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5-Animals: Controversary on health effects of xenotransplantation

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TITLE:  1) Novartis and CDC support case for pig-tissue grafts
        2) Comments on the underlaying study by I-SIS
SOURCE: 1) Wall Street Journal, by Stephen D. Moore
        2) Institute of Science of Society, UK, by Mae-wan Ho
DATE:   August 20, 1999

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Novartis and CDC support case for pig-tissue grafts

The science-fiction prospect of grafting genetically modified pig
organs into humans edged closer to reality as Swiss drug company
Novartis AG unveiled the strongest evidence yet that so-called
xenotransplantation isn't likely to spread epidemics of
previously unknown viral diseases. In the latest issue of the
journal Science, researchers from Novartis and the U.S. Centers
for Disease Control and Prevention report that 160 patients
treated with various types of living pig tissue remained free
from infection by a native porcine virus called PERV for years
after initial exposure.

Separately, Novartis officials disclosed that several hundred
monkeys or baboons that received genetically modified pig hearts
or kidneys also remained negative for PERV infections following
those experimental transplants. The authors of the Science
article conclude that their results "support the use of closely
monitored clinical trials . . . to assess the safety and efficacy
of using porcine cells, tissues or organs therapeutically in
humans." Corinne Savill, chief operating officer of Novartis's
United Kingdom unit Imutran Ltd., added in an interview that if
results of continuing research with immunosuppressant drugs "turn
out as well as our safety research, we'd hope to initiate a
clinical study with transplants of pig kidneys or hearts in about
two years." Regulatory agencies such as the U.S. Food and Drug
Administration will have the final say about when such a trial
takes place.

Proponents argue that genetically modified pig organs could save
the lives of thousands of prospective transplant recipients who
die each year while waiting for a human donor. "We all want it,"
said Sir Roy Calne, emeritus professor at Cambridge University
and a pioneer of conventional transplant surgery. Yet
xenotransplantation raises potential threats to public health,
which have prompted organizations such as the Council of Europe
to urge a moratorium until the risks are thoroughly assessed.
"This isn't the classical risk/benefit balance seen from the
perspective of an individual patient. There is potentially an
added risk to society here," said Paul Herrling, Novartis's
research director.

Along with such nagging scientific uncertainties,
xenotransplantation has spurred fierce opposition from animal-
rights groups. Some analysts cite Britain's recent acrimonious
public debate over genetically modified foods as an example of
what may be in store for Novartis and European regulators. Though
the possible risks of viral infection from xenografts still are
theoretical, it is nearly impossible for Novartis and the handful
of other companies racing to perfect xenotransplantation to prove
that their pig organs are risk- free. The most vexing problem has
been PERV, a so-called retrovirus that over thousands of years
has become permanently imbedded within pig DNA. Biological
defenses within pig cells keep PERV under tight control, and the
virus doesn't cause any known disease.

But in recent years, scientists have shown in test tubes that
PERV can infect human cells. Some researchers are concerned that
if a pig organ were transplanted into a human, the natural pig
controls on PERV may shut down, allowing it to recombine with
viruses in human DNA and create new, potentially deadly strains
that could trigger pandemics in humans. Moreover, nobody can rule
out the possibility of infection by an unknown virus for which no
effective diagnostic test is yet available. There are ominous
precedents of disease transmission between different species. A
strain of influenza virus originally infecting pigs is widely
believed to be the source of the swine- flu pandemic early this
century that killed an estimated 20 million people world-wide.
And the prion particles responsible for bovine spongiform
encephalopathy, or mad-cow disease, carried a deadly form of the
disorder to humans.


Institute of Science of Society
Dr Mae-wan Ho
Tel. +44-171-272 5636

Comments on
Paradis, K., Langford, G., Long, Z., Heneine, W., Sanstrom, P.,
Switzer, W.M., Chapman, L.E., Lockey, C., Onions, D., The Xen 111
study Group and Otta, E. (1999).
Search for Cross-Species Transmission of Porcine Endogenous
Retrovirus in Patients Treated with Living Pig Tissue.
Science 285, 1236-1241.

A new paper published in Science has been taken as proof that
transplantations from pig to human are safe:-  This is a
dangerous assumption.  It would be a mistake to read the paper as
proof or reassurance that cross-species viruses do not arise in
xeno-tranplant patients, and therefore xenotransplant should go

Most of the patients were only transiently exposed to pig tissue
and actual transplants involved only a small number of cells.
Only 23 patients, in fact, had any pig cells circulating. The
relevant sample size therefore is not 160 but only 23, an
unacceptably small number. Of these 23, the longest period of
observation is 8.5 years, again, not long enough to tell.

The PCR essays do not give clear results at all, even by the
admission of the paper:"..if PERV [porcine endogenous retrovirus]
DNA was detected, a second PCR was performed to assess whether
the sample contained pig-specific sequences...If no pig-specirfic
sequences were detected, the patient was reported as "infected" .
In contrast, if procine-specirfic DNA was detected, it was
reported as "microchimerism," although PERV infection could not
be excluded." (p.1237, italics mine)

These PCR probes are only good for two genes of one kind of
virus, and they will not detect other types of viruses nor
recombinant viruses, which are hybrids of pig and human viruses.

Finally, none of the patients were exposed to transgenic pig
tissues. Transgenic pig tissue may be more likely to give rise to
viruses. This may arise from the transgenic DNA itself, which
typically has viral genes in them, or those genes which have been
transferred into the transgenic pig may overcome mechanisms that
suppress viral infections. It would be dangerous to conclude that
xenotransplantation is safe from this paper.

Maewan Ho
Institute of Science in Society

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