Pig-to-Human Transplants on the Horizon

Thousands of patients die every year in the United States waiting for a suitable donor organ. So surgery professor David Sachs has been trying to figure out how to successfully put a pig organ into a primate. The Massachusetts General Hospital researcher and clinician thinks he has almost found the right protocol: a combination of organs from miniaturized, genetically engineered pigs and pig immune tissue that can prime the primate immune system to accept foreign parts.

The longest any animal has survived such a transplant is 83 days, still far short of the one-year survival time that Sachs, director of the Transplantation Biology Research Center at MGH, considers a benchmark to start human trials. But he thinks with a few minor tweaks, the procedure will be ready to try in patients, possibly in as little as five years.

Sachs believes that pig-to-human transplants are the best near-term solution to the drastic shortage of donor organs. As of September 25, 2006, more than 93,000 people in the United States were on the waiting list to receive an transplant organ. Last year, 6,500 people died waiting for such an organ. “People are dying every day for lack of organs,” says Sachs. “Genetic engineering and stem cells promise to cure these diseases–but not in the near term.”

Transplantation between two different species, which is known as xenotransplantation, is not easy. To date, pig skin and pig valves have been used in human transplants, but not entire organs. When patients get an organ transplant from a human donor, doctors stave off immune rejection with organs matched to the recipient’s tissue type and heavy doses of immunosuppressant drugs.

But when organs are transplanted between species, immune attack is swift and much more severe. Pigs and other animals have a specific sugar not present in humans and old-world primates. So when a pig organ is transplanted into a baboon, for example, antibodies circulating in the baboon’s blood immediately swarm and attack the pig tissue, leading to the death of the organ.

Scientists made a major advance in overcoming this immune barrier in 2002 by creating genetically engineered pigs that lack the enzyme that attaches the sugar to the surface of pig cells. In a paper published in Nature Medicine last year, Sachs showed that baboons given kidneys from these genetically modified pigs lived for up to 83 days, far longer than the average 30-day survival time for animals receiving regular pig kidneys.

Sachs’ team also transplanted an additional piece of pig tissue, an immune system organ called the thymus, to prime the baboons for the transplant.

“Engineering the graft itself in ways that might reduce toxicity to the recipient is revolutionary because it potentially makes transplantation much safer,” says Jeffrey Platt, head of the Transplantation Biology Program at the Mayo Clinic in Rochester, MN.

Scientists, including Sachs, are still tinkering with better ways to trick the primate immune system into accepting pig tissue. They ultimately want to find a protocol that minimizes the use of immunosuppressants, which raises the risk of infection. (Two of the eight baboons in Sachs’ last transplant experiments died of infections.)

One option, says Sachs, is to transplant bone-marrow cells along with the kidneys and thymus, which in some cases has been shown to improve tolerance for transplanted organs. Scientists are also developing additional genetic modifications that might improve the long-term survival of the organ, such as adding human genes for proteins involved in immune regulation or blood clotting.

Sachs says the team hasn’t yet decided on the exact measures of success to achieve in baboons before starting human trials. Ethical and safety discussions will likely be required to design a human study. The researchers are carefully monitoring potential viruses that might be passed between pigs and baboons or humans, which has been a major health concern with xenotransplantation.

Sach’s most recent research, though, published last month in the journal Transplantation, could be good news for people who are highly sensitive to proteins in human tissue, and are therefore much less likely to match organs from a human donor (about 20 percent of people on the waiting list for kidney transplants). By exposing blood from such patients to tissue from genetically modified pigs, Sachs and team found that the individuals’ hypersensitivity did not extend to pigs. Given their low chance of finding suitable human organs, these people might be the first candidates for pig-to-human transplants.

Platt says that transplants from pigs might actually be safer than human-to-human transplants in the long run. “You can screen the organ in advance for infectious agents and other problems,” he says, a process for which there isn’t much time in today’s urgent human transplants. And, he adds, because you can schedule the surgery in advance, you can plan pretreatments, such as bone-marrow transplants, that might better prepare the patient’s immune system for the foreign organ.