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Månad: januari 2016

Paolo Macchiarini may be cleared by Karolinska, but not by his peers

Swedish national television (SVT) shows the Italian “super surgeon” Paolo Macchiarini behaving in a highly questionable way. A three-part documentary that follows Macchiarini’s work during a full year gives a disturbing image of his medical practices.

Officially Macchiarini is cleared from the accusations of scientific misconduct by his employer, the prestigious Karolinska Institutet (KI) in Stockholm. But several serious questions remain unanswered.

These are questions about medical ethics and scientific truths. But also about the integrity and honesty of KI – the institute that awards the Nobel prizes in medicine – and of The Lancet – one of the world’s leading medical journals.

The famed doctor became a media sensation in December 2011 after an allegedly successful transplant of a bioengineered trachea to a patient living in Iceland. It was a world first and presented as a scientific miracle. New human organs could now be built in the laboratory. Macchiarini was hailed over the world for initiating a new era of regenerative medicine.

A plastic scaffold had been seeded with the patient’s own stem cells, and surgically inserted into the patient. According to the published results, this scaffold with stem cells had started a spontaneous self-assembly into a functional trachea “lined with a vascularised neomucosa, (…) partly covered by nearly healthy epithelium” according to the report published in The Lancet. In other words, the self-assembly was in full swing and a brand-new organ with blood vessels and a mucous membrane was forming inside the patient.

Later this statement and others like it have been seriously questioned. Firstly by four of Macchiarini’s colleagues at KI who participated in the operation. When the patient, a man from Eritrea with tracheal cancer, came in to KI for intensive care five months after the transplantation, there were serious problems with the seeded scaffold. The doctors had to widen the airway with a stent, and he was unable to cough up mucus that almost suffocated him. The bioengineered device didn’t work as expected. The doctors testify that the situation was critical, not at all like the description in The Lancet.

The KI surgeons who once were proud to be part of the pioneering medical team say they were shocked. One of them, Karl Henrik Grinnemo, says “We lived in denial until we realized how bad it really was.”

Later, when the patient had passed away, the autopsy showed no new tissue formation on the scaffold and the device could easily be lifted out of the body. It obviously didn’t work. Moreover, it actually damaged the man according to these doctors. They found bacteria, fungi and necrotic tissue around his synthetic trachea. He seems to have been rotting from the inside.

Matthias Corbascio, another of the doctors behind the accusation for misconduct:“We couldn’t imagine the number of lies that lay buried in these articles”

In his defence Macchiarini claimed that when they made the last check-up on the man before publishing this “proof of concept” in The Lancet, things looked good. But in the documentary we can see a video from a hospital in Iceland where the man recovered, made two months after the operation, several months before the Lancet article was accepted. This video tells a different story.

The Icelandic doctors try to make a biopsy to evaluate the progress of the expected regeneration of the new trachea. They find it difficult to extract any tissue with their equipment. They only find single cells; most of them dead and the tissue around the tube is heavily inflamed. “It feels like plastic, you can’t get any grip”, says one of the frustrated doctors about the surface of the trachea.

Consider this statement from one of the most open critics of the method, the Belgian surgeon Pierre Delaere, a man with wide experience of transplanting real tracheas:

The mechanism behind the transformation from nonviable construct to viable airway cannot be explained with our current knowledge of tissue healing, tissue transplantation, and tissue regeneration. In fact, cells have never been observed to adhere, grow, and regenerate into complex tissues when applied to an avascular or synthetic scaffold. Moreover, this advanced form of tissue regeneration has never been observed in laboratory-based research.”

What he says is basically that the whole idea of regenerating organs like this is a fantasy. According to him there is no way that you should expect any regenerated tissue. And this is exactly what the critics can see in the patients.

Dr Delaere is a very outspoken critic. In the SVT documentary he says bluntly, ”If I had the choice between one of these operations and the firing squad I would choose the latter. It is a much less painful way to die.”

The misconduct case concerns not only the Eritrean man and the article on the sensational transplant made on him. In total seven articles with Macchiarini as head author were criticized.

The Karolinska Institutet and it’s vice-chancellor Anders Hamsten, cleared Macchiarini of scientific misconduct in August 2015, and thereby overturned the verdict from the independent investigation of the case.

”Now that we have examined the allegations of scientific misconduct in all seven indicted articles, we have found that they contain certain flaws but nothing that can be considered scientific misconduct”, was the official statement to the press.

Hamsten claims that the article in The Lancet is basically a stringent and carefully investigated scientific case study. The independent investigator, prof emeritus Bengt Gerdin of Uppsala University stands by his original opinion. To him it is obvious that the report is “not in accordance with the clinical realities”, and that The Lancet article is misleading. What it states about the patient’s new trachea, says Gerdin, was not correct at the time of publication, and it never got any better.

Hamsten wants to make the accusation into a question of scientific disagreement, an issue of right and wrong that future research will clarify.

Quite everything is not perfect, though, but “Some aspects of Paolo Macchiarini’s research do not meet our high quality standards,” says Professor Hamsten. “We will now be remedying the deficiencies our inquiry uncovered with him.”

In spite of Hamstens decision in favour of Macchiarini, the Swedish Research Council (Vetenskapsrådet) decided already in June of 2015 to freeze Macchiarinis grants of 2 million SEK per year. In an official statement (swedish only) the director of the Council, Sven Stafström, says that Macchiarini has:

performed research without proper ethical approval, and in a number of cases has published false or incomplete statements in scientific journals.”

The Research Council is a government agency that grants more than 700 million USD yearly to scientific research.

Macchiarini is also under investigation by a Swedish state attorney (swedish only) for involuntary manslaughter and for causing bodily harm.

On the ethical approval issue, KI takes the stand that the operations were not experiments, research or trials. They were cases of emergency hospital care. Thus no approval from the ethical research committee was necessary.

Paolo Macchiarini is still employed by KI. His contract was renewed in December 2015.

The Lancet, on its side, adheres to the official KI line and stands by the original publication. In an editorial from September 5, 2015, the journal apparently tries to discredit the independent investigator, professor Gerdin, by calling his work flawed, mistaken and wanting to “drag the reputation of a scientist through the gutter” in a way that is “indefensible”.

The Lancet editor seeks to explain the accusations against Macchiarini as part of an “internal warfare at KI”.

Hamsten at KI, on the other hand, says in his press release that

In his investigation, Bengt Gerdin identified the key issues on which Karolinska Institutet had to pronounce its decision in an extremely structured manner and with great clarity. His statement was of considerable value to the main investigation process and pointed out flaws both in the activities on which the seven published papers were based and in the papers themselves.

The somewhat aggressive tone of the Lancet editorial strikes the reader as slightly high-strung. As if the journal had a stake in the matter, somehow. It does give one the impression that it is The Lancet that is involved in warfare.

However, in the theoretical world of science Macchiarinis method is now considered successful, since the article is there to be cited and learned from. And the experiments can be successfully replicated by other surgeons. Or can they?

Macchiarini and his different teams have performed this particular kind of operation, with a scaffold from the company HART of Holliston, Massachusetts, seeded with mesenchymal stem cells that are supposed to turn into a functioning trachea, at eight occasions. Six of the patients are no longer alive. One is in intensive care ever since the operation (three years) and the eighth had the device removed afterwards. He still lives.

All these cases are more or less tragic, but possibly the most disturbing one is the story of Julia Tuulik, a 33-year-old Russian mother who was breathing through a hole in the front of her neck, a tracheostomy, as the result of a car accident.

In 2012 she was convinced by her Russian doctors and by Paolo Macchiarini to go through with a transplant so that she could live a more normal life; to dance and play with her little son. She was to be part of a “clinical trial”.

The SVT documentary follows the case from the days before the operation, when the CEO of HART, David Green, sits on Julia’s bedside showing the scaffold from his company explaining the process:

”When it has the cells on it, this will look like normal tissue”, he says. ”It takes about seven days for your body to grow new blood vessels through the scaffold”.

He tells Julia to trust her surgeon Paolo, because he is “the best in the world”.

Julia died in October 2014 after a prolonged period of suffering. Her mother tells the story of her last months, that she had problems breathing, that she started to smell bad. In the end she coughed up pieces of her own tissue together with blue surgical thread.

No case report was ever published, but Macchiarini didn’t hesitate to describe Julia as a successful operation in German television at a time when it was clear that it wasn’t.

She had been re-operated in an effort to fix the problems, but the tube still didn´t perform as it should. “She is doing really well”, says Macchiarini to the German TV-interviewer. In reality Julia would be dead within five months.

To David Cyranovski at Nature he claimed that she had been “asymptomatic” two weeks before her death. Julia’s husband and mother say something quite different. “From day one until the end there was never a single moment when things were good”, says her husband Andrey Vasilyev. But he was never interviewed by any journal or tv-channel.

Macchiarini says to Nature that Julia’s death was unrelated to the surgery, but that it was pneumonia that killed her.

The Russian surgeon who took part in the transplantation, Igor Polyakov, says to SVT that today he regrets the operation.

This description is but a snapshot of the whole story. The main purpose of publishing this summary of the events as a blog-post is that on the web – the English speaking part of it – Macchiarini is still the hero of regenerative medicine – a man accused, even persecuted, but one who has been cleared of most accusations.

It might not be that clear-cut.

 

PS

Those who haven’t read this article in Vanity Fair about Macchiarini’s personal life should do so. I know that many in the scientific world frown upon such a publication. Can this story really be true? you might ask yourself. But I am willing to wager that the fact checkers at VF have done a better job than the reviewers for The Lancet when it comes to the Macchiarini case.

 

PPS

The day after part 3 of the SVT documentary Karolinska Institutet comments:

“My conclusion is that we need to examine and evaluate the claims made in the documentary, and will be reopening the inquiry if there is reason to do so,” says Karolinska Institutet’s vice-chancellor, Anders Hamsten.

Professor Hamsten reacted strongly to the material that was shown in the SVT documentary and that concerns operations Professor Macchiarini had performed in Russia.

“We’ve seen footage in SVT’s documentary that is truly alarming, and I empathise deeply with the patients and their relatives. Many of the circumstances, as portrayed in the programme, are wholly irreconcilable with KI’s values and with what we expect of our employees. If what the programme claims about patients being tricked or talked into undergoing surgery on dubious grounds is true, it is naturally altogether inacceptable.”

Professor Macchiarini is currently on a one-year research contract with Karolinska Institutet, and it is too early to say what will happen to his employment status.”

 

 

A new science blog, who needs it?

It is a wet and windy January in Gothenburg. Sleet and ice covering the sidewalks. What better self-invented assignment  than launching a neolithic project like this one? A blog in English for those overseas and far aways that might be interested in the goings on in the land of Nobels and extended parental leave.

This is a temporary place holder while I produce the first serious post. Stay tuned, it will turn up any day this week.

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