Wall Street Journal, August 28, 2000 Monday
From a Small Pig, a Big Advance for Transplanting Animal Organs --- Biotech Firm Breeds Swine Whose Cells May Not Pass
Scientists at a Boston biotechnology company say they have bred a line of miniature pigs that don't transmit potentially harmful viruses to human cells, advancing the prospects of using animal organs for human transplantation.
If confirmed by other scientists, the discovery -- slated to be presented today by BioTransplant Inc. at a conference in Rome -- would allay much of the concern about infection in xenotransplantation, or transplants across species.If other issues can be overcome, researchers have little doubt there will be a market for the miniature pigs' organs, including livers, kidneys and hearts. About 6,000 Americans died last year while waiting for human organs.
BioTransplant's work is likely to gain significant attention because its main reseacher, Clive Patience, is a member of a British academic team whose discovery in 1997 that pig viruses can infect human cells sounded a world-wide alarm. Dr. Patience, whom BioTransplant hired last year, said he had expected to disprove the company's preliminary findings that its pigs don't transmit viruses to humans. "I said I'd eat my hat if this turned out to be true," says Dr. Patience. He adds, "My colleagues are selecting the hat."
The transfer of animal organs into humans has been tried unsuccessfully for centuries -- stymied mainly by the human body's stunningly efficient mechanism for eradicating invaders. The BioTransplant finding doesn't address that hurdle, but other barriers to cross-species transplants are falling. Last month, the journal Nature announced that pigs had become the fourth mammal to be cloned. The development, achieved by Britain's PPL Therapeutics PLC, raises the possibility of the creation of an unlimited supply of pigs with organs designed for use in humans.
In the past year, BioTransplant, collaborating with Novartis AG, has managed to keep pig hearts and kidneys functioning in baboons for as long as a month. And Baxter International Inc.'s Nextran unit has kept desperately ill patients alive for as long as 10 hours by filtering their blood through external pig livers -- long enough to bridge the gap until a human organ arrived. Nextran says it could be ready to attempt a full-fledged pig-to-human transplant in as little as 18 months.
Attempts at full-organ xenotransplantation yielded poor results in the early 1990s, and widespread caution about renewing the efforts remains. But Robert Michler, chief of transplantation at Ohio State University Medical Center, believes human trials ought to begin as soon as possible after half of the pig hearts transplanted into baboons last three months. In the 1960s, researchers began transplanting human cadaver hearts into humans after such hearts had worked only 200 days in test animals. The first human heart recipient lived only 18 days. Today, half the humans who get heart transplants live 10 years, Dr. Michler says.
In 1992 and 1993, transplants of baboon livers into humans proved unsuccessful, either because the host rejected them or because the strong antirejection drugs killed the patients. Alarmingly, in at least one of the cases, a primate virus was transferred to a human recipient, who died of other causes. Amid an outcry that such transplants could unleash an AIDS-like epidemic, the Food and Drug Administration banned further primate-to-human transplants in 1996.
That left pigs. They are easy to breed. And given their widespread slaughter for meat, advocates figure few Americans would object to killing them for medical purposes. Pigs are physiologically close to humans, and their organs are of similar size.
Although infection from pigs is viewed as less likely than from baboons, pathogens known as porcine endogenous retroviruses, or PERVs, have raised concerns. As many as 50 different kinds of PERVs are present in each pig cell. They are harmless in pigs, but their effect in humans is unknown. In mice, similar viruses can cause leukemia.
PERVs aren't a problem in pig heart valves, which are routinely used in humans: The viruses are killed with chemicals used before transplant. And the FDA has approved the experimental transplant of carefully screened pig brain cells to humans with Parkinson's disease. The risk of infection in full-organ transplants, however, is higher, and use of the chemicals isn't possible because they would kill the organs.
In testing BioTransplant's swine, Dr. Patience mimicked the 1997 experiment that raised the initial alarm, taking cells from pigs and mixing them with human ones to see whether infection would occur. Unlike the earlier work, which used a type of full-size pigs, this time he found that in miniature swine, the viruses, while present, didn't infect the human cells. The smaller pigs have been specially bred by BioTransplant and Massachusetts General Hospital with an eye toward use in transplants. Although significantly in-bred, the pigs started out as a wild miniature breed.
BioTransplant says it doesn't know why the miniature pig cells didn't transmit the pathogens and is continuing research to find out. After generations of inbreeding, it could be that the pig viruses may have lost their power to infect.
Daniel R. Salomon, a scientist at the Scripps Research Institute, in La Jolla, Calif., and author of a report last month in Nature about the transmission of PERVs from pig pancreatic cells to mice, hailed BioTransplant's finding. But even if the research holds up to further testing, he cautions, the PERVs could mutate into a more infectious form after human transplant. And pigs may contain other, as yet unknown, pathogens, he says.
If scientists solve the PERV problem, they still must grapple with rejection by the human immune system, which generally turns foreign organs black and useless within hours. The red flag that alerts the human body to the invader's presence is a sugar called alpha galactosidase, the same one that sits on the outside of bacteria humans fight off daily.
Some companies, such as Alexion Pharmaceuticals Inc., of New Haven, Conn., are developing stronger and smarter drugs to suppress the immune system. Britain's pig-cloning PPL and other companies are working on making pigs that would lack the sugar. But this work could take as long as a year.
BioTransplant, in another gambit, is using full-size pigs genetically altered by Novartis to add a human protein that slows the defenses set off by the foreign sugar. It also is attaching pig thymuses to the transplanted organs -- hoping that the gland, which functions to educate the immune system, will teach human host cells that the new organ is family.
These approaches have more than doubled the length of time BioTransplant can keep pig organs working in baboons, to 30 days compared with about 10 to 12 days a year ago, says Julia L. Greenstein, the company's chief scientific officer. The next step is to breed miniature swine with the Novartis genetic modification. BioTransplant believes the pigs, which weigh about 250 pounds, or roughly a quarter the weight of a full-size pig, are also useful because they are closer to human dimensions.
Other companies plan to harvest organs from full-size pigs at the age of six to eight months old. What isn't known is "whether the organs will continue growing at a pig rate once they are transplanted into humans," says John Logan, Nexran's vice president of research, adding that preliminary evidence suggests they won't.
Even when corporate scientists say xenotransplantation is ready for human tests, critics will abound. Alix Fano founded an antixenotransplantation advocacy group called Campaign for Responsible Transplantation following Dr. Patience's 1997 work with pig viruses infecting human cells. She says she is skeptical of his latest work.
"It's amazing how scientists change their tune when biotechnology companies are paying their salary," she says. Dr. Patience replies, "If anybody wants to look at the data, they are welcome." |
