The deadly legacy of a stem cell charlatan

Avoiding a scandal

With Macchiarini’s career as a stem cell superstar ended, it’s tempting to draw a line under the whole affair. But a big awkward question remains: why was the scandal mostly confined to Stockholm? After all, Macchiarini implanted laboratory built windpipes into only three people there; he apparently did the same to another 17 elsewhere, including hospitals in Spain, Italy, Russia, the UK, and the US.4 Almost all these people are now dead and, so far as we know, none of the survivors got what they’d surely hoped for: a regenerated windpipe. Yet, to our knowledge, only the Karolinska has publicly admitted that, while there, Macchiarini engaged in scientific fraud and unethical human experimentation.

A hardened optimist might assume that Macchiarini committed his worst sins at the Karolinska. But that’s not the picture Experimenten painted. It suggested that Macchiarini behaved much the same wherever he went. Were the Swedish reporters right about him at Karolinska but wrong about him elsewhere? Perhaps. But we think there is a more plausible explanation: the other institutions that hosted Macchiarini managed to keep a lid on his misconduct better than Karolinska did.

Like any big organisations, universities and hospitals are jealous of their reputations and, for that reason, prone to hide their dirty laundry. That’s certainly what the Karolinska did. For years its vice chancellor, Anders Hamsten, tried his best to quash complaints raised by four of Macchiarini’s own colleagues. He might have succeeded had they not told their story to the reporters behind Experimenten and had this exposé not sparked public outrage. It was the combined efforts of whistleblowers, journalists, and the public that compelled the Karolinska to come clean. Perhaps the scandal didn’t spread beyond Stockholm because this combination of forces didn’t occur elsewhere.

Outside Sweden, Macchiarini has faced criminal charges only in Italy. These arose from his time at Careggi University Hospital, Florence, 2010-12, but had nothing to do with the windpipe replacements he carried out there, all of which failed miserably. Instead Careggi accused him of administrative misbehaviour, including forgery and abuse of office. After nine years of court cases and appeals, Macchiarini was cleared of those charges.

Apart from the Karolinska, only University College London has shown much concern about Macchiarini’s engineered airways. In 2017 it held a special inquiry into the matter that found that some mistakes had been made, but nothing major.5 UCL couldn’t have asked for a better outcome—especially as it put some distance between UCL’s head of regenerative medicine, Martin Birchall, and his former collaborator Macchiarini.

Birchall and Macchiarini had shared the glory for creating the world’s first tissue engineered airways. These were made of real windpipes, cut from cadavers and chemically stripped of all cells, leaving a scaffold ready to be repopulated with the patient’s own stem cells. After the pair parted company, in 2011, Birchall (mostly) stuck with this method, while Macchiarini developed an alternative: plastic scaffolds, made to order. With Macchiarini’s downfall, his plastic airways lost all credibility. Doubt also spread to the cadaver derived windpipes, but their reputation was to some extent rescued by UCL’s special inquiry, which found no fault with the work of Birchall and his team.

But the inquiry lacked the investigative grunt needed to find much fault. Its own report hints at the problem: “The Inquiry team are not experts in airway transplantation.” Apparently, they didn’t need such expertise because they were “focused principally on the governance and regulatory approval of cases.” A very narrow scope indeed, one bound to miss the bleeding heart of the matter. Surely the focus should have been on whether patients were properly cared for and their cases accurately reported.

Some of the issues and evidence that the special inquiry overlooked have come to light in the media under headlines such as “UK teen dies after stem cell windpipe transplant” and “‘Cover-up’ over UCL stem cell deaths.”67 These stories raised serious questions about the treatment of patients by UCL and its clinical partner, Great Ormond Street Hospital. For instance, was the windpipe replacement given to 15 year old Shauna Davison in 2012 really justified on compassionate grounds? Why wasn’t she and her family told about the death of another UCL patient, Keziah Shorten, who’d received a similar transplant? Why was Shauna’s new airway frozen and thawed before surgery, something bound to weaken it? And why wasn’t a tubular stent used to ensure it stayed open?

Not only was Shauna’s treatment questionable, her case was misreported in journal articles, grant applications, clinical trial approvals, patient information brochures, and other official documents. In some of these, her transplant was described as a “success,” with her death attributed to “unknown” or “unrelated” causes. In fact, she died two weeks after the operation when her new airway collapsed.8

This is just a sample of what UCL’s investigators didn’t uncover. Who knows what they’d have found had they looked more closely.

Success stories?

Birchall and his UCL colleagues continue to believe in Macchiarini’s early achievements. They insist that cadaver derived scaffolds seeded with stem cells really work. Occasionally. Enough to establish “proof of concept.” But let’s look at this proof.

In the scientific literature there remain only two big success stories: that of Claudia Castillo, the first person to receive a tissue engineered airway (Barcelona, 2008), and Ciaran Finn-Lynch, the first child to receive one (London, 2010). These were Macchiarini’s first breakthroughs in regenerative medicine, both made in collaboration with Birchall, and both reported in the Lancet.910 Macchiarini was the main author of the first, Birchall of the second.

According to these articles, Claudia and Ciaran were both doing well at the time of publication, their own stem cells busily turning their transplants into living, functioning airways. The truth, however, was rather different.

A couple of years before its special inquiry, UCL held an internal investigation into Ciaran’s case, after an external complaint from one of Macchiarini’s critics. The investigation found that Birchall’s paper downplayed the importance of a stent used to keep the new airway open and overstated the contribution of stem cells to tissue regeneration. The investigators said that “none of the evidence presented by Professor Birchall . . . demonstrate[s] that the addition of stem cells . . . played any therapeutic role.” In short, there was no proof of a breakthrough in regenerative medicine, a conclusion shared by others.11 Although UCL found a “misleading element” in Birchall’s paper, it put this down to error rather than deliberate fraud and decided to deal with it through “education and training.” It was all done on the quiet. UCL didn’t make its ruling public or ask the Lancet to correct the paper, much less retract it.

The misrepresentation of Claudia’s transplant is even more egregious. Here is the key outcome of Macchiarini’s 2008 Lancet paper: “The graft immediately provided the recipient with a functional airway, improved her quality of life, and had a normal appearance and mechanical properties at 4 months.” However, the Hospital Clinic Barcelona has an entirely different story. In 2018, its medical director informed the Lancet that Claudia’s new airway collapsed three weeks after her operation, needing a stent installed—the first of many—to keep it open. This was confirmed the following year by the hospital’s head of thoracic surgery in a letter published by the Lancet.12 The letter also revealed that Claudia struggled with her transplant for eight years. As it replaced only the left branch of her airway, she was able to survive its failure. It was finally removed in 2016 along with her left lung.

A stented windpipe cannot possibly look and act like a normal one, which means that the success that Macchiarini claimed in 2008 was bogus. All this is well known to the Lancet and the Hospital Clinic Barcelona, yet neither seems willing to draw the obvious conclusion: Macchiarini lied.

The Lancet has long resisted calls to retract Macchiarini’s 2008 paper, arguing that the Hospital Clinic Barcelona was best placed to investigate misconduct.13 It’s true enough that if the hospital requested a retraction the Lancet would be likely to oblige, as it did when the Karolinska asked it to withdraw two other articles by Macchiarini. Such requests are hard to deny. (That said, for five years the journal Respiration refused to heed the Karolinska’s recommendation that another Macchiarini paper be retracted. It only recently complied.14)

Does this let the Lancet off the hook? Not according to the authors of an open letter published last year in The BMJ.15 In their view the Lancet’s inaction shows that, like the hospital, it prefers to protect its reputation rather than denounce scientific fraud.

Recently the Lancet made a minimal concession to its critics by publishing “expressions of concern” for Macchiarini’s 2008 paper, along with its five year follow-up.16 Indeed, this was so minimal that the reasons for concern aren’t even mentioned, leaving readers to puzzle it out for themselves.

Deadly legacy

Millions of research dollars have been spent trying to build on Macchiarini’s bogus breakthroughs. Millions more might be spent if the scientific record is not set straight. The Macchiarini scandal forced Birchall and his colleagues to abandon three clinical trials, two in the UK (together worth almost £5m) and one Europe-wide (worth €6.8m). But some of Birchall’s associates have new plans and new funding to pursue their work on tissue engineered airways.

More important than wasted money is wasted life. The “success” of Claudia’s and Ciaran’s transplants justified giving other patients the same procedure, leading to the deaths of several, such as Shauna Davison and Keziah Shorten.8 Left unchallenged, Macchiarini’s legacy remains a deadly one.

We’ve all heard of dodgy clinics offering unproved stem cell therapies to desperately ill people who are unable to wait for mainstream medicine to provide a cure. Macchiarini’s case suggests that some of the world’s best hospitals and research institutes have done something similar.

We’ve named just a few of the institutions where Macchiarini performed his windpipe replacements. There’s every reason to think that, like the Karolinska, they each betrayed the trust of their patients along with that of the general public. To regain that trust they should undertake a full and independent investigation of Macchiarini and his associates. As the Karolinska was forced to do years ago.