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After four years, a verdict from Rome – Failure there too

«The outcome of the trial is severely negative,» «the overall outcome is strongly negative,» «the outcome is clearly unfavorable.» From Rome, Alessandro Nanni Costa repeated the concept three times in order to explain the judgment of the National Transplant Center (Cnt) – of which he is the director – on trachea transplants conducted by Paolo Macchiarini in Italy.

This is the lead paragraph of an article in yesterday’s Corriere Fiorentino, a Florence daily, translated into english.  Four years after the fact there is finally a verdict on Macchiarini’s transplants  from the medical authorities in Rome.

In the past, Corriere Fiorentino had already consulted the National Transplant Center, without obtaining comprehensive and complete responses. Now, after years of silence on the part of the Italian health care and scientific authorities (as well as political ones), there is a verdict. And Nanni Costa’s words represent a first real judgment on the effectiveness of transplants carried out by Macchiarini.”

The situation reminds  bit about the one in Sweden, where a number of responsible parties were aware of inconsistencies and suspicions of foul play, but nobody did or said anything until media blew the whistle.

It is also a fascinating example of how well Macchiarini has been able to compartmentalise his life. What happened in Italy stayed in Italy, the nature of the russian operations were allegedly unknown in Sweden, and the fabulous US wedding plans came as a surprise, even for the Swedish tv-producer who followed Macchiarini for a whole year. A master of deception. (Who is still recognised as a surgical pioneer by The Lancet, by the way).

The dangers of being a science reporter

In March 2012 The Lancet published a short portrait of Paolo Macchiarini. The text is based on a telephone interview made with a man on the go. With the knowledge we have today, parts of the first paragraph gives an almost surreal impression, particularly because you read it one of the most trusted medical publications in the world:

 

”In June, 2011, Macchiarini and his colleagues at the Karolinska Institutet in Stokholm (sic), Sweden, successfully undertook the world’s first transplant of a trachea made entirely from a synthetic nano-composite scaffold, seeded with the recipient’s own stem cells. “Although progress after such experimental therapy will have to be monitored closely”, Macchiarini explains, “so far the patient is doing better than great”. But how about the doctor? That, it turns out, is slightly more complicated.”

How many misleading statements can you find in that single paragraph?

As a science journalist I know the constant risk of being caught up in the hype surrounding the  conquistadors of science. It could have been me, I know that.

But still, why didn’t anybody ask him about the lab work behind the ”success”, or the mechanisms behind the sensational tissue regeneration? There were red flags flying, from Prof Delaere particularly.

The Lancet article portrays PM as a man who boldly keeps moving across the world – ”“I think if you stay in a single place for your entire life you restrict your capacity”, he says”.

He is almost like a shark who can’t stop swimming. Or like a con man  who constantly has to find new victims to seduce.

There is an obvious lesson here.

The question today is how could they recruit Macchiarini at all?

Less than a week after the airing of the third and final part of the tv-documentary on Paolo Macchiarini (PM) and his medical activities, the main issue in Swedish media and among medical professionals here is not whether the man has done something wrong. That is beyond doubt. The main question is how the recruitment of the star surgeon ever was made? Who was responsible and how much did the leadership at Karolinska Institutet (KI) know about him?

Leading daily Svenska Dagbladet of Stockholm presents today documents that show that the heads at KI were well aware of the fact that PM was accused of fraud in Italy while the recruitment was in process.  The accusations later became a criminal investigation which is still ongoing.

The KI professors then sent a letter to an Italian politician who was a known supporter of PM to ask him for a letter of recommendation, saying among other things

”We have also been informed  from different sources about the troublesome situation in Italy, not least in the media where Dr Macchiarini is involved in an unfortunate way.”

The paper also notes that the fact that ”renowned science journalists said that KI acted correctly when they cleared PM last year” (from the allegations of misconduct, TL) made the case even more complex.

For instance claimed renowned The Lancet that:

”First, responsibility for investigating allegations of research fraud falls to the institution where the work in question was completed.”

This is somehow The Law, according to The Lancet. Don’t let outsiders in to check your dirty laundry.

In this case, this principle didn’t work out well. Svenska Dagbladet writes:

”This case has showed us one thing – KI is not able to scrutinise itself. Instead, the media had do it for them. If this is a systematic problem or an internal one remains to be seen. Two other facts are clear, the Macchiarini case and the handling of it will go to history as one of the worst research scandals in Sweden.

 

Who will perform the next transplant with a plastic tube from HART? The Lancet still says it’s OK. (Karolinska and Macchiarini contd)

The miraculous method of growing new human organs inside the body of patients is still valid. You can read how to do it in The Lancet. Everything went fine, according to the authors. Critics, on the other hand, say that the article is full of misleading statements and is a potential recipe for disaster.

Eight patients have been subject to transplants from teams led by surgeon Paolo Macchiarini. Seven of them are dead. A number of them suffered from life-threatening conditions even before the operations, but the severity of their problems has been questioned by investigators and media in some cases. And in one case particularly we know that the patient, Julia Tuulik, could look forward to living many more years with her tracheostomy. That is if she hadn´t accepted an artificial biogenerated plastic trachea, a device from HART, Harvard Apparatus Regenerative Technology from Macchiarini and his team.

Macchiarini is now being investigated by his employer, Karolinska Institutet (KI) in Stockholm, mainly for his activities in Russia, especially the treatment of Julia Tuulik. This is based on information presented in the SVT documentary aired in Sweden in January. And it looks like he is going to lose his job over the activities in Krasnodar, activities the KI leadership claim they didn’t know anything about until they were exposed on tv.

It is still an open question whether KI will have a new look at the allegations of scientific misconduct against PM. The allegations concern seven articles connected to the work with the artificial tracheas. One of them is the “proof of concept”-study from 2011.

The KI leadership cleared PM from the allegations in December August. The study was not marred by misleading statements and the results will stand, according to the final verdict.

For anyone who has read the conclusions of prof emeritus Bengt Gerdins thorough investigation of the case, and also seen the video documentation on the status of the patient on tv, this decision seems more or less absurd.

Professor Gerdin can show, with documents like the hospital journals and video footage to support him, that a number of the key claims of the study are overstated, misleading or simply false.

Just one of several examples: The study says “The biopsy sample 2 months after transplantation showed large granulation areas with initial signs of epithelialisation and more organised vessel formations, and no bacterial or fungi contamination.”

(all Gerdin quotes from his unpublished letter to Vice Chancellor Hamsten written after PM was cleared. TL)

This means roughly that the regeneration had started. The new tissue was forming, with blood vessels, in a healthy environment.

But the records from pathologist Béla Bozóky – one of the many co-authors of this study – describes the same material as, biopsies from transplanted trachea with necrotic connective tissue with fungi and bacteria…

…meaning that the tissue is dying and showing infections of both bacteria and fungi.

Just one more example:

In a later paper PM claims that”After 12 months, an almost normal airway and improved lung function were assessed.” (we are still talking about the same patient, the ”proof of concept”-case.)

The medical record is clear on the state of the transplanted man at this point in time. Gerdin:

there was practically a total occlusion of the right primary bronchus which had been widened with a stent, and also a fistula. I developed this further in my first investigation and I am adamant in my opinion, which is the same now as it was then. There are facts in the medical record that says that the patient was in a bad state. The study says something different! I am sorry, but I really can’t understand how this can be explained away and how Macchiarini’s reply can be said to be ”satisfactory”.

An “almost normal airway” is in real life almost totally clogged on the right side. There was also a hole (fistula) in the trachea. The trachea was artificially widened to let the man breathe. Things were really bad.

But since KI has exonerated Macchiarini, the articles are still good. And as long as KI doesn’t reopen the investigation, they will remain in the scientific record. Which means that HART, of Holliston, Massachusetts still can market their plastic devices with statements like

“Our first generation tracheal implant has been used successfully in five adult human implant procedures.”

One of these ”successful procedures” is the prolonged suffering of Julia Tuulik.

As an aside, the share price of HART soared in August  when KI announced that Macchiarini was cleared; up 34 per cent.

How does The Lancet handle the situation? Well, we will see what happens if the investigation of misconduct is reopened. Until now they seem to have followed the simple principle of letting the process have its course and just follow the official decision, which is that no misconduct has been done and that the article is good.

But what surprises is the triumphant (it is hard to characterise it differently)  greeting of Macchiarini’s clearance in a Lancet editorial of Sept 5 2015. They really don’t sound very neutral. See for instance their frank opinion that ”the university needs to review its procedures for investigating allegations of misconduct” because this process (Gerdin’s investigation) was ”flawed”?

How did they know it was flawed? I wonder. It is a strange statement when you consider that KI Vice Chancellor praised it. Does The Lancet have access to privileged information in the case?

I just want to remind the reader that the whole idea of creating new human organs through the stem-cell seeding of a plastic scaffold and then inserting it into the patient, is a method that was untried before these “successful processes”. It was unheard of, almost science fiction. There has been hope and dreams and visions about regenerative medicine like this, but we were far from there yet.

In spite of that, the Macchiarini transplantations were accepted at face value, with cheers and glory, only on the evidence from what the team wrote in the formal scientific studies. And those studies are still valid. Ready for replication. At least for a while longer.

info on Hart share price added 16.20 1/2, thanks Johan Frisk

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.

Coming up for air

Coming up for air

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