University of Pittsburgh

Able Hands

A retired Air Force sergeant from Augusta, Ga., never expected to make history, especially in a Pittsburgh operating room. But, earlier this year, he and a surgical team led by the University’s W. P. Andrew Lee showed the nation what’s possible—and what’s ahead—in transplantation science.

Written by Jennifer Bails

Lee

Lee

For Jeff Kepner, the journey began on a Monday morning with a fever and chills—no signs of anything more serious than a mild case of the flu. The Air Force veteran and father of three stayed at home, in bed, waiting to feel better. But the bacterium Streptococcus had a different plan.

A few days passed. Instead of feeling better, he felt worse. He didn’t know it yet, but his body was afflicted with a particularly virulent strain of the bacteria. The invasive microbes set up breeding grounds in his liver, where they began multiplying and dumping their deadly progeny into his bloodstream.

On Saturday, he began struggling to breathe. His wife, Valarie, rushed him to an emergency room near the family’s home in Augusta, Ga. The battle was under way to save Kepner’s life as a deluge of bacteria ravaged his liver and kidneys, sending him into toxic shock. His immune system was thrust into overdrive, leading to severe inflammation that shut down his vital organs and triggered blood clotting in his limbs.

His doctors induced a coma so that Kepner could use every reserve to heal. When the patient regained consciousness weeks later, his hands and feet were black. His body had diverted blood from his extremities—his hands, arms, legs, and feet—to sustain his vital organs.

“I knew they were going to be taken off, that they couldn’t save them,” he recalls matter-of-factly. “I pretty much accepted it right then and there.” He was right. Doctors had to amputate Kepner’s hands and legs, and his life was forever altered by the challenges to come.

That trauma in the Kepner family occurred 10 years ago, about the same time that physician W.P. Andrew Lee was named chief of hand surgery service in the Department of Surgery at Massachusetts General Hospital and Harvard Medical School. In Boston, the young surgeon’s promising career was right on track, in line with his parents’ high expectations.

Lee’s parents came from the Canton and Szechuan regions of China. His father had flown a bomber for the Republic of China Air Force alongside the American Flying Tigers to fight the Japanese invasion in World War II. During the Communist Revolution, the family escaped to Taiwan, where Lee was born. When he reached age 15, his parents sent him to join his brother and three sisters, who were already in the United States. They wanted to give him every opportunity to succeed.

Even so, it was a rocky adolescence as Lee bounced from sibling to sibling, attending three high schools in three years while adjusting to a new language and culture. With little to do but study, he earned top grades and was accepted to Harvard College, an early achievement that spotlights his enduring work ethic and intense ability to focus.

Lee completed his undergraduate degree in physics, graduating from Harvard with honors in 1979. But at the urging of his older brother—a physicist at Princeton—he abandoned his studies of matter and energy for medical school at Johns Hopkins University and embraced plastic surgery following a general surgical residency at Hopkins. He became particularly fascinated by the challenges of hand surgery, where the outcome requires both form and function.

The hand consists of scores of intricate parts—bones, joints, ligaments, tendons, muscles, nerves, skin, and blood vessels—which must connect together perfectly for proper function. It also bestows the ability to touch and feel the physical world and to communicate human emotions.

Perhaps no one understands this better than Jeff Kepner, the Georgia resident who lost his hands to a pervasive strep infection. He has spent a decade adapting to life with prosthetic arms equipped with hooks to do everything from brushing his teeth to driving his daughter Jordan, now 14, to school. “Most of all,” he says, “I would love to hold my daughter’s hand, my wife’s hand, and actually feel something again.”

Transplant recipient Jeff Kepner spends many hours each week in active hand therapy.

Transplant recipient Jeff Kepner spends many hours each week in active hand therapy.

Plastic surgery has made huge strides in reconstructing tissue damaged by trauma, illness, or congenital anomalies. But there is a limit to what can be done for extremity amputation, says Lee, who is now chief of the Division of Plastic Surgery and professor of surgery in the University of Pittsburgh’s School of Medicine. “There is just no way to build a new arm with the body’s own tissue,” he explains. “It is too complex.”

That doesn’t mean scientists aren’t taking steps in that direction, says colleague Stephen Badylak, a professor in Pitt’s surgery department and director of tissue engineering at the Pitt-UPMC McGowan Institute for Regenerative Medicine, where Lee also is affiliated.

At the McGowan Institute, tissue engineering experts are studying how to grow nerves, muscle, and blood vessels with the aim of bringing these components together as whole body parts. Stem cell and developmental biologists also are trying to recapitulate the genetic and chemical signals in the womb that instruct a fetus to grow a limb or digit, for example.

The work is of special interest to the military. Because of improved body armor and better-equipped medics, soldiers today are surviving casualties that once meant certain death. But these advances also mean that hundreds of soldiers have undergone amputations since the start of wars in Iraq and Afghanistan. At a Texas military base, Badylak is overseeing an experimental protocol to extend soldiers’ lost fingers. So far, the clinical trial has documented remarkable data, with growth of about a half-inch in two patients.

“We are making terrific progress in learning how to instruct the body to think of the default response following injury as something other than ‘Stop the bleeding and form scar tissue,’” Badylak says. “I firmly believe within a couple of years we will have therapeutic strategies that can change that to ‘Let’s constructively make new functional tissue.’”

But Badylak chooses the words “functional tissue” carefully, agreeing with Lee that scientists won’t ever likely learn how to regrow an entire complex body part such as a hand. The alternative to these bottom-up approaches is known as composite tissue allotransplantation, or CTA, which includes the transplantation of whole body parts, such as hands.

This composite tissue approach involves the transplantation of multiple tissues, including nerves, skin, muscles, tendons, bones, cartilage, and fat.  It’s a particularly complex challenge, requiring expertise in immunology, anatomy, stem cell development, drug pharmacology, and much more.

After medical school and his residency, Lee joined the plastic surgery faculty at his alma mater Harvard, where he became recognized as one of the world’s foremost experts in the growing field of CTA. As head of Plastic Surgery Research at Massachusetts General Hospital and later at Pitt, he has published more than 100 peer-reviewed journal articles on CTA and secured millions of dollars in federal funding for his research on how to minimize the use of drugs to suppress the immune system following transplantation.

After undergoing CTA, patients must take powerful antirejection drugs to prevent their immune systems from attacking the multiple foreign-tissue grafts. The high doses and combinations of these medications can have toxic side effects such as diabetes, liver and kidney dysfunction, and infections—not to mention the possibility of chronic rejection that might require a patient to repeat the surgery years later.

The risk/benefit analysis of systemic immunosuppression is fairly straightforward in a lifesaving operation such as a liver or heart transplant. When it comes to a face or hand transplant, where quality of life is at stake, the ethics grow murkier. “It may not be in the patient’s best interest to replace disability from the loss of hands with the severe disability associated with antirejection medications,” says Abhinav Humar, a Pitt professor of surgery, chief of UPMC’s Division of Transplantation in the Department of Surgery, and clinical director of the Thomas E. Starzl Transplantation Institute.

That was the problem still consuming Lee when he was recruited to Pitt in 2002 to head the University’s top-flight plastic surgery program.

The hallway leading to Lee’s office in Scaife Hall is lined with portraits of every graduate in the storied 61-year history of the program, which has trained more chiefs in the highly competitive field than any other medical school in the nation. “I was very happy at Harvard and Mass General and never thought about leaving,” Lee says. “But then I realized how great the opportunities would be at Pitt, with its tradition of excellence in plastic surgery and transplantation and the willingness of the University and its medical institution to invest in the future.”

One bold vision for the future is that hand transplantation will become a routine reconstructive procedure for patients with this limb loss.

A year after coming to Pitt, Lee was named the Sterling Bunnell Traveling Fellow by the American Society for Surgery of the Hand. He spent 2003 examining and interviewing 11 of the 14 patients who had undergone hand transplants around the world.

The first-ever hand transplant was performed in Ecuador in 1964, and the patient’s immune system rejected the donor graft two weeks later. A second attempt at hand transplantation wasn’t made until September 1998 in Lyon, France. Four months later, the first American hand transplantation was performed by surgeons with the University of Louisville in Kentucky, and the graft remains successful. Additional single-hand transplants followed.

“Uniformly, these patients told me that hand transplantation had transformed their lives,” Lee says about his interviews with recipients. “It was especially touching to see how their operations had helped them to regain personal autonomy.” He returned to Pittsburgh convinced of the benefits of hand transplantation but still troubled by the risks of chronic immunosuppression.

At Pitt’s Starzl Institute, scientists and doctors have been working for decades to find ways to induce tolerance of transplanted organs without the need for antirejection drugs and to wean transplant recipients to the smallest doses possible.

In the late 1980s, Thomas Starzl himself became involved with finding new antirejection drugs, and he was the first to use tacrolimus, which was more powerful than other immunosuppressants and had fewer side effects. The drug is now used routinely in kidney and liver transplants performed at UPMC, says Humar. Doctors at UPMC also pioneered studies on whether infusing patients with the donor’s bone marrow after transplantation could coax the body into accepting the new tissue as its own.

Lee and his colleagues at the Starzl Institute decided to combine these approaches for CTA in what they called the “Pittsburgh Protocol.” It involves treating patients on the day of the transplant with a monoclonal antibody called Campath 1-H to suppress their immune systems, followed by a donor bone marrow infusion two weeks later.

Three years ago, studies in a pig model began to yield exciting results—animals that underwent limb transplantation under the Pittsburgh Protocol avoided rejection using only low doses of tacrolimus instead of the usual multidrug cocktail that can cause so much harm.

“We had finally reached the point where we had a reasonable likelihood of reducing immunosuppression for our patients, so we began to seek approval from our Institutional Review Board for this experimental procedure,” Lee says.

On March 14, 2009, Lee and a volunteer team of surgeons performed an 11-hour operation using the Pittsburgh Protocol to give 24-year-old former U.S. Marine Josh Maloney a new right hand to replace the one blown off during a military training accident.

On May 4, 2009, Lee and his team earned their place in the annals of medical history by performing the nation’s first bilateral hand transplant. The patient was from Augusta, Ga—Jeff Kepner—and he received a new pair of hands. Sixteen surgeons worked for nine hours to label and affix all of the bones, blood vessels, nerves, and muscles in the donor hands—from a 23-year-old father from DuBois, Pa., who had been killed in an accident. They connected the hands to what remained in Kepner’s forearms.

For Lee, these two operations marked the culmination of decades of intense, steadfast focus and research effort, says longtime colleague J. Peter Rubin, who was Lee’s research fellow in Boston and followed him to Pittsburgh.

“It was very gratifying for me to watch one of my key mentors achieve that level of success and also recognize that his hard work over time had come to fruition,” says Rubin, now on the plastic surgery faculty in Pitt’s School of Medicine.

Colleagues also praise Lee’s thoughtful long-term planning, which brought together the right team of experts at Pitt to tackle the surgical and scientific problems of CTA, including the significant work of immunologists, surgeons, and many other experts. “It took a lot of forethought for Dr. Lee to undertake a project of this size,” says Joseph Imbriglia, an orthopaedic surgeon who participated in both operations. “His work is keeping Pitt absolutely at the forefront of tissue transplantation throughout the world.”

Like a proud father showing off his newborn, Lee takes out his cell phone and plays a video of Josh Maloney bouncing a tiny basketball using his new right hand. Six months of intense physical therapy are beginning to pay off. Maloney can feel temperature changes and vibrations and is gaining fine motor control. The nerves in his arm are growing toward his transplanted hand at a rate of about an inch a month, and Lee is hopeful his patient will have restored sensation by next year.

About a half-dozen more people are now on the waiting list or being screened for hand transplantation at UPMC. Each operation costs more than $250,000, and the first procedures were paid for by grants from UPMC and the U.S. Department of Defense. Lee has been working with the DOD and the Department of Veterans Affairs to establish a hand-transplant center in Pittsburgh. He also wants to expand the program to other forms of CTA. A face transplant protocol is under review by the University, and abdominal wall, lower limb, and larynx transplants are just some of the future possibilities.

In his cherished free moments, Lee spends time with his wife and their three grown children. His daughter is a sophomore at Harvard and considering a career in medicine. “I tell her there are few fields that are as satisfying when it comes to helping people,” Lee says. “It sounds like a cliché, but it’s true.”

It’s especially true for people like Jeff Kepner, who is undergoing intense hand therapy as he waits for sensation and fine muscle control to develop in his new hands. Just a few months after the transplant, he can wiggle and clench his fingers and thumb, and he’s feeling hot and cold temperatures in his palms. And while it’s still too early to call the Pittsburgh Protocol a success, Kepner has shown no signs of rejection so far, even with just a low dose of tacrolimus.

His wife, Valarie, recalls the moment when she clasped her husband’s new hands for the first time during occupational therapy. “This is the first time I’ve held your hand in 10 years,” she remembers saying. Kepner smiled back at his wife and said: “It will be really nice when I’m actually able to squeeze it back.”

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