Nine years ago, an Ohio woman named Connie Culp was shot in the face by her husband. She lived, but the blast destroyed the middle of her face, including her nose, her cheeks, the roof of her mouth, and one eye. In the years that followed, doctors attempted to rebuild her face with portions of her own body: rib bones were used to recreate cheekbones, a leg bone replaced her jaw, thigh skin was transferred to her face. But even after 30 surgeries, Culp could not breathe normally, smell, taste, or reliably keep food and liquid in her mouth. And she rarely left the house. "I scared kids and everyone else," she says. "I really did look bad." Chad Gordon, clinical director of Johns Hopkins' new facial transplantation program, keeps a plaster cast of Culp's face at the time in a cardboard box on a shelf in his office. Two (closed) eyes and a cartoonish downturned mouth are its only distinguishing features. "That's what she looked like four years later," Gordon says, shaking his head.
Then, in 2008, Culp became the country's first face transplant recipient. Gordon was one of the eight surgeons who, over the course of a 22-hour surgery at the Cleveland Clinic, replaced 80 percent of her face with the veins, skin, nerves, muscle, and bone of a recently deceased donor. Culp's recovery was long and difficult. The drugs she takes to keep her body from rejecting the graft have numerous side effects. She had to learn to speak again, her vision is poor, and her features remain slightly distorted. But, while not perfect, the surgery transformed her life. "Sometimes people don't even know I had it done," she says. She describes a conversation she had recently at a banquet. "This couple was telling me everything that was wrong with them. They must have had 30 different things going on: back pain, headaches. When they found out who I was, they were like, 'Oh my God, I can't believe we're complaining.'"
Connie Culp's seemingly miraculous face transplant and the 23 or so others performed worldwide—not to mention the 50-some patients who've received hand or arm transplants—make for compelling stories, evoking a science fiction future. The media has largely focused on the surgeries themselves and the striking before and after images. Yet the microsurgical techniques used in the actual transplantations, while dazzling, have been used by plastic and reconstructive surgeons for decades. What is new for reconstructive surgeons is trying to tackle the problem of immune response. To keep the body from rejecting the graft, the patient must follow a burdensome regimen of immunosuppressive medication—for life.
The conventional trio of drugs—the same as those used by solid organ transplant recipients—carry with them a host of risks including renal failure, diabetes, hypertension, infection, and cancer. A typical patient awaiting, say, a liver transplant will happily accept these risks given the alternative. But face and hand transplants are not lifesaving procedures. Prospective patients—usually burn or trauma victims—thus must make a difficult decision: Forgo the surgery and live with their disfigurement and the disabilities that accompany it, or undergo surgery and put their overall health at not inconsequential risk.
A new face transplant team at Johns Hopkins, officially given the go-ahead in late July, is trying to build a new future for reconstructive transplantation patients—one where they won't have to choose between debilitating disfigurement and a procedure with serious health consequences. The team, headed by renowned hand transplant surgeon W. P. Andrew Lee, first took shape at the University of Pittsburgh, where Lee was head of plastic surgery before coming to Johns Hopkins to chair the newly formed Department of Plastic and Reconstructive Surgery in 2010. Before coming to Hopkins, Lee and his colleagues performed five upper-extremity transplants and have spent more than 20 years researching what is known as the Pittsburgh Protocol, on both small and large animal models. It employs just one immunosuppressive drug at a low dose, in place of the conventional therapy, which calls for three immunosuppressive drugs at high doses. By infusing bone marrow stem cells from the donor into the transplant recipient, the team has found that it can essentially trick the immune system into accepting the graft, thereby avoiding the necessity for intensive immunosuppression.
Six upper-extremity transplant patients are already being treated under the protocol and doing well, though long-term prospects remain unknown. The Johns Hopkins team plans to make the new treatment available to more patients, but their overall mission is more ambitious. They seek the holy grail of transplantation, a discovery that could transform the lives of solid organ transplant recipients as well as reconstructive ones: complete immune tolerance, in which patients would require no immunosuppressive medication at all.
The notion of transplanting a limb or part of the face from one person to another has excited the popular imagination for much of recorded history. Ancient medical folklore is riddled with references to grafting tissues, and even replacing decapitated heads. In the third century, Sts. Cosmas and Damian, twin brothers, were said to have grafted a new (black) leg onto a white man who'd lost his to cancer, an exploit depicted in numerous Renaissance paintings. The 1997 futuristic flick Face/Off served up a modern version of transplantation fantasy. But by then, the idea was not so far-fetched. In 1998, a New Zealand man was successfully fitted with a new hand; it was removed several years later at the patient's request after he reportedly neglected to take his anti-rejection medication. (A hand transplant had been attempted previously, in Ecuador in 1964, but quickly failed due to poor immunosuppression techniques.) In 1999, Matthew Scott received a new left hand after losing his own in a fireworks accident; more than a decade later, he's had no major problems and works as a paramedic trainer. The procedure has since become more and more common, and the surgeries are becoming increasingly complex. Last December, for instance, Lee's team performed Johns Hopkins' first double-arm transplant, on an Iraq war vet and quadruple amputee.
The first face transplant, a partial procedure that replaced the nose, lips, chin, and part of the cheek of a French woman who'd been mauled by her dog, took place in 2005. Each succeeding operation has upped the ante, replacing larger and larger portions of the face with material from the donor. The most extensive procedure to date occurred in March 2012 when a Virginia gun accident victim named Richard Lee Norris received teeth, part of a tongue, and an upper and lower jaw at the University of Maryland Medical Center. He can now smile, eat, and leave his house without a mask for the first time in 15 years.
The success of these early efforts has somewhat quelled speculation that reconstructive transplantation surgeons might be violating the Hippocratic Oath, but critics remain. The risks posed by immunosuppressive medication, this argument goes, are not justified when safer options—such as prosthetics or conventional plastic surgery—exist. But reconstructive transplantation proponents argue that the safer options are, for some individuals, hardly solutions at all. "A surprisingly large number of upper-extremity amputees choose not to wear a prosthetic for a variety of reasons, from poor fitting to pain to lack of function or just doesn't like the appearance of it," Lee says. "There is clearly a select group of patients for which hand transplantation should be strongly considered."
Patients who have experienced severe trauma to the face have even less appealing options. Patrick Byrne, director of the Division of Facial Plastic and Reconstructive Surgery and a member of the new face transplant team, says many of his patients have no need for a transplant, given the success of current treatments. But certain surgeries—for particularly massive defects, or those involving dental restoration or the eyelids or lips, can be very challenging. Even post-surgery, the best some patients can hope for is a skin flap over what had been a gaping hole, or a renewed capacity to keep saliva in their mouth. "I've realized the limitations of my ability to restore people to a normal life," Byrne says. Over the course of his career, he has performed over 500 microvascular facial reconstructions. "Twelve years of operating on people's faces, ranging from massive deformities to people who just want to look younger, and I probably haven't been this excited about anything in my career ever," he says.
Because these transplants are not lifesaving, the team is intensively focused on reducing or eliminating immunosuppressive medication. Simply put, it's important that a given procedure improve the life of a patient to a greater degree than it causes a negative impact. "The biggest problem is to really account for the risk-benefit balance," Lee says. "We're using this [Pittsburgh] protocol to minimize the risk with fewer medications so we can allow more patients to enjoy the benefits of transplantation without incurring the side effects of the medications."
Gerald Brandacher is spearheading the team's immunology research. Brandacher, whose background in solid organ transplantation is unique to the team, heads the vascularized composite allotransplantation research laboratory at Johns Hopkins, the only lab in the world whose main focus is reconstructive transplantation. Achieving complete immune tolerance will require interfering with "the fundamental evolutionary system," he says. "If the immune system were easy to trick, humankind would not be where it is." (One indication of its power: If a patient stops taking his immunosuppressive medication even decades after a transplant, the body will immediately begin to reject the graft.)
Because all immune cells are derived from bone marrow, the goal of the Pittsburgh Protocol is to create a situation in which, in a sense, two bone marrow systems exist in one person. The protocol calls for infusing billions of bone marrow cells from the donor into the recipient (along with a powerful induction agent). The result is a seesaw effect between donor and recipient immune cells, in which they constantly counteract one another, with, in ideal circumstances, neither side winning out. "We have learned in basic research and translational research that the immune system is not an on/off system," Brandacher says. "It is a constantly regulating system and by better understanding those mechanisms, we are now able to significantly reduce immunosuppression."
The protocol does not entirely eliminate rejection episodes. In fact, Brandacher says, some level of rejection is desirable. "In these types of transplants, we want to see some sort of rejection because that means the immune system has seen its target and it tries to mount a counterresponse. It's this response that needs to be kept in check to be able to create immune regulation."
And those rejection episodes are much easier to track in a face or hand transplant patient than in a solid organ recipient. For the first time in the history of transplantation, surgeons are dealing with grafts that can be monitored simply by looking at them. Rejection episodes in other types of transplantation are diagnosed through blood tests or tissue biopsies, and often are not discovered until the immunological effects are long over. With hand and face transplant patients, a region of inflamed skin can tip doctors off to a rejection episode very early in the process, allowing doctors to intervene while the episode is still in its infancy. One of the ongoing projects in Brandacher's lab may even allow surgeons to spot rejection before it is visible on the skin. Researchers are developing a piece of tape which, when placed on the skin and then pulled away, extracts proteins from underneath that indicate whether a patient is having a rejection response.
Face and hand transplant patients are unique in other ways, ways that the team hopes may spur innovation beneficial to the entire transplantation field. Solid organ transplant scientists have been researching the benefits of donor bone marrow for years, for instance, but reconstructive transplant patients may speed the process. That is because their transplants often include a portion of the body's bone marrow factory, a piece of bone. Thus, a face transplant that includes a portion of the jaw or a hand transplant with all of its bones contributes to immune modulation even without an extra infusion of bone marrow cells.
Long-term effects remain unknown, so Pittsburgh Protocol patients still take low doses of one anti-rejection drug, tacrolimus. But Brandacher's lab has already achieved complete immune tolerance in large animals by combining donor bone marrow with several specific biological agents. "This is the last step before going into the clinic," Brandacher says. The first clinical tolerance trials in humans will start in the near future, he says, certainly before the decade is out.
Joani Christensen peers into an operating microscope at 50 times magnification and probes a small gray mouse splayed on its back with its nose in a tube that delivers oxygen. Christensen, a fellow in Brandacher's lab, is transplanting a mouse limb, a feat that just a few years ago was considered impossible due to the animal's minuscule blood vessels. The Johns Hopkins reconstructive transplant lab has devised a new method that makes it possible, if excruciatingly difficult.
Three of the mouse's legs are carefully held down with masking tape. The fourth, a hind limb, is missing. The animal's blood vessels, which are only about 0.2 millimeters across, are too delicate to withstand direct contact with even the special forceps in Christensen's hand, which have superfine tips. So, with her forceps, she grips nearly invisible sutures that encircle the blood vessel she is working on, a maneuver akin to moving a noodle by lassoing it with another noodle solely employing a pair of chopsticks. She positions a vein so that it lines up with that of the detached hind limb. Ever so carefully, she slides a short polyethylene tube over the end of one vessel and proceeds to pull the ends of the vessel inside out over the tube as if folding down a tube sock. A tiny ring slides on next to hold the fold in place and the end of the second vessel slides over the top of the whole configuration, to be secured by another tiny ring. The two vessels are now joined.
Christensen sits back and takes a breath. "No coffee, no drinks the night before, no workouts before work," Georg Furtmueller, another fellow, jokes. "It's a life-changing procedure." Now Christensen must join the arteries, suture the muscles back together, and sew the skin in place, all the while making sure the mouse doesn't lose too much blood. (If it loses enough to soak the tip of a cotton swab, it will not survive.) So goes an average afternoon in the reconstructive transplant lab.
"People joke that maybe the most challenging microsurgical cases in the hospital happen in our lab," Brandacher says with a laugh. His lab developed the cuff technique for mice, whose blood vessels are too small for the standard suture method. The lab is the only one in the world with a reliable mouse model for hind limb and face transplants, both of which are technically very demanding. While the scientists also perform transplants on larger, less challenging animals like rats and pigs, developing a way to use mice has paid off. "The mouse still represents the gold standard in transplant immunology," Brandacher says. Its immune system is most like our own, and more importantly, nearly any gene knockout or transgenic mouse imaginable is available for research purposes, allowing the lab to study very specific immune responses.
Fourteen full-time fellows, engaged in numerous research projects, work in Brandacher's lab. At operating stations that neighbor Christensen's, two fellows perform a rat hind limb transplant for a study examining whether stem cells must come from the donor in order to confer an immunological benefit. As part of that study, rats receive recipient stem cells, donor stem cells, or cells from an unrelated third party following the transplantation. Their immune response is then monitored following the injection. Preliminary evidence suggests that the stem cells' origins don't matter; this means that patients may soon no longer be restricted to the limited number of bone marrow cells available from the donor cadaver. (The data also suggest that stem cells can enhance nerve regeneration, another key problem in face and hand transplantation, and a focus of the lab. Left to their own devices, nerves regenerate just one torturous millimeter a day.)
The field of reconstructive transplantation is so new that many questions remain. But that is also what makes it so engaging for the Johns Hopkins team. "It's the same excitement, I think, that was there 50 years ago when the first kidney and liver transplants were performed," Brandacher says. "Seeing that we can restore patients with missing limbs and missing faces. And I think we are on the brink of seeing major differences in how we treat transplant recipients in general, being on the verge of achieving immune tolerance. These types of transplants might help to reach this goal." If early successes in large animal models are any indication, that goal feels tantalizingly within reach. But immune tolerance is, of course, only one piece of a very complicated puzzle. Solving all the problems inherent to face and hand transplants will require a team of specialists one would never otherwise see in one place.
Burn specialists, craniofacial surgeons, transplant surgeons, military doctors from Walter Reed National Military Medical Center, anaplastologists (prosthesis artists who might be called upon to recreate the face or hand of the donor for funereal purposes), dentists, nurses, speech therapists, occupational therapists, and psychiatrists are among the astonishing variety of people associated with Johns Hopkins' new face transplant program who come together on a quarterly basis to discuss prospective patients. Unlike a solid organ transplant, every reconstructive transplant is unique, requiring specific advance planning. Donor and recipient not only must match up by blood and tissue type but also must be of the same skin color, gender, relative size, and age. And the surgical team must recreate a given defect on multiple cadavers and undergo practice runs prior to each surgery.
Those practice sessions are crucial for face transplants, where one wrong move can have serious functional as well as aesthetic repercussions. Patrick Byrne says the Johns Hopkins team has an advantage because he and his colleagues in the Division of Facial Plastic and Reconstructive Surgery concentrate exclusively on plastic surgery of the face as a matter of course. "When you look at how the public has reacted to the face transplant patients so far, there seems to be consistently a reaction of 'Wow! That's amazing,'" he says. "But in most of the results there's still a little, 'Hmm, there's something not quite right,' you know?" The face is the seat of both communication and emotion, and any stiffness or exaggerated movement in an area can make a transplant appear unnatural. "The difference between, say, anger and disgust is a little pull of the levator labii superioris alaeque nasi," Byrne says by example, pointing to a spot near his nostril, "and that slight difference totally changes the meaning of the facial expression."
The team is currently fielding both hand and face transplant patients; in the latter category, several possible candidates, including one wounded veteran, are under consideration. The team is already practicing on cadavers for those particular surgeries. But the relatively small number of patients with severe face and hand injuries is not the team's primary target. "It's obviously very catchy if you see somebody with new hands," Brandacher says, "but that's not where the numbers are, where the field is going." If the team succeeds in achieving immune tolerance, it could open up the field of reconstructive transplantation to thousands of patients who are currently not candidates. These include children with congenital deformities, patients missing smaller elements that cannot be easily replaced with conventional methods—eyelids, lips, or windpipes, for instance—and cancer patients with malignant tumors who have lost parts of their face to lifesaving surgical resections. This last category, a vast one, is currently a no-no for transplantation because it is too dangerous to jeopardize the immune system of a patient whose immunities are already compromised.
"This [research] is not for the rare person who needs a whole face," Brandacher says. "Those are the pioneers, as were the renal and liver transplants 50 years ago. . . . I'm convinced that in 30 or 40 years, we're going to look back at these early days and say, 'That's when we had done 15 faces and 20 hands. Can you imagine?'"