The Borderline

Science stories from the Near North

Månad: februari 2016

Keep cool, says Lancet editor

To Swedish medical newspaper ”Dagens Medicin” Richard Horton, editor in Chief of The Lancet , says that it is essential not to cast judgment too soon on Paolo Macchiarini.  The venerable journal waits for an official verdict from the new investigators of scientific fraud.

Innocent until proven guilty, is the principle, which is all well. But you may ask how The Lancet could publish such controversial  articles in the first place. How could the misleading information in the text pass by the reviewers? Is peer review like post-modern text analysis, where only the words on the page count, and nothing from the real world outside should interfere?

I know personally some of the investigative reporters who worked on the case already more than six months ago. They asked me if the reviewers who approved of the manuscripts didn’t have access to the medical records of the patients. Since I work with science issues they supposed I would know.  I said I’m not sure, but it seems like they don’t since the two sources say radically different things.

Already back then a lot of people were aware of the fact that when the Lancet article said ”the patient is fine”, the medical record said ”he’s dying” – to put it bluntly.

So the reporter in question looked at me, mouth agape, and said ”What?!” For someone working professionally with documentary facts it seemed unbelievable that the scientific fact is what the doctor chooses to present with no corroborating record .

The Macchiarini-transplants seemed to good to be true. Shouldn’t they have been treated accordingly? You know ”if something seems to good to be true, it probably is” is an age old antidote against con men.

Here is a good recap of the Macchiarini-story for a Canadian audience. We are still waiting for the UK media to wake up. The latest headline on the topic in The Guardian was How laboratory-grown organs will transform our lives. Transform lives, indeed.

 

Making waves after 100 years

It’s been thoroughly reported by now , but here is an added twist to the confirmation of Einsteins General theory of Relativity by the gravitational  wavehunters at LIGO.

Albert Einstein received the Nobel prize in physics for 1921 – but he got it in -22. By then it was more or less expected that Einstein was about to get the prize sooner or later. He had become the world’s most eminent scientist, and he already had an agreement with his first wife, Mileva Maric, how to divide the money when it eventually would arrive.

But the prize was awarded for his work on the photoelectric effect.  Not for his relativity theories – the special and the general. One of the important factors that held the Royal Academy of Sciences from rewarding that work was the adamant opposition from the great philosopher of the time, the frenchman Henri Bergson.

Here is the introduction of  the presentation speech by Svante Arrhenius (the very man who demonstrated the Greenhouse effect on the earth’s climate).

Your Majesty, Your Royal Highnesses, Ladies and Gentlemen.

There is probably no physicist living today whose name has become so widely known as that of Albert Einstein. Most discussion centres on his theory of relativity. This pertains essentially to epistemology and has therefore been the subject of lively debate in philosophical circles. It will be no secret that the famous philosopher Bergson in Paris has challenged this theory, while other philosophers have acclaimed it wholeheartedly. The theory in question also has astrophysical implications which are being rigorously examined at the present time.

Einstein wasn’t there. He was on a lecture tour to Japan. If he had been present he might have been a bit pissed off at hearing about Bergson’s criticism once again, in this place, and from this guy, a fellow scientist. But that’s how strong the intellectual influence of Bergson was in the early 1900:s.

Bergson didn’t like Einstein’s description of time. For him, Time was a fundamental aspect of being, something intuitive that shaped our perception of life and the universe. Not something that could be dilated or contracted by the speed with which you travel through space. Bergson considered the theory of relativity as a piece of metaphysics that Einstein had slammed upon physics. Something that empirical science shouldn’t dabble in.

Einstein is quoted as replying to the frenchman that ”there is no such thing as philosophical time”.

The first corroborations of Einsteins predictions came right after the Great War, in 1919, when Arthur Eddington saw that the light from stars was bent by the gravity of the sun. Those reports made headlines all over the world, for instance the wonderful NY Times front page ”Lights All Askew in the Heavens”

But Bergson’s voice still carried such weight that the physicist Arrhenius agreed that the theory  ”pertains essentially to epistemology”.  And the interesting phrase ”the theory in question also has astrophysical implications which are being rigorously examined at the present time” is of course very true – and prophetic. Now it has been so rigorously tested that very little remain to test.

Bergson himself got the prize for literature a couple of years later. But in the test of time Einstein wins hands down, of course.  Very few people read Bergson today, and few even know the basic tenets of his philosophy. A fact that gives an interesting perspective on the ups and downs of intellectual fashions. I sometimes compare the prizes in physics and literature from the same year to see whose heritage lives on and who is more or less forgotten.

Here’s a short list

1901 Phys: Röntgen  Litt: Sully Prudhomme

1903 Becquerel + the Curies Litt: Björnson

1918 Phys: Max Planck       Litt: None but 1919 Carl Spitteler

1932 Phys: Heisenberg      Litt: John Galsworthy

and so on…I have chosen some pretty famous physicists, agreed, but in general it seems that science has the longer shelf life.

Lancet almost reacts

One of the four surgeons who accused Paolo Macchiarini of scientific fraud (yes I prefer that term) has during the last months repeatedly tried to have his name erased from the ”proof of concept”-article in The Lancet, but without result.

 

After being prodded by the science department of Swedish Radio, editor in chief, Richard Horton of The Lancet  says he will look into it.

The problem is that the Lancet says that they need to discuss the matter with the other authors – among them PM himself…

But they have no intention of publishing any sort of comment on the controversy, as long as there isn’t any official verdict on the fraud issue.

Fair enough, you may say. But still – this is not a simple scientific disagreement. It is a scandal of wide proportions. The exoneration, which was greeted with joy in The Lancet last year, is now inhibited and a reinvestigation is under way. Why not retract, and comment on that, and on the gullible portrait of the great surgeon after his disastrous operation.

Swedish Radio

 

Hamsten resigns from Karolinska: ”Macchiarini comitted misconduct”

Vice Chancellor Hamsten resigns from Karolinska Institutet and in a statement he is as clear as he can be at this point in time  on the issue of the allegations regarding scientific misconduct from Macchiarini. Now he knows. Hamsten mentions for instance the state of ”the first patient” in Iceland, things that has been shown on Swedish tv already. The truth is slowly becoming officially established.

During the last few days it has become obvious that the information possessed by KI when the matter was investigated was not complete. Last Wednesday we were given a new impression of the period following the operation in Iceland on his first patient, whose case is the basis of some of Macchiarini’s articles. During the last few days KI has also received information that implies serious inaccuracies in an article describing trials with artificial tracheae in rats. This information was totally new for KI. We are now endeavouring to investigate this information thoroughly and arrange an independent examination. But there is much to indicate that the judgement reached by KI last summer should be amended to scientific misconduct, which in plain language means research fraud.”

Read the whole statement at daily Dagens Nyheter 

It’s Darwin Day!

(To celebrate Darwin Day, here’s a translated excerpt from an old article, a part of a series on the basics of evolution from Allt om Vetenskap published during the 150 years anniversary of ”Origin of Species” 2009.

This is the end part of a piece on evo-devo, the connection between evolution and fetal development and the latest research in that field at that time.  )

We are Family

The night vision of the owl, the small black dots along the edge of a mussel shell and the shimmering composite eyes of the dragonfly are all constructed with the help of a small group of very specific signalling proteins. You can even find the same proteins in a jellyfish.

One of the key genes for making an eye is called PAX-6. The protein produced by PAX-6 taken from a mouse can start the making of an eye in a housefly. This is proof of a deep kinship.

A carefully tuned interplay between the signalling proteins in the genetic toolbox results in a complete individual. Controls are turned on or switched off in a specific order, for a certain time. It is this chemical interaction that enables a limited number of genes to create the infinite variations we see in nature, and among all the extinct species we only encounter as fossils.

Changes in key genes opens up new possibilities in evolution. Small changes in fetal development can have major consequences in the long run.

A few more molecules of a transcription factor or an enhancer protein at precisely the right place and the right time can give a slightly longer leg, a beak that is just a littler harder or a skeleton with a thinner bone mass. Variations that can give an advantage in life and make its way into the gene pool and live on into the future.

And we are of course part of this endless variation too. You might say that all species come from the same factory, even though we are widely different models. You just need to look carefully to see that we have the same brand name stamped into our genome.

Once upon a time, hundreds of millions of years ago in the Cambrian seas, there existed a tunicate, a primitive marine animal maybe like a small sea squirt.

In its larval stage it swam for a short period in the water before it fastened itself on a rock surface. The rest of its life it lived a stationary life, straining the passing water and living off whatever nutritious particles that happened to float by.

As a larva it had a small string of neurons along the backside to help it move around. This string disappeared when it was time for the sedentary adult life.

But one of the larvae once had a technical hiccup in one of the genes that control the time plan for the construction of its body. It kept the string of nerves throughout life. That made it the first chordate animal. And thus it became the ancestor of all insects, fish, reptiles, birds and mammals living today. Us included. You can see it in the dna.

Darwin_restored2

Av Elliott & Fry – Library of Congress

What does The Lancet say??

I get this question from curious readers and of course I wonder myself. Reporters from all over the world must have been pestering them for comments during the last few weeks, and you might think it would be a good idea to post something on the web site. Maybe just something like ”we are awaiting an authoritative decision from Karolinska in Stockholm re the research/medical activities of Paolo Macchiarini in order to see if that possibly could affect the publication of certain disputed articles…etc” . But no.

They seem to stick to their guns.  The comment from the press department is still:

Dear Tomas,

Thank you for your email. We have nothing to add to our previously published comments on the topic.

Best wishes,

Just as a reminder, the latest comment:

Dragging the professional reputation of a scientist through the gutter of bad publicity before a final outcome of any investigation had been reached was indefensible. 

That is a statement that they may come to regret. The Royal Swedish Academy of Science has asked the journal to at least add the fact that the patient in the ”proof of concept article” actually died. That would be a start.

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

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