Having featured Paolo Macchiarini and his work on transplanting synthetic tracheas into humans when it was lauded (in an Aug. 2, 2011 post titled: Body parts nanostyle), it seems obligatory to provide an update now that he and his work are under a very large cloud. Some of this is not new, there were indications as early as this Dec. 27, 2013 post titled: Trachea transplants: an update which featured an article by Gretchen Vogel in Science magazine hinting at problems.

Now, a Feb. 4, 2016 article by Gretchen Vogel for Science magazine provides a more current update and opens with this (Note: Links have been removed),

The Karolinska Institute (KI) in Stockholm “has lost its confidence” in surgeon Paolo Macchiarini, a senior researcher at the institute, and will end its ties with him. In a statement issued today, KI said that it won’t renew Macchiarini’s contract after it expires on 30 November 2016.

The move comes in the wake of a chilling three-part TV documentary about Macchiarini, a former media darling who was cleared of scientific misconduct charges by KI vice-chancellor Anders Hamsten last summer. Among other things, The Experiments, broadcast in January by Swedish public television channel SVT, suggests that Macchiarini didn’t fully inform his patients about the risks of his pioneering trachea implants. Most of the patients died, including at least one—a woman treated in Krasnodar, Russia—who was not seriously ill before the surgery.

For a profession that has “do no harm” as one of its universal tenets, the hint that a patient not in dire need agreed to a very risky procedure without being properly apprised of the risks is chilling.

Macchiarini’s behavriour is not the only concern, the Karolinska Institute is also being held to account (from the Vogel article),

The film has also raised questions about the way Hamsten and other administrators at KI, Sweden’s most prestigious university and home of the selection committee for the Nobel Prize in Physiology or Medicine, have handled the scandal. Today [Feb. 4, 2016], the Institute’s Board decided to launch an independent review, to be led by an experienced lawyer, into KI’s 5-year relationship with Macchiarini. Among the things the inquiry should address is whether any errors were made or laws were broken when Macchiarini was hired; whether misconduct charges against him were handled properly; and why, given the controversy, he was given a new 1-year contract  as a senior researcher after his appointment as a visiting professor at KI ended in October 2015.

Getting back to Macchiarini (from the Vogel article),

In 2014, colleagues at KI alleged that Macchiarini’s papers made his transplants seem more successful than they were, omitting serious complications. Two patients treated at Karolinska died, and a third has been in intensive care since receiving a trachea in 2012. The Illinois patient also died, as did three patients in Russia. Bengt Gerdin, a professor emeritus of surgery at Uppsala University in Sweden who investigated the charges at KI’s request, concluded in May 2015 that differences between published papers and lab records constituted scientific misconduct. But Hamsten rejected that conclusion in August, based on additional material Macchiarini submitted later.

The documentary shows footage of a patient who says Macchiarini reassured him before the surgery that experiments had been done on pigs, when in fact none had taken place. It also follows the wrenching story of the first patient in Krasnodar. A 33-year-old woman, she was living with a tracheostomy that she said caused her pain, but her condition was not life-threatening. The film suggests that she wasn’t fully aware of the risks of the operation, and that Macchiarini and his colleagues knew about problems with the implant before the surgery. The patient’s first implant failed, and she received a second one in 2013. She died in 2014.

So in May 2015, an investigator concluded there had been scientific misconduct and, yet, Macchiarini’s contract is renewed in the fall of 2015.

Kerry Grens in a March 7, 2016 article for The Scientist provides information about the consequences of the latest investigation into Macchiarini’s work (Note: Links have been removed),

Karl-Henrik Grinnemo, a surgeon at the Karolinska Institute and one of a number of colleagues who voiced concerns about the conduct of fellow surgeon Paolo Macchiarini, is no longer a coauthor on a 2011 The Lancet study led by Macchiarini that described an artificial windpipe. Grinnemo asked to be removed from the paper, and the journal complied last week (March 3).

Grinnemo’s removal from the study is the latest in a string of repercussions related to an investigation of Macchiarini’s work. Last month, the head of the Karolinska Institute, Anders Hamsten, resigned because the institution’s initial investigation concluded no wrongdoing. Hamsten said he and his colleagues were probably wrong about Macchiarini; the institute has launched another investigation into the surgeon’s work.

A March 23, 2016 news item on phys.org announces Macchiarini’s firing from the Karolinska Institute and provides a brief description of his work with synthetic tracheas (Note: A link has been removed),

Sweden’s Karolinska Institute (KI), which awards the Nobel Prize for Medicine, on Wednesday [March 23, 2016] dismissed a Italian transplant surgeon suspected of research fraud and ethical breaches, in an affair that has plunged the renowned institution into crisis.

“It is impossible for KI to continue to have any cooperation with Paolo Macchiarini. He has acted in a way that has had very tragic consequences for the people affected and their families. His conduct has seriously damaged confidence in KI,” human resource director Mats Engelbrektson said in a statement.

Macchiarini, a 57-year-old visiting professor at Karolinska since 2010, rose to fame for carrying out the first synthetic trachea, or windpipe, transplant in 2011.

It was a plastic structure seeded with the patient’s own stem cells—immature cells that grow into specialised cells of the body’s organs.

The surgeon performed three such operations in Stockholm and five others around the world, and the exploit was initially hailed as a game-changer for transplant medicine.

But six of the eight patients reportedly died, and allegations ensued that the risky procedure had been carried out on at least one individual who had not been life-threateningly ill.

Macchiarini is also suspected of lying about his scientific research and his past experience with prestigious medical research centres.

“Paolo Macchiarini supplied false or misleading information in the CV he submitted to KI” and “demonstrated scientific negligence” in his research, said the institute.

H/t to Don Bright, a reader who informed me about this April 2, 2016 posting by Pierre Delaere (a long time Macchiarini critic), published in Leonid Schneider’s blog, For Better Science,

I have written this overview as a trachea surgeon working at KU Leuven and privileged witness of the “Tracheal regeneration scandal” from the very start.

Because of its immense scale, the scandal is difficult to grasp and explain. Fortunately, we have recently been provided with an excellent overview in the 3 x 1-hour documentary by Bosse Lindquist on Swedish national TV. Due to Paolo Macchiarini’s appetite for the spotlights and thanks to the professional standards of the Swedish top producer this is probably the very first case of a medical crime played out in the media. Anyone who has seen this brilliant investigative documentary cannot help but wonder why there are still people who doubt that this is a case of gross medical misconduct.

The story began in Barcelona in 2008 with the publication in The Lancet of a report on a regenerated windpipe, featuring Paolo Macchiarini (PM) as its first author (Macchiarini et al. Lancet 2008). This ground-breaking achievement consisted of bringing to life a dead windpipe from a donor, by putting it in a plastic box, a so-called ‘bioreactor’ together with bone marrow fluid (stem cells). A few weeks later, I wrote a letter to The Lancet, pointing out:

    “The main drawback of the proposed reconstruction is the lack of an intrinsic blood supply to the trachea. We know that a good blood supply is the first requirement in all other tissue and organ transplantations. Therefore, the reported success of this technique is questionable” (correspondence by Delaere and Hermans, Lancet 2009).

Delaere goes on to recount and critique the story of the first synthetic trachea,

…  PM had mounted bone marrow extract (‘stem cells’) on a plastic tube (‘bioartificial trachea’) in a plastic box (‘bioreactor’). After a day or two this creation was ‘successfully’ transplanted in a patient with a trachea defect. This occurred in the Karolinska hospital in July 2011 and was reported on in The Lancet shortly afterwards . Biologically speaking, the procedure is absolutely implausible.

In reality an important part of the windpipe had been replaced by a synthetic tube, and the presence of stem cells made no difference to this whatsoever.

For those not in the field, this procedure may still seem acceptable. A blood vessel can also be replaced by synthetic material because the material can grow into the sterile environment of the blood stream. However, this is completely impossible if the synthetic material is exposed to an environment of inhaled air full of bacteria. The laws of biology allow us to predict accurately what will happen after part of the windpipe has been replaced by a synthetic tube. After some time, the suturing between the synthetic tube and the surrounding tissue will come loose, leading to a number of serious complications. These complications inevitably lead to death in the short (months) or in the mid-long term (a few years). How long the patient will survive also depends on the options still left to treat complications. In most cases so far, a metal stent had to be implanted to keep the airway open in the sutured area.It is entirely predictable that additional complications after placement of the metal stent will ultimately lead to the patient’s death, usually by asphyxiation or by bleeding out after complete rupture of the sutures. This gruesome fate awaiting patients was clearly shown in the documentary. Replacing a part of the trachea by a synthetic tube can therefore be compared to death by medical torture. The amount of suffering it induces is directly proportional to the duration between implantation and the patient’s death.

Delaere describes his own and others’ efforts to bring these issues to light,

Since 2011, I have contacted both the President of KI and the Editors of The Lancet with well-documented information to clarify that what had happened was completely unacceptable. These alerts were repeated in 2013 and 2014. Since 2014, four doctors from KI, who had seen it all happen, have been collecting evidence to show the extent of misconduct [Matthias Corbascio, Thomas Fux, Karl-Henrik Grinnemo and Oscar Simonsson, their letter to Vice-Chancellor Hamsten from June 22, 2015, and its attachments available here; -LS]. Not only did KI not react to the doctors’ complaint, these doctors were in fact intimidated and threatened with dismissal. KI’s Ethical Commission came to a verdict of ‘no misconduct’ in April 2015 following an inquiry based on a series of complaints filed by myself [verdict available from SVT here, -LS]. The Lancet Editor did not even bother to reply to my complaints.

In the reports, eight patients were given synthetic tracheas with six now dead and, allegedly, two still living. Delaere comments,

… To prove that this transplantation technique is effective, reports about the long-term success of this technique in the first 2 patients in Barcelona and London is still being spread. What the real situation of the two patients is at the moment is very difficult to establish. For some time now, reports about these two cases seem to have disappeared from the face of the earth. After the air has been cleared in Sweden, the same will probably happen in London and Barcelona.

Comments

Sometimes medical research can be very dangerous. While, a 25% chance of success (two of Macchiarini’s eight patients undergoing the synthetic trachea transplant have allegedly survived) is not encouraging, it’s understandable that people in dire circumstances and with no other options might want to take a chance.

It’s troubling that the woman in Russia was not in dire straights and that she may not have known how dangerous the procedure is. It would have been unethical of Macchiarini to knowingly perform the procedure under those circumstances.

I am wrestling with some questions about the composite used to create the synthetic trachea and the surviving patients. My understanding is that the composite was designed for eventual deterioration as the patient’s own harvested stem cells fully formed the trachea. Whether the trachea is the one I imagined or he plastic one described by Delaere, how did two patients survive and what is their condition now? The first patient Andemariam Teklesenbet Beyene in 2011 had apparently completed his PhD studies by 2013 (my Dec. 27, 2013 posting). Assuming Beyene is one of the two survivors, what has happened to him and the other one?

As for Delaere’s comments, he certainly raises some red flags not only regarding the procedure but the behaviour of the Lancet editorial team and the Karolinska Institute (they seem to be addressing the issues by firing Macchiarini and with the  resignations of the staff and board).

There are two more twists to this story, which carries on in part 2.