Transplants: 50 years of saving lives
■ Many advances have occurred since the first successful transplant, but hurdles remain. Key among them is a shortage of donor organs.
By Susan J. Landers — Posted Feb. 16, 2004
Washington -- For hundreds of years, physicians knew that otherwise healthy patients were dying for lack of a functioning part. But the transplantation of a healthy organ from a body that could spare it to one that was needy remained a fantasy until, in 1954, a team of surgeons in Boston showed that it was possible.
Joseph E. Murray, MD, John Hartwell Harrison, MD, and John P. Merrill, MD, pulled off the astounding act. They successfully transplanted a fit kidney from Ronald Herrick into his identical twin, Richard, who was dying of kidney disease.
Before then, "the dogma was that it would never be possible and we were told we were playing God and shouldn't do it," said Dr. Murray, still writing and speaking at local high schools at age 85.
The first step was resolving these kinds of very basic ethical challenges. Thus, the actual surgery followed not only years of laboratory work and research, but also lengthy debate over moral questions.
"We discussed it with clergy of all denominations, with surgeons from other hospitals and with the general public. Many were critical. But we felt we were on proper medical, moral and ethical grounds," said Dr. Murray, a 1990 Nobel laureate.
Organ transplantation continues to inspire debate now, but the issues are different. They center on philosophical concerns such as fairness in awarding precious organs to those most in need and the risk to live donors who may be family members, co-workers or even strangers.
But 50 years ago, when all signals seemed to finally point to yes, the kidney was deemed a good starting place "because the good Lord has given us two," Dr. Murray said.
The fact that identical twins were the patients also influenced the decision to proceed. Their compatibility was almost guaranteed, and the calculation was that the transplanted kidney would not be rejected -- and it wasn't. It also was known that a person could live a long, healthy life with one kidney.
But the quest to overcome the immune system's innate rejection of a transplanted organ was the next, and perhaps even greater, hurdle for this new medical field.
The quest for tolerance -- the body's acceptance of a transplanted organ -- is still a goal transplant surgeons strive to achieve. Most patients must follow a regimen of medications for the rest of their lives to prevent rejection of the transplanted organ.
In the earliest years, radiation was used to subdue the immune system, often with fatal consequences to the patient.
Thomas Starzl, MD, PhD, a professor of surgery at the University of Pittsburgh School of Medicine, found an alternative while working on transplantation at the University of Colorado in Denver. "Everyone knew that transplantation as a true bona fide service was going to atrophy and die unless better immunosuppression came along."
Dr. Starzl began working with Imuran (azathioprine), one of the first drugs of this kind. He took it one step further and combined it with the steroid prednisone. "To everyone's surprise, and perhaps far exceeding my own expectations, we had one-year survival of kidney transplants from live familial donors, not twins, of about 80%." The transplantation field exploded, he said. "Suddenly what had been an idiosyncratic procedure was a real service, overnight."
That advance also paved the way for the transplantation of other organs. Dr. Starzl performed the first successful liver transplant in 1967. Soon after, the first heart, pancreas, lung and bone marrow transplants were performed.
Since then, the field's greatest advances have continued to occur in immunosuppressant drugs, said Norman Shumway, MD, PhD, who chairs the Dept. of Cardiothoracic Surgery at Stanford University. Dr. Shumway transplanted the first heart in the United States in 1968 following closely on the heels of the first such procedure by Dr. Christiaan Barnard in South Africa.
Dr. Starzl refers to transplantation as a 50-year war -- the first phase of which ended around 1968 with the establishment of a strong beachhead of transplanted organs.
But that early burst of successes was followed by a period of disillusionment. "Most of the people around phase one were burned out because of the generally poor results and the morbidity patients had to suffer in order to survive," he said.
The need was still great for effective immunosuppressive medications. "We were all rescued by the arrival of cyclosporine in 1980," Dr. Starzl said. For the first time, expectations of success were more realistic.
"To me, it's been a climb to the top of the mountain to achieve the perfect transplant," said Oscar Salvatierra, MD, professor of surgery and pediatrics at Stanford University School of Medicine.
Dr. Salvatierra has performed kidney transplants for 32 years and has seen survival rates rise dramatically.
Imuran and prednisone were the only two immunosuppressants available when Dr. Salvatierra began his work. Survival rates for cadaveric kidneys were then 50% for one year, and the best living donor matches produced one-year survival rates of 70%. Transplants also brought complications. "Now we have survival rates that are generally close to 90% after five years, with marked decrease in complications," he said.
And there are ongoing improvements. Dr. Salvatierra has been working on a steroid-free immunosuppression protocol for children to allow for normal growth and appearance. The change in medications has resulted in a greater adherence to medication regimen and a drop in rejection rates. "With the body disfigurement, particularly in adolescence, they stopped taking their medications," he said.
Dr. Salvatierra also points to the 1984 National Organ Transplant Act as a great advancement on a social scale. The legislation set forth a national organ procurement and transplantation network. "What that did was provide for maximum utilization of all organs procured, equitable distribution of those organs and a national registry," he said.
Brian Pereira, MD, president of the National Kidney Foundation, also points to the 1968 Uniform Anatomical Gift Act as another great gain that resulted in the widespread use of donor cards. "When we look at all these scientific discoveries, we have to remember that the government and public have also kept pace."
Getting more organs
While successful transplant operations number in the hundreds of thousands, there could be hundreds of thousands more if donors were more plentiful. There are more than 83,000 people on the waiting list, and most of those, 56,560, are awaiting a kidney. By 2010, the overall list is expected to reach 100,000. Thus, a key area of research is focused on furthering methods to ease the shortage.
Experiments in transplantation between humans and animals have been occurring for decades with mixed results. For xenotransplantation to work, researchers must find a way to block the human body's ability to recognize an animal organ as foreign and attack it. Scientists also must develop methods to keep viruses possibly carried by these organs from entering the human population.
On another path, some believe that stem cells could hold the key. The cells, which have the ability to adapt and regenerate into different cell types in the body, have the potential to replace tissues damaged by disease. It is even hoped that such tissue engineering might someday eliminate the need for many transplants and the anti-rejection drugs that go with them.
Researchers also continue to look for ways to eliminate transplanted patients' need for immunosuppression. Current medical thinking holds that pre-conditioning a transplant candidate before surgery might play a key role in this process. It is also believed that low doses of immunosuppression administered immediately after the transplant might allow the fighter cells to attack, become exhausted and eventually enable the body to accept the foreign organ as its own.
But the biggest challenge faced by those in the transplant field remains a shortage of donors. "I think we are probably not using half of the possible donors available today," Dr. Shumway said. "So I look for there to be a bigger use of donor material, a bigger fraction of those possible donors. But it will take time and education."