Weighing the Risks and Benefits of Xenotransplantion
By Jason Socrates
Bardi
If
thou art privy to thy country's fate, Which, happily, foreknowing
may avoid, O, speak!
——Shakespeare,
Hamlet, Prince of Denmark, 1600
The patient is put under general anesthesia for the duration
of this major operation.
When he was a teenager, this patient developed Type 1 ("insulin
dependent") diabetes—one of the most prevalent chronic
diseases among children in the United States. For reasons
that are not completely understood, his immune system began
destroying a certain type of cell in his pancreas called "islets."
These islets are the body's only source of insulin, a protein
responsible for regulating blood glucose levels. Without the
islets, the insulin disappears from the bloodstream, and without
insulin, the glucose in the bloodstream increases and is maintained
at levels much higher than normal, causing damage to the body's
organs.
For his entire adult life, he has injected insulin every
day. Now he is getting a more advanced treatment—one
necessitated by years of damage to his internal organs. He
is getting a new, healthy pancreas from a human donor.
A team of surgeons work several hours to place the pancreas
in the abdomen, connecting it to the major artery and major
vein that bring it blood, and to the intestine.
Some 1,500 to 1,800 pancreatic transplants are performed
every year in the United States, and most are successful.
Seventy-five percent of the grafts are viable five years after
the operation.
The operation is a significant scientific and medical breakthrough,
because when it is over, the patient's new pancreas begins
producing insulin and monitoring the body's blood sugar automatically.
But to fully recover from this major procedure, a patient
like the fictional one portrayed here usually must take at
least two weeks in the hospital and another three months at
home.
The Islets Have It?
A much less invasive and safer alternative involves injecting
"islet" cells isolated from the pancreas into the patient.
In this experimental procedure, a team of doctors removes
the pancreas from the donor and insufflates it with collagenase,
a proteolytic enzyme that breaks down the collagen in the
tissue. They then supervise a controlled digestion of the
pancreas that releases the islets, after which the islets
are purified using a specially designed density gradient and
a centrifugal cell separator device originally developed to
purify bone marrow stem cells.
Then, says Daniel R. Salomon, associate professor in The
Scripps Research Institute (TSRI) Department of Molecular
and Experimental Medicine, you deliver them via a single injection
into the liver. It is a much faster and less invasive procedure,
and the patient's recovery time is quicker than in the whole
organ transplant.
However, islet transplantation and whole pancreas transplantation
are both limited by the severe shortage of available human
donor organs—there are only about 5,000 available per
year in the United States. And because of this shortage, the
islet operation tends to be done much less than the whole
organ tansplant. Islet transplantation has just not been around
long enough for there to be sufficient data supporting the
long-term survival and normal function of these cell transplants.
"What are you going to do if you have a pancreas available
and a patient who has waited months to get it?" asks Salomon.
"You are not going to use it on an experimental procedure."
Still, pancreatic islet transplantation has the potential
to make a huge difference in the future because there are
far more diabetes patients than there are pancreata and if
pancreatic islets could be recovered from another source,
many more patients could be treated.
Towards this end, some U.S. scientists are trying to find
a way to grow and expand pancreatic islets in culture, for
instance. Other groups are looking at the potential of using
gene therapy to transfect insulin-producing genes into a patient's
liver or intestine cells. Some are looking at the possibility
of engineering islets from adult or fetal stem cells and then
transplanting these into the patient.
These are tantalizing ideas, but they may never pan out,
and their application is years away even if they do.
"Therapeutic gene delivery—don't even think about it
for 10 years," says Salomon. "Human stem cells—even without
the political barriers—don't even think about it for
10 or 15 years."
"The best short term bet for developing a clinically viable
therapy appropriate for treating tens of thousands of patients
in the next five to ten years," he adds, "is to use animals
as the source of the islets. Pig insulin works very well in
human patients and has been used for many years."
The Cases For and Against Xenotransplantation
The argument for using animal organs is a simple one—the
alleviation of human suffering. Type 1 diabetes afflicts about
1.5 to 1.8 million Americans, and accounts for 30,000 newly
diagnosed cases each year. But only about 5,000 whole pancreata
are available for transplantation in a given year.
"It doesn't require a degree in rocket science to be able
to do the math," Salomon says. "If you want something that's
over the horizon to deal with the millions of diabetes victims,
xenotransplantation is a good direction to go in."
Despite acknowledging the potential advantages of xenotransplantation,
Salomon is also one of the leading voices in acknowledging
its potential dangers. And his opinions are often sought.
He is chair of the National Institutes of Health's Center
for Research Resources Consortium for Clinical Islet Transplantation,
chair of the Food and Drug Administration's Biological Response
Advisory Committee, and member of the Secretary of Health's
Advisory Committee for Xenotransplantation.
Basically, the dangers come down to risk of infection and
risk of rejection.
As the recent case of three patients contracting West Nile
virus from transplanted organs from a single donor dramatically
demonstrates, the possibility of acquiring emerging infections
via transplantation is very real. However, in xenotransplantation,
this could be addressed with special precautions. Pigs could
be raised away from pathogens, in sterile conditions, the
way that smallpox vaccine used to be grown on the legs of
cows in sterile settings.
The risk of rejection is also a very real danger, since
immune systems have to be suppressed even when a patient receives
an "allo" transplant (from another human). Tissues used for
xenotransplants, like pig pancreata or islets, are even more
likely to be rejected.
But germlines could be transgenically altered to remove
genes that cause the tissue to be rejected. In fact, the primary
molecule responsible for eliciting a human immune response
against porcine tissue has been identified (a galactose sugar,
which pig cells carry on their surface) and can be removed
by knocking out a metabolic gene (the a-1,3-galactosyl
transferase).
And one could clone this new breed of donor animal to ensure
each organ was nearly identical.
And this has already been accomplished by the same Scottish
company that cloned the sheep Dolly. A few years after Dolly,
they announced their success in cloning five piglets from
an adult sow.
Because of these advances, Salomon says, there was a lot
of excitement about xenotransplantation about eight years
ago, accompanied by a large infusion of dollars into research
in the field.
"Many felt that [these advances] would change a xenotransplant
into an allotransplant [a transplant from one person to another],"
says Salomon. "I think that with continued engineering of
the pigs, that this is quite possible. However, like many
first approaches to major challenges in medicine, the hype
was far ahead of the reality and there has been a very appropriate
cooling of enthusiasm in the last three years."
However, even with super clean, cloned, and sugar-free cells,
xenotransplantation is still a potential risk because of the
danger of infection with what is known as porcine endogenous
retroviruses (PERV).
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