A new source of organs

The most obvious advantage of chimaera organs is that they would provide an inexhaustible source of organs for transplantation. Anyone in need of a new organ could provide iPSCs which would be inserted in a pig embryo prior to implantation and gestation (see box 1). After around 6 months, the resulting pig would be sacrificed and the human organ removed and implanted in the original donor. Hundreds of thousands of lives would be saved every year if this technique was widely adopted, and many more people would have their quality of life improved if chimaera organs removed the need for dialysis.

Lower risk of organ rejection

The second advantage is that personalised chimaera organs are likely to cause no immune response, as they will be created from the recipient's own DNA. This means that recipients should no longer have to take immunosuppressant drugs for the rest of their lives, and will be spared any of the side effects (and the associated financial costs) of these medications. Therefore, chimaera organs could provide an increase in the quantity, and in the quality of organs.

Organs created using the intended recipient's DNA are likely to be expensive to produce, and it is possible that allogenic organs derived from human leukocyte antigen-matched iPSC cell lines will also be used. It is possible that a ‘two-tier’ system of chimaera organ provision could develop, with richer countries and patients being able to afford autologous organs, and less well-off nations and patients receiving inferior allogenic organs. The equity issues this would raise are beyond the scope of this paper. However, it should be noted that although the risk of rejection of such allogenic therapies would be higher than in personalised autologous therapies, they are still potentially lower than is currently the case for many organ recipients who must take whichever organ is available at any given time. Moreover, autologous therapies may prove to be cheaper in the long term despite higher initial costs, as they would avoid the need for ongoing costs such as immunosuppressant drugs and repeated transplantations.

Risk of zoonosis

Objections to xenotransplantation have focused on the potential risks of zoonosis: infection with a mutated animal virus that could then be passed on to other humans, possibly creating a pandemic.18 Zoonosis poses a public health threat to people other than the recipient, which as such has played a major role in halting xenotransplantation as a potential solution to the organ-scarcity problem.. However, compared with traditional xenotransplantation, organs obtained from chimaeras are likely to further reduce the already small risk of virus transfer, as the organ being transplanted would be human despite its ‘gestation’ inside an animal host. It is thought that precautionary monitoring of the donor-chimaeras during their development and testing of the organ prior to transplantation could all but eliminate the risk of accidental transplantation of contaminated organs. However, even if the risk of zoonoses arising from chimaera organs is almost zero, we must also consider the magnitude of any harm that might result.19 A deadly zoonosis could theoretically kill millions of people, and one might question whether the benefits of creating a new source of organs is worth outweighing the potential harms flowing from even a small risk of zoonosis. Should it be concluded that the zoonosis risk is not prohibitive, any chimaera organ programme should be subject to strict conditions including a very close monitoring to assess any ongoing threat of zoonosis.

A related concern is the generation of cancer, rather than viruses, in recipients of chimaera organs. The use of direct stem cell transplants has caused cancer in some patients. However, the use of a patient's own stem cells to create a replacement organ in an animal is unlikely to have this effect for two reasons: it is not a direct transplant of cells into the patient, and the cells involved will be heavily programmed towards specific purposes, unlike the cells in traditional stem cell transplants. Nonetheless, this is one other uncertainty that affects the potential use of chimaera organs.

The human features problem

While chimaera-sourced organs offer prospective advantages, the process of creating them raises another ethically relevant issue. Injecting human PSCs into animal embryos could theoretically risk the resulting animal itself developing human physical or mental features such as human limb development or neuronal development. Fortunately, the chances of this happening are remote. Even if human neurons were present in a pig brain, it is likely that they would act like pig neurons, being influenced by their environment rather than their genomic makeup.16 Furthermore, if any pig were found to have human gametes, it could simply be prevented from reproducing. It should be relatively simple to reduce these risks further still by knocking out genes for neuronal and gamete development in the human PSCs that are to be injected into the animal. Furthermore, the human features problem is not unique to the creation of chimaera organs, and has been raised before with regard to transgenic animals; in these earlier debates, the risks of development of human features were not judged sufficient to prevent use of the new biotechnology.20 Although creating chimaera organs might pose slightly different risks because of the different method used to introduce human material to the animal, there is no reason to assume that the risks of human features developing will be any higher.

Animal welfare

The most obvious ethical objection to this means of producing organs is that (at least) one animal will be sacrificed for every human saved. This means that hundreds of thousands of animals will be killed each year in order to produce organs for humans if the technology is perfected. One possible response to this argument is that it seems strange to object to using pigs to save people's lives when it is generally regarded as acceptable to eat them. Eating meat is not necessary for survival, while working organs are: as such, it actually seems more reasonable for pigs to be used to grow life-saving organs than to provide the luxury of meat. However, any such argument is predicated on the assumption that it is ethical to eat animals in the first place. This assumption still persists all over the world, but may well be mistaken; given current prevalent attitudes, however, creating chimaera organs seems no worse than killing animals in order to eat them. It could also be objected that it is unfair to kill animals for their organs when many humans refuse to donate their organs after death. This is a valid point, but there would still be an organ scarcity problem even if all humans were willing to donate their organs after death, as most do not die in a way that makes organ donation possible. Furthermore, chimaera organs could ironically be a better medical solution than traditional transplants, due to the problem of immune rejection of organs from other humans.

Another potential objection is that pigs can be farmed in an ethical way, enjoying relatively happy lives before being used to produce meat, while chimaera animals would have relatively short lives in order to meet the supply for organs and would also have to be kept in very sterile conditions, with potential adverse effects on their well-being. There is also a possibility that genetically modified animals might suffer more than ‘normal’ animals, particularly if the developing human organ caused them discomfort. For example, the rat pancreas grown in the rat-mouse chimaeras maintained blood glucose levels at rat physiological levels, demonstrating that species-specific organ physiological parameters can dominate the entire organism. Nonetheless, given that society generally accords humans greater importance than animals, it appears that creating organs in this way would not threaten animal welfare in a new or unique way.

Finally, it should also be remembered that hundreds or perhaps thousands of animals will also need to be sacrificed as part of ongoing research into chimaera organs. While this is not very many in comparison with the number that will be sacrificed if the technique becomes widely used in humans, it should still be asked whether it is legitimate to use animals for this type of research. At first glance it might appear obvious that using them for research into a technology that could save dozens of human lives every day is more ethical than using them for research into a faint chance that a new drug might help a few dozen patients per year. However, there are two rebuttals to this point. First, the many uncertainties surrounding the creation of chimaera organs means that success is no more guaranteed than in any other animal research. Second, it could be argued that it is not in animals’ interests to contribute to the perfection of chimaera organ biotechnology, and that it is actually against the interests of future animals. In normal medical research on animals, no more animals are used for testing or killed once the drug reaches the stage of clinical trials. In the case of chimaera organs, however, the success of clinical trials would mean that thousands more animals will be killed every year as part of the organ production process. In terms of animal solidarity, chimaera organ research is therefore worse than most medical research involving animals. However, from the human perspective, this type of research meets the requirements of proportionality and subsidiarity much more easily than most animal research, though other potential sources of organs (see table 1) should also be pursued. Given the possibility that these other avenues might not be successful, it would be irresponsible to discontinue current funding for chimaera organ research. (If a stricter definition of subsidiarity were adopted, it might be concluded that chimaera organ research should only continue if all other options have already been tried. However, we regard it as reasonable to adopt a more lenient definition that favours simultaneous pursuit of different organ sources.)

Human dignity

Finally, is human dignity threatened simply by the very creation of human/animal chimaeras? As is often the case when the concept of dignity is put to use in bioethics, it depends very much on what is meant by human dignity: while some will argue that it is against human dignity to let people die when we could save them with chimaera organs, it has also been suggested that the creation of chimaeras could threaten human dignity by mixing our basic constituents with those of animals.21 Similar arguments have previously been found to be flawed,20 for a variety of reasons. Human dignity was raised as a concern in 2007 in response to the creation of human/rabbit chimaera embryos, even though any such embryos were to be destroyed within 14 days of creation and had only 0.04% animal DNA.22 It has been claimed that “to produce creatures that blur the boundaries between humans and animals could threaten to undermine the concept of human dignity since it is a dignity specifically reserved to humankind”.23 This argument appears to be camouflage for concerns about ‘playing God’ or the feelings of revulsion that the idea of chimaeras induces in many people. Just as revulsion does not constitute a sound reason for objecting to something, human dignity does not appear to be threatened merely by the act of creating human organs inside animals. Similarly, we cannot infer any ethical judgment from the fact that we would be ‘crossing species boundaries’; doing so might be unnatural, but so is much of human endeavour. It is important to make the distinction between human dignity arguments based on the mere fact of mixing between species, and dignity arguments based on the potentially unethical consequences of creating chimaeras. While an animal with human mental features might seem a threat to human dignity, the precautions taken to prevent human neuronal (or reproductive) development should minimise the risk of this happening. In the absence of any adverse consequences, objections based on human dignity are deprived of most of their force. As the Academy of Medical Sciences has stated:It has long been accepted that the dignity of man does not rule out many ways in which animal and human materials are combined….humans are not demeaned by the incorporation of parts of non-human animals (such as heart valves from pigs) through xenotransplantation, though it is possible to object to this practice on other grounds. Similarly, therefore, the creation by another form of xenotransplantation of animals which include significant human elements cannot be held to threaten human dignity just because it humanises the animals involved.21

Of course, anyone who did think that it violated human dignity to accept an organ that had been grown in an animal (or who had concerns about animal welfare) could simply refuse to accept one, although it may well be the case that weakly felt symbolic concerns about dignity might be abandoned if no other organ could be found. (This is not to suggest that everyone would abandon all ethical concerns if faced with death, but rather that many people's concerns about human dignity appear rather ephemeral, and that they might evaporate entirely or be refocused into concerns about the indignity of dying in the face of certain death.) Perhaps the most persuasive argument concerning human dignity is actually not that the proposed technology reduces us to mix our DNA with theirs, but that it is undignified for higher animals such as humans to instrumentalise and kill lesser animals in this way when there are other potential sources of organs. This is really an argument about animal welfare rephrased as one concerning human dignity. However, as already mentioned, all countries currently instrumentalise animals routinely, and using them to save lives may be ethically preferable to using them for non-essential purposes.