AR-News(US) NPPC on pig organ transplants

[Mary Finelli]

PIGS COULD ONE DAY SHORTEN THE WAIT FOR A TRANSPLANT
June 16, 2003
National Pork Producers Council
http://www.nppc.org/news/stories/2003/030616transplant.html

Parkinson's disease was eroding James Finn's ability to move and speak, and
none of the usual drugs helped. So when his doctor suggested an experimental
procedure, he decided to go for it. On Sept. 24, 1996, he had holes drilled
into his skull so that surgeons could implant millions of neurons to replace
a chemical his brain was not producing. The transplant came from an unusual
source: a pig, reports U.S. News & World Report.

Today, Finn's story traces the promise and disappointments of
animal-to-human transplantation, a strategy that could one day ease the
shortage of replacement organs like hearts and kidneys as well as tissues
for treating illnesses like diabetes. Finn himself is convinced that the pig
donation helped him: "It has allowed me to live a much more normal life."
But Diacrin, the company that sponsored the study, decided to abandon
animal-to-human transplants after lackluster results in other patients,
joining other companies that fled the xenotransplantation field after a
mid-1990s rush of enthusiasm. Now, however, there's a new, if cautious,
optimism that animal transplants may yet realize their promise, and do so
before the other great hope for replacement tissues, human stem cells. "We
all hope for stem cells, but before that we will have xenotransplantation,"
says Bernhard Hering at the University of Minnesota.

According to U.S. News & World Repot, scientists believe they are making
headway against the two big problems bedeviling the field: the intense
rejection that normally occurs when animal tissues are put into the human
body and the possibility that the transplants might introduce dangerous new
animal viruses into the human population. At the American Transplant
Congress in Washington last week, for example, researchers announced that
insulin-secreting "islet" cells from pig pancreases survived and functioned
for over two months when transplanted into diabetic monkeys. They also
reported early results on organs from a new breed of cloned pigs,
genetically altered in hopes of making their tissues more compatible with
other species. While their organs still seem to face rejection, the studies
hinted at new strategies for taming the problem. "A year or two ago there
was a lot of concern that the field would be dead," says Daniel Salomon at
the Scripps Research Institute in La Jolla, Calif. "The field isn't dead.
It's coming back."

For decades, doctors have occasionally turned to animal organs for patients
facing imminent death, like Baby Fae, the infant who famously lived with a
baboon heart for 21 days in 1984. Monkeys are no longer seen as good donors,
however, because their similarities to humans might make it easier for
unrecognized viruses to jump the species barrier. So surgeons have turned to
pigs, which have organs of the right size but lie a safer distance from
people. Pig cells, however, look so foreign to the human immune system that
they spark intense rejection.

In the mid-1990s, researchers genetically engineered pigs to give them
humanlike cell-surface molecules. This helped overcome the first swift stage
of rejection that normally would shut down transplanted pig organs within
hours, allowing the organs to survive in monkeys for weeks and even months.
By now, says Christopher McGregor of the Mayo Clinic in Rochester, Minn., a
monkey given a pig heart in his program can often live three months or more.
(To simplify the experiment, he leaves the monkeys' own hearts in place as
well.)

Many of McGregor's animals die not from rejection but from infections,
because their immune systems are suppressed. Clinicians have long experience
managing this problem in human transplant recipients, he says, so "it's very
likely that humans will do significantly better." He's about to start
experiments in which he will completely replace the monkey hearts with pig
organs, hoping to gather data within a year that might support starting a
trial of pig transplants in humans. But other experts say the organs would
have to live far longer than three months before that step would be
warranted.

Sugar free. That's why scientists are intensely interested in seeing how
organs from the new generation of genetically altered pigs will fare. These
pigs, rather than having extra human genes, have had one of their own genes
taken out. Created by two companies and cloned to make herds of identical
animals, the pigs don't make a sugar called gal, normally found on the
surface of pig cells. Gal is a red flag to antibodies circulating in the
human bloodstream, drawing an immediate attack.

The U.S. division of PPL Therapeutics, now part of Regenecor, made the
world's first gal-free pigs last July and will begin pig-to-primate trials
this month. Immerge BioTherapeutics already has started testing organs from
its rival herd. Last week Megan Sykes of Harvard University gave the first
glimpse of the results. So far, the sugar-free hearts don't appear to
survive any longer than transplants from earlier pigs. Eliminating the sugar
may help tame the first swift immune-system assault on an animal organ but
not the next stages of rejection, in which the immune system attacks the
organ's blood vessels.

In a separate experiment, however, Sykes and her Immerge colleagues
implanted a gal-free pig kidney into a monkey along with part of the same
pig's thymus gland. The thymus gland's normal role is to "instruct"
immune-system cells about what to attack, and the researchers hoped that the
transplanted thymus would retrain the monkey's immune cells to see the pig
kidney as its own. This extra pig bit may have made a difference. The monkey
died from an unrelated complication 68 days after the transplant, and
scientists examined the kidney. It looked "really good," with no signs of
rejection, says Sykes, and the group is now doing further tests of the
strategy.

Still, transplanting solid organs has proved so challenging that many
researchers think xenotransplantation may first become routine for isolated
cells that don't have the blood vessels targeted by
rejection--diabetes-curing islet cells, for example. "Most people are
thinking that islets are going to be the first," says Sykes.
The promise of islet cells was underscored last week at the transplant
meeting when Hering and other physicians announced preliminary results from
a closely watched trial of human islet-cell transplants. Twelve of the
recipients currently no longer have to take insulin, and 16 others need
less.

But it can take several donor pancreases to supply enough human cells for
one diabetic, and human organs are in short supply. Pig islet cells may be
the answer, says Hering, whose group found that the cells can survive and
pump out insulin in monkeys. A controversial study in Mexico has already
started testing pig islets in diabetic children.

None of the results so far is enough to overcome the nagging worry about
xenotransplants: that pig tissue could carry new infections into humans.
While pigs aren't likely to pick up a virus like SARS in the carefully
controlled labs where they live, they harbor viruses called porcine
endogenous retroviruses (PERV), which long ago became shoehorned into pig
DNA.

PERV can enter human cells, but scientists disagree on the risk they pose.
One study of 160 people exposed to various pig cells in early clinical
trials found no evidence of infection. But Jonathan Allan, a virologist at
the Southwest Foundation for Biomedical Research in San Antonio, says that
no one knows what symptoms the viruses might cause in humans. "You're not
really sure what you're looking for."

So scientists are trying to learn all they can about the viruses. Working
with Salomon and others, Immerge announced last month that it had discovered
the human receptor that PERV latches onto. Salomon's group is now making
transgenic mice that carry the human receptor, hoping to mimic a human PERV
infection in the lab. And Immerge says it has found a family of pigs whose
PERV either can't infect human cells or do so very ineffectively.
Even if the PERV problem were solved tomorrow, however, activists say that
other, unknown pathogens could hitchhike on the transplanted organs. "These
patients could be walking time bombs," says Alix Fano of the Campaign for
Responsible Transplantation. "The public has a right to know that if they
could potentially be exposed to the next AIDS."

But an unknown risk might prove worth taking if there's compelling evidence
that pig transplants can help. Scientists think they can build a case for
going forward. But the last thing they want is a new wave of hype. "When
people start to talk about enthusiasm, I get nervous," says Salomon. "Having
been through the high-flying 1990s with xenotransplantation, I think people
should just shut up a little bit and do the science."

Pigs to people
Places in the body where pig tissues and organs might help
Spinal cord: Researchers hope that pig cells could repair injuries.
Liver: Scientists have perfused blood from people with liver damage through
pig livers to allow the patients' own organs to recover or sustain them
until a transplant is available.

Kidney: Organs from pigs might help the people--currently more than
50,000--waiting for a kidney transplant.
Neural cells: Pig neural cells have been tried in patients with Parkinson's
disease, so far without success.
Thymus and bone marrow: Transplants of these pig tissues along with other
pig organs may train the recipients' immune systems not to reject the animal
tissue.
Heart: Hearts from pigs might tide patients over until a human transplant
became available.
Pancreas: Insulin-producing islet cells from pigs have been tested in
monkeys and people and may someday offer a cure for diabetes.

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