Martin Birchall (far left), Paolo Macchiarini (second from right), and collaborators in 2010, after the first transplant of a stem cell–seeded trachea into a child.

PA IMAGES/ALAMY STOCK PHOTO

Two controversial stem cell trials could harm patients, critics say

LIVERPOOL, U.K.—Replacing a failing windpipe, or trachea, with one partially made from a patient's own stem cells once looked like the cutting edge of regenerative medicine. But the concept took a severe blow in 2016 with the dramatic fall of Paolo Macchiarini, a surgeon at the Karolinska Institute (KI) in Stockholm. Macchiarini was fired by KI for scientific negligence and has been found guilty of misconduct in more than half a dozen papers. Most of his patients have died, and Swedish prosecutors are considering whether to reopen a criminal case against him that was closed last October.

But is the idea underlying Macchiarini's work—"seeding" a scaffold with a patient's own stem cells, in hopes of regenerating a healthy, functional organ—still worth testing in patients? That's the question facing scientists in the United Kingdom, where two trials of stem cell–based larynx (voice box) and trachea transplants are planned but on hold in the wake of the scandal.

Both studies, led by former Macchiarini collaborator and University College London (UCL) laryngologist Martin Birchall, received approval from the Medicine and Healthcare Products Regulatory Agency more than 2 years ago and have obtained close to £5 million from U.K. funding agencies. An independent inquiry last year concluded there was no reason to cancel the trials, and UCL says they can proceed.

But some scientists say the studies, like Macchiarini's operations, are based on flimsy evidence and could harm patients. In November 2017, cellular and molecular biologist Patricia Murray and biochemist Raphaël Lévy of the University of Liverpool filed a detailed complaint with the U.K. Parliament's Science and Technology Committee, which is holding an inquiry into research integrity, in an effort to stop the studies. (They followed up with a second submission in January.) "I'd really like to see [the trials] taken off the table completely," Murray says. So would head and neck surgeon Pierre Delaere of the Catholic University of Leuven in Belgium, a ferocious critic of the trachea transplants long before Macchiarini's downfall.

Birchall did not respond to requests for comment; UCL has submitted a response to Parliament but said it could not answer questions pending the completion of the inquiry.

In the studies, a larynx or trachea would be taken from a donor and all its cells removed using detergents and enzymes. The outside of the structure would be repopulated with mesenchymal stem cells from the patient's own bone marrow, and the inside seeded with their epithelial cells. Then it would be grafted into the patient.

Birchall and Macchiarini first used this procedure to replace one of the bronchi—the ducts leading from the trachea to the lungs—in a patient in Barcelona, Spain, in 2008, a case globally publicized as heralding a new era of regenerative medicine. The duo replaced a child's trachea with the technique in 2010 before going their separate ways, reportedly amid a patent conflict. Macchiarini operated on more than a dozen other patients, but switched to using tracheas made from a polymer instead of donor organs in 2011. Meanwhile, the UCL team gave donor tracheas to two more children in the United Kingdom, and a UCL surgeon attended when Macchiarini operated in Italy on a U.K. adult.

So far, the operations occurred under "compassionate use" guidelines, which allow doctors to try untested treatments in patients with a serious or life-threatening illness when there are no other options. The clinical trials are designed to examine safety and effectiveness more rigorously. INSPIRE, a collaboration between UCL and regenerative medicine company Videregen, intends to recruit four patients suffering from narrowing or softening of the trachea, while a study named RegenVox would recruit 10 patients with similar defects in the larynx. Later, UCL and Videregen plan to lead a Europe-wide trial in 48 patients, which was awarded €6.8 million under Europe's Horizon 2020 funding program in 2015.

Delaere has long claimed that there is no evidence that stem cells can grow into new tissues on a decellularized or polymer trachea, calling the idea "completely unrealistic." In 2015, he accused Macchiarini and Birchall of misconduct in an eight-page document sent to UCL, KI, and two scientific journals, suggesting the pair was guilty of "the biggest lie in medical history."

I just don't see why there's a need to rush into these things until clear evidence is brought to bear.

John Rasko, Royal Prince Alfred Hospital

UCL set up a panel to examine Delaere's claims. Its 2015 report has not been made public, but a draft version seen by Science cleared Birchall and a UCL collaborator. But the report did cite a "misleading element" in a 2012 paper in The Lancet describing a patient given a tissue-engineered trachea. It said that, although there was no "deliberate fraud or intent to mislead," Birchall did not sufficiently acknowledge that the patient's recovery may have been aided by procedures not directly related to the stem cells, namely the introduction of a stent and a "tissue wrap" to support the transplant. The report also said Birchall had failed to present evidence that the stem cells "played any therapeutic role," and that he should be more careful in his papers and receive "education and training," lest he "jeopardise his future research efforts and subject both himself and UCL to reputational risk."

After Macchiarini's firing the next year, UCL put the trials on hold while another panel investigated UCL's relationship with Macchiarini. In September 2017, that group concluded that the trials had the appropriate approvals in place and should go ahead. It didn't examine the preclinical evidence underlying the studies in detail, however.

Murray and Lévy's submissions to the parliamentary committee echo Delaere's concerns and add several accusations. They say the five compassionate-use cases show that the procedure doesn't work and isn't safe. In two patients the transplanted trachea collapsed, and one died soon afterward; the other required further surgery and died some months later. Neither was in immediate danger of losing their lives before the transplants, the duo says, based on evidence from UCL's 2017 inquiry and a BBC documentary featuring one of the patients.

The duo also charges that Birchall's team provided inaccurate descriptions of its patients to funders and regulators. For example, in an application to the U.K. Medical Research Council obtained by German blogger Leonid Schneider, the researchers write that one of their patients "died of non-graft related causes," but in a recent case study in Stem Cells Translational Medicine, the team concludes that the death may have been the result of a failure of the transplant.

Animal studies underlying the procedure have problems as well, Murray and Lévy say. One key paper investigating the procedure in pigs provides "insufficient evidence to support the authors' claims," they write. They also assert that identical images showing transplanted larynxes appear to have been used in two separate papers, even though the papers describe distinct surgical procedures. Murray says the duo has referred the case to UCL as potential research misconduct, and that the university has told her it will look into the matter.

Birchall's statements on what the stem cells actually do contradict each other, Murray and Lévy add. Some documents, including the RegenVox trial's entry on ClinicalTrials.gov, state that they form new cartilage, but in one of the pig studies of larynx transplants, the authors acknowledge that they were unable to follow the fate of the stem cells and found "no evidence of regeneration of the de-cellularised cartilage."

UCL's response to the Science and Technology Committee, which is public, says that the deceased patients would also have died without treatment, and that the transplants offered them a chance to live longer. That three of five patients remain alive today supports the case for formal clinical trials, UCL says. When introducing new technologies, "It is rare for everything to work perfectly [the] first time," the university writes, "and the introduction of tissue engineered treatments is no exception." As to the animal studies, UCL doesn't address many of the issues raised by Murray and Lévy but says its researchers "have done as much as they can already to show safety and efficacy in animals," and further animal work would be unethical.

Other scientists say the jury is still out on the effects of stem cells in these kinds of grafts. "The impact of seeded cells for us is unclear at this point," says Tendy Chiang, a pediatric otolaryngologist at Nationwide Children's Hospital and The Ohio State University in Columbus, who is conducting preclinical research into tissue-engineered trachea transplants.

John Rasko, a clinical hematologist and pathologist at Royal Prince Alfred Hospital in Sydney, Australia, says U.K. funding bodies have a "declared enthusiasm" for research on stem cell therapy. But given the issues raised by critics, "to now have this substantial investment in Birchall and others' trials in the U.K. is something of concern," says Rasko, who is president-elect of the International Society for Cellular Therapy but says he's speaking in a personal capacity. "I just don't see why there's a need to rush into these things until clear evidence is brought to bear," he adds.

Once people were seeing pictures of the patients, maybe no one's really looking at the hard evidence so much anymore.

Patricia Murray, University of Liverpool

The parliamentary committee is expected to publish its report in the next few months, but it appears unlikely to render any judgment about Birchall's trials. A source at the committee says the inquiry's intention is to examine how institutions respond to allegations of research misconduct, rather than to investigate any particular case.

What will happen to the studies remains unclear. In the wake of UCL's 2017 inquiry, the INSPIRE consortium decided to conduct a further risk assessment. As a result, say spokespeople for the Cell and Gene Therapy Catapult, a nonprofit center that serves as the trial's sponsor, the group has decided to "gather more data" and "will only recommend the restart of any trials … if supported by expert opinion with regulatory and ethical approval." UCL did not respond to questions about the future of the RegenVox trial, but for now it remains listed as "suspended" on the university's website.

Murray says Macchiarini and Birchall both rode on the high hopes for stem cells. Media stories about their operations—sometimes with photos of patients taken shortly after surgery—projected an air of success that blinded even respected institutes and funders to potential flaws in the research, she says: "Once people were seeing pictures of the patients, maybe no one's really looking at the hard evidence so much anymore."

*Correction 30 March, 12 p.m.: An earlier version of this story incorrectly listed John Rasko's title at the International Society for Cellular Therapy.