Xenotransplantation
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Xenotransplantation is any procedure that involves the transplantation, implantation or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues or organs. The development of xenotransplantation is, in part, driven by the fact that the demand for human organs for clinical transplantation far exceeds the supply.
Currently ten patients die each day in the United States while on the waiting list to receive lifesaving vital organ transplants. Moreover, recent evidence has suggested that transplantation of cells and tissues may be therapeutic for certain diseases such as neurodegenerative disorders and diabetes, where, again human materials are not usually available.
Although the potential benefits are considerable, the use of xenotransplantation raises concerns regarding the potential infection of recipients with both recognized and unrecognized infectious agents and the possible subsequent transmission to their close contacts and into the general human population. Of public health concern is the potential for cross-species infection by retroviruses, which may be latent and lead to disease years after infection. Moreover, new infectious agents may not be readily identifiable with current techniques.
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http://www.fda.gov/BiologicsBloodVaccin ... efault.htm (http://www.fda.gov/BiologicsBloodVaccines/Xenotransplantation/default.htm)
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Xenotransplantation: The Next Biotech Disaster?
Xenotransplantation: A Biotech Disaster Just Waiting to Happen by Alix
Fano
from the Ecologist magazine (UK) December 2000 issue
<www.theecologist.org>
Falsified reports, incompetence, the possible introduction of AIDS and
other new diseases, and not one single success story. All this lies
behind the attempts to transfer the organs of one species into
another, yet still the biotech companies continue to experiment,
dollar signs in their eyes. Alix Fano wonders if they'll ever get the
message.
On 21 September 2000, The Daily Express landed on the news stands with
an explosive story that caught the British public - and much of the GM
industry - on the hop. The expose' was based on leaked internal
reports describing xenotransplantation experiments on higher
primates - including cynomolgus monkeys and wild caught ******s -
commissioned by Imutran, the British subsidiary of Novartis, and
conducted by the controversial contract research laboratory, Huntingdon Life
Sciences in Cambridgeshire.
Now, although many people know that xenotransplantation experiments -
the process of transplanting organs, tissues and cells between
different species - takes place, few were aware of the horrors that
were being perpetrated at Huntingdon in the name of science. The
article not only highlighted extraordinary levels of animal suffering
in the laboratories, but revealed glaring technical failures in the
experiments conducted by the company, despite Imutran/Novartis's
earlier claims that they were succeeding. These failures had been
brought to the newspaper's attention by the British advocacy group,
Uncaged Campaigns, whose 150 page report, Diaries of Despair: The
Secret History of Pig to Primate Organ Transplant Experiments, was
based on an extensive cache of leaked documents from an anonymous
source.
Imutran has taken legal measures to prevent Uncaged from disseminating
the report. A court date was set for late November. The extent of the
incompetence surrounding these experiments was staggering: the report
revealed at least 520 errors and omissions in the conduct of studies,
including organ weights not recorded, unlabelled and uncovered
veterinary medications, inadequate surgery records, a quadruple
overdose, the illegal reuse of animals, conflicting pathology reports,
the accidental freezing of a kidney during transplantation surgery and
a case of a swab being left inside a primate, which resulted in his
death. In one particular incident, seven ******s appear to have been
experimented upon despite a warning that they 'must not be worked on
due to positivity for Herpes B' - a virus lethal to humans.
READING BETWEEN THE LINES
Was this just pure incompetence, or is there an even more serious
charge here? The documents demonstrated that, after five years of
research, Imutran had improved the average survival time of monkeys
with functioning pig kidneys from two to just four weeks. The success
rate of heart xenotransplantation is even less tangible - just 11 days
according to the documents. As a result of these statistics, in April
2000, Novartis had set an 18month time limit to achieve major
improvements in survival times. Uncaged Campaigns charge that
Imutran/Novartis greatly exaggerated the success of their pigtoprimate
experiments in published articles, by selectively using their 'best'
data while ignoring data on average survival times and the overall
health of the primate recipients.
The 'success' of Imutran's pigtoprimate experiments should now be
called into question based on the complete picture revealed by the
leaked documents. What is so remarkable about this information is that
the research was being carried out in a field that is so dangerous.
Here was a corporate sponsored, government sanctioned, laboratory
apparently overstating its success in a branch of science that will
have extreme repercussions for mankind. Was Imutran/Novartis really
prepared to sanction shoddy and seemingly deceptive work in
pigtoprimate organ transplantation - a stepping block to pigtohuman
organ transplantation - merely to hit a deadline?
The implications are highly disturbing, particularly as
xenotransplantation hasn't had that great a track record. Since 1905,
82 humans have received whole organs from chimpanzees, ******s, pigs,
goats and other animals, and all have died from infections and
complications related to hyperacute rejection within hours or days of
the surgeries. Human and animal organs have evolved over the millennia
to be able to deal with viruses, necessary immunities and other
foibles and subtleties that each species requires. The trouble with
xenotransplantation is that you just don't know what comes with each
organ.
Numerous published documents have warned of the dangers and
unpredictability of animal viruses. The swine flu epidemic of 1918
killed 2040 million people worldwide. During 1998 and 1999, the novel
Malaysian 'Nipah' encephalitis virus, which originated in fruit bats,
jumped from pigs to humans, infected 269 people, killed 117, and led
to the mass slaughter of one million pigs. The virus, which caused
brain damage in dozens of victims, has resurfaced this year in several
Malaysian villages. In May 2000, a British farmer died after
contracting a rare pig disease, streptococcus suis. It appears he
inhaled the virus after it was breathed out by his pigs. A 1999 study
by British scientists found that cancer causing retroviruses are
transmitted much more frequently and easily between different species
in the wild than previously thought, adding concerns regarding the
xenotransplantation of pig organs to humans.
In September 2000, scientists gathered at the Royal Society of London
to determine whether polio vaccines made with chimp kidneys and
contaminated with the simian form of HIV could have triggered the
epidemic of the AIDS virus, which has stricken 53 million people, most
of them in Africa. If this theory proves true, it increases the odds
that a potentially lethal microbe from another species could
accidentally be introduced into the human population via
xenotransplantation.
COMPOUNDING THE FOLLY
Despite these complex and largely unforeseeable cans of worms opened
every time an organ is transplanted from one species to another, the
scientists won't leave xenotransplantation alone. Pigs, they say, are
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09-17-2005 11:49 PM #29
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source animals of choice because they breed quickly, have been
extensively farmed, and have organs that are allegedly 'similar' in
size to ours. Today, multinational biotechnology companies claim that they have bred 'germfree' pigs with human genes whose organs are less likely to be rejected by the human body. Soon, farms could be filled
with cloned 'humanised' pigs - living factories, genetically
engineered to meet the world's growing demand for replacement organs.
For there's money to be made.
According to the United Network for Organ Sharing, a quasigovernmental
organisation that coordinates human organ and tissue donation in the
US, approximately 4,000 Americans die each year waiting for
transplantable organs. Compared to the number who die from heart
disease (726,974), cancer (539,577), pneumonia/influenza (86,449),
AIDS (16,516), and by suicide (30,535), this may not seem high. But
with over 60,000 Americans on transplant waiting lists (180,000
worldwide), a perceived chronic shortage of human organs and tissues,
and a potential market in pig parts and expensive antirejection drugs
worth $6$10 billion annually, the race to cash in on this market is
officially on. Some researchers and biotechnology companies claim that
putting pig organs into people may become a commercial reality within
two years. Robert Michler, chief of transplantation at Ohio State
University Medical Center in Columbus, believes that human trials
should begin as soon as possible, as soon as 50 per cent of a group of
******s with transplanted pig hearts survive for three months - a
target set by the US Food and Drug Administration (FDA).
In August, scientists at BioTransplant, a Massachusetts based
xenotransplantation company, in collaboration with Massachusetts
General Hospital, announced that they had bred a line of miniature
pigs that could provide a 'safer source of cells, tissues, and organs
for xenotransplants' because they allegedly do not transmit
potentially harmful viruses to human ells. (Patents are being filed in
the US and abroad to protect such allegedly lucrative 'inventions'. On
8 October 2000, The Sunday Times UK announced that BioTransplant had
submitted an application to the European Patent Office for an
'embryonic pighuman hybrid', the uses for which have not been defined
by the company.)
BioTransplant researchers theorise that generations of inbreeding
could have weakened the viruses and taken away their ability to
infect. However, Porcine Endogenous Retroviruses (PERVs) - a family
of AIDS like viruses that are harmless to their hosts but potentially
lethal when transferred to other species - are incorporated in the
pig's genome and cannot be bred out. It has been estimated that
hundreds of different endogenous retroviruses may be present in a
given animal. BioTransplant admits that their minipigs still carry
PERVs in their DNA, and thus in very organ, cell and tissue destined
for transplantation.
MUTATION FEARS
Virologists like Dominic Borie and Robin Weiss have cautioned that
endogenous retroviruses in pigs could recombine with human viruses
and/or mutate into more infectious forms after transplant. Pigs may
also contain other as yet unknown viruses. Daniel Salomon, a
researcher at the Scripps Research Institute in La Jolla,
California, has said that earlier studies, which suggested that PERVs
have not infected people, 'may not have looked in the right places'.
Patients injected with pig pancreatic islet cells to treat diabetes
have had their peripheral blood lymphocytes (white blood cells) and
blood serum tested for PERVs, and have been declared free of
infection. But PERVs do not usually infect blood lymphocytes. They
prefer epithelial tissues - tissues that line the inside and outside
of organs. Only biopsies of these tissues could reveal the presence of
the pig virus(es), and such biopsies have not been done in humans.
****** cytomegalovirus was, in fact, recently detected in stored
tissue samples from a recipient of a ****** liver who died after a
xenotransplant in 1992. A blood test will only pick up an active
infection; but many infections (eg AIDS or 'mad cow disease') may
remain latent in the body for years before they're ready to surface.
So the fact that a blood test does not detect PERV in a patient's
blood at a particular point in time, does not mean that that patient
is not harbouring the virus. Moreover, most studies of xenotransplant
patients have been retrospective, meaning that patients' blood was not
sampled for PERVs periodically from the moment treatment began, as
would be done in a controlled study. Most studies have also lacked a
control group - a group receiving a placebo transplant.
Peter Collignon, an infectious diseases physician at Canberra Hospital
in Australia, observes that, without a control group, there is no way
to determine whether the treatment really worked. Indeed, the testing
of xenograft patients that has been done to date has not established
the technology's safety or its efficacy. One could go so far as to say
that tests have been designed to conceal unfavourable outcomes. Many
other questions and concerns remain, one of the most important being
whether animal organs will ever be able to sustain human life. Will
pig organs continue to grow at a 'pig rate' once transplanted into
humans; will they become susceptible to human diseases; will they be
able to carry out functions necessary for human survival? For example,
unlike the human organ, the pig kidney lacks a mechanism for
controlling levels of medicines, which could have a significant impact
on a xenotransplant patient who requires several drugs. The porcine
kidney cannot handle the high levels of uric acid found in the human
bloodstream, which could lead to kidney stones or kidney failure; and
it may not respond normally to the hormone vasopressin, which is
released from the human brain. Such discrepancies could affect blood
pressure, hydration and fluid balance.
Human red blood cells are larger than those of the pig and there are
incompatibilities in bloodclotting mechanisms, so that in a grafted
pig organ, blood clotting, organ failure and death may occur from
blockages in the tiny blood capillaries. A pig's heart normally pumps
smaller amounts of blood per minute than required by a human, due to
its horizontal posture. If the output of the heart is too low,
multiple organ failure and death would result. In Transplantation
Proceedings (1999, Vol 31, pp9058), M E Breimer describes
physiological incompatibilities between humans and pigs, including
differences in anatomy, physiology (regulation of blood circulation,
hormone systems), immunology, complement and coagulation systems,
pharmacology and metabolism. Despite these seemingly insurmountable
problems, pig research continues unabated. The prospect of commercial
crossspecies transplantation has created huge financial incentives for
multinational drug and biotechnology companies.
Novartis (which also makes cyclosporine, the leading antirejection
drug), Baxter Health Care and their many subsidiaries that dominate
the field have already invested over $100 million in research. Such
enormous capital investment has prompted research collaborations
between different companies and medical centres in an attempt to share
risks and costs. Novartis is also sponsoring xenotransplant research
at several American, European, and Canadian medical centres, to save
on contract lab and research costs. Novartis is funding pigtoprimate
xenotransplantation experiments at the Universities of Ohio State
(Columbus), Pennsylvania (Philadelphia), Wisconsin (Madison), Stanford
University, Massachusetts General Hospital and, in Canada, at the
Universities of Western Ontario, Toronto, and Guelph. The Mayo Clinic
in Rochester, Minnesota, which opened a large xenotransplant programme
and pigbreeding facility last year, has forged an alliance with Baxter
Health Care/Nextran, a New Jersey based biotech company, to breed
transgenic pigs whose organs would not be prone to rejection.
Christopher McGregor, Mayo's director of cardiothoracic
transplantation, has declined to say how much money Mayo has received
from Baxter. Despite these collaborations, there is fierce competition
between each individual company or medical centre to be the first to
successfully transplant pig organs into humans, driven by the desire
to reap financial rewards, to gain publicity and to pacify anxious
investors.
Alexion Pharmaceuticals in New Haven, Connecticut, is developing
stronger drugs to suppress the immune system. PPL Therapeutics,
associated with the Roslin Institute in Scotland (famous for cloning
Dolly the sheep and filing a world patent on the cloning of all animal
species, including humans), is trying to breed transgenic pigs whose
organs will not provoke hyperacute rejection when transplanted into
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humans because they lack a specific sugar called alphagalactosidase.
In March 2000, PPL announced it had cloned a litter of five female
pigs using a double nuclear transfer technique. The company claims that pig cloning will ensure a plentiful supply of pigs for
xenotransplantation. However, cloning pigs for transplants is an
expensive, technically difficult and inhumane proposition. Last May, BBC News Online reported that PPL was having trouble producing cloned pigs because none of the genetically modified embryos were surviving to term in their surrogate mothers. PPL acknowledges a 50 per cent postnatal loss of cloned animals.
Cloned animals are typically weaker than their traditionally bred
counterparts and may be prone to congenital abnormalities, chronic organ dysfunction, premature ageing (due to changes in chromosome
structure), high infant and juvenile mortality and cancer (see Michael
W Fox, Beyond Evolution, Lyons Press, 1999). Moreover, cloning pigs
will not rid the animals of the numerous viruses, bacteria, and
parasites they carry, which may lead to dangerous infections in
humans. Nevertheless, over the last several decades, US federal
agencies have dispensed tens of millions of dollars to university
researchers and private corporations for cloning and related
xenotransplantation projects.
The Commerce Department's Advanced Technology Program, established
under the Bush Administration, has given multimillion dollar grants to
corporations like Alexion Pharmaceuticals and Organogenesis Inc, and
to PPL for their pig cloning projects. A B Cosimi, a researcher at
Massachusetts General Hospital in Boston, received over $15 million
from the National Institutes of Health (NIH) between 1992 and 2000 to
study the immune response involved in xenograft rejection between pigs
and ******s. A team of researchers at Duke University in North
Carolina received almost $2.5 million from 1997 to 1998 to transplant
pig hearts into monkeys and other animals in an effort to elucidate
the 'immunological barrier to cardiac xenotransplantation'. In 1997,
the NIH published an announcement on the Internet soliciting
'applications [from domestic and foreign researchers] to enhance [the]
ability to transplant organs and tissues across species barriers
(xenotransplantation)'. The NIH even promotes xenotransplantation in
articles designed for children on its website under the guise of
'science education'.
CHANGE OF OPINION?
But not all US companies continue to be enthusiastic about
xenotransplantation. In August, Geron BioMed, a US biotech firm,
announced that it was cutting back funding for its Scottish
subsidiary's xenotransplant research programme, Roslin BioMed, citing
concerns about public health risks. Geron stated it would redirect its
efforts to cultivating human stem cells for research and
transplantation. Ian Wilmut, Roslin's chief scientist, said he was
disappointed by Geron's decision but understood concerns about
'unknown [pig] viruses being released into the human population'.
Shortly after the Geron announcement, PPL Therapeutics, which is a
Roslin offshoot, distributed a press release stating that it was not
abandoning its xenotransplantation research programme, least of all
because of virus fears, leading critics to question the motives behind
the company's sudden retraction.
In April 2000, the US FDA suspended cellular xenotransplant
experiments in which foetal pig brain cells were injected into the
brains of stroke patients. Thomas Fraser, president of the
Charlestown, Massachusetts based company Diacrin, admitted that one
patient developed seizures a week after a transplant and another had
minor brain swelling and muscular fatigue. The company said it would
try to determine whether the pig cells or the equipment used to
deliver them to the brain are to blame for the 'side effects'. A study
published in the British journal Nature on 17 August 2000 raised
further questions about the safety of cellular xenotransplants.
Salomon et al showed that when insulin making pig pancreatic islet
cells were transplanted into mice with deficient immune systems,
PERVs jumped the species barrier, migrated from the site of
transplantation, and infected mouse tissues such as the spleen, liver,
salivary gland, skin, small bowel and lung. Given this chain of
events, the pig virus would likely be present in saliva, faeces,
broken skin and coughed up lung secretions. Salomon and colleagues
concluded that pigtohuman islet xenotransplantation could result in
patients becoming exposed to infectious PERVs that might be able to
replicate. It is unlikely, however, that Salomon's study, or any
other, will be heeded by US regulatory officials or companies
investing in xenotransplantation. After all, reports in 1997 and 1998,
stating that various strains of PERV from different breeds of pigs
infected human cells, didn't seem to raise enough of a red flag for
anyone to actually halt xenotransplantation research.
Andr* Jestin and his colleagues at the French Agency for Food Safety
in Ploufragan found that the complete genomes of, amazingly, 11 types
of PERV are expressed in pig organs, including the heart, liver,
pancreas and kidneys. Jestin believes that controlling these viruses,
or eliminating them via genetic engineering, will be much harder than
anyone thought. Porcine pseudorabies virus has been detected in
Swedish diabetes patients treated with porcine cells in 1997. And in
August 1999, Science published the results of a Novartis sponsored
study of 160 patients in nine countries exposed to living pig tissue
over a 12year period. Some patients in the study reported persistent
rashes and strange fevers. But most worrisome was the finding that 30
patients who had their blood 'filtered' through pig spleens tested
positive for PERV DNA; 23 patients had pig cells circulating in their
bodies 8.5 years after teatment; and four patients, injected with pig
cells, produced antibodies against PERVs, leading the authors to admit
that 'PERV infection [could not] be excluded'.
WHO WILL ACT?
So where do we go from here? At a public meeting in January 2000, Dr
Phil Noguchi, Director of the US FDA's Division of Cellular and Gene
Therapies, acknowledged that xenotransplantation is 'fraught with
danger'. FDA documents have openly stated that '[X]enotransplantation
may facilitate the transmission of known or as yet unrecognised agents
to humans'. New pig viruses, like 'Nipah', and strains of PERVs, are
continually being discovered. A pig virus, contracted via
xenotransplantation, could spread to other humans undetected, causing
an AIDS like plague. Yet there are currently 12 FDA approved
xenotransplant clinical trials ongoing in the US. Most, if not all,
are industry sponsored, and involve the use of pig cells to treat
diabetes and neurological diseases, and whole pig livers and cells to
perfuse ('filter') the blood of patients with acute liver failure. The
FDA (which has also sanctioned the sale of unlabelled and untested
genetically engineered foods) has refused to enact even a temporary
moratorium on such trials, claiming that it will monitor patients
closely to ensure public safety. Sound familiar? In the 1980s, the FDA
allowed thousands of people to receive HIV tainted blood and blood
products, resulting in thousands of cases of HIV infection and the
deaths of over 10,000 haemophiliacs. Clearly, governments have chosen
to ignore the Precautionary Principle in the xenotransplantation
debate. They have also completely ignored alternatives to
xenotransplantation, including prevention of disease, use of human
tissue for transplant and increased human organ donation.
Each and every day in the United States, 6,000 bodies full of human
organs are buried or burned. That's two million each year, many times
the number of organs required for all types of transplants. In 1998,
the General Accounting Office found that the US is doing a poor job of
retrieving organs for transplantation. Many nations, including the
Netherlands, Austria, Spain, Belgium and Singapore, have seen organ
donation rates soar after the passage of 'presumed consent' laws,
which assume that citizens will donate their organs after death unless
they 'opt out'. Although a majority of Americans (85 per cent) support
organ donation, the feasibility of such a law has not been considered.
Meanwhile, in the wake of the Huntingdon scandal on 22 September 2000,
Uncaged Campaigns called for an independent judicial inquiry into the
information contained in the leaked documents, as well as a ban on
animal based xenotransplantation research in the UK. On 26 September
2000 Novartis announced it was closing down operations at Imutran.
However, the announcement added that the company was merging with US
based BioTransplant, perhaps hoping to leave a scandal behind and
transfer its operations to the US, with its notoriously lax animal
welfare and biotechnology regulations. Novartis, which had been
collaborating with BioTransplant to breed lines of pigs with human
genes, will own 67 per cent of the company and retain the rights to
commercialisation of research from the new merger. In return,
BioTransplant will receive royalty payments from Novartis sales.
Elliot Lebowitz, BioTransplant CEO, revealed that commercialisation of
xenotransplantation could generate 100 million dollars in annual
revenue for his company. The work continues. Alix Fano, MA, is
executive director of the Campaign for Responsible Transplantation
(CRT) and author of a chapter on xenotransplantation in the book,
Redesigning Life? The Worldwide Challenge to Genetic Engineering,CRT, an international coalition of physicians,
scientists and 90 public interest groups, is promoting a ban on
xenotransplantation and advocating for safer, and
humane farming alternatives.