Xenotransplantation

There is a considerable 'yuck factor' associated with the transplantation of pig hearts to humans. But is it unethical? 'Xeno' is Greek for 'foreign', and xenotransplantation therefore denotes the transplantation of cells, tissue or organs between individuals of different species ‒ or in our context, from animals to humans.

Introduction

The purpose of xenotransplantation is to ensure an almost unlimited supply of organs for transplantation. There is currently a severe shortage of organs, particularly of hearts and lungs, for persons with life-threatening and irreversible organ failure. A further advantage of xenotransplantation is that in principle the organs can be adapted to the individual recipient, and that it is possible to choose the time and place of the surgical procedure. Transplantation of animal cells may also represent a new form of treatment for diseases such as diabetes, Parkinson's disease and epilepsy.

Xenotransplantation has not yet arrived in clinical practice. Clinical trials began in the mid-1960s, but the results have been disappointing, the biggest barrier being immunological rejection of organs from non-human species. In experiments with transplantation of entire organs from pigs to non-human primates, it has only been possible to postpone acute rejection through the use of immunosuppressive agents, but not to eliminate it entirely. However, gene technology and new drugs have once again made xenotransplantation a possibility.
Xenotransplantation is nevertheless a rich source of interesting ethical and research ethics issues.

Species ethics: Are we on the brink of a new ethical boundary?

Xenotransplantation is new in the sense that it entails living biological material crossing species boundaries. Moreover, it will need to be based on genetic modification and cloning of animals. Is xenotransplantation therefore 'unnatural' and hence unethical?

The first question concerns the clarity of the division between nature and culture. Medical treatment frequently entails reversing or halting natural processes. Is medicine therefore unnatural? If humans are part of nature, can all human actions therefore be considered natural?

Second, is everything that is 'natural' justifiable? Although xenotransplantation might be regarded as 'contrary to nature', it may be an ethical duty to develop this technology in order to save lives. But that depends on other factors, such as the integrity of the affected party, availability of alternatives and cost-benefit-risk analyses.

This brings us to the real question of the ethics of species: Does xenotransplantation threaten the dignity of humans or other living beings – their opportunity to fulfil the purpose of their own species?
Until now, the genetic modification of pigs for xenotransplantation has been limited to harvesting a few porcine cells and adding a handful of human genes which make it more difficult for the source pig's organs and cells to be recognised by the human immune system. This does not affect the pig's bodily structure or mental functions. Xeno pigs are therefore not essentially different from other pigs. But where do we draw the line? Some laboratory mice with altered rejection characteristics have developed cataracts and become blind. Does this compromise their integrity?

A related question applies to humans who receive animal organs. Does this make them less human? One reply to this is that humans and pigs already share 90 per cent of their DNA, and this is the very reason why pigs are appropriate source animals. Are our fundamental human characteristics altered by replacing an organ? What about transplantation between humans – or artificial organs?

Risk: Public health versus the patient

Xenotransplantation by definition crosses the species boundary, and the risk of transmission of infectious material from animals to humans is therefore an important aspect. Swine influenza, avian influenza and AIDS (via HIV 1) are known examples of so-called zoonoses – diseases of animals that can be transferred to humans.

Viruses that are harmless in one species may cause diseases in another, and porcine endogenous retrovirus (PERV) has featured prominently in the debate on the risks of xenotransplantation. It is present as part of the pig's DNA, and cannot normally be eliminated. It can therefore infect human cells. However, in order to represent a threat to public health, the virus must also be able to express itself in humans, be transmitted to others and result in disease. As of now, there are no indications of this.

The benefit for the patient of a life-saving xenotransplantation must be weighed against the collective risk to public health. In one sense, this is a reversal of established research ethics ‒ it is society that must be protected from the wishes of the individual patient (and doctor). For the patients, a theoretical risk of infection will be trivial compared to life-threatening organ failure!

To what extent is it right for an individual in such a situation to inflict a risk on others in order to improve her/his own health situation? Where are the lines to be drawn with regard to patient autonomy? Many researchers will nevertheless apply the precautionary principle as a premise for xenotransplantation research, given the considerable scientific uncertainty and specific scenarios to indicate potential harmful effects. But how radical should such precautionary strategies be? Some favour a moratorium until all basic research questions are clarified, while others favour careful escalation of research under highly controlled conditions. Once again, this is a question of how we emphasise balancing public health against saving individual lives.

Prioritisation

The costs of developing xenotransplantation will be high, especially in the introductory phases. Will this treatment only benefit patients in wealthy countries? Could the resources be used on many more patients in poor countries? Or is it a matter of important basic research on behalf of many – which can also reduce the sale of organs by the poor?

Patient selection

If preclinical trials are promising, which patients will be selected for inclusion in clinical trials? Those who are most ill, or those who are most interesting from the scientific viewpoint? Should there be a right to be included in clinical trials?

On the other hand, should patients who refuse to receive xenotransplants retain their place in the queue for human organs?

Consent

To minimise the consequences of a potential infection from the source animal, proper monitoring following xenotransplantation is essential, the purpose of which is to detect and contain infection as early as possible. It is therefore necessary for patients to commit to lifelong follow-up involving a separate xeno-register and biobank. All signs of abnormal and unexplained symptoms must be reported immediately. Where an infection is suspected, the patient's close contacts should also be called in, registered and samples taken.

Is it acceptable to withdraw consent?

According to the Helsinki Declaration, research subjects are fully entitled to withdraw their consent to participate at any time without fear of reprisal. But does this also apply to follow-up of patients who have received animal organs or cells? What about the risk of infection?

What about consent by next of kin?

The requirement for clinical monitoring, duty to report and restrictions may also need to be placed on the patient's close contacts ‒ family members, sexual partners and others. Should these persons have the right of co-determination before the patient is included in clinical trials? Or will this undermine the patient's autonomy when his/her life and health is at stake?

Can children take part in trials?

Children have less autonomy and therefore need extra protection. Is it ethically correct for children to receive xenotransplants and thus be subjected to lifelong monitoring and potential restrictions on their lives? On the other hand, can we deny children the option of receiving life-saving treatment? What degree of uncertainty can we accept? Do terminally ill, desperate patients possess a real capacity to consent – or are they better served by an approach of acceptance with regard to their death?

Ethical issues vis à vis pigs: Is it right to use pigs as source animals?

Many people would regard this question as a "no-brainer", since in our society there is already a broad acceptance of the use of animals in food production.

However, it is far from being that simple. Xenotransplantation is a new way of exploiting animals and must therefore be considered as a separate issue. Although humans as morally responsible agents may be ascribed a higher inherent value than animals, this does not mean that the needs of animals have no value. On the contrary, the special status of humans imparts significant moral obligations towards animals. Do we have the right to breed large populations of pigs destined to live their lives under the particular conditions that xenotransplantation demands?

The UK Farm Animal Welfare Council has drawn up five freedoms for farm animals, which can serve as a good basis for consideration. Freedom is required from: 1) hunger, thirst and malnutrition, 2) physical discomfort and an inappropriate environment, 3) pain, injury or disease, 4) fear and stress. 5) There is an additional requirement for freedom to express normal behaviour.

A pig is an intelligent and social animal that bonds very strongly with its mother and litter-mates. The production of source animals will involve early weaning from the mother for some piglets, and total removal from her for others. This will engender fear and distress in the piglet. It is advantageous for each litter to remain as a social group throughout.

Special housing conditions will be necessary due to the hygiene requirements. Pigs have a very strong urge to root, and special provision must be made to fulfil this need. However, since their quality as source animals requires them to thrive and be active, their housing conditions will presumably be satisfactory.

Pigs react instinctively with fear and protestation when restrained. Constant taking of samples is stressful, especially since the risk of infection and requirements for quarantine will make it difficult for the personnel to become part of the animals' social group.

In other words, the production of source animals may deviate from the five freedoms on several points, particularly freedom from fear and pain, since because of repeated sample-taking the animals will experience more "abuse" than normal pigs for slaughter. The freedom to express natural behaviour will also be somewhat reduced, but perhaps the pigs can have acceptable living conditions as source animals despite this, given proper routines and monitoring?

This article has been translated from Norwegian by Jane Thompson, Akasie språktjenester AS.