Amy Otchet, UNESCO Courier journalist
In
Homer’s Odyssey, Circe the enchantress turns men into swine.
Should humans harvest spare parts from animals?
The problem
is that discussions take place between people with vested interests of one kind or
another. They fail to include the largest group affected, the public.
Animal organ transplantation
into humans may save many lives or cause untold harm from diseases crossing the species
barrier. How should society decide whether or not to go ahead?
Just over
15 years ago, Baby Fae became a household name when American doctors replaced her
ailing heart with the heart of a baboon. From Australia to Brazil, millions were
riveted by the news reports and followed her progress with baited breath. If they
were half-expecting a Frankenstein’s monster, they were disappointed. Baby Fae looked
like any other wee newborn child. But the sci-fi lullaby turned grim 20 days after
the transplant. On November 15, 1984 Baby Fae died. Later her mother angrily maintained
that she hadn’t been informed about the possible dangers involved. Unbeknownst to
the doctors at the time, however, the stakes concerned far more than a single infant’s
life. We now know there is a possibility that the transplantation of animal organs
into humans might unleash infectious diseases similar to Aids.
The scientific community is only beginning to understand the possible risks of xenotransplantation–the
use of animal organs and tissue in “spare-part” surgery for humans. Over the past
century, there have been about 25 documented cases of such organ transplants, the
most recent case being reported in 1993. Kidneys, hearts and livers from baboons
and monkeys were the organs of choice. Survival rates were dismal–most patients died
within weeks. Today, however, thanks to progress in biotechnology and drug treatments,
there is renewed interest in opening another round of human experiments. Scientists
in the United States have already begun implanting pig cells to treat patients with
Parkinson’s disease and diabetes. Others await the green light to begin transplanting
organs from pigs into people.
This growing interest is matched by rising fear, however, that an animal virus could
jump from the pig to the human patient, spread to others and unleash a pandemic.
When viruses cross the species
barrier, the results can be catastrophic. At least one strain of HIV is believed
to have jumped from monkeys to people after a single infectious event 60 years ago.
The influenza epidemic of 1918-19, which killed tens of millions, may have been triggered
by a pig infecting one person.
Xenotransplantation thus confronts the whole of society–not just individual patients–with
the promise of saving thousands of lives and the possible risk of causing tremendous
harm. The lack of scientific data transforms the safety issues into an ethical dilemma
which scientists alone cannot answer.
Human transplantation has been a victim of its own success. Surgeons can now transplant
about 25 different kinds of human organs and tissue, and survival rates are constantly
improving (60 per cent of patients live more than five years). More than one million
people worldwide have benefited since 1954, when the first transplant was made. But
supply cannot meet demand. In the United States, for
example, 3,900 people died while waiting for an organ transplant in 1996, compared
to around 1,500 in 1988.
There are also strong economic arguments in favour of xenotransplantation. About
700,000 patients suffering from kidney disease world-wide are strapped to dialysis
machines at an annual cost of about $19 billion, according to the Organization for
Economic Co-operation and Development (OECD). It costs about 60 per cent less to
transplant a kidney than to keep the patient on life-long dialysis. Success in xenotransplantation
could open up an international market worth $6 billion plus another $5 billion in
related drug treatments (to prevent the immune system from rejecting the organs).
One of the biggest contenders is the pharmaceutical giant Novartis–which not only
produced cyclosporin A, the leading drug used in human transplants, but also owns
Imutran, a UK-based biotech company famous for genetically engineering pigs for xenotransplantation.
Pigs are the xeno-prize-winners. Non-human primates, like baboons, have been ruled
out because their biological similarities to human beings could increase the risk
of disease transmission, so brutally highlighted by the Aids and Ebola viruses. Many
people also have ethical qualms about using our “cousins” for spare parts, whereas
we have been slaughtering and eating pigs for many centuries. Finally, pigs are easier
to breed and genetically engineer.
Duping
the human immune system
The human body would
normally consider a pig organ to be a dangerous “foreign agent” and kill it within
minutes by cutting off its blood supply. Imutran and other laboratories are trying
to get past this defence (immune) system by lining the pigs’ organs with human proteins
through genetic engineering. These proteins endow the pig organ with a kind of human
disguise. After a time, however, the human body would gradually realize that the
pig organ isn’t acceptable and would launch an attack on it. Imutran is now trying
to develop new drugs and may add more human genes to the pigs, says Dr Corinne Savill,
the company’s chief operating officer.
These “designer pigs” may, however, make it easier for the animals’ germs to infect
people, says Dr Robin Weiss of University College London. About two years ago, Weiss
began publishing articles showing how pig viruses could hide behind the human proteins
(added to the pigs) and slip past a patient’s immune system. The human proteins might
also invite the viruses into human cells. For example, one of the human proteins
used by Imutran and other biotech companies is CD55. This protein makes the human
body vulnerable to several polio-related viruses. Suppose, says Weiss, that pigs
have similar viruses. Ordinarily, they wouldn’t affect humans because of genetic
differences. But imagine that the pig viruses learn (through genetic modification)
to use CD55 and infect the patient who receives the pig organ. Once a pig disease
has crossed over into a single human being, it could mutate further and spread to
others.
None of these questions would matter if the pigs could be issued with a “clean bill
of health”, says Weiss. Imutran, for example, is trying to breed germ-free pigs in
tightly controlled facilities. But even in a hermetically sealed tank all the risks
would not be eliminated, particularly those arising from viruses known as PERV retroviruses
which are found in the animal’s genes. Weiss has focused on three strains of PERV,
which have been described as “second cousins” to HIV or human immunodeficiency virus
which causes Aids. Two of them can infect human cells.
Weiss’s findings sent shockwaves through public health organizations and the industry.
Researchers immediately set out to survey as many patients as they could find who
had been exposed to porcine tissue. Out of about 175 patients screened, none were
infected by PERV.
“It’s a relief,” says Weiss, but it’s not conclusive. “This particular virus is not
going to be highly contagious but this doesn’t necessarily mean that xenotransplantation
is safe.” The patients in question received porcine tissue not organs, whose sheer
volume may increase the risk of infection. Second, they were screened for the three
known retroviruses. What about unknown germs? Weiss also wonders whether the retroviruses
might be hiding somewhere in the body and become more powerful over time.
François Meslin of the World Health Organization describes a worst-case scenario:
a xeno-patient harbours an undetected virus which is passed to others by sexual intercourse,
a likely means of transmission. As the virus moves from one host to another, it becomes
increasingly dangerous.
“You can take a lot of precautions but you never know how far to go to bring the
risks down to an acceptable level,” says Meslin, who points to the case of bovine
spongiform encephalopathy–“mad cow disease”–as the closest example of this kind of
dilemma. Since Weiss sounded the alert, public health authorities around the world
have observed a de facto moratorium on human experiments with xenotransplantation,
which doctors describe as clinical trials. This doesn’t mean that they are giving
up on the research, however. What is happening is that most Western governments are
setting up special advisory or regulatory bodies to review any future clinical trials
and prepare strict guidelines for monitoring them.
The U.S. and Britain, who are the leaders in xeno-research, are currently finalizing
guidelines to monitor not just the patients, but their family-members and health-workers.
While the authorities refuse to release the details, it has been said that xeno-patients
should refrain from having children, marrying or even travelling internationally.
This sounds like a replay of discussions concerning people infected with HIV, says
Prof Bartha Maria Knoppers, a Canadian bioethicist regularly called on by OECD to
examine the ethics of xeno-research. Close monitoring of patients should not mean
trampling on their human rights, Knoppers believes. “Besides,” she says, “are we
really going to be able to enforce these conditions?” Would it be possible, for example,
to take legal steps to prevent a patient from deciding to have a child two years
after a clinical trial?
Assessing
the riskof viral infections
The sponsors of these
trials–mostly biotech companies–will also come under the microscope. Ordinarily,
proposals to test new medical procedures or treatments on humans are considered commercial
secrets which are restricted to the company involved and the relevant governmental
regulatory body, e.g. the U.S. Food and Drug Administration (FDA) which is responsible
for approving tests on humans for new medical drugs or procedures. This is not so
with xenotransplantation, however. In the United States, a special advisory committee
composed of some 15 scientific experts will openly review all requests to test animal
organs in people before the FDA renders a decision.
“Absence of evidence is not absence of risk,” says Phil Noguchi, director of the
FDA’s division of cellular and gene therapies. For example, two years ago bio-tech
companies proudly insisted that their pigs were germ-free. But when news of the PERV
retroviruses came out, Noguchi says, the companies suddenly “worked a lot harder”
to examine the risks. Noguchi also maintains that viral infections are difficult
to evaluate. “They may not happen often enough to be a publishable event,” he says.
“But in a clinical experiment one tenth of a sixth of a chance of infection is a
whole lot.” This is why the FDA is counting on help from the advisory committee to
look in all the “nooks and crannies” where a virus might hide. “We’re still in a
very difficult position because to a large extent we rely on industry to provide
the proof that a clinical experiment is safe,” Noguchi notes. “But we also depend
on our own scientists.”
For Noguchi, the advisory body also scores extra points by offering a “public forum”
to discuss the ethical issues–from animal welfare concerns to deciding who should
receive an animal organ. First, companies might focus on patients with the greatest
chances of surviving instead of those most in need of a transplant. Second, it will
take years–if ever–before pig organs are effective. For a patient on the verge of
death a pig organ could buy a few extra weeks until a human organ becomes available.
Should such patients receive priority on the waiting list? There is a third major
concern, says John Davies of the U.S. National Kidney Foundation, the world’s largest
non-profit charity for kidney patients. “We don’t want people to stop donating the
organs of their loved ones [for human transplants] after the first animal transplant
trials,” says Davies, “because they think the problem has been resolved.” While Davies
supports xeno-research, he is not convinced that it will prove successful.
The problem is that these discussions take place between people with vested interests
of one kind or another. They fail to include the largest group affected, the public.
“It can be argued that there should be some sort of ‘community consent’,” says Dr
A.S. Daar of Oman, who chaired the World Health Organization’s consultation on xenotransplantation.
“Is the FDA mandate to protect the public enough of a proxy for community consent?”
asks Daar. “Until the public is informed about the issues and is discussing them,
I don’t think you would want to go ahead with clinical trials.”
Daar is looking for ways of stimulating public debate and consent by working with
an international committee of “concerned” citizens–mostly scientists and bioethicists
brought together by the prestigious Hastings Center, a bioethics think-tank in New
York. The aim is to help countries to develop national but non-governmental committees
of individuals from various walks of life–economics, law, religion, the media, etc.–who
will take time to become informed about xenotransplantation but don’t themselves
have any vested interests in the matter. These committees would hold “consensus conferences”–what
Americans call “townhall meetings”–to spread information about xenotransplantation
and gauge the public’s response to it.
This idea is the brainchild of Fritz Bach, a scientist at Harvard Medical School
who first called for a legal moratorium on clinical trials in the U.S. Bach is often
portrayed as a virulent opponent of xenotransplantation and yet he is a leading scientist
in the field as well as a paid consultant for Novartis. His corporate sponsor isn’t
thrilled by his idea of townhall meetings. “You cannot go forward by publicly discussing
such complicated subjects,” says Imutran/Novartis’s Dr Savill. “Now, whether governments
have set up the right agencies is another question. Like anything else in society,
are the right people in the right place making the decisions? And does the public
have confidence in them?”
Bach isn’t convinced. “Some insiders think this [moratorium and public consultation]
would be a good thing for Novartis,” he says. “Just look at the tremendous hullabaloo
over genetically modified organisms. If a blue ribbon committee–without any connections
to Monsanto–had informed the public that they thought the [GM] food was safe on the
shelves, we wouldn’t have had this reaction. The scariest thing is always the unknown.”
• To
find out more or to express your views on ethical and policy issues related to xenotransplantation,
contact the electronic discussion group set up by the World Health Organization and
Health Canada: www.oecd.org/dsti/sti/s_t/biotech/xenosite/country.htm
