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Endogenous retroviruses, are unlike viruses like West Nile
in that they do not cause disease in their animal hosts. They
are the remnants of viral infections that long ago infected
the species and long ago retired into dormancy. The hypothesis
is that they are remnants of past epidemics where the viruses
moved into the entire species, actually becoming part of the
germ cell line. For instance, gibbon ape leukemia virus, a
retrovirus endogenous to that species, was most likely introduced
into the gibbon ape from Asian mouse populations. All mammalian
species have these endogenous retroviruses.
"It is estimated that from three to eight percent of our
genome is endogenous retroviral sequence," says Salomon. "It
is not functional, but our genome is filled with these sequences."
Many of these are defective, but some of them can code for
a complete and infectious viral particle. The fear with xenotransplantation
is that the viral genes may come out of retirement.
"A group of us said, 'Wait a minute, what about the potential
of [PERV] infections being introduced into humans by xenotransplantation
and then spreading to the public at large?'" says Salomon.
"We were not very popular at the time."
Around the same time, in 1997, Robin Weiss and his colleagues
at Oxford reported to Nature that porcine endogenous retroviruses
could infect human cells in vitro. That result sparked
a great deal of debate and led some to call for a moratorium
on xenotransplantation.
Salomon rejected those calls and instead advocated for proceeding
with clinical trials, but cautiously and in carefully defined,
highly controlled, and well monitored trials. And if there
is any evidence of real and productive infection, he adds,
then everything should be closed down. Xenotransplantation
is a new field and with any new technology there are potential
risks. If we close down new directions in medicine every time
there is a theoretical risk identified than there will be
little progress made.
"The bottom line is this: we need to advance our understanding
of PERV to make an informed prediction of risk to the human
patient and human population," he says. "[And] we need to
assess the risk based on good science and not on dramatics."
A Hierarchy of Questions
Weiss's 1997 study demonstrated that a risk exists, but
did not determine how much of a risk it is.
Would a pig cell transplanted into a human make a virus?
If it made a virus, would the virus be transmitted to the
human cells? If the transmission occurred, would the virus
become productive or would it stay dormant? If the virus were
productive, would it spread to other cells and organs? If
the virus spread, would it cause disease in the person? If
it caused disease, would it also be transmissible? If so,
how? What would be the consequences to public health?
And even if one were able to answer all these questions,
determining how to shape policy based on them may not be so
straightforward. If, for instance, a person's xenotransplant
will cause disease, he/she can still make an informed consent
to receive it. After all, having the transplant and living
with the risk of disease is better than not having it and
dying with no disease. However, if there is also a risk that
the transplant recipient could infect others, then the solution
is not so straightforward. One cannot consent to placing someone
else at risk.
"It is the transition from individual risk to public health
risk where the real controversy comes," says Salomon.
Salomon has spent the last several years trying to work
out some of the science-based answers to this hierarchy of
risk questions.
Productive Infection
Two years ago Salomon and his colleagues demonstrated that
pig islets make infectious virus and infect mouse and human
cells that have been implanted into in vivo models.
In other words, when scientists transplanted pig islets under
conditions similar to what might be seen in the clinic, they
saw PERV replicate and infect other cells.
"You have to face the fact that there is virus coming out
of that transplanted pig tissue and that [the virus] is replication
competent and infectious," he says.
He recently cloned, with investigator Clive Patience at
Immerge Biotherapeutics and investigator Robin Weiss and his
colleagues at Oxford, two previously unknown genes that encode
human receptors of PERV. They are in the process of transfecting
the receptors into the germline of mice and demonstrating
whether they are able to get productive infection.
"If it works, we will have a new model," he says. This will
allow them to study the pathology of PERV in living tissue—since
in pigs, the viruses cause no disease.
Even before they finish these models they have already demonstrated
that the human receptor works well when transfected into mouse
cells. They are currently defining the functionality of the
receptors, expression in different human tissues and studying
their binding mechanisms in order to ascertain what is happening.
This is all simply establishing whether the possibility
exists for productive infection, which is an important issue
because the family of retroviruses to which PERV belongs are
all leukemia viruses—diseases that cause hematological
malignancies.
"We're still working our way through the hierarchy," cautions
Salomon. "We haven't talked about disease yet and we haven't
talked about potential public health risks. But our understanding
of how PERV enters cells and produces productive infection
has increased significantly."
Xenotourism
But patients are not waiting for these answers. Shortly
before agreeing to an interview, Salomon had established contact
with a doctor in Mexico who has already transplanted pig islets
obtained from a company in New Zealand into 12 adolescents
and is planning to expand his trials to include 24 more.
Would people go to Mexico or some other country for the
transplant and then return to the United States or elsewhere
the procedure is not yet approved?
There is already a booming black market in organ transplants,
which Salomon has witnessed first-hand in the clinic. Unlike
transplant tourism, though, what Salomon has called "xenotourism"
is a far greater concern because of the unanswered questions
about possible dangers of disease and infection caused by
PERV and other animal pathogens that might be introduced into
humans especially in uncontrolled trials."
"It is in no way exaggerated to raise the concern," Salomon
says. In fact, he is now working with the staff of the U.S.
Secretary of Health to formulate a plan to disseminate basic
information on the potential danger of xenotourism and, hopefully,
discourage U.S. citizens from participating in such foreign
adventures.
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