Evan
David Rosen, M.D., Ph.D.
Assistant
Professor of Medicine, Harvard Medical School
One
of the holy grails of diabetes research is a safe and
effective way to transplant new insulin-producing beta
cells. While there are many ways to accomplish this feat
in theory, few attempts have had any lasting success.
Whole pancreas transplantation has been used successfully,
but a severe shortage of organs, combined with the need
for lifelong immune suppression, has restricted the use
of this technique. Pancreas transplantation is also a
difficult operation, and there is still a significant
amount of morbidity associated with the surgery itself.
Transplanting
just the pancreatic islets, however, can be performed
with a minimally invasive procedure, involving infusion
of the cells directly into a large vein called the portal
vein, almost like a blood transfusion. The injected islets
then take up residence in the liver, where they secrete
insulin in response to ingested carbohydrates. This
approach has worked in some animal experiments, and has
been partially successful in a few limited human trials,
but there are still numerous obstacles to overcome. Many
of the best results have been achieved, for example, using
two to four human donors per each recipient, making the
chronic shortage of donor organs even worse. Furthermore,
immunosuppressive regimens are still required to prevent
rejection, and expose patients to numerous complications.
Because
of these limitations, current research is focused on more
easily attainable or renewable sources of islets, including
islets transplanted from animals (known as “xenotransplantation”),
the use of islets derived from stem cells, or gene therapy.
While the latter two approaches may be the ultimate goal,
they are both a very long way from clinical readiness.
Xenotransplantation, however, offers the promise of a
virtually unlimited supply of islets, and various immunological
tricks may reduce the need for dangerous immunosuppression.
The
source of xenotransplanted islets is likely to be the
pig. Pig insulin is virtually identical to human
insulin. In fact, insulin obtained from pigs was used
to treat diabetes for decades, until biotechnology advances
led to the advent of recombinant human insulin. There
are two major problems with pig islets, or islets from
any non-human species: rejection and the introduction
of porcine viruses into humans. Let's discuss these
problems and their possible solutions separately.
Our
immune systems are extremely effective at rejecting cells
that are not originally our own, whether they be from
human donors, or another species like pigs. Rejection
can occur early after transplantation, or after a significant
delay. This reflects two very different immunological
processes, and therefore different strategies are necessary
to prevent each form of rejection. In xenotransplantation,
the early form of rejection is primarily the result of
a reaction against a carbohydrate (galactose alpha-1-3galactose)
found on the surface of pig cells, but not human cells.
Our bodies recognize this carbohydrate as a foreign invader,
and attack it. Interestingly, researchers have generated
a strain of pig that lacks the enzyme necessary to make
galactose a1-3galactose, which may prove to be a terrific
source of islets that cannot be rejected hyperacutely,
although this remains to be studied.
Another
strategy to prevent rejection is called microencapsulation:
coating transplanted islets with substances that allow
nutrients and oxygen to get into the islet (and insulin
to get out) while blocking the ability of antibodies and
immune cells to attach to and destroy the islets. Several
compounds have been tested, and a few have shown promise.
In one report, microencapsulated pig islets maintained
normal blood sugar levels in a diabetic monkey for more
than two years without any immunosuppression. A similar
result has been reported in a human patient with type
1 diabetes, who did take immunosuppressive drugs.
What
about the risk of transmitting a porcine virus into the
human population? The threat is not entirely theoretical,
as there are potentially nasty viruses called “porcine
endogenous retroviruses” (given the unfortunate acronym
PERVs) that have been shown to infect human cells in the
laboratory. Despite extensive searching, however, the
transmission of PERVs has never been documented in humans
exposed to living porcine tissue.
These
promising indicators have encouraged at least one researcher
to move directly into human trials with a significant
numbers of patients—a move that has incited controversy
in the diabetes and xenotransplantation communities. An
investigator in Mexico announced recently that he had
implanted porcine islets into twelve adolescents with
type 1 diabetes. Success was variable, with one child
able to stop taking insulin and five others able to reduce
their dose of insulin. Amazingly, these results were obtained
without the use of immunosuppressant drugs, a feat never
before accomplished in diabetic humans. The controversy
relates to the fact that many researchers feel that not
enough groundwork was performed on monkeys and other animals
before proceeding to humans, coupled with the fact that
subjects chosen were too young to have given proper informed
consent. In addition, despite the encouraging early results
that PERVs and other pig viruses don't seem to be a major
problem in humans, the Mexican studies have been taken
to task for exposing children to the risk of serious infection.
My
own view is that discretion is the better part of valor,
and I wish that more studies had been performed in diabetic
monkeys or other animal models before proceeding to humans.
This would help establish both the effectiveness of the
procedure, as well as provide more data about the risks
of infection with pig viruses. Nonetheless, the diabetes
community will be watching the results of these studies
carefully. Eventually, I hope (and believe) that stem
cell technology will advance to the point that xenotransplantation
is no longer necessary, but for the near-to-midterm future,
we may be getting more from our porcine friends than bacon
and ham.
References:
1.Check
E. Diabetes trial stirs debate on safety of xenotransplants.
Nature 2002 Sep 5;419(6902):5.
2.Swiss
Medical Weekly 132: 671 2002
3.Dai
Y, Vaught TD, Boone J, Chen SH, Phelps CJ, Ball S, Monahan
JA, Jobst PM, McCreath KJ, Lamborn AE, Cowell-Lucero JL,
Wells KD, Colman A, Polejaeva IA,Ayares DL. Targeted disruption
of the alpha1, 3-galactosyltransferase gene in cloned
pigs. Nature Biotechnology. 2002 Mar;20(3):251-5.
Check
out other articles by Dr. Rosen: Dr.
Rosens Archives
