any details, hiding behind privacy of “sensitive personal data” even if by then both cases were published, with a full experimental methods section, UCL even sent me the links in the previous reply. This secrecy about the experimental details was nothing but trolling now. So what about the oesophagus, why should it regenerate where tracheas failed? There, UCL simply resend me their previous statement quoted above. Which is basically more of their trolling, if you compared what details they had Devlin publish in Guardian.
Basically, just like Birchall was toying with the idea of vascularising decellurised larynges and trachea by implanting them into the neck or other skeletal muscle (even that apparently didn’t work too well to pursue properly), De Coppi plans to stuff the decellurised oesophagus into the stomach and expect it to vascularise and come to life. UCL chose not to explain the differences between trachea and oesophagus vascularisation techniques because there are basically none, except for the choice of place. Vascularisation of oesophagus is bound to happen because it is a more complex organ than trachea. This is how UCL does clinical research.
The amount of funding money De Coppi alone brought GOSH and UCL with his regenerative medicine ambitions is just mind boggling. There were £3 million from the Oak Foundation, Catapult Cell Therapy, and UK Stem Cell Foundation to develop a regmed oesophagus. UK National Institute of Health Research (NIHR) gave De Coppi £2 million for that clinical trial with engineered oesophagus on 10 babies which didn’t happen. Instead, pigs are now going to be experimented upon, paid by UCL from own pocket, because NIHR does not pay for preclinical studies.
This is why De Coppi was given by UCL, from their own pocket, £75k to experiment on pigs. The project had no start date as of January 2018 and was scheduled to take 1 year. This is an official lay summary of his porcine oesophagus replacement project, as provided by UCL under FOIA:
“Oesophageal atresia (OA) is a rare congenital condition in which the oesophagus ends in a blind-ended pouch as opposed to joining normally with the stomach. This malformation occurs in approximately 1 in 4,000 births in the UK and requires invasive surgical intervention. These surgeries often result in major complications including anastomotic strictures and leaks, gastric/colonic emptying problems, gastro-oesophageal reflux and respiratory issues. Our project aims at creating a functional tissue engineering graft that could substitute these major surgeries, to provide a valuable alternative for the treatment of OA. To reach this target we are developing a bioengineered product based on a size-matched acellular oesophageal scaffold seeded with primary autologous patient cells. After seeding, the constructs are positioned into a dynamic culture bioreactor that allows and promotes cell distribution and differentiation. Assessing these parameters will be a fundamental requirement to proceed towards the clinical translation of our product. For this reason, after a consultation with the MHRA, we propose here a large-animal study in which we will utilise the mini-pig as recipients of our constructs. This species share anatomical and physiological similarities with humans. In addition, it will allow us to use constructs that matches the size of our final product. The set of data generated with this large-animal study, will give us a better understanding on the applicability of our strategy. “
Maybe oesophagus needs some marinading before it can be used on humans. What about other products of De Coppi’s organ factory at UCL?
From the opposite end of gastrointestinal tract, €1.3 mn were given to UCL alone (of €7.1 mn total) with the EU funded project INTENS which promises to deliver lab-grown lower intestine. That project “is designed to lead directly to a clinical trial for the application of the optimal protocol for tissue-engineered intestine“, only that even EU Commission prefers not to talk about that goal. In late 2015, when everyone was still pitying Macchiarini as a victim of slanderous accusations, and celebrating his UCL partners as true visionary life-saving geniuses of regenerative medicine, De Coppi got that €7.1 million grant under Horizon 2020. INTENS started in January 2016 and is set to deliver
“functional intestine for transplantation and engaging with patients, scientists and public. The work is designed to lead directly to a clinical trial for the application of the optimal protocol for tissue-engineered intestine”
The INTENS project’s website declares:
“The output of the INTENS project will provide the foundations of the post project activities to achieve GMP production and conduct a clinical trial. During the entire project (WP6-7), we will also continue to engage with patients associations, their families, and the European Medicines Agency (EMA) to promote our research and prepare the regulatory requirements to make the basis for the subsequent clinical trial”.
The Work package 5, the clinical transplantations, are meant to take place at UCL and at Children’s Hospital Los Angeles (CHLA) in USA. Other partners at INTENS are the star of intestinal stem cell research Hans Clevers, head of Hubrecht Institute for Developmental Biology and Stem Cell Research in Utrecht, Netherlands, and Kim Jensen of University of Copenhagen/BRIC, plus several others, including a stem cell culture product company.
“We regret to inform you that the Commission does not hold any documents that would
correspond to the description provided in your application.
The Horizon 2020 project INTENS (INtestinal Tissue ENgineering Solution) does not have any deliverables related to clinical trials on patients under Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC.”
After I reminded them that the project description explicitly makes reference of clinical trials, I received this new reply on 20 November 2018. It basically declares that a clinical trial is only a theoretical possibility:
“the description of the work programme of the Intestinal Tissue Engineering Solution project, available on the website to which you refer in your confirmatory application (see footnote 5), clearly provides that ‘The project will first optimize the derivation, culture and differentiation of cells and seed on decellularised
scaffolds or synthetic polymers and maintained in bioreactors (WP1-3)’. It is underlined in
the programme of the project that only ‘Once established, the project will focus on in vivo
testing in animal models (WP4-5)’. The output of the the Intestinal Tissue Engineering
Solution project ‘will provide the foundations of the post project activities to achieve
G[ood] M[anufacturing ] P[ractices] production and conduct a clinical trial. During the
entire project (WP6-7), we will also continue to engage with patients’ associations, their
families, and the European Medicines Agency to promote our research and prepare the
regulatory requirements to make the basis for the subsequent clinical trial.”’
Consequently, no clinical trials are envisaged in the grant agreement of the Intestinal Tissue
Engineering Solution project and therefore the European Commission does not hold any
related documents concerning ‘ethical approvals for clinical trials on patients’, ‘approvals
issued by E[uropean] M[edicines] A[gency]’, ‘recruiting clinical trials’ or ‘transplantations
already performed’ under Regulation 536/2014.
As mentioned above, the Intestinal Tissue Engineering Solution project is currently focused
on in vivo testing in animal models. The deliverables of work package 5, “Transplantation of engineered intestine”, are research analysis of TEI in mice, outcome and function of TEI in piglets and outcome and function of TEI in short bowel syndrome piglets.
The results of this research, with the other envisaged project results, will provide the
foundations for the future clinical trial projects. “
Oesophagus gone nowhere, intestine got tangled, and don’t mention trachea. Unless you wish to talk about Ciaran, the lucky survivor? Professor De Coppi can always tell you about Ciaran, and take you for a spin in his organ factory. Especially if you bring funding money, are with The Guardian, or a concerned parent interested to explore the possibilities of “compassionate use”.
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