A Donor Named Wilbur
By Erika Jonietz
Medicine: Pig-to-human transplants could become standard
practice in just a few years.
The numbers are grim. According to the United Network for Organ
Sharing, more than three times as many people in the United States
were waiting for heart, kidney and liver transplants than received
them in 1999; over 5,500 people died waiting for organs.
And many more patients could benefit from organ transplants
than ever make the waiting list, either because they are too sick or too
healthy to qualify. According to one estimate, 45,000 Americans
could benefit each year from heart transplants, but only 2,000 or
so human hearts are available.
One promising solution to this medical predicament is to harvest organs
from suitable animals and use them for human transplant. It may sound
outlandish, but several biotech and pharmaceutical heavyweights, as well
as some smaller biotech firms, are gearing up to do just that (see table).
In preliminary experiments, these companies have already implanted
animal cells in human volunteers to treat such diseases as Parkinson's
and epilepsy. Researchers plan to start whole-organ clinical trials in the
next two to three years.
The use of animal organs in human transplants is not exactly
new. You may remember "Baby Fae," the 12-day-old California
infant who, in 1984, received a heart transplant from a most
unusual donor—a baby baboon. This controversial experiment
marked the first time most people had ever heard of
"xenotransplantation," transplanting tissues or organs between
species, and Baby Fae's very public death only 20 days after her
surgery chilled the climate for xenotransplantation work. Still,
medical researchers quietly pressed ahead, and their efforts
may soon pay off.
The animal of choice in the new generation of experiments?
Pigs. That's because pigs are both plentiful and easy to raise,
and "the similarities to man are amazing," says Julia Greenstein,
CEO of Immerge BioTherapeutics, a joint venture between
Swiss drug giant Novartis and Charlestown, MA-based
BioTransplant.
But transplanting tissues from pigs to people does present a few
problems. The most critical is "hyperacute rejection," an immune
reaction that causes organs from pigs to turn black and cease
functioning within minutes of transplant into humans. The cause
of this reaction is a sugar called alpha-gal that laces the surface
of every pig cell. Since human cells don't make this sugar, the
immune system produces antibodies against it and kills all cells
bearing it.
For whole-organ transplants to become reality, a strategy is
needed to deal with the troublesome sugar. That's why
companies such as Princeton, NJ-based Nextran are genetically
engineering pigs to make proteins that help repress the immune
reaction that the sugar causes. Nextran, owned by
pharmaceutical giant Baxter, has already used the livers of such
pigs to keep patients with acute liver failure alive until donor
organs were found. In these early human tests, the pig livers
remained outside the body, but "it's just a prelude to going into a
human," says University of Pittsburgh transplant surgeon John
Fung. The company plans to apply for permission to conduct
preliminary human trials of such xenotransplants by the end of
next year.
Other companies, including Immerge, PPL Therapeutics and
Advanced Cell Technology, are combining this strategy with
efforts to completely eliminate the guilty pig sugar. To do this,
they must "knock out"—disable or remove entirely—the gene for
the enzyme that makes the sugar. There is some concern,
however, over whether pigs can survive without the sugar.
"Chances are the pigs will be healthy, but no one's 100 percent
sure," says immunologist David Cooper of Massachusetts
General Hospital's Transplantation Biology Research Center.
Even if the pigs do survive, genetic modifications alone might
not be enough to conquer transplant rejection problems, even
with antirejection drugs. So PPL, Immerge and Advanced Cell
Technology are pursuing additional strategies for blocking
rejection. Each hopes to fool the human immune system into
thinking that a new pig organ belongs in the body, usually by
infusing or implanting pig bone-marrow cells into the recipient
several weeks before a transplant operation. The idea is to use
antirejection drugs to keep the marrow cells alive long enough
for the human immune system to start thinking of the pig cells as
"self"—reducing the patient's dependence on very large doses
of the powerful drugs after the organ transplant. Fung is
skeptical, though: "Trying to get animal organs to be accepted
using approaches that haven't worked in human organ
transplantation requires a leap of faith."
Omaha, NE-based Ximerex is even more ambitious, trying to
completely eliminate the need for antirejection drugs by
"introducing" individual pigs and transplant recipients prior to
surgery. A patient's bone marrow cells would be infused into a
pig fetus, educating both the pig and human immune cells to
think of each other as self. After the pig's birth, hybrid pig/human
bone marrow would be put back into the patient. One drawback:
patients would have to wait four to five months between bone
marrow sampling and transplant operations. Ximerex president
William Beschorner doesn't think the obstacle is insurmountable:
"The typical wait for a human transplant is well over a year. It
would not be a major problem for most patients."
Each of these companies hopes to begin clinical testing of heart
and kidney xenotransplants in the next few years. Although
Cooper is generally optimistic, he sounds a note of caution. "It's
like peeling an onion: every time you pull off one layer, you find
another problem underneath." The thousands who die each year
waiting for new organs hope those problems are solved soon.
Erika Jonietz is an associate editor at Technology Review.
Table - technologyreview.com|
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