HARPAL KAUR can still see the terrible events of that day unfolding in her mind’s eye. Her nine-year-old daughter Sandeep was chopping grass to feed the family buffalo at their home in Chak Khurd in northern India, when Sandeep’s hair got caught in the threshing machine. As it was relentlessly dragged in, the skin above her neck tore, and her entire scalp and face were ripped off. “I started to scream when I realised what happened,” recalls Sandeep’s mother. “I didn’t know where her face was.”
Despite their shock and distress, the family managed to salvage Sandeep’s face and scalp, and get her on a moped. After a fraught three-and-a-half-hour journey that involved several break-downs, Sandeep arrived at the Christian Medical College and Hospital in Ludhiana, her face in a plastic bag.
By a stroke of luck, an experienced microsurgeon was on duty. Abraham Thomas knew that repairing Sandeep’s face with skin grafts from elsewhere on her body would leave her profoundly disfigured, so he decided to attempt something bolder – to return the plastic bag’s contents to their rightful place.
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It was the right call. In the early hours of the next day, as Thomas reconnected the first artery the reattached face flushed pink as blood perfused it once more. Against the odds Thomas and his team had performed the world’s first reported “replant” of an entire face and scalp.
Since that day in 1994 there have been two other known cases of surgeons heroically replacing entire faces, in Australia and the US. And surgeons have asked the obvious question: if it’s possible to reattach such messily torn-off faces, couldn’t we also carry out face transplants, using the faces of the newly deceased to treat people with disfigurements?
It is a grisly yet fascinating subject that in recent years has divided opinions among doctors, ethicists and disfigured patients. Indeed for a while it looked like the world’s first face transplant was only a matter of time. Several teams of surgeons around the world argued that face transplants could transform the lives of people with severe disfigurements. Critics questioned whether the benefits were worth the medical risks. And newspaper columnists quipped about George Clooney being a better-qualified donor than George Bush.
Then, last November, came a setback: an inquiry by the UK’s prestigious Royal College of Surgeons concluded that doctors should wait until more was known about risks both of tissue rejection and the psychological impacts on the recipient and the donor’s family.
But not everyone agrees with that verdict. And not all teams have put their plans on hold. żěè¶ĚĘÓƵ has learned that surgeons and scientists at the University of Louisville in Kentucky are in the process of requesting formal approval to carry out a face transplant. They have described their plans in detail in a 30-page document being submitted to their university’s ethics committee or institutional review board. Despite the earlier Royal College of Surgeons’ report, the US team says enough research has now been done, and they plan to start screening prospective patients and looking for donors as soon as they get the go-ahead from the IRB.
So who are these doctors so willing to court controversy? A leading team-member is John Barker, director of plastic surgery research at the University of Louisville. My first contact with Barker came in September 1998. News had just broken that an international team working in Lyon, France, had carried out what appeared to be the world’s first successful hand transplant. I knew surgeons in Louisville had been working toward the same goal and so I called Barker for a comment.
In the event Barker was keener to talk about what he saw as the next milestone in the field – face transplants. Some patients, Barker explained, were so severely injured that even after scores of skin grafts and other operations, they barely had a functioning face, let alone a normal-looking one. They included victims of severe burns, cancers, gunshot wounds or dog attacks. Louisville surgeons, Barker disclosed, were now seriously investigating the possibility of giving such patients face transplants.
żěè¶ĚĘÓƵ ran the story (3 October 1998, p 13) and news organisations across the world picked it up. With the movie Face/Off recently released, headline writers had an easy, if less than scientifically grounded, point of reference. The following January, Barker and his colleagues made news again when they carried out the world’s second successful hand transplant operation.
The French hand transplant of the previous autumn had come out of the blue with no public debate beforehand. Behind the scenes, however, surgeons had faced similar objections to those now being levelled at face grafts. Ever since the first human kidney transplant in 1954, transplant surgery has been seen as the risky and expensive therapy of last resort (see “Transplant milestones”). The orthodoxy has always been that exposing patients to the dangers of organ rejection and the risks of immunosuppressant drugs simply isn’t worth it for someone who was not in mortal danger in the first place.
And as well as being non-lifesaving, hand transplants involved giving the patient skin – a tissue nobody had previously succeeded in transplanting (other than between identical twins). Because of its role in protecting the body from invading bacteria and viruses, skin contains myriad immune cells and proteins, and is thus one of the body’s most immunologically active organs.
So why risk a hand transplant? The Louisville team began exploring how to prevent skin rejecting in the mid-1990s. Testing their procedures on pigs, they initially thought their best hope was to deliver drugs directly to a transplanted limb. In one test they used miniature pumps implanted under the skin to deliver a drug. As a control, they gave a cocktail of drugs orally to another group of animals. In the end the pumps became blocked and the pigs rejected their grafts. But many of the control animals unexpectedly thrived.
Suddenly the idea of human skin – and limb – transplants was no longer an impossible dream. Rejection, it appeared, could be stopped by a cocktail of drugs that was already being used for other transplants. “All of a sudden the light went on,” says Barker. “We realised the control group was doing great with a treatment that was already being used widely for kidney transplants.”
Almost immediately teams in Louisville and elsewhere decided to attempt a hand transplant. Since then there have been more than 20 such grafts in countries including the US, Austria and China, all relying on the same three drugs that were given to the Louisville pigs. And as far as we know, there has been just one failure. Ironically it was the very first patient, a New Zealander called Clint Hallam, who stopped taking the drugs and had to have his new limb amputated. Other patients have experienced some early signs of rejection, but doctors have so far been able to suppress these by temporarily upping the drug dosage.
The results have scotched some of the concerns about non-lifesaving transplants and triggered a wave of other operations. In recent years there have been eight thigh and knee bone transplants, four double hand transplants (one to a French house painter whose hands were blown off by a home-made model rocket) and a combined arm-and-hand transplant to a one-month baby girl. A larynx, a tongue and an abdominal wall have also been transplanted. There has been speculative talk about breast, neck and even penis transplants.
Yet not all experts are convinced that the benefits justify the risks involved in this growing list of non-lifesaving transplants. Opponents say that even with the latest drugs, transplanted kidneys survive less than 10 years on average; hand or face transplants, they claim, are unlikely to do any better. And if or when a transplanted face triggers an uncontrollable rejection, what then? The face would have to be removed and the patient given either skin grafts from their own body or a second transplant. Plus, even if the transplant stays healthy, immunosuppressants cost tens of thousands of dollars per year and carry serious long-term risks of infections, diabetes and certain cancers.
In light of these risks, even some proponents of face transplants believe it may be best to wait for better techniques for preventing rejection (see “The importance of tolerance”). But the Louisville team are more optimistic. Without playing down the risks, they are increasingly convinced that for the most severely disfigured patients, the benefits of a face transplant could justify a lifetime’s dependency on even the present generation of drugs. “The whole driving force behind this is there is a patient need,” says Louisville surgeon Joseph Banis. “Over 20 years I’ve seen patients whose faces have been so severely damaged that they are non-human faces.”
Skin from elsewhere on the body has a different texture to that of the face and is notoriously difficult to turn into natural-looking noses and mouths. Patients with severe facial burns may undergo over 50 painful operations, to achieve only modest results. “You lose animation, you lose normalcy of texture, of colour,” says Banis, who in one case even created a makeshift nose from a patient’s toe.
To help make their case, the Louisville researchers have spent the past couple of years probing attitudes to transplant risks. They used questionnaires to ask how many years of life expectancy people would sacrifice in return for particular transplanted organs. The results are still being processed, but a preliminary analysis reveals something surprising. People are willing to trade more years for a hand, should they need one, than, say, a foot, and more years for a larynx than a hand. But the body part for which people are willing to trade most years of life is by some margin a transplanted face. For a face they would take on even more risk than for a kidney, and, as Barker points out, kidney transplants are already seen as worth the risk.
So assuming the team gets clearance, what are the challenges involved? Banis, the plastic surgeon who is likely to lead the operation, says they will need to cut out and lift off the full surface of the donor’s face. The borders of this graft would probably trace a line running across the hairline, down the temples on either side, passing just in front of the ears, and round the jawline. Eyebrows, eyelids, nose, mouth and lips could all be included.
And that’s just for starters. As well as the skin and its fine undercoat of fat, the surgeons would also need to take the underlying arteries and veins that keep the face supplied with blood. Depending on the extent of the patient’s injuries, the team might even have to go deeper still, taking from the donor nose cartilage, facial nerves and even muscles. “I could see it taking as long as 10 to 12 hours to harvest the graft,” Serge Martinez, another surgeon in the Louisville team, told us. “Then to transplant it you might be looking at 24 hours.”
And when the bandages come off? Perhaps what most spooks people about face transplants is the idea that the recipient will end up looking just like the dead donor. In Face/Off, the swap between the two lead characters is so flawless that even the women in their lives are misled. In reality, that couldn’t happen: our looks are strongly influenced by the underlying bone structure and muscle movement, not just the soft tissues that would be transplanted.
Nevertheless, working out just how much of the donor’s looks would be transferred has become an important goal for the Louisville team. “One of the questions that has come up is whether the family of a donor will recognise the donor in the face of the recipient,” says Barker. “And would they donate knowing they might one day see their loved one in the face of somebody walking down the street?”
The surgeons in Louisville have been practising for the operation by swapping the faces of bodies donated for medical research. The team has used these practice sessions to discover whether recipients of donated faces are likely to be mistaken for the donor.
Even for a seasoned reconstructive surgeon like Martinez it has been an eye-opener. “It is really awesome to lift up a whole face and lay it back down,” he says. “I have to sit back sometimes and say, am I really part of doing this?”
In a typical recognition test, the researchers will show photographs of a dead person’s face to a group of volunteers. After removing the photos, the researchers will lay out photos of a dozen more heads. One of these has had the first person’s face transplanted onto them. The volunteers are asked whether that person is in the crowd and if so, where they are.
The full results will be submitted to a journal and so cannot be revealed here but what Barker will say is that they suggest a transplanted face won’t be strongly recognisable as either the donor or recipient. In effect, says Barker, a third face is created: “More often than not you don’t recognise the person.”
To get a more vivid idea of how a patient might look afterwards, żěè¶ĚĘÓƵ teamed up with a TV company, UK-based Mentorn, and commissioned an animation firm to carry out a virtual face transplant. The results, which will be shown in a TV documentary on the subject, are published here for the first time (see graphic), and appear to back the Louisville team’s conclusions.
The firm, Darkside Animation, needed to create an anatomically accurate head for their virtual patient. So they digitally scanned the face of a living woman and placed this face on a standard 3D anatomy model of a human skull, cartilage and musculature. This was re-sized and re-shaped to make its bone structure fit the contours of the scanned face. For the virtual donor, the team took the same standard model of a human head and re-shaped its bone structure, adding skin, eyebrows, lips and so on, to create a second head.
To perform the transplant, the team took the skin and underlying fat off the donor and stretched it over the bone structure and musculature of the virtual patient. The recipient ends up sharing certain features with the donor – the shape of the mouth for example – yet has her own distinct identity. In the case of the mouth, the team found this part of the face to be strongly influenced by the underlying fat that was transplanted along with the skin and lips.
A harder question to answer is what level of movement, feeling and expression the transplanted face would have. The surgeons I spoke to agreed that restoring expression and sensation to the face, and getting the eyelids and mouth moving properly, would be major challenges – just as they are when rebuilding a face with conventional skin grafts. “No transplant will ever have the fine activity that the normal body part would have,” says Banis. “We hope to get about 50 per cent return of nerve function.”
For a better idea of how face transplant recipients might fare, surgeons are turning to “replant” patients like Sandeep Kaur. Ten years after the accident, she is now 19 and studying to be a nurse. Her face still bears scars and lacks mobility. But her doctor is hopeful that further surgery will help. And conventional skin grafts would have left her a lot worse off.
Reflecting on Sandeep’s case, Barker is optimistic that transplanting a face from a dead donor would be easier than replanting one that has been ripped off. “It’s all surgically clean, pristine tissue and you have plenty to work with,” he says. “You remove it from the donor; drape it over and tailor; sew it in place. There’s no dead tissue that has been crushed.”
While that may be true, there is a note of caution from the only US surgeon to have carried out a face replant, Bradon Wilhelmi, of Southern Illinois University. Two years ago Wilhelmi led a team at Massachusetts General Hospital that replaced the face and scalp of a 21-year-old man who’d caught his hair in a conveyor belt at work. The victim’s skin had been peeled off cleanly, leaving the underlying muscles and nerves intact. The peeling happens because of a specific weak plane underneath the skin and fat, says Wilhelmi. This makes replant patients more likely to regain facial expression and sensation.
During a transplant, in contrast, surgeons may have to remove and reattach a deeper layer of muscles and nerves. That could limit the patient’s recovery. Despite this, Wilhelmi is broadly optimistic about the prospects for transplanting faces. With any reattachment or transplant operation, establishing a good blood supply to the graft is crucial. Fortunately, the face is so dense with blood vessels that reattaching just a few arteries can allow the tissue to be well perfused. Indeed, Wilhelmi’s team found that a single repaired artery gave their replanted face all the blood it needed.
In Paris, a second team has also been preparing to carry out a face transplant. However the French surgeons, led by Laurent Lantieri at the University of Henri Mondor Hospital, have decided to limit their transplant to the part of the face that is hardest to reconstruct using conventional skin grafts – the upper lip and nose. Lantieri believes that a partial transplant would avoid the risk of having to strip off so much tissue if it goes wrong: in the event of rejection the nose and upper lip could be removed and the patient could go back to wearing a mask over that section of the face. But others question whether such a transplant would be worth the side-effects of anti-rejection drugs.
Meanwhile, in London at the Royal Free Hospital, surgeon Peter Butler has also spent a lot of time in recent years practising the techniques necessary for a face transplant. Like the Louisville team, Butler has been assessing people’s attitudes to the risks, and has studied the recipient’s likely resemblance to the donor.
Butler drew world attention in autumn 2002 when he told a plastic surgery conference that the technical expertise for a face transplant was now in place and that it was time to decide whether the surgery would be ethical. Since then he has been hounded by the world’s media wanting to know when he is going to take the plunge.
In recent months, Butler has been voicing caution. “These drugs have significant complications and they don’t always work,” he says. “Is it really worth it for the patient?” He will continue with his research, but has announced no immediate plans to proceed.
The Louisville surgeons know that if or when their plans get the green light, their success or failure will depend greatly on the patient they select. Nobody has yet been lined up, and finding the right person won’t be easy. “It really has to be a severe, severe injury to the face, so that the benefit will outweigh the risk,” says Barker. And the person will also need to understand the risks as well as be able to handle the immense media pressure that is bound to surround the first patient.
But having got this far, the team have no truck with arguments to delay the first attempt. “Tell me what you are going to do during that cautionary period that will get us closer to doing this,” Barker says. “Caution by itself will not get us any closer. If Christopher Columbus were cautious I’d probably be speaking with a British accent.”
Transplant milestones
After a long history of animal experimentation, it was in the mid-20th century that scientists began to understand that organ transplants from unrelated individuals are rejected by the immune system, and started trying to prevent this happening. Since then, the boundaries of transplant medicine have been continually pushed back:
1940s – Attempts are made to give skin grafts to second world war burns victims. These only succeed when performed between identical twins.
1954 – The first successful kidney transplant, also between identical twins, is carried out by doctors at what is now the Brigham and Women’s Hospital in Boston
1960s – Doctors experiment with using irradiation and drugs such as steroids to suppress the immune system, to allow transplants between unrelated individuals. Many patients die from drug toxicity or infections caused by the blanket immunosuppression.
1967 – Christiaan Barnard from Cape Town, South Africa, performs first successful heart transplant, although recipient dies from an infection after 18 days.
1968 – The first heart-and-lung graft is performed, on a 2-month-old infant, who dies within 14 hours.
1971 – Anti-rejection therapy is revolutionised by Swiss biochemist Jean-François Borel’s discovery of cyclosporin, a potent yet relatively safe immunosuppressant.
1980s – Surgeons now regularly transplanting kidneys, heart, lungs, liver, and pancreas. Survival rates are slowly improving.
1984 – In one of the most notorious cases of “xenotransplantation” (between different species), 12-day-old “Baby Fae” receives a heart from a baboon. It is rejected after three weeks, and critics say the procedure should never have been attempted.
1998 – First successful hand transplant, carried out in Lyon, France, despite criticism that where transplants are not lifesaving, the risks may not be worth the benefits. The limb has to be amputated after 16 months because the patient stops taking anti-rejection therapy, but it leads to other hand transplants.
1998 – Surgeons in Cleveland, Ohio, carry out world’s first larynx transplant on victim of motorbike accident.
Beating rejection
Two key objections to face transplants is that recipients would have to spend the rest of their lives taking anti-rejection medicines – with serious side effects – and might still suffer rejection anyway. But these arguments would vanish if scientists could succeed in developing new ways to teach a patient’s immune system to permanently tolerate the transplanted organ.
żěè¶ĚĘÓƵs have been trying for decades to understand why the immune system reacts to molecules, or “antigens”, from invading microbes or transplanted organs, yet is tolerant of self-antigens, those from the body’s own cells. Encouragingly, a small number of transplant recipients who have stopped taking their immunosuppressant drugs have by some fluke avoided organ rejection, suggesting tolerance can in some cases be acquired.
Several experimental strategies for inducing tolerance have proved successful in small animals such as mice and rats, but have failed when transferred to primates. “In the last decade, our knowledge of the immune system has accelerated,” says transplant immunologist Mohammed Sayegh of the Brigham and Women’s Hospital in Boston. “But we don’t know if these strategies will induce tolerance in humans.”
Part of the problem is that the immune system is hugely complex, comprising many dozens of different cell types governed through a multitude of chemical signals.
The master controllers of the immune system are T-cells, which recognise antigens presented on the surface of specialised “antigen-presenting cells” (APCs), alongside a second “co-stimulatory” signal. There are several natural mechanisms by which T-cells can become tolerant.
The main method occurs in the developing fetus and during childhood, in the thymus gland located in the neck. Most T-cells that react to self-antigens on APCs in the thymus are made to commit suicide. Any that survive have to be suppressed later by other mechanisms.
One means is via another type of cell called regulatory T-cells, which learn to recognise self-antigens in the thymus, then signal other T-cells elsewhere in the body not to react to them. Alternatively, APCs can present self-antigens without the co-stimulatory signal, which sends any reacting T-cells into a dormant state.
All of these natural mechanisms are being investigated as ways to induce tolerance to transplanted organs. For example, researchers have developed drugs that block the co-stimulatory signal. They should make the patient become tolerant to the new organ – but also to any bacteria or viruses that happen to be infecting the patient at the time.
Another approach is to give the patient drugs that kill off all or most of their T-cell population just before the transplant operation. As new T-cells mature, they come to see the foreign molecules from the donor organ as self because of antigen presentation in the thymus or the action of regulatory T-cells. “These are the most promising strategies,” says Sayegh.
Some of these agents are already used as general immunosuppressants, but if used at the right dose at the right time they may be able to induce transplant-specific tolerance. The few lucky transplant patients who have achieved tolerance may have by fluke received the right combination of immunosuppressants.
Suzanne Ildstad at the University of Louisville in Kentucky is investigating a different approach. She has discovered a new type of immune cell called facilitating cells.
Although their natural function is unclear, if they are isolated from one animal’s bone marrow, concentrated and injected into a second animal, they allow the recipient to receive bone marrow and organ transplants from the original donor without rejection. Ildstad is now testing this strategy in humans receiving heart transplants.
Clare Wilson
- This article was researched during the making of a TV documentary co-produced by żěè¶ĚĘÓƵ and Mentorn. Face Transplant will be shown on the Discovery Health Channel in the US at 8 pm on 28 May and the UK’s Channel 4 at a later date.