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 DESIGNER PIGS GOAL OF
MED CENTER RESEARCH -- Lincoln Journal Star Dr. William Beschorner is an inventor. He is also the leader of a University of Nebraska Medical Center team working to transplant hearts and major blood vessels from pigs to sheep. The goal: using pigs as a source of transplant organs for humans. One of the toughest obstacles to transplanting any organ is the body's natural rejection to anything alien. It is strong against tissues from other primates, even stronger against tissues from animals less closely related to humans - pigs, for example. Most researchers have tried to overcome the problem by modifying the host's response, usually through powerful immunosuppressant drugs. But the drugs have serious side effects: kidney damage, high blood pressure, infections and tumors. Beschorner got involved in 1992 while on staff at Johns Hopkins University Medical Center in Maryland. "I started doing a mental exercise," he said. "Every Wednesday, I'd come up with a new invention." They were purely mental exercises, but Beschorner wouldn't leave his office on Wednesdays without having the idea down in writing. One day a colleague challenged him to apply the principle of neo-natal tolerance: If cells from a potential donor animal are injected into a newborn mouse, the mouse will later accept a skin graft from the donor without rejecting it. The challenge was to create the same kind of tolerance in adults. During one of his Wednesday sessions, Beschorner went through 20 or 30 ways to try to modify the recipient. "Then I turned things around and said, 'OK, let's do it within the donor.' Then everything made sense," he said.
He left Johns Hopkins to form his own company, Ximerex. Using ordinary pigs and sheep in Maryland and Pennsylvania, he developed a technique for injecting bone marrow from a sheep into fetal pigs. The pigs were born with a tolerance to sheep cells. The modified pigs are transgenic, or chimeric, animals, meaning they have genetic material from two different species. It was from the latter term that Beschorner derived the name for his company. When the pigs matured, Beschorner was able to graft an aorta from chimeric pigs into sheep from which the marrow had been taken. In four cases, the grafts survived 10 times as long as those in eight control sheep that received aortas from normal pigs. He joined the staff of the University of Nebraska Medical Center in 1997 and continued his work. Eventually, researchers there harvested hearts and spleens from transgenic pigs and transplanted them into sheep. The corresponding spleen was ground up and injected into the sheep. "The tolerance goes both directions," Beschorner said. The pig becomes tolerant to the sheep cells, and the sheep cells in the pig are programmed to become tolerant to pig cells. As with the aortas in the earlier experiment, the pig hearts were grafted onto the necks of the sheep. The sheep's blood flowed through the heart, which continued to pump, but it didn't replace the sheep's own heart. In those experiments, 35 sheep received transplants, 13 from chimeric pigs. Of those, two showed vascular rejection - antibodies attacked the foreign organ and caused it to bleed to death. Another five showed cellular rejection, in which white blood cells attack the organ, which was controlled by administering a "modest amount" of an immunosuppressant drug. The remaining six accepted the hearts. All the sheep receiving hearts from unmodified pigs exhibited vascular rejection. At the end of the experiment, all the sheep were euthanized and the hearts examined to determine what damage, if any, had been done to the tissue. The hearts that were not rejected showed little evidence of injury. The sows were anesthetized while their fetuses received bone marrow injections, and they received pain-killing drugs to help with any discomfort following the surgery, Beschorner said. The rejection of the grafted hearts caused little discomfort, he said, because they were not connected to the sheep's sensory nervous systems. "Animal rights people mean well, but they have a lot of misconceptions," Beschorner said. "They believe there's a lot of suffering going on and that isn't true." His company recently received a $2 million grant from the Advanced Technology Program for a three-year study involving pig livers. The program is administered by the U.S. Department of Commerce. Researchers will inject human liver cells into fetal pigs bred with a "suicide gene" that can be triggered to destroy their own liver cells. The human cells then will "repopulate" the liver, creating a hybrid pig-human liver. The study could lead to breeding pigs specifically as a source of human liver transplants. Pig livers now are used as a bridge to help patients survive a few hours while awaiting a human liver, but pig livers don't produce all the proteins a human liver does. The goal is to design a hybrid liver, which also could be used in research on human liver diseases, Beschorner explained. Beschorner plans to seek $3 million to $4 million in private funding to experiment on transplanting pig livers to baboons, a necessary step before it can be tested on a human subject - something he said could conceivably happen in three to four years. Beschorner said he formed Ximerex so he could get money from private investors rather than depend on grants alone. "My feeling was this was going to be very expensive to develop," he said. "It was more than you could do with a normal NIH (National Institutes of Health) grant." One disadvantage, Beschorner said, is that private investors may want results within a certain time frame. "Are we going to move this thing before it's safe? I don't think that's an issue. If we do something that is dangerous either for the patient or the public health, malpractice suits would be far worse than the stockholder liability suits." Reach Bob Reeves at 473-7212 or breeves@journalstar.com.
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