Surgeon Paolo Macchiarini, who is under investigation for allegedly downplaying dangers of an experimental surgery, has been cleared of some misconduct allegations by the Karolinska Institutet in Stockholm.
Macchiarini, a thoracic surgeon, has made headlines for repairing damaged airways using tracheas from cadavers and even synthetic tracheas, both treated with the patients’ own stem cells to assist in the transplant.
In a letter to Vice-Chancellor Anders Hamsten dated last month, KI’s Ethics Council refuted a number of accusations leveled against Macchiarini by Pierre Delaere at KU Leuven in Belgium, who had suggested the surgeon had engaged in scientific misconduct, including fabricating data.
The Ethics Council, however, disagreed:
The Ethics Council’s general conclusion is that apart from the clinical outcome of the transplanted patients – whose medical records we have not examined and which are being examined in another investigation – we find that the issues raised by Professor Delaere are of a philosophy-of-science kind rather than of a research-ethical kind. Accordingly, the Ethics Council concludes that, on the backdrop of the examined issues, Professor Delaere’s allegations of scientific misconduct are unfounded.
You can read the entire statement here. Delaere also suggested The Lancet, which published the first paper describing the synthetic trachea transplant, had issues with its peer review. The Ethics Council refuted that accusation, as well.
Professor Macchiarini has allowed the Ethics Council to see the correspondence between the authors and The Lancet. The Ethics Council can confirm that the paper was critically reviewed by four reviewers in The Lancet. The authors revised the paper in accordance with the reviewers’ comments. We have also seen the changes made in the original version. The Ethics Council’s conclusion is that the review process has been correct.
Macchiarini told us he was pleased with the outcome:
As I have emphatically stated all along that the allegations from Dr. Delaere are unfounded, I am pleased that the Ethics Council has now also affirmed their lack of substance.
Delaere also received a letter from Hamsten saying the Vice-Chancellor will uphold the Ethics Council’s conclusion, a decision taken “in the presence of University Director Per Bengtsson.”
Delaere is not happy with the Ethics Council’s decision:
I am stunned about such outright injustice.
Macchiarini has also been accused of failing to obtain proper consent from patients before performing the experimental procedures, as well as downplaying the dangers of the surgery, including minimizing the complications. In filing documents to support these accusations, doctors revealed information about the patients who underwent the procedure; the Karolinska hospital has now filed a complaint with the police against the unnamed person who passed these documents onto “an English-language blog on research fraud and retracted scientific papers,” which we believe is us (based on our translation of the link in Swedish).
Update 1:50 p.m. eastern 4/16/15: Claes Keisu, press officer at Karolinska, told us that the Swedish version of the decision by the Ethics Council included information about conflicts of interest among council members, which was left out of the English version. We have uploaded the new version. Here is the additional text:
In the discussion of and decision on the matter, the following members of the Ethics Council participated: Gert Helgesson, Marie Arsenian-Henriksson, Göran Lambertz, Patricia De Palma, Nina Rehnqvist och Niels Lynöe. The other members, Anders Ekbom, Ola Hermanson and Annika Tibell have a conflict of interest and therefore did not participate in the discussion or decision.
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Hooray! Hopefully, Dr. Macchiarini can now get back to his important work. Professor Delaere needs to accept the outcome of this investigation. Outright injustice? Not hardly.
I’m really happy of this official statement of the Karolinska.
I’ve never had any doubt about the work of prof. Macchiarini.
I note that Delaere is a competitor of prof. Macchiarini.
It is hard for most people to track the references in Swedish, there is in particular some interesting information in Läkartidningen (the bulletin of the Swedish Medical Association), which seems to indicate that the story indeed is rather thorny and may originate in competition. One additional clarification: the police complaint concerns that fact that some of the documents posted earlier here are Swedish medical records, leaked to reporters without the consent of the patients.
One of the members of the ethics council (on the present web site) is a co-author on a contested 2011 Macchiarini paper. It would be nice to confirm that this person was not involved in the report of that council on this case.
I was of course not involved in this or any of the investigations or decisions of the Ethics council concerning PM since I am a co-author on the Lancet ms. Two additional members of the Ethics council were also not participating in this or any investigation or decision. This is clearly stated in the original document in Swedish but is missing in this earlier version of the translation. It has now been corrected and will be provided to RetractionWatch.com.
Am I wrong in thinking that the whole Ethics Council has a conflict of interest, given that potential negative outcome of the investigation would damage the University’s reputation? Should’t the investigation be independent?
Dario, according to the Karolinska document, Delaere’s allegations are actually personal hypotheses rather than objective findings. Prof. Delaere affirm that trachea engineering with stem cells is “Impossible”. But Claudia Castillo, who received the first artificial trachea in June 2008, is still alive and in good condition. And Ciaran Finn-Lynch, the second transplanted patient, is alive and in very good condition, five years after surgery http://www.ukspa.org.uk/blog/14/10/life-saving-stem-cell-medicine-liverpool-science-park
Does anyone believe that it is possible to live for years with a trachea without mucosa or any blood supply?
Chiara, thanks for your reply. Nice to hear that those people are well. But what do you actually think about my question?
Since the Ethic Council has made its conclusions public, I think that any undue favor to prof. Macchiarini would damage the University’s reputation much more than fire a visiting professor claiming that he acted without following the internal rules.
Castillo isn’t doing well either.
Castillo needs her left part of the lung removed: https://forbetterscience.wordpress.com/2016/05/07/macchiarinis-patients-the-real-situation/
The reason why these 2 patients are still in ‘good condition,’ I believe, is because of a stent, a synthetic tube that keeps the airway open. The stent was in place from the very beginning. Until now, devoted doctors have succeeded in treating the complications, which are typically linked with an airway stent. This has nothing to do with tissue engineering or regeneration. What would be the reason Prof. Macchiarini has “moved forward” and no longer works on tracheae (http://news.sciencemag.org/people-events/2015/04/artificial-trachea-pioneer-cleared-first-two-misconduct-cases)?
Dear Prof. Delaere,
Claudia Castillo, actually, has been reported to have a stenosis (requiring stent) a cicatricial stenosis of the native trachea (not of the transplanted one) near the anastomosis (non such a rare event in surgery, I presume) http://www.ncbi.nlm.nih.gov/pubmed/24161821
Ciaran received the transplant after failure of mechanical stents, and required a support to the transplanted trachea for 18 months, according to the two years follow-up report. http://www.ncbi.nlm.nih.gov/pubmed/22841419.
This is sharp contrast with your statement “The sad truth for the synthetic trachea is that implantation inside the airway will always lead to the death of the patient in the short or mid-term. Patients die due to anastomotic breakdown, which becomes visible within a couple of months after surgery.”
Moreover, I’ ve been in touch with the relatives of three more transplanted patient (two had been operated on in July 2010; the last one was the child operated in April 2013 and died 3 months later). One -a girl with a cancer- died one year later of metastases, the other one operated in 2010, was in good condition after 3 years; the last one (Hannah Warren, born with complete trachea agenesia) died after a second surgery to fix her esophagus (since birth, she had been ventilated trough an esophagus fistula, and the oesophagus-sthomach connection).
Actually, overall survival in cancer patients (as most of Macchiarini’s were) depends not only on surgical outcome, but on much more variables, including metastases and infections in immunocompromised patients.
Do you have any proof that the patients dead after the trachea transplant died of surgery failure?
Dear Prof Delaere,
Do you also doubt the many publication where similar methods have been used (transplantation of decellularized tissue) to for example repair tendons, skeletal muscle, abdominal wall, esophagus etc?
Do you also doubt Prof Badylaks publication from 2011, where part of the upper gastrointestinal tract was replaced by decellularized tissue in patients?
Or are you just focusing on doubting the work of Prof Macchiarini?
Best regards,
Matthias
Dear Matthias. This is not the forum to evaluate the entire field of tissue-engineering. The sad truth for the synthetic trachea is that implantation inside the airway will always lead to the death of the patient in the short or mid-term. Patients die due to anastomotic breakdown, which becomes visible within a couple of months after surgery. Moreover, although most people are willing to believe anything as soon they hear the term ‘stem cells’, transformation of a synthetic or de-cellularized trachea into a vital structure that is built up by living cells is theoretically impossible. Indeed, no experimental evidence for such a miraculous transformation is available.
For more information on involved patients please visit: http://retractionwatch.com/2014/12/12/revealed-complaint-lodged-macchiarini-super-surgeon-investigation/
Dear Prof Delaere,
Thank you for your reply. As I am myself involved in tissue engineering but for skin replacement rather than internal organs I am very interested in the current topic.
I would love to understand why you think that it is “theoretically impossible” that a synthetic or decellularized tracheal graft can become revascularized and repopulated with cells. New blood vessel form throughout life and in almost all tissues, in health and in disease. Most cells are constantly being replaced, as is the extracellular matrix. Why could not this happen in a transplanted “scaffold”?
Although you don’t want to draw parallels to other studies, fact is that other organs have been repaired in the same way, with new blood vessels growing into the scaffold and as well repopularization with cells. Famous examples are Atala’s work with urinary bladder and more recently vaginal replacements.
Please don’t take this as criticism; I just want to understand your expert opinion.
Thank you for the link. I have already been following the cases closely. One important question: why did neither Grinnemo, Corbascio nor Simonson object or report any irregularities that they now claim, when the articles were written or submitted? They were co-authors on several papers that they now report. Why wait, in some cases years to report?
I also note that they filed the complaints in very close temporal relation to when Grinnemo was reported from Macchiarinis side, for ethical breach regarding a grant application.
Best regards,
Matthias
Dear Matthias
-Why is tissue engineering of a trachea not possible? Please visit: http://www.jtcvsonline.org/article/S0022-5223(13)01519-5/pdf.
-Your other queries are currently under investigation by Karolinska Institute. The President’s conclusion is expected soon.
Here is the reply of prof. Macchiarini:
http://www.jtcvsonline.org/article/S0022-5223(14)00331-6/fulltext
Dear Prof Delaere,
I have read your article previously and although it summarizes your views I think some statements should be reconsidered.
Tissue engineering, in most applications, rely on in growth of new blood vessels and re-population of the scaffold in vivo. There are numerous publications where this has been shown and I find the following quote very angled and incorrect; “No example of successful prosthetic repair can be cited in the respiratory, gastrointestinal, or genitourinary tract. ”
Again, what about the research from Atala and Badylak, on genitourinary and gastrointestinal tract respectively? And how could products based on ECM (for example SurgiSIS) be approved by FDA, and commercially available, if they could never lead to a successful tissue regeneration? I can give you a list of 40+ papers where scaffolds have been revascularized and repopulated with cells. Surely, you cannot believe that all these are fabricated?
And if your aim is to prove that Macchiarini’s method, and the two papers from 2008 and 2011 are “theoretically impossible”, it is a bit questionable to reference a paper from 2002 to support your opinion:
”
In recent years, most synthetic materials used for tracheal
replacement have been tested in experimental animal
research. From these studies, it became clear that
definitive prosthetic replacement of the airway wall is not
possible.
”
Referencing: Grillo et al 2002.
And to call 2002 “in recent years” in 2014 is again questionable, especially considering the research fields fast progress.
– Matthias
What about esophagus? Do the same problems should emerge with the esophagus or not?
However, Macchiarini has provided the proofs of the regeneration of epithelial and muscle-like cells starting from mesenchimal stem cells.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354271/pdf/ncomms4562.pdf
Why this should be considered “IMPOSSIBLE” for trachea?
<
Indeed Chiara, another harmful consequence is that many researchers working in the field of ‘trachea repair’ and ‘tissue engineering’ are being misguided. Based on the so-called success of tissue engineering of the windpipe, unrealistic expectations are being created about the feasibility of producing other organs. In fact, it has been announced that the next step in this evolution will be tissue engineering of other hollow organs such as the gullet. As if ‘on demand’, in March 2014 a publication appeared in the journal ‘Nature Communications’ describing the regeneration of the esophagus in rats. All the remarks made on trachea regeneration apply here as well.
to pierre delaere,
In your own work, can you say whether your “clinical experiments” in humans are only based on 1 publication (delaere et al. Arch Otolaryngol Head Neck Surg.) from 1996…an experimental study in “rabbits”…that (and this is most remarkable) demonstrated that under no circumstances the immunosuppressive medication should be withdraw after transplanting the trachea (following your concept).
nearly 10 years later your group transplanted tracheae in patients, following the exact same protocol of the rabbit study (1996) with one significant protocol modification: you withdraw the immunosuppression after transplantation. how is this possible without any further animal experiments?
Can you report about the follow-up of your first transplanted patient in your most recent publication Delaere et al.: Learning curve in tracheal allotransplantation. Am J Transplant. 2012?-
why do you only provide technical drawings of your clinical findings?
Dear Anders,
In case you are interested in the most recent information on the vascularized tracheal allotransplant and how immunosuppressive medication can be stopped (New Engl J Med, 2014):
http://www.nejm.org/doi/full/10.1056/NEJMc1315273
dear pierre delaere,
I asked how you can perform such transplantation with animal data showing the opposite. Besides, your article does not provide any data of the first transplanted patient but technical drawings of the other patients.
Final reply to Anders Jacobsson :
1. The experimental and clinical data on vascularized tracheal allotransplants are NOT in contradiction. This is described in detail in the book:
‘Replacement and Transplantation of the Larynx and Trachea’ Pierre Delaere, LannooCampus, Leuven, 2013.
2. First patient: until today, patient and transplant are excellent. See also:
-New Engl J Med 2010;362:138-145.
-Am J Transpl 2012;12:2538-2545. Supporting information Figure S1.
dear pierre delaere,
1) I do not think you have any supportive data for changing the protocol. your detailed description is YOUR OWN book..without any peer reviewing process or other higher authority (than you as the editor and a professor of art, namely Nick Ervinck)…and, again the book does not provide any evidenced or (at least) experimental data that support the changes of your clinical concept.
2) Again, why do you not provide data of the first transplanted patient in you most RECENT article (aside from technical drawings)
Professor Delaere:
This conversation was years ago, and you might not ever see this. But if by some chance you do, please know that, as someone who first heard about Macchiarini in early 2016 and is still shocked and horrified by what transpired, I believe you are a hero. I’m disgusted by the way you (and others) were treated during all of this. I hope you are happy and well today, and I both admire you and thank you for standing up–and refusing to sit back down.
The second investigation has found prof. Macchiarini guilty. (Article in Swedish)
http://www.svd.se/nyheter/inrikes/utredare-ki-kirurgen-fuskade-i-forskningen_4573664.svd