ONE MAN'S MEAT
Extract from The
Ecologist, 22 November 2000, by Alix Fano
ON 21 SEPTEMBER 2000, The Daily Express landed on the newsstands
with an explosive story that caught the British public - and much
of the GM industry - on the hop. The exposé was based on
leaked internal reports describing xenotransplantation experiments
on higher primates - including cynomolgus monkeys and wild-caught
baboons - 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,1
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 baboons
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 18-month time limit to achieve
major improvements in survival times. Uncaged Campaigns charges
that Imutran/Novartis greatly exaggerated the success of their pig-to-primate
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 pig-to-primate
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 pig-to-primate
organ transplantation - a stepping block to pig-to-human 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, baboons, 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 20-40 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 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 'germ-free' 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 quasi-governmental organisation that co-ordinates
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 anti-rejection
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 baboons
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 cells. (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 pig-human
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 mini-pigs still
carry PERVs in their DNA, and thus in every 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. Baboon cytomegalovirus
was, in fact, recently detected in stored tissue samples from a
recipient of a baboon 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 blood-clotting 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, pp905-8), 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 cross-species transplantation has created
huge financial incentives for multinational drug and biotechnology
companies. Novartis (which also makes cyclosporine, the leading
anti-rejection 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 pig-to-primate 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 pig-breeding 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 humans because they lack a specific sugar called alpha-galactosidase.
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 baboons. 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 Bio-Med, a US biotech firm, announced that it was
cutting back funding for its Scottish subsidiary's xenotransplant
research programme, Roslin Bio-Med, 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
were 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
pig-to-human 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. André 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 12-year 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
treatment; 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, (Zed Books, February 2001). CRT,
an international coalition of physicians, scientists and 90 public-interest
groups, is promoting a ban on xenotransplantation and advocating
for safer, more cost-effective and humane alternatives. Check out
www.crt-online.org
to learn more, sign an online petition and get involved. |
