Experimental surgery scandal dr Macchiarini, Karolinska Institutet & Nobel Assembly

the-macchiarini-case-summary-eng
Report by Kjell Asplund Aug. 31 2016 on the request of Karolinska University Hospital

Reading about embattled trachea surgeon Paolo Macchiarini? Here’s what you need to know

source: retractionwatch.com

Paolo Macchiarini

Paolo Macchiarini

The media has been abuzz in the last few weeks with developments in the ongoing story about “super surgeon” Paolo Macchiarini. We’ve been covering the allegations against him for years (and invited him to publish a guest post on our site). Below, we present a timeline of recent events, to keep you abreast of what we know so far.

Macchiarini was famous long before accusations of misconduct arose, once-heralded for creating tracheas from cadavers and patients’ own stem cells. However, the glow of his success was diminished somewhat after some Karolinska Institutet (KI) surgeons filed a complaint in 2014 — alleging, for instance, Macchiarini had downplayed the risks of the procedure and not obtained proper consent. In response, KI issued an external review by Bengt Gerdin of Uppsala University.

Here’s what’s happened since:

April 12, 2015: KI’s Ethics Council clears Macchiarini of a number of accusations leveled against him by Pierre Delaere at KU Leuven in Belgium, who had suggested the surgeon had engaged in scientific misconduct, including fabricating data. This is one of two ongoing KI investigations into his work.

May 27, 2015: KI releases an English translation of the report of Gerdin’s investigation, which found examples of misconduct in seven of Macchiarini’s published papers. KI gives the co-authors of his articles time to respond to the finding, after which it will make its final ruling.

June 22, 2015: Swedish Research Council freezes grant payments to the KI center run by Macchiarini.

June 26, 2015: Macchiarini calls Gerdin’s misconduct investigation “a potentially disastrous miscarriage of justice.”

June 29, 2015: Ola Hermanson, Macchiarini’s co-author on his 2011 Lancet paper, says the misconduct investigation contains “serious flaws and formal errors.”

August 28, 2015: After reviewing the evidence gathered during Gerdin’s investigation, KI’s Vice Chancellor Anders Hamsten rules that Macchiarini acted in some cases “without due care,” but that his behavior “does not qualify as scientific misconduct.”

October 9, 2015: We publish a guest post by Macchiarini, in which he criticizes us for including de-identified medical information about some of his patients in a post, and covering allegations before they have been thoroughly investigated.

January 5, 2016: Vanity Fair publishes a story about how Macchiarini romanced an NBC producer while she was working on a story about him, and in the process raises the allegation he lied on his CV when applying to the KI position.

January 13, 2016: Swedish Television airs a series of documentaries about Macchiarini and his work, alleging, in part, that he operated on patients in Russia whose conditions were not life-threatening enough to warrant such a risky procedure.

January 28, 2016: KI announces it may reopen its misconduct investigation into Macchiarini following the allegations revealed by SVT.

February 4, 2016: KI announces it will not extend Macchiarini’s contract, and he will “phase out” his research from now until November 30.

February 5, 2016: KI says it will issue a new external investigation of Macchiarini, examining questions about his recruitment and the handling of previous allegations of misconduct.

That same day, four whistleblowers release a statement arguing they had provided evidence of misconduct long before the SVT documentary series aired.

February 6, 2016: The secretary general of the Nobel Assembly — the body responsible for choosing the Nobel Prizes — resigns after saying “he may be involved” in KI’s investigation of Macchiarini.

February 9, 2016: KI confirms that Macchiarini’s CV did, in fact, contain inaccuracies when he applied for his adjunct position in 2010.

February 11, 2016: The Royal Swedish Academy of Science asks for a new investigation, and for changes to a 2011 Lancet paper, Science reports:

The Academy find it deeply unfortunate that the well-publicised report about the first operation with an artificial trachea, published in The Lancet in 2011, remains unchanged on the journal’s website. The Academy demands that a supplement is added to the journal, accounting for the further events, the complications and the patient’s death.

February 12, 2016: SVT releases additional short films comparing one patient’s medical record to what is reported in Macchiarini’s articles.

February 13, 2016: Hamsten resigns, citing criticism of the investigation.

February 23, 2016: The Royal Swedish Academy of Sciences voices its concerns about Macchiarini’s 2011 Lancet paper, claiming it severely misrepresents the state of the patient who received the transplant, who experienced severe complications and eventually died.

March 15, 2016: A KI spokesperson confirms that a new ethics council will be appointed, but the new members have yet to be determined.

March 23, 2016: KI dismisses Macchiarini, effective immediately.

April 1, 2016: The Lancet issues an expression of concern for Macchiarini’s 2011 paper, and removes three more authors, upon their request.

August 31, 2016: A report headed by the chairperson of the Swedish National Council on Medical Ethics (and commissioned by the Karolinska University Hospital) found the environment contributed to Macchiarini’s problems. According to Nature News, Macchiarini’s work environment:

provided a “culture of silence”, a lack of respect for rules and “group thinking”.

September 6, 2016: The results of another external inquiry into KI’s handling of the Macchiarini case criticized the institution:

including that Macchiarini’s recruitment in 2010 and the extension of his contract in 2013 were pushed through improperly. The report also found that KI cannot be completely absolved of responsibility for the synthetic trachea transplantations performed at Karolinska University Hospital.

September 9, 2016: Science reports that Sweden’s Central Ethical Review Board has found Paolo Macchiarini guilty of misconduct in a 2014 paper.


Retraction Watch

Tracking retractions as a window into the scientific process

Macchiarini did not obtain necessary ethics approvals, says Swedish Research Council

lancetSurgeon Paolo Macchiarini did not apply for the necessary ethics approval to perform the pioneering transplants he’s known for, according to the Swedish Research Council.

Chief Legal Counsel Anna Hörnlund, who wrote a letter in this week’s The Lancet, says Macchiarini’s work needed to obtain ethical approval from one of six regional ethical review boards, as required by Swedish law — and neither Macchiarini nor his former employer, Karolinska Institutet, did so:

On Jan 1, 2004, a law came into force in Sweden concerning the ethical review of research conducted in human beings. This law covers research conducted in living human beings, on human cadavers, and on biological material from human beings, and the handling of sensitive personal information. The Swedish Research Council considers Paolo Macchiarini’s activities to be research conducted in human beings.

When research is conducted in human beings, the principal investigator (defined as the state agency or the physical or legal entity under whose organisation the research will be conducted) is obligated by Swedish law to apply for an ethical review. The application must be submitted to one of six regional ethical review boards. These review boards are individual public authorities. Neither Macchiarini, nor the Karolinska Institutet, has submitted such an application.

According to a news article in Svenska Dagbladet, Macchiarini and KI have argued that the surgeries were performed for health reasons, not research, which require different ethical approvals. The Swedish Research Council disagrees.

Earlier this year, Macchiarini defended his work in another The Lancet letter, which detailed the steps he and his co-authors took to okay the research presented in his seminal 2011 paper, “Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study.” That paper described a first-of-its-kind procedure: A 36-year-old man with recurrent tracheal cancer received an artificial airway seeded with his own stem cells.

In “Tracheobronchial transplantation,” Macchiarini said he consulted the Medical Products Agency and the Regional Ethics Committee, confirmed the patient had no other therapeutic options, got an okay from the chairman of the Ethics Council of Karolinska University Hospital, and asked the patient to sign a consent form.

Since 2014, Macchiarini has had to defend himself against a number of charges, including downplaying the risks of the life-threatening procedure.

Although (KI) initially ruled after an external investigation that Macchiarini’s behavior “does not qualify as scientific misconduct,” the fallout continued after a documentary series on Swedish Television suggested he had operated on patients in Russia whose conditions were not life-threatening enough to warrant such a risky procedure, among other allegations. KI recently ordered a new external investigation, and dismissed him from his post. Both the secretary general of the Nobel Assembly and KI’s vice chancellor have resigned over the debacle.


  • Full Text

    On Jan 1, 2004, a law came into force in Sweden concerning the ethical review of research conducted in human beings. This law covers research conducted in living human beings, on human cadavers, and on biological material from human beings, and the handling of sensitive personal information. The Swedish Research Council considers Paolo Macchiarini’s activities1 to be research conducted in human beings.

When research is conducted in human beings, the principal investigator (defined as the state agency or the physical or legal entity under whose organisation the research will be conducted) is obligated by Swedish law to apply for an ethical review. The application must be submitted to one of six regional ethical review boards. These review boards are individual public authorities. Neither Macchiarini, nor the Karolinska Institutet, has submitted such an application.

I am Chief Legal Counsel at the Swedish Research Council. I declare no competing interests.

Reference

  1. Macchiarini, P. Tracheobronchial transplantation. Lancet. 2016; 387: 339
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    Misconduct found in 7 papers by Macchiarini, says English write-up of investigation

    Paolo MacchiariniPaolo Macchiarini

    source: retractionwatch.com 28 May 2015
    The Karolinska Institutet in Sweden has released an English translation of an external review that found Paolo Macchiarini, a celebrated surgeon who is credited with creating tracheas from cadavers and patients’ own stem cells, committed misconduct in a series of papers describing the work.You can read the entire report, news of which was first reported by Sciencehere.

    The investigator, Bengt Gerdin, of Uppsala University, considered a series of allegations about Macchiarini’s papers, and found a number of them lived up to the verdict of misconduct. There were seven affected papers, not six, as was reported last week based on the initial findings (reported in Swedish).

    For instance, in a 2014 Nature Communications paper describing the procedure in rats, Gerdin found that the scientists erred when none of the listed authors could assume responsibility for a CT image showing rats with “a smooth and patent oesophagus” (the researcher who took it asked to be left off the author list when he disagreed with how it was being interpreted), among other issues:

    …the principally most outstanding fault is that the authors have decided to present research results for which none of them can take responsibility. This is inconsistent with accepted research practice and therefore qualifies as misconduct, and the lead author (or in Nature Communication’s words “corresponding author”) bears the blame for this. The paper also contains a number of other weaknesses/faults in the presentation of the animal experiments that had been conducted. These experiments are presented so vaguely that it is surprising that a journal of Nature Communication’s calibre accepted the paper without demanding extensive clarifications, which should have been dealt with in an effective referee-process.

    In a series of six papers describing the results of experiments with three human subjects, Gerdin concluded that several other incidents of misconduct had occurred:

    To describe a clinical result after five months without conducting any examination of the patient at this point in time is significant; it is inconsistent with accepted scientific practice and therefore qualifies as misconduct (Paper 1).

    To explicitly state that an ethical permit exists despite the absence of one is a false claim that affects the reliability of the research; this is a serious departure from accepted scientific practice and therefore qualifies as misconduct (Paper 1) .

    To refer to paper 1 and make out that it accounts for a longer follow-up than actually was the case is false. This also applies to the actual description of the healing of the mucosa over the prosthesis, which in no way matches the accounts given in the medical records. In any case, it is an act of carelessness and a departure from accepted scientific practice and therefore qualifies as misconduct (Paper 2).

    To describe the postoperative condition of a patient in such a way that leaves readers unable to make any other interpretation than that the postoperative conditions are good when in reality the patient has serious problems is to deliberately dress up the results. This is inconsistent with accepted scientific practice and therefore qualifies as misconduct, regardless of the fact that the paper’s main purpose is not purely clinical (Paper 3).

    To state that the circumstances 12 months after the operation were good despite the patient being in an extremely serious clinical condition and to claim by way of excuse that no check was made of the patient’s status in the hospital records is significant; it is inconsistent with accepted scientific practice and therefore qualifies as misconduct (Paper 4).

    To omit to mention that one of the reported patients had to undergo a new operation because of material failure was an active withholding of information and a dressing-up of the results. Such withholding of information is inconsistent with accepted scientific practice and therefore qualifies as misconduct (Paper 5).

    To selectively describe certain minor postoperative problems while omitting the really major problems that led to the operated patient’s death is a false embellishment of the results. This constitutes active withholding of information, which is inconsistent with accepted scientific practice and therefore qualifies as misconduct (Paper 6).

    According to a statement released May 27 by Karolinska Institutet, all co-authors of the papers Gerdin investigated have two weeks to respond. After that, the vice-chancellor will reach an official decision.

    Macchiarini declined to comment when Retraction Watch asked him to respond to the report, but said he may once the vice-chancellor renders an official verdict.

    This is one of two reviews commissioned by the Karolinska. The other cleared him of different misconduct allegations brought by Pierre Delaere. An investigation in Italy has also cleared him of most charges.

    ————————————–
    source: karolinska.se sept. 5th 2016

    Karolinska University Hospital’s management comment Kjell Asplund investigation: “An exceptional and unacceptable series of events”.

    News

    On August 31 2016, Kjell Asplund presented the external investigation concerning the circumstances around which three patients underwent windpipe surgery, led by Paolo Macchiarini between 2011-2013, at Karolinska University Hospital.

    On August 31 2016, Kjell Asplund presented the external investigation concerning the circumstances around which three patients underwent windpipe surgery led by Paolo Macchiarini between 2011-2013. The investigation revealed serious irregularities in the management of the three patients and serious flaws in hospital procedures, systems and culture.

    – We take the results of the investigation very seriously, said Head of Karolinska University Hospital, Melvin Samsom. What has happened is totally unacceptable; and in many ways exceptional. The study shows a sequence of events enabling Paolo Macchiarini to operate completely outside the hospital’s standard rules and procedures, and without any warning from our internal systems. Our primary tasks now are to ensure that this situation never arises again and to regain the trust of our patients that we always put the patient first.

    – This is a thorough investigation that provides a comprehensive overview of the entire series of events, said Chief Medical Officer Nina Nelson Follin. We will now focus closely on the recommendations presented by Kjell Asplund and take the necessary steps to strengthen our procedures, adherence to laws and regulations and clarify responsibilities of managers and doctors for patient safety.

    In parallel with the investigation, Karolinska has already taken a number of measures:

    • We are working with leadership issues such as an open culture and clarification of responsibilities.
    • We have installed a whistleblower function as a complement to other systems.
    • Strengthened processes for joint recruitment with Karolinska Institute where hospital responsibilities are clarified.
    • Developed an internal routine for the start of clinical trials.
    • Responsibility for adherence to laws and regulations has been clarified and emphasized to managers on all levels.
    • Initiated an investigation of all other operations performed by Paolo Macchiarini between 2010-2013.

    The hospital’s new business model is based on the patient’s journey through the health care system; integrating care, research and education. This further specifies responsibility and cooperation in the organization.

    – What has happened affects the reputation of Karolinska University Hospital. We are committed to doing everything we can to restore the trust of our patients. The hospital has 15 000 employees who take care of many patients everyday and do their job in an excellent way, says Melvin Samsom.

    More information

    A summary on the investigation: The Macchiarini Case – Investigation of the synthetic trachea transplantations at Karolinska University Hospital (öppnas i nytt fönster)

    Background

    In February 2016, the Director of Karolinska University Hospital commissioned an investigation with the directive to answer a number of questions surrounding Macchiarini and the trachea transplants he performed at the hospital. The task also included making improvement recommendations based on the facts that came forth in the investigation.

    The task was assigned to Kjell Asplund, Professor Emeritus in Medicine at Umeå University, Chairman of the Swedish Council on Medical Ethics (Smer) and former Director-General of the National Board of Health and Welfare.

    Paolo Macchiarini: A surgeon’s downfall

    Ground-breaking work on synthetic organ transplants made Paolo Macchiarini one of the most famous doctors in the world. But some of his academic research is now seen as misleading, and most of the patients who received his revolutionary treatment have died. What went wrong?

    In July 2011, the world was told about a sensational medical breakthrough that had taken place in Stockholm, Sweden. The Italian surgeon Paolo Macchiarini had performed the world’s first synthetic organ transplant, replacing a patient’s trachea, or windpipe, with a plastic tube.

    The operation promised to reshape organ transplantation. No longer would patients have to wait for a donor organ, only to run the risk of biological rejection. Plastic tracheas – and possibly other organs – would be produced quickly, safely, and made-to-measure for each patient.

    It was a story that befitted the reputation of Dr Macchiarini’s workplace, the prestigious Karolinska Institute, whose professors decide each year who will receive the Nobel Prize in Medicine.

    But five years on, Macchiarini’s headline-making work has brought KI and its sister organisation, the Karolinska University Hospital, no glory. Of the nine patients that received the treatment, in Sweden and elsewhere, seven have died. The two still alive have had their synthetic tracheas removed and replaced with a windpipe from a donor.

    Last week, an independent report sharply criticised the three synthetic trachea operations that took place at Karolinska University Hospital.

    The investigation, led by Kjell Asplund, Chairman of the Swedish Council on Medical Ethics, found that the scientific foundation for the new operation was weak, and condemned the failure to carry out risk analyses before the patients received their operations, or seek the necessary ethical approval.

    On Monday, a separate investigation at KI identified mistakes made when Macchiarini was recruited and when allegations of misconduct were made against him two years ago.

    In the picture that emerges from these reports, we see a doctor persisting with a technique that showed few signs of working and able to take extraordinary risks with his patients, and a medical institution so attached to their star doctor that they ignore mounting evidence of his poor judgement.

    Image copyright Staffan Larsson

    Macchiarini arrived in Stockholm in 2010, already a leader in the field of regenerative medicine – the project of growing tissue or organs to be implanted in sick patients.

    Not only was Macchiarini known as a brilliant surgeon, he was handsome and impressive – able to give press conferences in several languages.

    At the hospital, a “bandwagon effect” emerged around his work. “Regenerative medicine” was at the cutting edge of scientific fashion, and few colleagues raised questions or objections about the basic science underlying the procedures.

    The patient who received that first synthetic organ transplant, in 2011, was 36-year-old Andemariam Beyene, a graduate student from Eritrea living in Iceland. After unsuccessful treatment for a rare form of cancer, he had been referred by his Icelandic doctors to the experts at Karolinska University Hospital.

    Macchiarini told Beyene that the revolutionary surgery was his only chance of survival and persuaded him to agree to the new procedure.

    The synthetic “scaffold” for Beyene’s new trachea was made in a lab in London. It was seeded with stem cells taken from the patient’s bone marrow, then placed in a shoe-box sized machine called a bioreactor, where it rotated in a solution designed to encourage cell growth.

    Image copyright Conan Fitzpatrick
    Image caption A synthetic trachea before being placed in a bioreactor
    Image copyright Conan Fitzpatrick
    Image caption Stem cells being drizzled on to a synthetic trachea

    The idea was that these cells would divide and turn into tracheal cells. Before the operation, Macchiarini also deposited slivers of cells from the patient’s nose on the scaffold. It was hoped these would grow into a lining of epithelial cells. In effect, the doctors were trying to grow a new trachea inside Beyene’s body.

    A month after the operation, reporters from around the world were able to interview Beyene in bed. He told the BBC: “I was very scared, very scared about the operation. But it was live or die.”

    By the end of the year, Macchiarini and his colleagues were writing in the Lancet that Beyene had an “almost normal airway” that was free of infection and growing new tissue.

    The publication of this sent a signal to the medical community that the miraculous-sounding project of growing and implanting synthetic transplants was a viable treatment.

    By this time, two more synthetic tracheas had been implanted. In the first – an operation not overseen by Macchiarini – a young British woman in a serious condition received a trachea at University College London. In the second, Macchiarini himself fitted a 30-year-old American man with a new kind of scaffold.

    These two patients only survived for a few months. No autopsy was performed on the American man so his exact cause of death is unknown, but we know that the British woman’s synthetic trachea did not function well.

    Image copyright University of Iceland
    Image caption Andemariam Beyene met up with Paolo Macchiarini in Iceland in 2012, one year after his operation

    “The biggest problem with the materials used at that time was lack of integration into the surrounding bodily tissue, both outside it and at the ends where you join it on to the bronchi and the larynx,” says one of the surgeons, Prof Martin Birchall at UCL.

    “At those junctions it always seems to be loose and healing tissue can become an obstruction to breathing.

    “The second thing that seemed to happen was that you are putting the trachea on to a bed, which is made up of the oesophagus, the swallowing tube, and the synthetic material could press into the oesophagus.

    “Finally, the lining didn’t seem to grow into the scaffolds either, so you are left with something chronically infected and unable to clear mucus properly.”

    The patient was able to go home after the operation, but died two months later.

    Over the next three years, Macchiarini implanted six more synthetic tracheas, and four of these patients died. It is unknown whether their deaths were all related to the tracheas, or whether they were due to underlying illnesses or even unrelated events.

    Karolinska University Hospital stopped Macchiarini’s work in November 2013, but he continued to perform the transplants as part of a clinical trial in Russia.

    Meanwhile, reports about the health of the first patient, Andemariam Beyene, remained positive. In a 2014 article published in the Journal of Biomedical Materials Research, Macchiarini reported that he had an “almost normal” airway a year after the operation, repeating the phrase from the Lancet article.

    But by the time that article appeared Beyene too had died. He had suffered repeated infections, and his trachea needed to be held open by a series of stents. His autopsy revealed the synthetic trachea had come loose.


    The nine synthetic trachea patients

    Image copyright SVT
    Patient Location When operated Outcome
    Andemariam Beyene Stockholm June 2011 Deceased Jan 2014
    Keziah Shorten London Sept 2011 Deceased Jan 2012
    Christopher Lyles Stockholm Nov 2011 Deceased March 2012
    Julia Tuulik Krasnodar June 2012, Aug 2013 Deceased Sept 2014
    Alexander Zozulya Krasnodar June 2012, Nov 2013 Deceased Feb 2014
    Yasim Cetir Stockholm Aug 2012, July 2013 Survives (remains hospitalised)
    Hannah Warren Peoria, US April 2013 Deceased July 2013
    Sadiq Kanaan Krasnodar Aug 2013 Deceased (date unknown)
    Dmitri Onogda Krasnodar June 2014 Survives (synthetic trachea removed)

    Source: SVT production team. Image: Macchiarini and Julia Tuulik, courtesy of SVT


    However, the questions that have dogged Paolo Macchiarini are related less to disappointing patient outcomes, and more to the decision-making around operations. Had the risk of each operation been properly assessed? Were the patients ill enough to require such drastic intervention? Did the patients understand the risks involved?

    Then there is a second set of questions that relate to the way Macchiarini has described the operations in academic publications.

    After Beyene’s death, four doctors at the Karolinska Institute began to have doubts about synthetic transplants, and about Macchiarini himself. The group included Karl-Henrik Grinnemo, who had assisted Macchiarini in Beyene’s organ transplant operation in 2011, and Thomas Fux, who was involved in the aftercare of Macchiarini’s patients at the hospital.

    They alleged that Macchiarini had misrepresented the success of the operations, omitting or even fabricating data in his published articles.

    KI’s vice chancellor at the time, Dr Anders Hamsten, called in an outside expert, Dr Bengt Gerdin, from Uppsala University Hospital, to lead an investigation. In May 2015, Gerdin reported back, concluding that by-and-large the whistleblowers were right: Macchiarini was guilty of scientific misconduct.

    But in August 2015 Hamsten and the KI management threw out Gerdin’s report. Based on undisclosed evidence they had seen – which Gerdin had not – they reaffirmed their faith in the surgeon and extended his contract.

    Image copyright Karolinska Institute
    Image caption The Karolinska Institute’s striking campus

    In the end, it was not a scientist, doctor or lawyer that grounded Macchiarini’s high-flying career, but a TV journalist.

    Bosse Lindquist followed the surgeon for months for a documentary series for the Swedish public broadcaster, SVT.

    Lindquist also scoured the world’s media archives for footage of Macchiarini, and he was rewarded with a wealth of material. “It turned out that Macchiarini had always liked journalists and had often invited TV teams to his surgeries,” Lindquist says.

    Some of the most striking moments of the series come from these archive rushes.

    For example, Lindquist uncovered footage of Andemariam Beyene undergoing bronchoscopies, the procedure in which doctors view a patient’s airways with a miniature camera. The footage from the surgical camera seemed to conflict with the descriptions of the patient in Macchiarini’s published articles.

    Instead of an “almost normal airway” the footage showed that a build-up of scar tissue was impeding the passage of air to the right lung. The clips also showed a fistula – a hole into the rest of the body – at the end of the trachea.

    Image copyright SVT
    Image caption Bronchoscopy footage of a normal airway, and Andemariam Beyene’s 12 months after his operation

    The articles are currently the subject of yet another investigation. On Friday, the Central Ethical Review Board in Sweden ruled that a 2014 article by Macchiarini, published in the journal Nature Communications, involved research misconduct. The article described a transplant trial in rats, which, the committee ruled, was not as successful as had been implied.

    The Review Board will rule on the other contentious articles soon. The 2011 article in the Lancet now carries an “expression of concern”. The senior editor of the Journal of Biomedical Materials Research tells the BBC that his journal will issue a similar warning soon.

    Macchiarini says that some mistakes were made in the preparation of the articles, but there was no intention to mislead.

    Lindquist agreed not to ask Macchiarini about the allegations against him until the outcome of KI’s internal investigation in 2015, but eventually the two men sat down for a long and very awkward interview.

    The normally urbane Macchiarini becomes increasingly rattled as Lindquist presses him to answer why five human beings received plastic tracheas before any experiments checking the suitability of the scaffolds in animals were published.

    At first, Macchiarini says that his team conducted animal studies before 2011 at KI, but they have yet to be published. When Lindquist points out that he has found no official approvals for such research, Macchiarini changes tack, asking, “How do you know that we didn’t do animal studies in Russia?”

    Finally the doctor admits in an irritated tone, “We didn’t do any animal study that involves large animals – of course not, we didn’t have the time. The material was proven, the material was studied. We used fibres that were approved by the FDA [the US Food and Drug Administration]. And now all the studies are coming.”

    Lindquist called his documentary series The Experiments. The implication is that Macchiarini was treating humans as guinea pigs, instead of doing preliminary research on animals.


    Find out more


    When it was broadcast in Sweden in January, The Experiments caused a sensation, with about 15% of the population tuning in to watch this complicated medical story unfold.

    Anders Hamsten stood down as vice-chancellor of KI, as did Urban Lendahl, the general secretary of the Nobel Committee. Macchiarini was fired, and half a dozen inquiries launched.

    Last week, the Swedish government sacked all members of KI’s board who remained in position.

    Bo Risberg, professor emeritus of surgery at the University of Gothenberg and a former chairman of the Swedish Ethics Council, has called for the Nobel Prize to be suspended for two years as an “apology” to Macchiarini’s patients and their families. He has said the events amount to the biggest research scandal Sweden has experienced in modern times.

    “It is very strange that it should take a TV programme to make this public,” Risberg said earlier this year. “Everything was swept under the carpet.”

    The failure to do pre-clinical tests on animals, he said, was “the worst crime you can commit.”

    Image copyright Lars Granstrand

    In May, Macchiarini discussed his decision to operate on Andemariam Beyene on SVT. “We had a human being that we wanted to save,” he said, “And in these circumstances what would you do? Do you just leave him dying at that young age? I don’t think it’s correct.”

    This touches on the blurred distinction between trying out a new treatment as part of a clinical research programme, and innovating in an emergency to save or prolong a life. The Swedish government is investigating whether guidelines differentiating the different scenarios need to be clearer.

    Last week’s report into the synthetic transplant operations that took place at Karolinska University Hospital concluded that while there was a compassionate element to the operations, they still involved clinical research. Therefore, Macchiarini should have sought approval from an ethical review board. “It is unlikely that the project would have been approved,” the report notes.

    Moreover, it states that there was no immediate threat to life for Macchiarini’s three patients before the operations.

    In an email to the BBC, Macchiarini says he accepts the findings of the report, but he adds that it was the responsibility of the hospital administration to apply for ethical permissions.

    “I would welcome international discussion and clarification of the ethical processes to be undertaken in such difficult circumstances as these – where experimental treatments are involved,” he writes.

    “It is clearly a difficult area for clinicians and researchers to be involved in, and yet vitally important that new treatments are developed and tried…”

    Macchiarini says that the report highlights “the very great amount of pre-clinical research that has been done into synthetic tracheal scaffolds”, though he concedes that Andemariam Beyene was the recipient of an untested procedure.

    “I would like to add that the welfare of patients has always been my driving concern. Although there may be criticisms of decision-making processes and administrative processes, and these may have had tragic consequences that with hindsight are deeply regrettable, everyone involved in the clinical care of these patients felt that they were doing their very best for these individuals. That should never be overlooked.”

    Image copyright Conan Fitzpatrick
    Image caption Macchiarini with colleagues in Krasnodar, Russia

    When asked about the transplants, Macchiarini has often mentioned that he was not the only one responsible for the decision to operate, but discussed his patients in multidisciplinary conferences. “There were 30 or more professionals involved in the decision-making process,” he told SVT, “and then even in the inter-operative and postoperative care of the patient.”

    Yet one of the most critical issues was not discussed in the meetings – whether there was enough scientific evidence to support the procedure.

    Some experts claim that the entire project of growing human organs, although appealing to popular science journalists, is flawed.

    Dr Pierre Delaere, a professor of respiratory surgery at KU Leuven in Belgium, has said that it is impossible for surgeons to establish a new blood supply to a trachea – donated or synthetic. Delaere has called Macchiarini’s method “one of the biggest lies in medical history, because you are doing something that is impossible from a theoretical point of view”.

    The use of bone marrow cells has also come under scrutiny. “There is absolutely no evidence that these cells differentiate into mucosal epithelia (lining tissue) or blood vessels,” says Leonid Schneider, a science blogger who trained as a molecular cell biologist and used to work in stem cell research.

    Image copyright Lars Granstrand

    “This claim that bone marrow cells can create any kind of tissue is based on old papers, which are long discredited by science, and every single stem cell scientist will tell you they cannot do it.”

    He adds: “Everybody switched off their brain. The stem cell scientists switched off their brains to the science, and the clinicians switched off their brains to the use of the plastic, which couldn’t even be sutured into patients, and everybody went along with it.”

    Macchiarini maintains, in his email to the BBC, that “there is no doubt that it is a viable technology”. He adds that he is continuing his work with biological scaffolds, expanding his focus from the trachea to other organs.

    A public prosecutor in Stockholm is currently gathering as much information as she can about the three operations that took place at Karolinska University Hospital, and says she will decide next year whether to press charges equivalent to manslaughter and grievous bodily harm.

    The hospital is already the subject of two police investigations, triggered last year by complaints from government healthcare agencies.

    Despite his many appearances in the media, the man at the centre of the scandal remains something of an enigma.

    Image copyright Staffan Larsson

    By chance, the transmission of The Experiments in Sweden coincided with the publication of an article in Vanity Fair in which it was alleged that Macchiarini had had a relationship with a television producer who was making a film about him. The story alleged that the producer had ordered her wedding dress before learning that Macchiarini was married with children.

    Macchiarini has declined to comment on the story.

    “He’s an exceptional person for sure, and he has this faculty for stretching the truth just the right amount,” says Bosse Lindquist.

    “But in order to be able to seduce the medical community you need to have a whole host of professors who would like to be seduced and who would like to believe that the Nobel prize is very close, or you can make lots of patent money, for example, or corporate money.

    “I think he has an acute ability to suss out the faults and cracks in the system where he could manoeuvre.”

    Additional reporting from Christine Westerhaus. Listen to Christine Westerhaus’s report on the Macchiarini scandal, which was originally broadcast in February 2016 on the BBC World Service. The Experiments will be broadcast in the UK in BBC4’s Storyville strand in October.

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The Macchiarini case: The external inquiry into Karolinska Institutet criticises KI on several counts
www.ki.se sept. 5 2016

Sten Heckscher. Photo credit: Gunnar Ask

On Monday, the external investigators presented the results of their inquiry into Karolinska Institutet’s handling of visiting professor Paolo Macchiarini. Their report criticises KI on several counts, including that Macchiarini’s recruitment in 2010 and the extension of his contract in 2013 were pushed through improperly. The report also found that KI cannot be completely absolved of responsibility for the synthetic trachea transplantations performed at Karolinska University Hospital.

The external investigation was conducted by Sten Heckscher, Ingrid Carlberg and Carl Gahmberg, and covers the initial correspondence between KI and Macchiarini in autumn 2009 through 4 February 2016. Matters under scrutiny include the recruitment of Macchiarini in 2010, the extensions of his contract in 2013 and 2015, the division of responsibilities between KI and Karolinska University Hospital regarding the controversial transplantations, and KI’s handling of the scientific misconduct allegations levelled against Macchiarini.

Their report concludes that Karolinska University Hospital bears responsibility for the transplantations of synthetic tracheae performed there. However, the investigators also found that Karolinska Institutet cannot be completely absolved of responsibility for these operations. For example, the university cited the transplantations as research successes in its evaluations of research funding utilization. Furthermore, individuals from KI took part in discussions preceding and following the operations. Consequently it was also KI’s responsibility to ensure that they were performed in accordance with relevant rules and regulations.

Moreover, Karolinska Institutet is accused of nonchalance in the application of the law, including the Freedom of the Press Act and the Administrative Procedure Act, an attitude that caused failings in Macchiarini’s recruitment and the extensions of his contract. The report also criticises the manner in which the allegations of scientific misconduct against Macchiarini were managed. For example, decisions were not justified in the way provided by the Administrative Procedure Act.

The investigators proceed to discuss how responsibility should be divided and how the consequences of failing to act upon this responsibility should be assessed. The report concludes with a discussion on structural issues that could have contributed to the mistakes made.

Read a summary in English.

Read more about the Macchiarini case.

About the investigators

Sten Heckscher is a former president and justice of the Supreme Administrative Court of Sweden, cabinet minister, under-secretary of state and national police commissioner.

Ingrid Carlberg is an author and journalist, and honorary doctor of medicine at Uppsala University.

Carl Gahmberg is professor of biochemistry at Helsinki University.

Pia Cedermark, Justice of the Swedish Administrative Court of Appeal, served as secretary to the inquiry.

Investigation