TWO separate teams have taken a key step towards creating pigs whose organs
won鈥檛 be instantly rejected by our immune system. But there is still a lot of
work to do before pig organs could permanently replace failing human ones.
At any time, more than 60,000 people are waiting for transplants in the US
alone. Thousands die each year because not enough organs are available. Some
doctors think pig organs could fill the gap. Though primates are a closer
immunological match, pigs are easier to breed and raise.
But the human body doesn鈥檛 take kindly to pig parts. Pig cells have a sugary
chemical on their surface that antibodies in our blood immediately latch onto,
causing an immune system attack so severe it merits its own
name鈥攈yperacute rejection. This can disrupt the blood supply of a healthy
organ and destroy it within hours.
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The best way to prevent hyperacute rejection is to 鈥渒nock out鈥� the gene for
alpha-1,3-galactosyltransferase (GGTA1), the enzyme that makes the sugary
coating of pig cells. Two groups have now accomplished this goal, one at the
biotech company PPL Therapeutics and another led by Randall Prather of the
University of Missouri-Columbia. His piglets were born months before PPL鈥檚,
but PPL last week announced the birth of its piglets the day before Prather鈥檚
work was published online by Science.
Both teams began by disabling the GGTA1 gene in skin cells from pig
fetuses. Thanks to the advent of cloning, they were then able to create embryos
that had the altered DNA from these cells. The world鈥檚 first cloned pigs were
only born in March last year.
In total, there are now nine female cloned piglets all lacking one copy of
GGTA1. Normal breeding or another round of cloning will be necessary to
knock out both copies of the gene. The researchers are confident that organs
from animals lacking both copies won鈥檛 provoke hyperacute rejection.
But there are other, slower forms of rejection that can destroy
xenotransplants. Immune cells called natural killer cells attack the tissue.
Mismatches between the pig and human blood-clotting system can cause massive
clots to form in the transplanted organ and beyond. And work by Hugh Auchincloss
at Massachusetts General Hospital in Boston suggests that T-cell mediated
rejection, the major cause of rejection in human-to-human transplants, is more
severe鈥攁nd harder to control with conventional immunosuppressive
drugs.
Julia Greenstein of Immerge BioTherapeutics in Charlestown, Massachusetts,
which has been working with Prather, says that many of these responses may be
triggered or exacerbated by the same sugar that causes hyperacute rejection.
鈥淲e鈥檙e hopeful that eliminating the sugar gets us past a number of obstacles,鈥�
she says.
Not everyone is so confident. 鈥淲e don鈥檛 know yet whether this is a major
breakthrough clinically, or just another layer on a dense onion of
xenotransplant issues,鈥� says Auchincloss, also an adviser to Immerge
BioTherapeutics. 鈥淚 suspect the second.鈥� Only now that the GGTA1
knockout pigs exist, he points out, will it be possible to assess the severity
of other forms of rejection.
Greenstein expects that xenotransplantation will still
require the help of so-called tolerance therapies that make recipients鈥� immune
systems more receptive to foreign organs. For its part, PPL plans to make at
least three more genetic changes to the knockout pigs to try to prevent other
forms of immune rejection.
Even if rejection can be overcome, would-be xenotransplanters will still have
to convince regulators that viruses lurking in the DNA of pigs don鈥檛 pose a threat
(快猫短视频, 26 August 2000, p 7).
Some of these porcine endogenous retroviruses (PERVs) can infect human cells. But the
breed of pig Prather used doesn鈥檛 appear to have such PERVs, and PPL says it may try to
knock out active PERVs in its animals.