Towards Xenotransplantation via Transgenic Pigs

There are two paths to xenotransplantation, the use of animal organs from species such as pigs in human medicine. The first is decellularization, clearing out all of the cells from the organ and then repopulating it with cell types derived from the patient's stem cells. The second is genetic engineering of a donor lineage, such as the transgenic pigs mentioned in this article. In both cases this is a sizable incremental improvement on the present day situation in transplant medicine, either minimizing immune rejection issues or removing limits on the availability of donor organs. Bear in mind, however, that xenotransplantation and decellularization are only stepping stones on the way to future technologies of organ tissue engineering and regenerative medicine capable of organ repair in situ; these are unlikely to have a long life spans as active technologies given the present pace of progress.

Researchers have been shattering records in xenotransplantation, or between-species organ transplants. The researchers say they have kept a pig heart alive in a baboon for 945 days and also reported the longest-ever kidney swap between these species, lasting 136 days. The experiments used organs from pigs "humanized" with the addition of as many as five human genes, a strategy designed to stop organ rejection. The GM pigs are being produced by Revivicor, a division of the biotechnology company United Therapeutics. That company's founder and co-CEO, Martine Rothblatt, is a noted futurist who four years ago began spending millions to supply researchers with pig organs and has quickly become the largest commercial backer of xenotransplantation research. Rothblatt says her goal is to create "an unlimited supply of transplantable organs" and to carry out the first successful pig-to-human lung transplant within a few years.

The problem with xenotransplantation is that animal organs set off a ferocious immune response. Even powerful drugs to block the immune attack can't entirely stop it. All human tests of pig organs have ended quickly, and badly. Researchers continue to work with pigs because they're in ready supply, and the organs of young pigs are about the right size. In order to beat the rejection problem, researchers began trying to genetically modify the animals. One major step came in 2003 with pigs whose organs lacked a sugar molecule that normally lines their blood vessels. That molecule was the major culprit behind what's called hyperacute rejection, which had almost instantaneously destroyed transplanted pig organs. Removing the sugar molecule helped. But it wasn't enough. Tests in monkeys showed that other forms of organ rejection still damaged the pig tissue, albeit more slowly. To combat these effects, researchers have made pigs with more and more human genes. For instance, one gene that's been added produces the human version of thrombomodulin, a molecule that prevents clotting in blood vessels. Although pigs have their own version of thrombomodulin, it's the wrong shape and doesn't work correctly with human blood.

Transplant surgeons say one of the largest obstacles they face is the immense cost of carrying out xenotransplant experiments. A single transplant surgery costs $100,000 and involves eight people. Then there's the cost of keeping the primates, the red tape of animal regulations, and limited government grants. That's where Rothblatt's personal interest and her fortune have made a difference, they say. "She is the one that has rejuvenated the field. She has the money and a personal attachment. She wants to get it done fast."



Agree with you Reason, it is interesting but I suspect regenerative medicine of organs in-situ ala Conboy and Blasco etc... are likely to render this obsolete soon enough.

Posted by: Steve H at August 12th, 2015 7:09 AM

The third way is using chimeras to grow a genetic match of the patients organ in a pig. Back in 2012 they'd done this with a rat pancreas in a mouse. They should try to grow a baboons pancreas in a pig next. Genetically humanising the pig may help with this.

Posted by: jim at August 12th, 2015 7:16 AM
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