Two years ago, Hassan’s father was faced with questions that he had no good answers for. “Why do I have this disease?” his seven-year-old son asked him. “Why do I have to live this life?”
Hassan was born with a rare genetic skin condition, called epidermolysis bullosa, that causes fragile, blistering skin. His first blister appeared when he was a week old, but soon after his family fled their native Syria and arrived as refugees in Germany, things got much worse. By June 2015, Hassan was admitted to hospital, critically ill, having lost the skin from almost the entire surface of his body. “Except for his face, hands and feet, he didn’t have any skin left,” his father recalls.
Having run out of conventional treatments, his doctors were preparing to start palliative care. But, as a last resort, they contacted an Italian scientist, Michele de Luca, who had carried out genetically modified skin transplants – but on nothing approaching this scale.
In a remarkable scientific breakthrough, De Luca’s team went on to grow an entire replacement skin for Hassan. It was grafted on, like a patchwork quilt, and after spending months bandaged from head to toe, Hassan emerged effectively cured of his devastating illness. Two years on, he is well, his skin no longer blisters, he needs no medication or ointments, he plays football and, when he gets a cut, he heals normally.
“It felt like a dream for us,” the boy’s father says.
De Luca says that witnessing the recovery produced “one of the strongest emotions in my whole life … For a scientist working in this field, having these results justifies an entire career.”
It also marked a rare and long-awaited clinical success for the field of regenerative medicine, which has faced criticism for delivering just a handful of therapies after years of hype.
Scientists first succeeded in culturing human embryonic stem cells in 1998. The cells, extracted from donated IVF embryos, can divide and multiply indefinitely and morph into any other cell type in the body. The advance raised the prospect of limitless supplies of lab-grown cells – blood, liver, skin – and ultimately spare organs and body parts, grown from scratch in the laboratory. The image of the infamous “earmouse”, published a year earlier, seemed to hint that scientists were already on the brink of such capabilities. In fact, the “ear” was cow cartilage and no human cells were involved, but the seed of expectation was sown.
De Luca says that, from the start, there was an unrealistic sense of how quickly therapeutic uses would arrive, fuelling frenzied competition within the field, and people taking shortcuts or, worse, falsifying results.
Most notorious among these was Paolo Macchiarini, an Italian surgeon, who was feted as a medical superstar when he claimed in 2011 to have successfully transplanted the world’s first synthetic windpipe, a plastic scaffold seeded with a patient’s own stem cells. The remarkable story later unravelled as it emerged that seven (now eight) of the nine patients to receive the synthetic tracheas had died and, last year, Macchiarini was fired from Sweden’s Karolinska Institute for misconduct.
“The Macchiarini case was detrimental to the entire field, but we should not generalise,” says De Luca. “We don’t have to stop doing regenerative medicine, even in that specific field, because of what happened. We just have to do things properly.”
De Luca’s next project, a collaboration with scientists at Great Ormond Street Children’s hospital in London, aims to create a functioning oesophagus, the food pipe, from a pig organ that has been decellurised – a process in which all the cells and genetic material are washed away – and lined with human stem cells taken from patients.
Growing skin required scientific ingenuity, but the oesophagus also presents a substantial engineering challenge. The organ comprises a tube of smooth muscle covered by the internal skin, or epithelium. It must be rigid enough to stay open, but be able to contract to squeeze down food, and, without a blood supply, necrosis – or cell death – will set in.
The project is led by Paolo De Coppi, a paediatric surgeon at Great Ormond Street, who specialises in treating babies with congenital malformations. Before I visit his lab, three separate people tell me De Coppi is “very charismatic”, then add “but sensible”, or a similar disclaimer. Post-Macchiarini, too much showmanship can raise red flags.
De Coppi takes me on a swift tour of the research department he leads at University College London. At one point, as we zoom down a corridor, he opens what looks like a broom cupboard, revealing instead a small walk-in fridge lined with shelves loaded with tiny organs. “This is a decellurised rat liver,” he says, picking up a jar with what looks like a small, translucent ball of mozzarella floating within. “This one’s an intestine.” Bladder, kidney, cartilage and lung tissue are being grown elsewhere in the building, he says.
He describes the protocol for creating a new oesophagus. The decellurised scaffold is basted in patient stem cells, called mesoangioblasts, that are found around blood vessels. “Normally, when there is an injury these cells can migrate and proliferate to regenerate new muscle fibres,” De Coppi says.
When placed in a bioreactor – a jar that has nutrients pumped in one end and waste products sucked out the other – these cells begin to form a tube of smooth muscle. This is then placed under the skin of the stomach and blood vessels automatically begin to vascularise it.
Meanwhile, outside the body, a second set of stem cells taken from the gullet will be cultured into thin sheets that are wrapped around a dissolvable polymer scaffold to make the organ’s epithelium lining. This is where De Luca’s expertise will come in, as growing epithelium efficiently relies on similar techniques to those he refined for cultivating external skin.
Finally, the vascularised muscle tube will be taken out from the stomach, the lining slotted inside and the transplant stitched into the patient – although no one has been treated yet.
The team have had “promising” results in a study in rabbits, expected to be published in the next few months, and intend to move to pigs before beginning in human patients in 2019 if all goes to plan. The human trial will involve babies with a condition called oesophageal atresia, in which part of the oesophagus is missing from birth.
Treating the first patient, even one with few alternatives, still requires a leap of faith, De Coppi says. “You wouldn’t be a good doctor if you didn’t feel some fear in these situations. The only time you can’t have fear is in theatre; at that point, the decision has been made and you have to think this is the best thing. Before that you have a lot of doubt.”
The ultimate goal remains to make synthetic organs from scratch using a synthetic scaffold, as Macchiarini tried and failed to do with tracheas. Pig scaffolds do not pose a risk, but manufacturing them does not readily scale up to treating hundreds or thousands of patients. However, De Coppi says that matching the quality of a natural scaffold is probably still 20 years away. “Despite [attempts at] synthetic organs, we are still far away from mimicking what mother nature has done,” he says.
His colleague Prof Patrizia Ferretti is leading a team working on lab-grown cartilage. Eventually they want to build new ears for children born without any – a bit like earmouse, except the real deal.
The team have worked out how to coax stem cells found in fat into cartilage and can grow small pieces that look and feel like the natural version. But natural ear cartilage, it turns out, is too soft to build an ear from scratch; when placed under the skin, scar tissue forms around it, slowly crushing it. The next problem, then, is to create something tougher, more like the cartilage found around the ribs.
The team are at the stage of experimenting with how to grow big enough pieces for an ear. One option is squirting the cells into a gel in the desired shape, using a 3D printer; or growing lots of small pellets of cartilage and pouring them into a mould to set, like jelly cubes.
After this, they will carry out trials with large animals, probably attaching the ear on the side of a pig’s face, to check that it has the right mechanical properties. Ferretti hopes to begin a patient trial within five years. “We need to see how close to the real McCoy what we’re producing is,” says Ferretti. “I don’t think we’re super far.”
Scientists classify stem cells according to a hierarchy of “stem-ness”. Embryonic stem cells are the ultimate master cells – they can divide indefinitely and, with the correct biochemical cues, turn into any cell type in the body. Adult stem cells, found in tissues such as skin and bone marrow, are already somewhat specialised, but can still divide, proliferate and mature. Scientists have also found ways to “rewind” adult cells into a state of greater plasticity, so-called induced pluripotent stem (IPS) cells.
Realising regenerative medicine’s most ambitious goals means working out which cells to start with and how to streamline the pathway towards specialisation. Prof Doug Melton, a stem cell scientist at Harvard University, has been working on this problem for two decades. His mission began when his son, Sam, was diagnosed with type 1 diabetes at six months old. He recalls the shock and feeling: “What’s happening to my world? This isn’t something we’ve planned for.” His daughter, Emma, later received the same diagnosis, by which time Melton had abandoned his research on frog eggs and embarked on his quest for a cure.
In diabetes, the immune system kills off all the body’s pancreatic beta cells, leaving it unable to produce insulin. In its absence, the body’s sugar levels fluctuate wildly, meaning that patients need to monitor glucose and typically inject insulin several times each day. “Injecting insulin has been the treatment for nearly 100 years and the only real advances have been the way it’s provided, via a pen or a pump,” says Melton.
Although insulin injections help to keep glucose levels broadly in check, the system is crude in comparison with the body’s fine tuning, and the lack of control can eventually lead to complications, from blindness to the loss of limbs, and shortens life by a decade, on average.
“The starting point was: why don’t you just make the beta cell and put it back?” says Melton. “You’d replace the finger pricks and the injections with nature’s own invention.”
Yet nature turned out to be hard to replicate and Melton worked for 15 years to get to the point where his lab could transform embryonic stem cells into pancreatic beta cells at large enough volumes to treat patients.
“The challenge was how to get mastery over that process,” says Melton. “It’s not a one-step process; it’s a six-step, 30- to 40-day process.”
The pancreas, a large gland in the stomach, contains hundreds of millions of beta cells – together they would occupy the volume of a pea. Melton’s lab can grow around a million cells per millilitre – enough cells to replace those lost in diabetes can be grown in a teapot-sized vessel.
In mice, Melton’s lab-grown cells have been shown to work normally for many months, automatically detecting glucose and secreting insulin as required. Before transplanting, the cells are placed inside a porous capsule, which allows insulin to diffuse out, but protects the cells from attacks by the body’s immune system. This also eliminates the need for genetic-matching to patients, which Melton hopes will allow the cells, one day, to be produced on an industrial scale.
“I think of beer commercials with people standing next to giant stainless steel vats,” says Melton. “That is what will happen, but it’s not going to happen in the next few years.”
Through his startup company, Semma (named after his children Sam and Emma) Therapeutics, Melton is carrying out the final phase of animal trials and hoping to begin his first clinical trial by 2020. Patients will have a thin capsule of cells, about the size of a credit card, placed beneath the skin (the arm or inner thigh, perhaps). The first steps will be establishing safety and how long the cells are active for – the hope is a year or more, but they could last for more than a decade; mice don’t live long enough to test this. At his family’s recent Thanksgiving dinner, Melton asked his children, now in their 20s, whether they would like to be involved in the first trial.
“It’s the first time they heard about the dates when the trial might be happening,” he says. “They’re both thinking about it.”
Melton jokes that his children probably wonder: “What the hell is taking so long, Dad?”
In a field that has such incredible potential, delays are hard to live with. Every year of waiting means that babies with fatal congenital defects can’t be treated, diabetics continue to die early, damaged hearts can’t be healed.
Scientists who have been working for decades to harness the curative powers of stem cells have not forgotten these grand goals. Many are now within touching distance of delivering transformative therapies. Cell therapy trials for age-related macular degeneration (one at Moorfields Eye hospital) and other forms of blindness are delivering promising results; this year, scientists came significantly closer to building a pipeline to manufacture vast quantities of lab-grown blood; a study in monkeys suggested that implanting neurons derived from stem cells could help treat Parkinson’s.
“I do realise that talking to reporters, when I say ‘years away’, they think ‘our readers don’t care about this’,” Melton says. “But when you’re successful, that lasts for 100 years.”