Shauna Davison: 'I might have had her for a bit longer'
British teenager Shauna Davison was given an experimental transplant in 2012, in the hope of prolonging her life. Her mother says she was told in advance about two patients who had survived a similar operation - but not about others who had died. The BBC's Deborah Cohen asks whether Shauna, who died after two weeks, was a casualty of the rush to develop stem cell technology?
Shauna Davison was born with one lung, a cleft palate and a major heart defect. But despite spending her life in and out of hospital she remained a happy child.
"Her illness never got her down and she always had a smile on her face," says Shauna's mother, Karen Davison. "Everyone was so nice to her. They looked beyond her problems."
When she was 12 weeks old, doctors found problems with her trachea - or windpipe. It was very narrow and when it became obstructed, she couldn't breathe. She was given 48 hours to live.
A surgeon in Leeds came to the rescue. David Crabbe warned that it might not work, but he managed to rebuild Shauna's windpipe out of her ribs.
Shauna had to stay in hospital for six months and had ring-shaped stents put in her windpipe to keep it open.
Mr Crabbe was really caring, Karen Davison says. "The hospital was outstanding."
Over the years, Shauna's stents needed dilating as she grew bigger. She had a tracheostomy - an opening in the front of her neck - to help her breathe.
"There were times we didn't think she'd make it because she kept collapsing," Karen Davison says.
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At home in Middlesbrough, she learned how to change Shauna's tracheostomy tube, use a ventilator, do physiotherapy to help her clear her airway, suction her airway, do CPR, and give her intravenous antibiotics.
"I did everything for her," she says. "Shauna coped marvellously. But she didn't know any different."
An avid Middlesbrough Football Club fan, Shauna loved wearing a football kit. She went to a mainstream school, with the support of a carer, where she could mix with other children.
"She was a cheeky child, but loved by everybody," her mother says. "She brightened everyone's day."
Shauna had many operations but she'd always come through. At times, she didn't go near a hospital for ages, Karen says.
A time came, however, when David Crabbe told her that his technique for treating Shauna was no longer going to be sufficient. Her airway was too small and they would have to look for other options.
"Mr Crabbe showed me pictures of a normal airway and her airway. It was tiny," Karen Davison says.
Shauna started to go to Great Ormond Street Hospital (GOSH) in London for tests and to have her stent changed. In 2011, doctors there told her the airway wouldn't last much longer.
At 15, Shauna suffered a respiratory arrest - a serious incident in which she became unable to breathe - and the family was told about pioneering surgery by Prof Martin Elliott, a cardiothoracic surgeon and former medical director of Great Ormond Street Hospital.
"They said there'd been some research into tracheal transplants and there'd been two other cases where it'd been done, but they couldn't discuss them with me because of patient confidentiality," Karen Davison says. One of them was a 10-year-old boy, she adds.
"It would be the only chance she'd have."
Shauna's transplant wasn't a conventional one.
She would receive a donor windpipe, but it would be laced with her own stem cells, making it almost like her own. She wouldn't need drugs to stop her body rejecting it. It was at the forefront of the new stem cell technology - and still very experimental.
Doctors can use experimental treatments if someone is terminally ill and there is no alternative treatment. It's called "compassionate use".
Karen says she was told Shauna wouldn't need a tracheostomy or a ventilator and she'd lead a normal life. But she was told about risks too, she adds - Shauna might still reject the transplant, and having a general anaesthetic is never risk-free.
Martin Elliott had previously worked closely with the internationally renowned Martin Birchall, professor of ENT at University College London (UCL), on implanting a stem-cell-laced donor trachea in another child. They would work together again in Shauna's case.
Shauna was being treated at Great Ormond Street at the time of a BBC documentary about the hospital in 2012. She was assessed by different specialists and asked what her hopes for the future were. Shauna told respiratory consultant Dr Martin Wallis she wanted to be able to go swimming.
It was not an easy decision to have the operation. In Martin Wallis's words, it was not a situation where there was nothing to lose.
"They've got quite a bit to lose. And this is going to make for a difficult decision," he said. "She's got a reasonable quality of life, she's got her good friend, she clearly has a sense of humour and is enjoying herself - it makes it harder."
"I wanted her to have it done while she was well rather than wait until she was unwell and it might not happen," Karen Davison says.
But because it was such an experimental procedure, her medical team discussed it with the Great Ormond Street Hospital ethics committee.
"I don't think she will die if we do the procedure. We're trying to do the procedure so that she doesn't. Or at least we prolong her life and her quality of life for as long as possible," the surgeon, Martin Elliott, tells the committee on camera.
"They couldn't give me a time when she'd die but they said she will die eventually. Because her airway would just give up. So there was this procedure they said they were willing to do," Karen Davison says. "Like any other parent, if you thought this was going to help your child live, I agreed to it."
So in February 2012, Shauna was given a transplant of a donor trachea newly populated with her own stem cells.
Initially, everything seemed to go well. "For the first couple of days she was marvellous," her mother recalls. "I couldn't believe how well she recovered after it."
Two weeks after her operation Shauna was moved from Great Ormond Street by ambulance to a hospital in Leeds. But during the transfer Shauna started to cough a lot and was in need of suction to clear her throat.
"We thought that was strange, but thought it might have been due to the journey," Karen Davison says. "I just thought, 'Another couple of weeks and we'll be home.'"
But the next morning, Shauna took a turn for the worse.
"Her chest was pulling in," Karen says. She remembers Shauna saying, "Help me, help me."
"It was the worst day of my life because I couldn't help her."
Shauna's new trachea had collapsed.
"They said she'd struggled that much to breathe, her heart had given up," Karen Davison says.
"She was a wonderful child. I miss her so much."
When the first transplant using a donated windpipe coated with the patient's own stem cells was carried out in 2008 it made global headlines.
It was thought that stripping the donor's cells from the surface of the trachea and seeding it with the patient's own stem cells created a new organ that would be like the patient's own tissue. No anti-rejection drugs would be needed for the "tissue-engineered" trachea.
The operation was carried out by Italian surgeon Paolo Macchiarini with the help of Martin Birchall, then a surgeon at Bristol University. The recipient was 30-year-old Claudia Castillo, who had tuberculosis in part of her windpipe that leads to the lungs - the bronchus.
Her case was written up in The Lancet. Five months after she'd had her operation, she was reported to be in perfect health.
Martin Birchall, who had helped to prepare the donor trachea, said at the time that it would "represent a huge step change in surgery. Surgeons can now start to see and understand the potential for adult stem cells and tissue engineering to radically improve their ability to treat patients with serious diseases."
"It was seen as revolutionary, as highly innovative… opening the door for new and exciting tech using a marriage between stem cells and artificial scaffolds that could bring forth this entirely new field of regenerative medicine," recalls Prof John Rasko, of the University of Sydney Faculty of Health Sciences.
It had "the whiff of a Nobel Prize about it," he says.
Indeed, soon the university that hands out the Nobel Prize for medicine, Stockholm's prestigious Karolinska Institute, offered Macchiarini a post. Birchall, for his part, moved to University College London (UCL), where Macchiarini was also made an honorary professor.
Claudia Castillo's operation served as a template and soon others had similar procedures. In 2010, Professor Birchall told a conference "we have done a further five adults".
Apart from Shauna, UK patients given a tissue-engineered trachea include 19-year-old Keziah Shorten and 10-year-old Ciaran Finn-Lynch. Shauna's surgeon, Martin Elliott, led the transplant team that performed Ciaran's operation, with the help of Macchiarini and Birchall.
Like Claudia Castillo, his procedure was published in a medical journal and it garnered global headlines. Martin Birchall told journalists: "He is left with a healthy organ there, made from his own stem cells, and that in a way is a kind of miracle."
But soon questions started to be asked about the stem-cell-laced tracheas.
For Macchiarini, this meant his meteoric rise was mirrored by a rapid fall from grace. He had switched from using donated tracheas to plastic ones, also laced with stem cells. The results were disastrous - his patients died.
Macchiarini was investigated several times by Karolinska before he was fired. Allegations made against him were initially dismissed but the institute has since found him guilty of scientific misconduct and many of his scientific papers have been retracted. Swedish prosecutors reopened a criminal negligence investigation against him in December last year. He has previously denied any negligence.
Bo Risberg, professor emeritus of surgery at the University of Gothenberg and a former chairman of the Swedish Ethics Council has said the events amount to the biggest research scandal Sweden has experienced in modern times.
"Everything was swept under the carpet," he said. Macchiarini's failure to do pre-clinical tests on animals using the plastic tracheas was "the worst crime you can commit", he added.
One of Macchiarini's early critics was Pierre Delaere, professor of ENT at University Hospital Leuven in Belgium, who has argued that it is "impossible from a theoretical point of view" to establish a new blood supply to a tissue-engineered trachea, whether plastic or donated.
In 2015, he wrote to UCL casting doubt on the idea of "tracheal regeneration", calling it "the biggest lie in medical history". By this time Macchiarini had left UCL.
In its subsequent unpublished report into Delaere's claims, seen by the BBC, UCL cast doubt on the suggestion that stem cells "played any therapeutic role" in Ciaran's operation.
But, it said, there was no "deliberate fraud" or "intent to mislead" on Martin Birchall's part. Because of the "lack of intent to deceive" the university recommended education and training rather than other formal procedures.
Meanwhile, the university was gearing up to conduct clinical trials into stem-cell-regenerated tracheas and larynxes - called Inspire and RegenVox respectively. Martin Birchall was principal investigator with responsibility for leading the trials. He and his team would bring in millions of pounds of research funding to the university.
It wasn't the only time UCL produced a report into regenerative medicine at the university. In 2017, it published the findings of a special inquiry, set up after the Macchiarini revelations. This found no fault with Martin Birchall and cleared the way for future clinical trials to proceed.
It said that, when asked, Shauna's family "were grateful for the opportunity that her daughter received and held no rancour with the tracheal team at GOSH".
UCL told the BBC this was "reported to the inquiry by the clinicians involved in the care of Shauna Davison".
But Shauna's mother, Karen Davison, says no-one connected to the inquiry had ever asked for her views.
The more I have looked into Shauna Davison's story the more I have discovered that Karen Davison did not know.
The two patients Karen and Shauna heard about were the 10-year-old boy, Ciaran Finn-Lynch, and Claudia Castillo, both of whom are still alive.
But they weren't told that Claudia Castillo's windpipe transplant collapsed just over three weeks after she'd had it and she needed stents to keep it open. (She's since had to have a lung removed.)
Nor did Karen and Shauna hear about most of the other cases Martin Birchall talked about in 2010.
One of these operations was on Kent teenager Keziah Shorten, who about two years previously had been given a tissue-engineered donor trachea by Macchiarini in Florence, after she had been diagnosed with a rare form of cancer.
But around a year after the operation, her transplant failed. Martin Birchall told a Swedish documentary in 2016 that her tissue-engineered windpipe had broken down. When she was subsequently operated on at University College London Hospital they replaced it with a plastic one. She died a month before Shauna's operation.
According to John Rasko there is a "strong obligation to give a full and frank account of all the information that's available. Exceptionalism and excluding bad cases is really something that is not acceptable."
A spokesperson for GOSH said: "As a patient, Keziah's condition and her graft were very different to Shauna, so it was not clinically relevant to discuss her case."
The hospital added that the other patients were not discussed "because the team did not know of other relevant cases from overseas at this time".
There was more that Karen and Shauna did not know. They did hear about Ciaran Finn-Lynch. But there were key differences between Shauna's operation and his.
Ciaran had received a stent - but Shauna didn't. According to the 2017 UCL inquiry report, Martin Elliott said that he had wanted to use a stent but was advised not to.
Ciaran had also received a fresh donor trachea. Shauna's wasn't fresh. It had been frozen and then thawed.
It was a treatment that hadn't been used before - after the trachea had been thawed, the donor's cells had been removed using a special vacuum technique exclusive to members of Shauna's medical team.
Trish Murray, professor of stem cell biology and regenerative medicine at Liverpool University, has a number of criticisms.
"The reality is that if you don't have a stent, the trachea will collapse, that's been the unanimous experience of all patients who've experienced trachea transplantation," she says.
"So although it's well-known that stents cause problems, if you don't have a stent, then the trachea will collapse and the patient will suffocate."
Another issue was the frozen trachea.
For the team it made perfect sense to freeze a trachea, as the trachea could be stored up in advance and thawed when needed. But Trish Murray is critical of this decision too.
"Ciaran's trachea was not frozen beforehand whereas Shauna's was freeze-thawed and we know from papers that the group themselves have published that that would weaken the trachea... and that would make it more likely to collapse after it had been implanted," she says.
However, UCL questions the relevance of these studies. It has told the BBC that they do not refer to the technique used on Shauna.
Trish Murray says other worrying studies should have rung alarm bells. She points to an unpublished study looking at the vacuum technique, which shows that one pig that received a transplant died spontaneously and another developed "respiratory compromise" and had to be put down. The study was stopped on humane grounds.
"We know from information that's been obtained from FOI requests that the team in UCL have tried the technique on two pigs and both pigs died quite quickly. We also know that they've tried it on rabbits and there was 100% mortality in the rabbits as well," she says.
The BBC asked UCL and Great Ormond Street whether the animal studies were done before or after Shauna's operation, but received no reply to this question.
And like Belgian ENT professor Pierre Delaere, Trish Murray questions the role the stem cells played.
"There's actually no evidence that any of those cells survive, in fact quite a lot of evidence that they don't survive," she says.
But how were doctors and scientists involved in the care of seriously ill patients able to use these tracheas when there was little evidence that they worked?
Usually, researchers have to test their innovation in the lab and then on animals in preclinical research. Only then - with formal approval from a research ethics committee and the regulators - does it move into humans.
Martin Birchall, however, wrote in the Lancet that "compassionate studies", the procedure for using new treatments on very ill patients, were "powerful ways to inform robustly designed formal trials" and would "expedite the testing of novel therapies".
"The surgeons involved have used this apparent loophole of compassionate use to actually experiment on patients and then they've used the data that they've obtained to go to the regulatory authorities to get permission for the trials," Trish Murray says.
John Rasko agrees with Trish Murray that this is not how the system should work.
"Exercising the option of compassionate use brings with it great responsibility. It shouldn't be used as a way that doctors can fly under the radar of properly undertaken regulated medical practice," he says.
And Great Ormond Street agrees too. "We do not see compassionate use as a way of testing novel treatments," a spokesperson said.
But Shauna's transplant, and those of other patients, were used to obtain funding and approval for clinical trials, as well as being written about in medical journals and an application to the European Medicines Agency.
The BBC has found that at least seven of these documents and publications misrepresent Shauna's treatment or death in some way.
For example, in one 2016 application to the European Medicines Agency, Martin Birchall is cited as saying Shauna's initial surgery was successful but she suffered a "fatal cardiovascular event six weeks following surgery" - whereas in fact she died after two weeks, because her trachea had collapsed.
By the time the clinical trial to test the tissue-engineered trachea transplants was approved and funded by public bodies, a change had been made to the procedure. Having learned from what happened to Shauna, the team would make sure patients in the trial had a stent.
And even then, the approved patient information sheets accompanying one of the trials contained erroneous information about Shauna and indeed about Claudia Castillo. Only they and Ciaran Finn-Lynch were included in the information sheet - despite the team knowing about at least 10 cases worldwide.
As early as 2014, Martin Elliott had told a conference 10 patients had received a tissue-engineered trachea, all of whom had died apart from Claudia and Ciaran.
Last year, the clinical trials were suspended. UCL says no-one had been recruited to participate.
Much of what the BBC has uncovered about what happened to Shauna does not appear in UCL's special inquiry report.
Leonid Schneider is a molecular-cell-biologist-turned-journalist who has been covering regenerative medicine since 2016. He was called to give evidence at UCL's inquiry and is damning in his appraisal of their report.
"Why didn't Shauna's mother have the full information? And whose idea it was not to give her a stent?" he asks.
"Finally, how could UCL investigators recommend the donor trachea clinical trials to resume, after Prof Delaere and myself told them how many people have died of it?" he adds.
UCL says that clinical care was "beyond the scope of the inquiry".
It adds: "Any research undertaken at UCL is required to conform to the highest legal, ethical and regulatory standards, and we will not hesitate to take the necessary action, if and when this falls short."
After receiving ethical advice, I told Karen what the BBC had found out about tissue-engineered transplants.
She was upset. She said this might have changed her decision about allowing Shauna's operation to go ahead.
"I hope that nobody else has to go through what I've gone through, I really do. They should be stopped. That is such a shock. People ask me, 'How did Shauna die?' And I always say, heart attack. I've never once blamed those surgeons for her death. They have a lot to account for."
GOSH said: "Before Shauna's operation was carried out a comprehensive review was conducted of all the relevant published scientific and medical evidence."
They also said: "We are sorry the treatment did not work for Shauna and the family feel they did not receive all relevant information. We are contacting Shauna's family to offer to meet them to talk through any concerns."
"It's taken them all this time, but you'd think they would have phoned me and said something to me," says Karen Davison. "I know I wouldn't have had her forever, but at least I might have had her for a bit longer."
Photographs of Shauna Davison courtesy of Karen Davison