For some bizarre frosting on this disturbing cake (see part 1 of the Macchiarini controversy and synthetic trachea transplants for the medical science aspects), a January 5, 2016 Vanity Fair article by Adam Ciralsky documents Macchiarini’s courtship of an NBC ([US] National Broadcasting Corporation) news producer who was preparing a documentary about him and his work,

Macchiarini, 57, is a magnet for superlatives. He is commonly referred to as “world-renowned” and a “super-surgeon.” He is credited with medical miracles, including the world’s first synthetic organ transplant, which involved fashioning a trachea, or windpipe, out of plastic and then coating it with a patient’s own stem cells. That feat, in 2011, appeared to solve two of medicine’s more intractable problems—organ rejection and the lack of donor organs—and brought with it major media exposure for Macchiarini and his employer, Stockholm’s Karolinska Institute, home of the Nobel Prize in Physiology or Medicine. Macchiarini was now planning another first: a synthetic-trachea transplant on a child, a two-year-old Korean-Canadian girl named Hannah Warren, who had spent her entire life in a Seoul hospital. …

Macchiarini had come to Vieira’s [Meredith Vieira, American journalist] attention in September 2012, when she read a front-page New York Times story about the doctor. She turned to [Benita] Alexander, one of her most seasoned and levelheaded producers, to look into a regenerative-medicine story for television.

…

When Alexander and Macchiarini found themselves together in Illinois for a period of weeks in the spring of 2013—brought there by the NBC special—they met frequently for quiet dinners. The trachea transplant on Hannah Warren, the Korean-Canadian girl, was being performed at Children’s Hospital of Illinois, in Peoria, and the procedure was fraught with risks, not least because Macchiarini’s technique was still a work in progress even for adults. (Christopher Lyles, an American who became the second person to receive an artificial trachea, died less than four months after his surgery at Karolinska.) “He’s a brilliant scientist and a great technical surgeon,” said Dr. Richard Pearl, who operated alongside Macchiarini in Illinois. Like others, Pearl described his Italian colleague as a Renaissance man, fluent in half a dozen languages. Another person, who would get to know him through Alexander, compared Macchiarini to “the Most Interesting Man in the World,” the character made famous in Dos Equis beer commercials.

In Peoria, Macchiarini’s medical magic appeared to have its limitations. Hannah Warren died from post-surgical complications less than three months after the transplant. Her anatomy “was much more challenging than we realized,” Pearl recounted. “Scientifically, the operation itself worked. It was just a shame what happened. When you’re doing something for the first time, you don’t have a textbook. It was the hardest operation I’ve ever scrubbed on.”

Then, there was the romance (from the Ciralsky article),

The personal relationship between Alexander and Macchiarini continued to blossom. In June 2013, they flew to Venice for what Alexander called “an incredibly romantic weekend.” Macchiarini bought her red roses and Venetian-glass earrings and took her on a gondola ride under the Bridge of Sighs. Like a pair of teenagers, they attached love locks to the Ponte dell’Accademia bridge, one of them bearing the inscription “B—P 23/6/13, 4 Ever.” Alexander told me that, “when he took me to Venice, we were still shooting the story … He always paid for everything … gifts, expensive dinners, flowers—the works. When it came to money, he was incredibly generous.”

It is a bedrock principle at NBC and every other news organization that journalists must avoid conflicts of interest, real or apparent. Alexander was not oblivious to this. “I knew that I was crossing the line in the sense that it’s a basic and well-understood rule of journalism that you don’t become involved with one of the subjects of your story, because your objectivity could clearly become compromised,” she told me. “I never once thought about him paying for the trip as him ‘buying’ me in some fashion, or potentially using money to influence me, because, from my perspective anyway … that just wasn’t the case. We were just crazy about each other, and I was falling in love.”

Alexander made her way to Stockholm at a later date (from the Ciralsky article),

Macchiarini was in Stockholm to attend to Yesim Cetir, a 25-year-old Turkish woman whose artificial trachea had failed. As Swedish television later reported, “It has taken nearly 100 surgeries to support the cell tissue around the airpipes. Her breathing is bad, and to avoid suffocation, her respiratory tract must be cleansed from mucus every fourth hour. She has now been lying in the hospital for nearly 1,000 days.” NBC’s special would come to include skeptical commentary from Dr. Joseph Vacanti, who questioned the sufficiency of Macchiarini’s research, but Cetir’s post-operative complications were not mentioned.

Prior to the NBC documentary’s (A Leap of Faith) airing, the romance became an engagement (from the Ciralsky article),

Macchiarini proposed to Benita Alexander on Christmas Day 2013, Alexander said. In the months leading up to the airing of A Leap of Faith, in June 2014, Macchiarini and Alexander went on trips to the Bahamas, Turkey, Mexico, Greece, and Italy. They went on shopping sprees and ate their way through Michelin-starred restaurants. Macchiarini even took Alexander and her daughter to meet his mother at her home, in Lucca. “She cooked homemade gnocchi,” Alexander recalled. Macchiarini’s mother shared pictures from the family photo album while her son translated. Emanuela Pecchia, the woman whom Macchiarini had married years earlier, lived only a short distance away. When Macchiarini informed Alexander, during a dinner cruise later that summer, that his divorce had finally come through, she recounted, he gave her an engagement ring.

…

In the months that followed, the doctor and his fiancée began planning their wedding in earnest. They set a date for July 11, 2015, in Rome. But their desire to marry in the Catholic Church was complicated by the fact that she is Episcopalian and divorced. Divorce would have been an issue for Macchiarini as well. However, Alexander said, Macchiarini insisted that he would fix things by visiting his friend and patient in the Vatican.

In October 2014, Alexander recalled, Macchiarini told her that he had met with Pope Francis for four hours and that the Pontiff consented to the couple’s marriage and, in yet another sign of his progressive tenure, vowed to officiate. Alexander said Macchiarini referred to himself as Pope Francis’s “personal doctor” and maintained that in subsequent meetings his patient offered to host the wedding at his summer residence, the Apostolic Palace of Castel Gandolfo.

Shortly after quitting her job in anticipation of her July 2015 wedding to Macchiarini, Alexander learned that Pope Francis who was supposed to officiate was in fact scheduled to be in South America during that time.  From the Ciralsky article,

As Alexander would discover with the help of a private investigator named Frank Murphy, virtually every detail Macchiarini provided about the wedding was false. A review of public records in Italy would also seem to indicate that Macchiarini remains married to Emanuela Pecchia, his wife of nearly 30 years. Murphy, who spent 15 years as a Pennsylvania State Police detective, told me, “I’ve never in my experience witnessed a fraud like this, with this level of international flair…. The fact that he could keep all the details straight and compartmentalize these different lives and lies is really amazing.

Ciralsky broaches the question of why someone with Macchiarini’s accomplishments would jeopardize his position in such a way,

To understand why someone of considerable stature could construct such elaborate tales and how he could seemingly make others believe them, I turned to Dr. Ronald Schouten, a Harvard professor who directs the Law and Psychiatry Service at Massachusetts General Hospital. “We’re taught from an early age that when something is too good to be true, it’s not true,” he said. “And yet we ignore the signals. People’s critical judgment gets suspended. In this case, that happened at both the personal and institutional level.” Though he will not diagnose from a distance, Schouten, who is one of the nation’s foremost authorities on psychopathy, observed, “Macchiarini is the extreme form of a con man. He’s clearly bright and has accomplishments, but he can’t contain himself. There’s a void in his personality that he seems to want to fill by conning more and more people.” When I asked how Macchiarini stacks up to, say, Bernie Madoff, he laughed and said, “Madoff was an ordinary con man with a Ponzi scheme. He never claimed to be the chairman of the Federal Reserve. He didn’t suggest he was part of a secret international society of bankers. This guy is really good.”

In addition to the romance, Ciralsky and Vanity Fair checked out Macchiarini’s résumé,

Vanity Fair contacted many of the schools at which Macchiarini claimed to have either earned a degree or held an academic post. While the University of Pisa confirmed that he indeed received an M.D. and had specialized in surgery, the University of Alabama at Birmingham denied that Macchiarini earned a master’s in biostatistics or that he participated in a two-year fellowship in thoracic surgery. In fact, according to U.A.B. spokesman Bob Shepard, the only record the school has for Macchiarini indicates that he did a six-month non-surgical fellowship in hematology/oncology—which according to the current Accreditation Council for Graduate Medical Education guidelines is 30 months shy of what is required for a clinical fellowship in that field. The University of Paris—Sud never responded to repeated requests for comment, but Hannover Medical School wrote to say that Macchiarini had been neither a full nor an associate professor there, merely an adjunct.

Comments

As I noted in part 1, there are medical science and ethical issues to be considered. As well, Macchiarini’s romantic behaviour certainly seems fraudulent as do parts of his curriculum vitae (CV) and there’s more about Macchiarini’s professional accomplishments (read Ciralsky’s entire January 5, 2016 Vanity Fair article for details).

The romantic and CV chicanery may or may not suggest serious problems with Macchiarini’s revolutionary procedure and ethics. History is littered with stories of people who achieved extraordinary advances and were not the most exemplary human beings. Paracelsus, founder of the field of toxicology and an important contributor in the fields of medicine and science, was reputedly a sketchy character. Caravaggio now remembered for his art, killed someone (accidentally or not) and was known for his violent behaviour even in a time when there was higher tolerance for it.

What I’m saying is that Macchiarini may be pioneering something important regardless of how you view his romantic chicanery and falsified CV. Medical research can be high risk and there is no way to avoid that sad fact. However, criticisms of the work from Macchiarini’s colleagues need to be addressed and the charge that a Russian patient who was not in imminent danger and not properly advised of the extremely high risk must also be addressed.

It should also be remembered that Macchiarini did not pull this off by himself. Institutions such as the Karolinska Institute failed to respond appropriately in the initial stages. As well, the venerable medical journal, The Lancet seems reluctant to address the situation even now.

Before dissecting the Alexander situation, it should be said that she showed courage in admitting her professional transgression and discussing a painful and humiliating romantic failure. All of us are capable of misjudgments and wishful thinking, unfortunately for her, this became an international affair.

More critically, Alexander, a journalist, set aside her ethics for a romance and what seems to be surprisingly poor research by Alexander’s team.  (Even I had a little something about this in 2013.) How did a crack NBC research team miss the problems? (For the curious, this Bryan Burrough April 30, 2015 article for Vanity Fair highlighting scandals plaguing NBC News may help to answer the question about NBC research.)

Finally, there’s an enormous amount of pressure on stem cell scientists due to the amounts of money and the degree of prestige involved. Ciralsky’s story notes the pressure when he describes how Macchiarini got one of this positions at an Italian facility in Florence through political machinations. (The situation is a little more complicated than I’ve described here but an accommodation in Macchiarini’s favour was made.) Laura Margottini’s Oct. 7, 2014 article for Science magazine provides a synopsis of another stem cell controversy in Italy.

Stem cell controversies have not been confined to Italy or Europe for that matter. There was the South Korean scandal in 2006 (see a Sept. 19, 2011 BBC [British Broadcasting Corporation] news online post for an update and synopsis) when a respected scientist was found to have falsified research results. Up to that  point, South Korea was considered the world leader in the field.

Finally,  if there are two survivors, is there a possibility that this procedure could be made successful for more patients or that some patients are better candidates than others?

Additional notes

Macchiarini is mounting a defence for himself according to a March 30, 2016 news item on phys.org and a Swedish survey indicates that the average Swede’s trust in researchers still remains high despite the Macchiarini imbroglio according to an April 15, 2016 news item on phys.org.

For anyone interested in the timeline and updates for this scandal, Retraction Watch offers this: http://retractionwatch.com/2016/02/12/reading-about-embattled-trachea-surgeon-paolo-macchiarini-heres-what-you-need-to-know/

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.