Guest post medicine Research integrity University Affairs

Karolinska’s haunted leadership

Johan Thyberg discusses the Macchiarini affair in the context of ethical shortcomings of Karolinska's own leadership.

If the Karolinska Institutet (KI) was just some provincial hospital up in the Swedish north, their excessive intrigues, affairs, harassment, racism, fraud, embezzlement, cover-ups and lies would be shrugged off and ignored by the international community. Yet KI is one of the world’s most important biomedical universities and a major clinical research centre, the biggest in Sweden. On top of everything, KI issues the Nobel Prize in Physiology or Medicine, this probably made the case of deadly surgeon and pathological liar Paolo Macchiarini such an international scandal. The following guest post by KI emeritus professor and now a biomedical ethics activist, Johan Thyberg, lets one wonder if KI and its university hospital can really continue as they do.

Nobody looks too good in the Macchiarini affair, especially after KI decided to accuse the whistleblowers of research misconduct while protecting those really guilty parties, the KI senior staff who supported the Italian stem cell enthusiast and tried to hush up the affair. The university hospital CEO Melvin Samsom evaded his responsibility masterfully, but he eventually stepped down due to catastrophic misspending of public funds. Another top official involved, the former KI Vice-Rector Karin Dahlman-Wright, recently had to resign after having been found guilty of research misconduct herself.

Macchiarini’s data fakery was not misconduct

The irony is that Dahlman-Wright was previously absolving others of all suspicions of research misconduct, for exactly the same kind of data manipulations found in her own papers. Including Macchiarini and his right-hand man Philipp Jungebluth, before both were sacked and found guilty of research fraud. A Swedish criminal investigation into Macchiarini affair is still ongoing, although so far one person has been sentenced in the court of law in Germany, in connection with the Macchiarini-Jungebluth scandal: Leonid Schneider, yours truly.

In 2016, first evidence of image data manipulations was reported for Macchiarini papers on PubPeer, KI was notified. Also I reported a list of evidence, posted by a reader as comments on my site. Dahlman-Wright, the interim rector of KI, investigated two papers, Ajalloueian et al Biomaterials 2014 and Jungebluth et al Biomaterials 2013. No research misconduct was found. The two papers were later retracted for fraud, although not for data manipulation but because they advertised plastic trachea grafts, a deadly tool which slowly and painfully killed all patients.

The full KI report from 2016 is available here.

KI Interim-President Karin Dahlman-Wright requested on 18 March 2016 an opinion from the Expert Group for scientific misconduct at the Swedish Central Ethics Review Board (CEPN), which provided its assessment on 14 September 2016:

” Compare fig 7D of this paper to fig 3C of Jungebluth et al, Biomaterials 2013

“The expert group also stated that it lacked possibilities to investigate whether a confusion of the images occurred because of negligence, as Paolo Macchiarini claims, or whether it was deliberate. The expert group considered that serious criticism must be directed at the error, but that it cannot be considered as dishonesty in research. However, the Expert Group considered that Paolo Macchiarini deliberately mislead the Karolinska Institutet by explicitly stating that he had sent a request for correction to the journal, which, according to the Expert group, had not occurred, and that this is to be regarded as research misconduct.”

Macchiarini kept lying about having requested a correction, while the Elsevier journal Biomaterials refused communication with KI:

“…on 16 February, 2016 the Expert Group received a message from Paolo Macchiarini where a file was attached which could not be opened. Paolo Macchiarini has stated that this file contained such information that the Expert Group’s opinion on deliberate deception is not correct. KI contacted Biomaterials at the latest in December 2016 to try to get clarity on the issue, but without getting any response from the journal”.

Dahlman-Wright then closed the case without any findings of any misconduct or even negligence, because image duplications can happen to everyone, and there was no reason at all to question Macchiarini’s honesty:

“KI believes that Paolo Macchiarini as the principal author deserves criticism for the mistake regarding the false images but that the matter in that part can not be investigated further as it can not clear what was included or not included in the file sent to the journal. It is clear, however, that the lead author Paolo Macchiarini, with the support of co-authors, has admitted mistakes and confusion and has sent to KI supporting documents for the article correction. KI intends to send this material to the journal. The investigation is thus concluded in this part”. 

Now, Johan Thyberg’s opinion piece on this whole affair. All hyperlinks and illustrations are mine.

Screenshot Sljukhusläraren

The Macchiarini affair continues to haunt Karolinska Institutet and its leadership

By Johan Thyberg

The scandal around the recruitment of the surgeon Paolo Macchiarini to Karolinska Institutet (KI) and the Karolinska University Hospital (KUH) has pressed the leadership of these institutions for more than ten years. It all started in August/September 2009 when KI’s Vice-Chancellor Harriet Wallberg met Macchiarini on a conference in Gothenburg. This led to that Macchiarini about a year later was employed as guest professor at KI and chief physician at KUH in spite of serious warnings from his earlier superiors in Hannover, Barcelona and Florence.

Another half year later the first transplantation of an artificial trachea was carried out, the first in a series of four on three patients. A few months later, this first operation was reported in a scientific article in the journal The Lancet and described as a success. The truth, in this case, as in those to follow, should however turn out to be something completely different. This was realized by four colleagues of Macchiarini who carefully went through a number of articles in which the operations were described and compared what was stated there with what appeared in the medical records.

In order to make a long story short, this led to that the so-called “whistle blowers” in 2014 submitted two reports to KI about suspected misconduct in research, one in June concerning an article on transplantation of esophagus in rats and one in August concerning six articles on transplantation of an artificial trachea in humans. Last and main author of all articles was Macchiarini. Obviously, the most serious of these reports was the second one concerning human interventions: (1) without ethical consent; (2) without necessary permissions from the Swedish Medical Products Agency; (3) without prior animal testing; and (4) using substances which, according to the manufacturer, must not be used on either humans or animals.

What happened next can be regarded as an unparalleled process of silence and denial. When the first account regarding an article on rat experiments was received, KI’s newly appointed Vice-Chancellor Anders Hamsten immediately sent it to Macchiarini for comments. However, when the second report regarding six articles on human trials were submitted two months later, nothing happened for a long time. What surprised the whistle blowers at the time was that they heard nothing from KI about how the misconduct allegations were handled. On the contrary, they were threatened by the hospital management with dismissal for alleged illegal entry into medical records, a charge they later were completely cleared from. And this was just the start of the harassments they were about to meet from KI and KUH.

Whistleblowers Matthias Corbascio, Oscar Simonson, Thomas Fux and Karl-Henrik Grinnemo. (Courtesy Grinnemo, for Leap magazine)

In Sweden, a university that receives a report of misconduct is under the law required to investigate the suspicions. After three months of reflection, and on the day after The New York Times published an article on the case, KI’s Vice-Chancellor Anders Hamsten finally decided to appoint an external investigator. This was done in a written account stating that he had received a report of suspected misconduct in research in an article regarding transplantation of esophagus in rats. With respect to the considerably more extensive and serious notification concerning six articles about the transplantation of an artificial trachea in humans, the only thing that is said is the following: “The report was supplemented in August 2014 with further documents“. Thereafter, it is stated that Professor Emeritus Bengt Gerdin is assigned as external reviewer with the task to “review the article and on the basis of other documents in the case assess whether there has been any misconduct”. This way of hiding the most important of the two reports is almost unbelievable. However, it would turn out to be just the beginning of an attempt to cover up a scandal.

In May 2015, Gerdin submits his statement, stating that all seven articles reviewed contain parts that are characterized by misconduct. Another three months later, the Vice-Chancellor Anders Hamsten announces his decision. Referring to comments made primarily by Macchiarini himself (never shown to Gerdin), he concludes that Macchiarini “has shown negligence” but “did not commit misconduct in research”. Perhaps, he believed that an unpleasant matter in this way could be swept under the carpet. However, this in no way turned out to be the case.

Of course, the external reviewer Bengt Gerdin could not be anything but surprised at the decision. He requested access to the material Macchiarini and others had submitted in response to his verdict and in December 2015 he wrote a ten-page letter to Hamsten. This concludes as follows:

“Sorry to have to say it, but nothing has emerged that has changed my view on the matter. Thus, there has been dishonesty in writing the essays, which I show by highlighting some undeniable facts; facts that are so unmistakable that I cannot understand how it is possible to maneuver around them with preserved credibility”.

This letter must have been highly embarrassing for Hamsten to receive, but that was only the beginning of what was to come. In January 2015, I had personally informed the managing editor of the program Dokument Inifrån at the Swedish Television (SVT) about the Macchiarini case and also continued to provide them with plenty of information. Under the direction of the reporter and producer Bosse Lindquist, they made an in-depth digging work that in the beginning of 2016 resulted in a three-part documentary under the name Experimenten. This became a bit of a bomb and the programs eventually spread to many countries. The result for KI’s part can hardly be described as anything but devastating.

Anders Hamsten now seems to have realized how troublesome his position was and in a debate article in the large daily journal Dagens Nyheter on February 13, 2016 he declared that “I myself have made a near total misjudgment of Paolo Macchiarini and KI should have separated from him far earlier“. He also says that his decision in the misconduct case was wrong and that the case must be addressed again. At the end of this confession it is announced that he makes his position as Vice-Chancellor of KI available.

The person who was now appointed to step in as temporary Vice-Chancellor and, among others, take over the handling of the Macchiarini case was the Vice Rector Karin Dahlman-Wright. One of her first actions was to refer the two reports regarding Macchiarini to the Expert Group on misconduct issues at the Central Ethics Review Board (CEPN), citing new circumstances. The four whistle blowers objected to this, claiming that all the facts needed were in the original reports, as also confirmed in Bengt Gerdin’s review. In their opinion, this would only lead to a delay in the final decision and make it difficult to put an end to possible interventions of a similar kind in different parts of the world. In parallel, there had now been an anonymous third complaint against Macchiarini regarding incorrect images in an article in the journal Biomaterials. This report was also forwarded by Dahlman-Wright to CEPN for review.

Image duplications in Ajalloueian et al Biomaterials 2013

At the beginning of September 2016, CEPN issued a statement regarding the article on transplantation of rat esophagus. It is there concluded that “the presentation of the results in the article does not correspond to the outcome of the research conducted which is scientific misconduct”. On December 20 the same year, Dahlman-Wright decides in accordance with this assessment that there is misconduct and blames it on Paolo Macchiarini and three co-authors. Thus, the earlier acquittal decision was now annulled. On the same day, KI also wrote to the journal and requested that the article be withdrawn.

The ruling of CEPN regarding the major notification against six articles dealing with the transplantation of an artificial trachea in humans was delayed until October 2017. Again, the Expert Group together with two external experts concluded that “all six articles contain information that constitutes misconduct in research“. It was further considered that all authors of the articles should be considered as guilty and that all six articles should be retracted. At this time, a new Vice-Chancellor had taken over at KI, Ole Petter Ottersen. It was now he who came to make decisions on the matter. However, this was delayed until June 25, 2018. In accordance with the original report from the whistle blowers as well as Bengt Gerdin’s and CEPN’s assessments, it is concluded that all six articles contain examples of misconduct. The main responsibility for this is laid on Paolo Macchiarini and his closest associate, Philipp Jungebluth. A further five authors are convicted of misconduct, among them one of the whistle blowers. None of these five were members of Macchiarini’s research group but had been brought in either as surgeons to assist in the procedures or as specialists with methodological knowledge to be used in the projects. In addition, a larger number of co-authors were judged as “blameworthy”, a new concept in these contexts.

In most of the comments that came after this decision, it was considered well justified that Macchiarini and Jungebluth were declared responsible for all six articles. On the other hand, many reacted to the judgments directed to a large number of co-authors with limited insight into the work as a whole, and not least in the contents of the medical records (covered with confidentiality). In particular, it was considered questionable that three of the whistle blowers were convicted, one for scientific misconduct and two for being blameworthy.

With regard to the third, anonymous notification against Macchiarini and others regarding image manipulation, an opinion from CEPN came in September 2016. The conclusion was that there were several examples of misconduct. It then took until June 2017 before Dahlman-Wright, as deputy Vice-Chancellor, decided on the matter. After hearing the view of the authors on CEPN’s opinion, she concluded that no dishonesty had occurred. The question is, however, if she was the right person to handle a case like this.

Thus, a circumstance that has recently redirected attention to KI’s handling of the Macchiarini case is the investigation of suspected misconduct in research initiated in July 2018 after three reports on image manipulations in ten articles with Karin Dahlman-Wright as the main author or as a co-author. One of the accounts also highlighted an older article with KI’s current Vice-Chancellor Ole Petter Ottersen as co-author.

Jia et al Cancer Research 2013. First author and Dahlman -Wright found guilty of research misconduct here.

With regard to the reports regarding the Vice Rector Karin Dahlman-Wright, KI considered it inappropriate to allow the Vice-Chancellor Ole Petter Ottersen to be responsible for investigating his closest associate in the management of the institute. KI’s Chairman of the Board Mikael Odenberg therefore contacted his colleague at the University of Gothenburg (GU). This led to an agreement between the rectors of the two universities according to which GU on behalf of KI would investigate the complaints against Dahlman-Wright in order to ensure an impartial and objective assessment. On request from one of the whistle blowers, GU asked the Expert Group at CEPN for help in the investigation and they hired Professor Nils Billestrup in Copenhagen as an expert.

Billestrup submitted his report on March 8, 2019. There he stated that in three out of eight articles reviewed, image manipulations were found but were not considered to affect the conclusions made. However, the errors were considered as a sign of inadequate processing of data and lack of quality control in both the analysis of results and in the publication process. In two other articles, the authors admitted image manipulations and, according to the investigator, these could influence the interpretation of the results. In still another article, the authors denied that manipulations had occurred which, however, the investigator considered to be the case.

When the Expert Group then dealt with the case, it was concluded that “even if serious criticism should be directed at several of the errors and mistakes that afflict the articles, it cannot be considered clear that the deficiencies are of the kind that they constitute misconduct in research“. However, the decision was not unanimous and two of seven members, including the chairman, considered that there was misconduct in three of the articles.

When this ruling was passed on to the Misconduct Council at GU, it was again modified. In its statement to KI on September 5, 2019, they conclude that in four out of ten articles reviewed there is no misconduct. In six of the articles, on the other hand, errors were considered and in two of these they were classified as misconduct. In one of these articles, Karin-Dahlman-Wright is regarded as responsible in her capacity of communicating author and in the other article, professor Jan-Åke Gustafsson is held accountable for the same reason. Four days after this report was received, and although a definitive decision on the matter had not yet been made by KI’s Vice-Chancellor Ole Petter Ottesen, Karin Dahlman-Wright asked to be dismissed from her assignment as Vice Rector at KI with immediate effect. At an extra meeting on the same day, the KI Board decided to do so.

Fig 1 Arroyo-Jiminez et al J Neurosc 1999. 3 lanes appear identical

In one of the reports submitted to KI in July 2018, attention was also drawn to an article from the Pasteur Institute in Paris with Ole Petter Ottersen as a co-author. He was at this time working at the University of Oslo and it was in his laboratory a central part of the study had been carried out. The object of the investigation was to use immuno-electron microscopy to locate an acetylcholine receptor subunit in a part of the brain. In a study of this kind, it is of vital importance that the antibody used is specific. And it is precisely at this point the objections emerge. In a post on PubPeer, a US database for reviewing scientific articles, it was in 2016 made likely that in the immunoblot analysis used to show the specificity of the antibody used, one and the same image was used to show three different controls. This obviously makes it difficult to trust the results presented.

The two uncut lanes of the left moiety correspond to the part A of the Fig. 1 while the two lanes of the right part correspond to the part B of the Fig. 1″

Since KI was not involved in this study, they contacted the Pasteur Institute to ask for an examination of the article in question. On September 5, 2018, just over two weeks after being asked for help, a response was received from Francois Rougeon, chairman of the ethics committee at the Pasteur Institute. According to a KI press release on the same day, it had been established that there was no basis for the allegation of misconduct in research. The attached report stated that they had recovered the original images and claimed that there were differences between the three images that look identical in the printed article. According to the first author, this could be due to that before publication they had used the computer program Photoshop to adjust the gray scale of the images in order to remove background (now prohibited). What should be noted in this context is that the last and communicating author responsible for the study is a famous senior member of the Pasteur Institute, Professor Jean-Pierre Changeux, formerly student and collaborator of the Nobel Laureates Jacques Monod and Francois Jacob. It is easy to get the impression that one did not want to compromise a person like this. Conceivably, the feelings were the same regarding the head of the institution that distributes the Nobel Prize in Physiology or Medicine.

To check the matter myself, I wrote to Professor Rougeon in March 2019 and asked for a copy of the original pictures referred to in his investigation six months earlier. In his reply, he initially emphasizes that they have not excluded that the three control images PubPeer claimed to be identical really are so. Regarding the original images referred to in their report as evidence, I am now informed that they are not available and that I therefore cannot receive copies of them. Instead, I get two completely different immunoblot images without direct connection to those that doubts had been raised about. The whole thing is very vague and confusing. What to believe? One reflection is that a serious co-author of a work like this should have asked him- or herself if the three control images in the disputed figure did not look too much similar to be true.

In summary, Karolinska Institutet and the Karolinska University Hospital have been living with a scandal that they have not succeeded to release for more than ten years. The Macchiarini case went awry from the day he was recruited as a visiting professor and chief physician. He was applauded and allowed to realize his plans of transplanting an artificial trachea into human beings without statutory permissions and without previous animal testing. On purely theoretical grounds, the idea was doomed to fail, which every student with basic knowledge of the structure and physiology of this organ should understand. When four colleagues and whistle blowers warned about the suffering caused by the surgeries, the responsible heads at Karolinska Institutet and the Karolinska University Hospital closed their eyes and tried to silence the scandal.

And as it turns out, it is not only Macchiarini who has engaged in irregularities, but also at least one of the two highest officials in KI’s senior management who, for almost two years, was in charge for the investigation that was resumed after the resignation of the initially responsible rector who totally had failed his mission. Many questions remain unanswered and from the whistle blowers who opened up the scandal, it has recently been suggested that a new independent investigation around this whole affair is needed.

Johan Thyberg

Retired professor of cell and molecular biology at KI, Licensed physician


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1 comment on “Karolinska’s haunted leadership

  1. Karolinska Researcher

    The karolinska Institutet is geting more corrupt. Is’s like working for the maffia. .

    Like

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