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http://www.latimes.com/news/state/20000817/t000077173.html

Thursday, August 17, 2000

Study Suggests Pig Organ Transplants Could Imperil Humans

Health: Virus appears in mice injected with pancreas tissue. The results are released as British prepare to approve procedures.

By CATHY PASCUAL, THOMAS H. MAUGH II, Times Staff Writers

The heated race to transplant pig organs into human recipients hit a stumbling block Wednesday with the release of research that seems to buttress the greatest fear of opponents--that such transplants would circulate dangerous pig viruses into the human population.

The discovery comes at a time when British authorities are poised to grant permission for the first such xenotransplants in humans. Moreover, two research groups are reporting in Friday's Science and a forthcoming Nature that they have cloned pigs, viewed as a major step toward making transplantable organs more widely available.

A team centered at the Scripps Research Institute in La Jolla transplanted pig pancreas tissue into diabetic mice with no immune systems. The researchers found that the mice quickly became infected with a so-called porcine endogenous retrovirus or PERV.

The virus does not produce disease in pigs or in mice, but related viruses cause leukemias in a variety of species. And critics fear that such viruses could interact with human viruses to breed more dangerous species, as is believed to have happened with the virus that causes AIDS.

The discovery "is not a nail in the coffin for [such transplants], but it alerts us to the fact that we need to do more research to find out the potential of PERV to be an infectious disease risk," said epidemiologist Jonathan Allen of the Southwest Foundation for Biomedical Research in San Antonio.

It is not yet clear how the findings will affect the potential xenotransplant industry, which annually could serve tens of thousands of patients for whom no conventional organs are available and could produce annual revenues estimated at more than $6 billion.

Proponents argue that tests in more than 160 humans exposed to pig tissues and in large numbers of primates that have received pig organs show no evidence of such cross-species infections. The Scripps results, they argue, are an aberration resulting from the fact that the mice had no immune system.

"The animals used in this study were completely immunodeficient," said Deborah Spak, a spokeswoman for Nextran Inc., of Princeton, N.J., one of the leading companies developing pig organs for transplants. "This was an extreme situation that would not occur in primates."

But critics of xenotransplantation argue that the findings are clear evidence of unwarranted risk. "We need prudent public health authorities to really adhere to precautionary procedure and say, 'It's too dangerous; we need to stop,' " said Alix Fano, executive director of the Campaign for Responsible Transplantation.

Although critics charge that research on xenotransplants is motivated primarily by the fabulous sums of money such organs could produce, proponents argue that there is an equally immense medical need.

As of Aug. 6, 71,105 Americans were on waiting lists for organ transplants, according to the United Network for Organ Sharing. Because supplies were limited, however, only 21,692 people received transplants last year. Experts say that as many as 50,000 Americans and 5,000 Britons die each year while waiting for donor organs to become available.

"Xenotransplantation would have tremendous value," said Dr. Daniel R. Salomon of Scripps, who led the new study. "This is an incredibly clinically relevant problem."

And pigs are an obvious choice because their organs are the right size and they can be grown easily under the sterile conditions necessary to limit conventional viral infections.

Salomon and his colleagues isolated insulin-secreting islet cells from the pancreases of adult pigs and transplanted them into diabetic mice. They used mice with no immune systems to eliminate any problems associated with rejection. A similar procedure would be used in treating human diabetics, but the pig tissue would be genetically engineered to reduce the risk of rejection.

The transplanted cells cured the mice's diabetes. But Salomon's team found that the mice developed PERV infections that lasted for as long as two months. Salomon and others previously had shown that PERV could infect human cells grown in culture, but this was the first evidence that the retrovirus could cross the species barrier under actual transplant conditions. Their report will be published in a future issue of Nature, but was released Wednesday.

"So far, this is not a killer virus," Salomon said. The virus replicates one or two times in a variety of mouse tissues, then goes dormant.

"The risk here is unclear," he said. "It doesn't appear to be very great."

But the results do show that there is a scientific foundation for the public debate over the risks of xenotransplants, he said.

The pig cloning generated much excitement Wednesday among xenotransplant proponents because it could sharply increase the number of useful organs available. Previously, researchers have reported cloning cattle, sheep, goats, mice and monkeys to improve the quality of their meat or to use them as living factories for the production of human proteins and drugs.

Pigs represent a different challenge because of the plans to put their organs into humans.

Animal organs transplanted into humans undergo what is known as a hyperacute rejection, in which the recipient's body attacks them viciously, even in the presence of immune suppressing drugs. The organs are quickly rejected, in periods ranging from minutes to hours.

Companies such as Nextran and Imutran of Great Britain have genetically engineered pigs to make them look more human to a recipient's immune system. Such engineered organs have now been shown to persist for three months or longer in primates, setting the stage for experiments in humans.

But genetic engineering is a hit-or-miss proposition. For every 20 pig embryos that scientists try to modify genetically, only one is a success. Researchers hope that cloning a genetically engineered pig will allow them to produce much larger numbers.

Genetic engineering of pigs is "extremely difficult, expensive and time-consuming," said molecular embryologist Anthony C.F. Perry of Rockefeller University. "But if we can replicate such pigs, we can make it easier and quicker."

Last March, scientists from PPL Therapeutics Plc in Edinburgh Scotland--the group that startled the scientific community by cloning Dolly the sheep--reported that they had used a new technique to clone five piglets, but released no scientific information about the procedure.

Those details are in a Nature paper that will be published later this year, but that also was released Wednesday.

The Scotland on Sunday newspaper reported Sunday that PPL was abandoning pig cloning, in part because of the fears of virus infections. But PPL Chief Executive Grahame Bulfield said later in the week that no decision had been made yet. If pig cloning is dropped, he said, it would be only because the company is better suited to pursue other cloning problems.

The second report, in Friday's Science, is from a multinational team headed by animal breeder Akira Onishi of Japan's National Institute of Animal Industry in Tsukuba. The Japanese researchers reported using a different technique--the same one used by Hawaiian researchers to clone mice--to clone a black piglet named Xena using cells from an adult pig. Xena was born July 2 from a genetically white surrogate mother.

"Pig cloning . . . is here to stay," Perry concluded.

Copyright 2000, Los Angeles Times. Reprinted with permission.