Xenotransplantation: the hopes and fears

Martin Wilkinson, Bioethics Council

Xenotransplantation: putting living material from creatures of one species into creatures of another species. The focus today is animal:human transplantation. This paper covers:

• the science and medicine of xenotransplantation
• the ethics of xenotransplantation

There are many different techniques of xenotransplantation

• Inserting cells e.g. pancreatic islet cells to treat diabetes, brain cells to treat Parkinson’s disease
• Inserting whole organs, e.g. kidneys, hearts
• Therapies outside the body, such as sending the blood of a person with acute liver failure through a type of dialysis machine and back.

NB 1: all of these are at an experimental stage, although some are much further along than others.
NB 2: not included are pig valves, which are not living tissue and so, technically, are not xenografts.

Which animals would be used?

We should distinguish:

• Source animals i.e. those whose bits would be put into humans
• Animals in research those used as a precursor to use in humans.

Source animals largely pigs

This is despite pigs being a discordant species, that is, ones that are especially incompatible with the human immune system.

Primates (baboons, monkeys, chimpanzees) are concordant with us, but they are ruled out as source animals because

• They are much harder to breed in captivity
• They are more likely to spread disease to the recipient, and perhaps beyond
• Ethically, it seems problematic to use animals that seem closer to us in moral status.

Pigs, by contrast, are easy to breed, less likely to spread disease and cheerfully eaten by many. They are also animals about which a great deal is known, following centuries of rearing.

Animals in research

Notwithstanding the remarks about ethics, some regulators e.g. the FDA, insist on testing on primates before approval for use in humans. Other animals are also widely used, e.g. mice.

Scientific/medical problems for xenotransplantation

One problem, hardly unique to xenotransplantation is, will it work? For instance, would pig neural cells do in a human what they do in a pig? In principle, this problem is no different from `will this mould kill these bacteria?' But there are two more specific scientific\medical problems for xenotransplantation. These are:

Immune rejection

The risk of disease spreading from animal to human.

Medical problem #1: immune rejection

The body’s immune system recognizes the animal’s material as foreign and destroys its cells. This has been particularly problematic for organs.

Many think of xenotransplantation as primarily involving organs, but in fact these are the most difficult. Pig organs, the ones most likely to be used, contain molecules that the human immune system recognizes as familiar viruses and bacteria. The immune system is already primed to attack these and the result, at this stage, of transplanting pig organs is hyperacute rejection, that is, destruction within an hour or less. Even with enormous quantities of immunosuppressant drugs, pig organs offer no benefit at the moment.

The problem of immune rejection is present, but less so, for smaller entities, like cells.

A good deal of medical research attempts to deal with the problem of immune rejection

In less dramatic form, immune rejection was the problem preventing human:human transplants, and the solution there was careful matching, especially of kidneys, and immunosuppressant drugs. So one method of dealing with the problem for xenotransplantation is to find drugs to suppress the immune system.

Another method is to try to remove the part of the animal’s material that triggers the immune system e.g. pigs with the GAL molecule knocked out through genetic engineering.

Yet another is to prevent the material having an effect e.g. coating pig cells with collagen.

How do things stand?

This is a matter of disagreement, but it looks at least as if whole organs are further off than cell therapies. The actual transplant of whole organs as a treatment, rather than experiment, could be 50 years off, or only a few. Cell therapies for diabetes are much closer. And the external therapies (`liver dialysis’) are definitely promising.

Medical problem #2: the spread of disease

Some diseases can spread from animals to humans, and then stop. Avian flu, as of 18th March, is like this. Other diseases spread from animals to humans, and then on to other humans. Avian flu might become like this. AIDS already is, being originally a disease of chimpanzees. The fear is that xenotransplantation will spread diseases from animal to humans and, at worst, beyond to other humans in a pandemic.

Some of the risk can be minimized or even removed by careful selection and husbandry of animals. However, not all the risk can be removed. This is because pigs have a virus in their cells called Porcine Endogenous Retrovirus (PERV).

PERVs have been shown to invade human cells in glass. The worry is that they could combine with human cells in the body of a xenograft recipient and then spread.

How much of a risk is the spread of disease?

This depends on

• How bad the bad thing is. In the limiting case, this would be a pandemic, which is very bad.
• How likely the bad thing is to eventuate. I don't think anyone thinks the probability of disease is high, but there is disagreement. Some say the risk is merely theoretical. They say: people have been exposed to pigs for years and not developed anything from these PERVs; haemophiliacs received pig Factor 8 in the 1980s in large numbers in the US, and there were no PERV problems. People in this group believe the probability is of the order of the probability of being hit by an asteroid. Others think the probability is unknown, but that there are plenty of instances of other catastrophic diseases being spread from animal to human.

It might be that the risks of disease vary from one type of xenotransplantation to another, for instance depending on how much animal material is inserted or whether it has a protective coating.

Given the problems of immune rejection and the public health risk, why even consider xenotransplantation?

Because xenotransplantation has the potential to treat serious diseases that affect many people and for which there is currently either no treatment (e.g. Parkinson's), not very good treatment (severe diabetes), or good treatment but in ineliminably short supply (whole organ transplants).

The ethical problems

• Cultural and spiritual objections
• The use or abuse of animals
• Public health and the allocation of risk
• Infringements on the rights of xenograft recipients.

Cultural and spiritual objections

This is something of a grab bag heading for ideas you will be familiar with in the context of other biotechnologies e.g. Xenotransplantation is unnatural, it interferes wrongly with the human essence, it plays God, it is part of a desperate grab for immortality. However, in discussion around the world, the official position of many religions has been to permit xenotransplantation.

About the cultural and spiritual objections, one can ask:

• What objections, if any, are there to xenotransplantation?
• To the extent that there are, should these play a role in determining whether people are allowed xenografts?

The use or abuse of animals

The ethical controversy can be broken down into:

• Factual disagreements about the extent to which animals suffer. Which animals get used as source animals or in research, in what numbers, and what happens to them.
• Factual disagreements about the size of the benefits of xenotransplantation compared with other methods, e.g. stem cell research.
• Ethical disagreements about significance of any suffering and the extent of any priority to be given to human interests.

Public health and the allocation of risk

If xenotransplantation were simply a risky trial treatment, it might be that individual consent would be enough to justify the risk. But the risk of xenotransplantation to public health cannot be justified merely on the grounds of individual consent. So we have a set of techniques that potentially helps a large number of badly off people and potentially threatens the health of a very large number. The ethical problem is to decide how to allocate the risk of harm and chance of benefit.

Infringements on the rights of xenograft recipients

The risk of disease spreading might be reduced by forcing xenograft recipients to submit to lifelong monitoring and treatment, breaching confidentiality, preventing their reproducing, and compulsorily quarantining them. These measures appear to infringe on rights, so the ethical question is: would this be justified? There is also a factual question: would infringing actually do any good?

NB: these questions arise whether or not New Zealand bans xenotransplantation. This is because some people will be xenotourists.

5 April 2005

2005 Speakers Science Forum