It was the case of the superstar surgeon, the prestigious Swedish institute and the ill-fated windpipe transplants that escalated into allegations of misconduct, dismissal and a criminal investigation.
Now, a leading British university has launched an inquiry into its own links with the endeavours of Paolo Macchiarini, the surgeon at the centre of the trachea operations following which six patients died.
The surgery, pioneered five years ago with the world’s first synthetic windpipe transplant at Stockholm’s prestigious Karolinska Institute, appeared to mark the beginning of an era in which artificial organs could be created from scratch by scientists and seamlessly integrated into the human body.
However, the remarkable success story began to unravel. In March, the Italian surgeon was dismissed from the Karolinska Institute amid an unfolding medical scandal and Swedish prosecutors are conducting a criminal investigation.
Now, in a case that has sent ripples across the scientific world, University College London has launched an inquiry into links with the controversial surgeon.
The latest investigation will probe its relationship with regenerative medicine research that may have taken place at Karolinska. Several of its senior scientists contributed to the procedures pioneered by Macchiarini, in which donor or synthetic tracheas were seeded with the patient’s own stem cells with the aim of creating new, functioning organs.
There is no suggestion that the UCL academics are implicated in any misconduct.
The regenerative surgery initially appeared to have gone well, and was described as successful in high profile journal articles, but it later emerged that six of the eight patients to receive synthetic tracheas had died, while another remains in intensive care. Karolinska’s vice chancellor resigned and its entire board were sacked earlier this year after they continued to back the Italian surgeon despite warnings of clinical and scientific misconduct.
Karl-Henrik Grinnemo, a surgeon who worked alongside Macchiarini at Karolinska, said of his former colleague that there was always a sense of emergency that led to him bypassing standard ethical safeguards in international collaborations.
“It was ‘They’re severely ill and they will die very soon and ... we can’t wait to get the permissions from the regulators’,” he said. “Everything was always in a hurry when it came to Paolo Macchiarini.”
Alexander Seifalian, a former UCL professor of biomaterials, created the first synthetic trachea to be transplanted into a patient. The 36-year old Eritrean man, Andemariam Beyene, had been suffering from advanced tracheal cancer and died two-and-a-half years after the transplant. Seifalian was dismissed from UCL in July, after a tribunal in an unrelated case found that he had dishonestly obtained £24,000 from an overseas student.
Seifalian, who had developed a polymer material to make artificial ears and noses, said he agreed to produce a synthetic trachea in just 10 days after being approached by Macchiarini, who told him his patient had only two weeks to live. In a 2013 TED talk, Seifalian recalled asking his PhD student to obtain sheep and pig tracheas from the butchers, because they did not know what the organ looked like.
“I said ‘Go on Google and type in trachea’,” he recalled in the talk.
According to Grinnemo, who assisted in the operation, “none of the [Stockholm] patients needed an operation that urgently. They would have survived even years. You could have waited for the regulators to look at the material and the cells.”
Grinnemo later concluded that the entire synthetic trachea concept was doomed to fail because the plastic would inevitably become infected as it was exposed to bacteria and viruses with each breath, adding that he now views the synthetic transplant as a “death tube”.
While the material was approved as safe for clinical use, the actual trachea was never formally assessed as a new medical device, meaning this risk was not fully considered.
Seifalian told the Guardian: “At the time he came to our laboratory and he said this is the only chance of survival for this patient ... Yes if we had a longer time, we would have made a better scaffold. Everything was in a rush.”
Seifalian later made a synthetic trachea for a 20-year-old British woman, Keziah Shorten, who was treated at University College Hospital London in 2011.
Martin Birchall, a UCL professor of laryngology who coordinated the surgery, said that on the back of positive reports from Karolinska, the team were given approval to perform a synthetic trachea transplant under compassionate use rules. The surgery allowed Shorten, who had been in a critical condition in intensive care following cancer treatment, to return home for a brief period, but she died three months later.
“At the time it was the rational thing to do,” said Birchall. “We wouldn’t do it again now.”
Birchall had collaborated with Macchiarini on a transplant carried out in a Spanish clinic in 2008.
He too recalls a sense of urgency when helping to prepare the donor trachea that had been stripped of its cells and re-populated with stem cells taken from the bone marrow of the 30-year-old patient, Claudia Castillo.
Birchall, then at Bristol University, was given permission by the Human Tissue Authority to prepare the cells in a veterinary laboratory, that was not licensed for clinical applications. In a 2008 letter the HTA said it would not stand in the way of what “could in this particular case be life-saving therapy” for a “carcinoma patient”.
The surgery was required because one branch of Castillo’s windpipe (the bronchus) had been damaged by a TB infection. Her left lung was at risk of being surgically removed, but she was not at immediate risk of dying, according to the Barcelona clinic where she was treated.
Birchall told the Guardian that he believed the additional risk this carried was justified because “my firm belief was her life was in danger and we needed to move quickly”, adding that even so he would not have carried out the work without HTA approval.
There is no suggestion that the cells caused any health problems, but Castillo suffered extensive complications and ultimately had her lung removed earlier this year, raising questions about whether the risk was warranted.
In a statement, UCL said: “Following recent events at the Karolinska Institute in Sweden relating to some aspects of regenerative medicine research, UCL’s Vice Provost (Research) has instigated a special inquiry in order to establish the nature and scope of regenerative medicine research at UCL and to establish the nature of UCL’s relationship with regenerative medicine research that may have taken place at the Karolinska Institute.”
Macchiarini rejected claims that he misrepresented the clinical condition of patients to collaborators. Of the first synthetic transplant, he said: “All of us involved in Andemariam Beyene’s care wanted to give him the very best chance possible, and he and his family expressed their gratitude for the extra years we gave him.”