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Bioethics

Xenotransplantation: For and Against

by Ololade Olakanmi and Laura Purdy

Organ transplantation saves thousands of lives every year, and is arguably one of the most significant medical innovations of the past century. At present however, the worldwide demand for organs far outstrips supply. For instance, in 2004, the United Network for Organ Sharing (United States) found that over 100,000 patients could have benefited from an organ transplant, whereas only 29,000 were available. In the US, 17 patients die each day while on the organ donor waiting list – a dismal statistic which, unfortunately reflects a global trend. In an effort to satisfy the growing demand for organs, the scientific community is once again turning to xenotransplantation, a cutting-edge medical technique that involves the transplantation of biological material from nonhuman animals (primarily pigs) to humans. If properly developed, xenotransplantation has the potential to one day not only ameliorate the present organ donor shortage, but also to help address the ravages of Parkinson’s disease, childhood-onset diabetes, Huntington’s disease, and a number of other conditions. Ololade Olakanmi


The Case Against

Laura Purdy considers some of the problems associated with animal organ transfer.

In January 2003, U.S. scientist Randall Prather announced that he had successfully cloned a miniature pig lacking the protein which triggers hyperacute rejection. If this result can be replicated, clinical trials of xenotransplantation could take place in as little as three years, according to Dr David Cooper, professor of surgery at Harvard Medical School.

Long, healthy life is both valued and valuable. So a new technology that promises longer, healthier life is, other things being equal, a good thing. With this in mind, let’s look at xenotransplantation. This article will focus on organs, although the use of animal tissue raises many of the same questions. Sick patients now live ‘on call’ for years, waiting for an organ that matches their particular need, never knowing whether it will appear in time. Once xenotransplantation is well-established, organs could be provided as soon as a surgeon could operate. The ready availability of organs could also reduce morally worrisome practices now on the rise, such as buying kidneys, lungs, or chunks of liver from healthy donors. It could also reassure the dying that they won’t be hurried toward the grave by overly-enthusiastic surgeons [cf, Mrs Brown in Ward A is dying anyway, and Mrs Green in Ward C might recover if she gets Mrs Brown’s kidney now... Ed].

So, with all this good news, why not go full steam ahead with xeno research? Alas, free lunches are in short supply, and xeno is no exception. Several major moral issues need to be resolved before proceeding. What about animal rights and animal welfare? Would people accept animal organs? Could standards of informed consent be maintained? Last, does the use of animal organs pose unreasonable threats to third parties? If so, are there good grounds for them (us) to accept such risks? We’ll look at each of these questions in turn.

Animal Issues

Xeno would be impossible without using animal materials, by definition. Do we have a right to use them?

Xeno research may be more problematic than any subsequent use of animals for organs. In current research, animals are both donors and recipients. Donor issues are similar to those that would arise once xeno is well established. But animal test recipients may be subjected to procedures that cause serious suffering. Some such suffering may be caused by the social context of the research: for example, profit-oriented research groups may perceive the demands of humane treatment of animals as obstacles to winning the race, not moral necessities. Even in the best circumstances, some suffering may be unavoidable: surgery causes pain, and drugs can cause a variety of seriously unpleasant symptoms. Donor animals may also suffer because of the conditions necessary for producing safe organs. To maintain a sterile environment, infant animals will be delivered by cesarean and kept isolated, causing much emotional suffering in social animals like pigs. However, the primary moral question that arises for donor animals is whether they (morally) may be killed for their donations.

Many people, including some scientists, regard these as trivial concerns. Although most believe that avoidable animal suffering and death should be prevented, their overriding concern is human welfare. Others believe that it could be morally acceptable to painlessly kill animals for human welfare, but that our aims do not justify animal suffering. Still others believe that it is wrong to do to animals what one wouldn’t do to humans.

In Western societies, the first perspective predominates. Huge industries cater to our appetite for meat – several pounds a week per person in North America – and vegetarianism is the exception. Western societies also tolerate the widespread testing of drugs and cosmetics on animals, and leather and fur products are popular. But as we all know in our more introspective moments, accepted social practices don’t necessarily reflect considered moral judgments.

In the last few years, because of my concerns about animals, the environment and health, my introductory ethics classes have examined the case for vegetarianism, and it has been fascinating to watch the changes in students’ attitudes. Once they understand the meat economy, most acknowledge that it rests on important moral choices, and some become vegetarians. This point is not intended to do an end run around the sophisticated philosophical debates on this topic, but rather to suggest that there is less moral authority than might seem in the apparently commonsense retort about animal welfare, “Well, we eat them, don’t we?”

A less emotionally gripping but still pressing question is the extent to which we morally may tinker with animals’ genetic endowments. Discussion of this matter is much less well-developed than the ones about animal suffering and killing.

It is important to notice that no moral conclusions about animals are scientific. That is, they depend on judgments about values, not about which means are best for achieving a particular goal. Scientists may be in a position to help the public understand what is at issue, but have no special expertise in deciding how best to reason about competing values. Because these judgments implicate fundamental and deeply-held beliefs, there needs to be full, honest, public discussion about what is proposed. This has not yet occurred.

Acceptability and Informed Consent

Acceptability and informed consent are two sides of the same coin. The first question is whether candidates for xeno would assent to the procedure. Xeno researchers assume that desperate people would gladly take any relevant organ. But studies suggest that might not be true. Some resistance might come from religious beliefs concerning this type of close relationship with non-human creatures. Some resistance might also come from realism concerning the risks and benefits of xeno.

The second issue is whether candidates for xeno could ever provide fully informed voluntary consent. Such consent is difficult enough to obtain from seriously ill patients for whom any invasive treatment is proposed. The special problems associated with xeno exacerbate these difficulties.

When people are very ill, pain or fear may prevent them from reasoning well about their alternatives. This problem is compounded by reservations health care providers may have in fully disclosing the risks inherent in the kind of last-ditch treatments available. These factors often lead patients to consent to treatments that are unlikely to deliver any benefit because they think they have nothing to lose. But patients can be made worse off: treatment can impose suffering without any compensating benefit. Thus although (normal) transplant procedures have improved enormously, for example, it is still a chancy affair, with no guarantee that it will prolong life or improve its quality.

Informed consent for xenotransplantation raises its own questions. On the one hand, it is hard to be very precise about what could go wrong and what patients would experience with such a new technology. On the other, patients and their intimates must be prepared to consent to intrusive and demanding conditions because of potential risks to third parties (see below). Among the conditions that have been proposed are, lifelong monitoring, using barrier methods of contraception, reporting sexual partners, educating close contacts about risk, refraining from childbearing, and accepting quarantine in case of infection. The recent SARS epidemic suggests that plenty of people will be ready to flout voluntary quarantine guidelines. Will democratic societies take stronger measures to protect the public in case xenotransplantation goes wrong?

Risk of Disease Transmission

The most distinctive xeno problem is in fact, this risk of disease transmission to third parties. This is a problem that changes a decision to pursue xeno research and treatment from a private matter to a public one about justice.

Why is this a public matter? We generally believe that some decisions are personal because the benefits and burdens of those decisions are largely borne by the person making the decisions. Where they are not only borne by that person and they are of interest to society at large, it becomes a question of justice, not just individual prudence.

Xeno raise questions about justice through the possibility of creating new and dangerous diseases that could infect the gen-eral population. Fritz Bach, a prominent xeno researcher and his colleagues rang the alarm in 1998. The central problem is that xeno risks inserting pathogens from the donor animal into the organ recipient; from there, these diseases could spread to others. In addition, a number of factors magnify the risk of spreading serious disease, at least theoretically.

We know that animal pathogens can be transmitted to humans. Diseases like HIV, Ebola, Hepatitis B, and, most recently, bird flu, originated in animals. Pigs, where current xeno research is now focused, are thought to have been the vector of the devastating 1918 influenza epidemic. Pigs also harbor a variety of other known and unknown bacteria and viruses, and, like all mammals, have potentially dangerous viruses embedded in their DNA.

What factors increase the risk of epidemics? One is the power of living organisms to swop DNA with each other. So currently harmless organisms, like the e. coli that lives in our guts, could pick up new, possibly harmful traits from the micro-organisms that came along for the ride on pig organs. Moreover, the faster their mutation rates, the greater the risk – and retroviruses, like the porcine endogenous retrovirus now embedded in pig DNA, multiply especially fast. Yet another risk factor is the tendency for pathogens to increase in virulence when they infect new species. For example, some herpes viruses are inactive in one monkey species but wreak death from leukemia or lymphoma in others. So organisms harmless to pigs might still be a source of danger to humans.

Scientists are now attempting to determine whether pig pathogens might infect humans. However, the studies involve small samples and are short-term. Thus even negative results don’t necessarily reflect the real danger. The underlying problem is that judgments about risk are inductive. But no matter how many ‘safe’ results accumulate, the very next case might reveal catastrophic infection. Although it may be tempting to dismiss this point as trivial, that would be a serious mistake. If technical obstacles to xeno such as organ rejection can be overcome, and the practice becomes widespread, no obvious disease might emerge for years. But even an extremely low risk could eventually produce something like AIDS, or worse. Consider, for instance, a cancer-causing herpes virus that spreads in the air.

Two additional risk factors should give us still more pause. One is that transplant – any transplant – now requires the recipient’s immune system to be suppressed, otherwise an organ perceived as alien would be rejected. But this immunosuppressed environment encourages bacteria and viruses to flourish, unchecked by the host’s defense mechanisms. Moreover, if animals intended as sources for xeno are engineered with human genes, their microbes will have a chance to become adapted to the human environment while still ‘at home’ in their animal hosts. That state of affairs would make it harder for our human immune systems to crush them. In short, as one writer has suggested, if you wanted to design an environment for creating new diseases, xeno would be ideal.

Should We Continue to do Research on Xeno?

These facts suggest that there is no way to ensure that xeno might not kill many more people than it could save. So despite its promise, I believe that we should instead seek alternative ways to address the problem it is intended to fix.

This approach is consonant with the Precautionary Principle (PP). A recent articulation of the PP says that a range of alternatives to new technologies should be considered (including no action), and that discussion be open, informed, and democratic (ie include all potentially affected [human] parties). A key element in the PP is that when potential harm is foreseen, proof that it will occur is not required to elicit precaution. Causal relationships don’t have to be established.

Because of this last point, the PP has been accused of being unscientific and dangerous by those who want to move forward with new technologies like xeno. This accusation cannot withstand serious scrutiny however. Using the PP to decide about xeno can’t be unscientific (unless the decision rests on false empirical claims) because that decision is inherently moral and political. Whether xeno is dangerous or not depends on the facts of the case and one’s conception of danger, rather than whether one decides to be precautious. A decision about xeno is a moral decision because it distributes benefits and burdens among individuals in ways that are either fair or unfair. It can reasonably be argued that pursuing xeno may result in benefits to some, possibly at great cost to many others: those with organ failure may benefit, but all of humanity will be put at risk. A decision about xeno is a political decision because it is a moral decision, and the differing interests at stake may reflect different entrenched priorities. For example, successful xeno is expected to be enormously profitable; a successful xeno protocol might also bag a Nobel prize for its inventor. And patient groups may well be focusing on their own plight at the expense of the public interest.

Is using the PP itself dangerous? The relevant questions are, what kind of dangers are there, and to whom? Stopping xeno could certainly endanger the political interests just listed: researchers and health care providers might not get the fortune and fame they seek, and patients with end-stage organ failure could lose hope of a remedy. However, stopping xeno ends the danger of epidemics caused by it. So it is oversimplified to say that the PP is dangerous itself – indeed, it’s more plausible to say that not using the PP puts humanity in more danger than using it. Refusing to subject xeno to the PP is tantamount to demanding dead bodies to prove that xeno is bad and only then stopping it: it also assumes any resulting disease can be controlled. But not all genies can be stuffed back in their bottles, as AIDS and other diseases have shown.

The legitimate moral interest that appears to be left out by the PP is, of course, the welfare of patients with end-stage organ failure. This problem is addressed by considering the alternatives to precaution. Also, alternatives to xeno itself that now seem remote might soon be competitive.

The central question is how to diminish the gap between the low supply of organs and the high demand for them. The obvious first step would be to universally apply the most successful strategies for increasing donation rates, and to develop new ones. Another step would be to apply other existing treatments and develop others. Existing treatments might rescue some who now face organ failure; for example some treatments, such as heart assist devices, currently considered as bridges to transplant, are showing promising signs of providing sufficient respite for damaged organs to repair themselves. New technologies such as tissue engineer-ing also show promise. Astoundingly, researchers have already constructed a functioning dog bladder. And, the potential of stem cells is still unknown, but perhaps revolutionary.

Preventing disease in the first place would be best, naturally. Yet some cases of organ failure are caused by accidents and poorly understood diseases. Better regulation and enforcement could probably reduce the number of accidents significantly, and hopefully research will continue to decrease the number of poorly understood diseases. But what is interesting is the extent to which the remaining cases of organ failure could be headed off at the pass altogether. Diabetes, smoking and sedentariness, for instance, are major causes of organ failure. An all-out public health campaign – one not fettered by commercial interests – could therefore much reduce the number of those who, as things now stand, will wind up on transplant lists. We can already make a big difference in the amount of disease, disability, and death caused by self-neglect.

Most of those now on transplant lists cannot be saved by these suggestions. I’m afraid that there are moral limits to what can be offered to them – a perspective we normally take for granted, but which tends to get lost in the xeno debate. If it were proposed that we kill a healthy individual to distribute her or his organs to five needy others, everybody would laugh [see Three Guys With Failing Organs in this very issue - Ed]. The perhaps worse potential risk to others seems less problematic since it is more remote, indirect, ‘statistical’ rather than personal. But this tendency is widespread, leading us to ignore huge moral issues that are not ‘in our faces’. The AIDS disaster in Africa is barely on U.S. radar screens, whereas 9/11 is being used as an excuse to turn the world upside down.

The xeno debate proceeds as if saving lives is our top moral priority. From this perspective, lives that might be lost down the line because of xeno don’t seem to count. Nor does the fact that if we diverted world resources from bloated military budgets to meet human needs, countless lives would be saved. What about the eleven million babies and children who die every year from diarrhoea, malaria, measles, pneumonia, AIDS and malnutrition? What about the half-million women who die every year during pregnancy and childbirth when simple measures could save most of them? If saving lives is truly our top moral priority, then why don’t we start with those people – people whose lives we know how to save, cheaply, and without risk? Once the world faces the fact that it cannot have both guns and health, there would be resources left over for treatment and research. Refusing to face this fact means that many health-related needs cannot be met. In this case, allocating the bulk of resources to social determinants and primary prevention, and ensuring that a top priority is alleviating pain, would probably enhance human welfare far more than our current priority, attempting to treat disease once it is established.

© Laura Purdy 2006

Laura Purdy is Professor of Philosophy at Wells College, in Aurora, NY. She has written extensively on applied ethics.


The Case For

Ololade Olakanmi talks about whose turn it is to get the pig’s heart (not the pig’s, clearly).

New medical techniques like xenotransplantation elicit many weighty ethical questions I will focus on two key dilemmas which still plague this procedure:

(1) How will researchers know when it is appropriate to move from purely animal studies to clinical activity involving humans? and

(2) Can we ethically justify the vast amount of money spent on xenotransplantation research given that it will benefit relatively few individuals?

What Is An Acceptable Risk?

The first objection to xenotransplantation research is that it imposes substantial risks upon both patients and the general public [see above]. Researchers and public health scientists have devised a number of pre-transplant and post-transplant safety measures to minimize these risks, but can’t eliminate them altogether.

To ensure that xenotransplantation is safe enough for human applications, ethicists and policy-makers generally agree that researchers should first perform preclinical studies in animals [animal-animal transplants]. Only after these animal experiments suggest that xenotransplantation techniques are safe and effective can we say that there is a good reason to proceed with human clinical trials. At the same time, however, these same ethicists and policy makers rarely offer guidance as to when this jump to the clinical arena will be ethically justified. Discovering this is the task we now have before us.

Just how safe and effective should these procedures be? In my view, the answer directly hinges upon how much risk we as a society are willing to bear in order to promote the welfare of those of us who suffer from the scourges of disease. At first glance, reflecting upon these risks may appear to be a task for the empirical sciences; but this could not be further from the truth. It is the job of philosophy to determine what constitutes an acceptable risk – to negotiate how our final decisions will align with our personal and communal values.

How should we go about defining acceptable risk with respect to xenotransplantation? For decisions involving risks, most people turn to a quantitative method of risk assessment, such as cost-benefit analysis. As the name suggests, this involves evaluating the benefits and costs of a course of action, such that the decision-maker is able to act upon the choice that presents the most favorable balance of benefits over costs. This procedure is useful insofar as it is standardized and straightforward. However, because xenotransplantation is a fairly new field, there is relatively little data for risk assessors to base their predictions on. Thus it appears that cost-benefit analysis can’t help us much.

In the absence of a quantitative method of risk assessment, the prevailing attitude towards xenotransplants is one of risk aversion. To the extent that xenotransplantation involves unquantifiable risks to patients and third parties, many commentators conclude that the potential costs automatically outweigh the potential benefits. They warn that xenotransplantation should not be performed unless the risks of incurring these costs are sufficiently minimized. I do not think that many people would be opposed to this precautionary advice [see Purdey on the PP, above]. Most, I am sure, would think it prudent that we look before we leap. Nevertheless, I don’t believe that this precautionary approach is suitable for assessing the risks of xenotransplantation per se.

The precautionary approach falsely assumes that the worst-case scenario will unavoidably occur, and so it flounders as a satisfactory method of risk assessment because it fails to acknowledge that risks cannot be separated from innovative research. Let me illustrate. Researchers will continue with animal-animal tests until they have proven that the basic techniques are safe. Let us equate safety with the survival time of experimental animals. So assume that a survival time of 30 days will yield a safety rating of X. Should researchers stop here, or should they pursue a safety rating of 3X, with a corresponding survival time of 90 days, or perhaps a safety rating of 4X, or 10X? It may be evident where this line of thought is going. Precautionary approaches are irrational insofar as they cannot prescribe any definite stopping point to trials. This is simply because the precautionary approach implic-itly seeks to eliminate risks altogether – which is in principle impossible. Since xenotransplantation is imbued with uncertainty, its risks will never be eradicated. However this should not deter us from finding a better way to evaluate acceptable risks. I propose the following decision-making scheme.

In theorizing about acceptable risk, we mustn’t think of it as a process of minimizing risk, lest we fall victim to the hazards occasioned by the precautionary approach. Instead, we must see acceptable risk as a goal or aspiration level. Once this goal is reached, we would consider xenotransplantation techniques safe enough for clinical use.

Allow me to flesh this concept out [to use an appropriate metaphor] in more practical terms. Before xeno techniques can be considered safe enough, we must first have a conception of what a successful trial ought to be. To accomplish this, we should clearly state that animal studies must consistently yield specific survival times, disease and mortality rates, etc. When researchers are able to consistently reproduce these demanding results, scientists will then be justified in proceeding to the clinical phase involving humans.

But who should decide when safe is safe enough? The first logical choice would be the xenotransplantation researchers themselves, because they have the most relevant knowledge and technical expertise. I advise however that we avoid defaulting to the ‘doctor knows best’ paradigm that characterizes the majority of the history of health care. A great deal of empirical evidence suggests that physicians don’t always know whether a treatment will benefit a patient. For this reason, I don’t recommend that researchers alone should be allowed to decide what risks society should endure. In fact I don’t think that any single interest group should make decisions that affect society as a whole. In order for us to consider the many perspectives of our pluralistic society, the decision must be democratic - although not necessarily majority rule. Therefore I suggest that we assemble a group who will serve as advocates for the many xenotransplantation stakeholders: patients, physicians, researchers, lawyers, and ordinary citizens. These advocates will then engage in a critical, Habermasian discourse about acceptable risks.

Is it Right Anyway?

Even if researchers could guarantee that xenotransplantation products are safe, the fact remains that this technology is very expensive. Therefore, we must now discuss whether our society’s collective resources could be better spent elsewhere.

Critics often point out that xenotransplantation is an exotic and costly procedure which will benefit very few individuals, arguing that the resources it consumes should be allocated to primary care and preventative medicine. I agree that xeno will be expensive and I don’t deny that the potential benefits to patients will be modest in the short term. However, I do not believe that these facts necessitate that we should divert health care resources away from xenotransplantation research.

Many ethicists and public health officials argue that health care should serve the most individuals possible. The underlying assumption of this policy is that an investment in health care resources should maximize the net welfare of its recipients. The idea that the purpose of health care is to maximize net benefits is firmly rooted in the utilitarianism of Jeremy Bentham and John Stuart Mill, which stipulates that society should aim to bring about the greatest benefit to the greatest number. From this perspective, it is exceedingly difficult to defend xenotransplantation. Insofar as the immediate benefits will likely not equal the costs, it follows that xenotransplantation does not merit its current input of capital, ingenuity, or trained professionals. In the long run, after xenotransplantation is further developed, its clinical potential will increase, and likewise, the attending benefits will be much greater. But even so, it is still hard to believe that the benefits of xenotransplantation will ever exceed the benefits of primary and preventative care with the same resources.

Thus these utilitarians would likely not even see xeno as a technology worth pursuing. But utilitarianism is not the only ethical theory that can offer guidance for the proper distribution of health care resources. With regard to distributive justice, I personally favor the egalitarian ethics espoused by John Rawls in A Theory of Justice. This theory is applied by Robert Veatch in his book Transplantation Ethics.

Discarding the idea that the right act is always the one that produces the greatest good for the greatest number of individuals, egalitarians instead argue that we are under obligation to give consideration to the interests of society’s least-well-off. Hence, when we decide who ought to benefit from a particular pool of health care resources, the least-well-off should be given special consideration. This policy would be followed irrespective of whether the net welfare of society is maximized; and unlike utilitarianism, it takes into account the distribution of harms as well as benefits.

If we examine xenotransplantation through these egalitarian lenses, it’s not difficult to see such research as important for health care. Assuming that our society subscribes to egalitarian principles, at least to some extent, people with impending major organ failure can easily be identified as some of the least-well-off. The candidates for xenotransplantation research trials will be terminally ill patients whose deaths are imminent. They will often be in such dire straits that high-risk transplantation surgery will seem like a blessing. This candidate pool will partly consist of individuals who for whatever reason can’t receive a human organ (eg because of blood, tissue or size incompatibilities) or who aren’t eligible for the organ donor waiting list (eg individuals with hepatitis or individuals with certain autoimmune disorders like HIV/AIDS).

As egalitarians we are obliged to give special weight to such citizens, even though doing so will not maximize our overall social payoffs. It does not follow, however, that every candidate will be among the least-well-off, and xenotransplant-ation candidates who do not satisfy this requirement should not be entitled to what Veatch calls a “high-priority claim of justice.” It ultimately works out that primary and preventative care ought to be given priority when those who require it but will not receive it will be worse-off than those who need xenotransplantation but will not receive it.

Egalitarian principles are valued by Western society. Take for example socialized medicine, Medicare, Medicaid, or Britain’s National Health Service. These social programs were established in order to more equally distribute health care opportunities, by serving the health care needs of society’s least privileged. Allocating public funds to such programs reflects our commitment to egalitarianism.

Taking an egalitarian approach to distributive justice isn’t a new idea, and neither will it always be the most appropriate theory of justice. But its usefulness to the ethics of xenotransplantation is quite evident.

Conclusion

Xenotransplantation might very well prove to be a powerful medical technique, but it will also demand much from us as individuals and as societies. It will demand our economic and social resources, and it will place an increased burden of risk upon all of us. Nonetheless, I wholeheartedly agree with the words of the Institute of Medicine that “[our] own humanity is diminished if, in order to protect ourselves, we turn away from others whose suffering is both clearly visible to us and even more clearly devastating in its impact on them.”

© Ololade Olakanmi 2006

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