Xenotransplantation: A Good Human Use or Animal Abuse?
As medical technology improves, humans are living progressively longer lives. While this speaks well to our medical prowess, it also creates some challenges, one of which is that our organs begin to fail us. According to the Canadian Institute for Health Information (2013) there were 3,525 patients waiting for an organ transplant in 2012, 163 of who died while on that list. Unfortunately, the supply of human organ donations for allotropic transplants is not able to keep up as the demand becomes increasingly larger. It has become evident in recent years that we need another solution to fill the growing organ gap. One proposed alternative has been xenotransplantation. For the purposes of this paper, xenotransplantation will mostly refer to whole organ transplants, but in reality it can be the exchange of any living cells, tissues or organs between different species. While this technology may have the ability to save thousands of lives worldwide, it is not without ethical dilemmas from both a human and non-human perspective.
Regulations
In Canada, xenotransplantation is currently legally permissible, but needs to be preceded by a clinical trial authorized by Health Canada (Health Canada, 2010; Laderoute, 2001). To date, no applications have been received or approved in Canada, and thus no actual procedures have taken place (Health Canada, 2010).
In Europe and the United States, genetically modified (GM) animals have been approved for pharmaceutical use (Frewer, 2013). The UK is currently accepting applications for clinical trials, though none have been approved (Health Canada, 2010). Other European countries such as Spain, Belgium and Germany have ongoing or planned trials (Health Canada, 2010). In the United States, the Food and Drug Administration (FDA) has approved some clinical trials of xenotransplantation, though they are in very early stages (Health Canada, 2010).
In medicine today, animal cells and tissues are already helping to address health problems such as diabetes, Parkinson’s disease and various other neurological disorders (Einsiedel & Ross, 2002; Nuffield Report, 1996; Samstein & Platt, 2001). Pig heart valves are commonly used as replacements in human hearts, however Health Canada (2010) does not classify this treatment as xenotransplantation because the tissue has been chemically treated and is no longer functional living tissue.
Biological Knowledge
In terms of what donor animal to use, only a few options were ever in serious consideration. Perhaps the most logical choice would be non-human primates. Indeed, some of the earliest attempts at xenotransplantation used non-human primate organs and fluids (Deschamp et al., 2005). There were several reasons for this initial choice, one being their biological similarity to humans. Primate tissues were predicted to be the least likely to be rejected by the human immune system. However, precisely because they are so closely related to humans, primates are also the most likely to harbour pathogens that could potentially be harmful to us (Daar & Phil, 1997).
The close relationship primates have with humans also raises ethical concerns. For example, how should we consider non-human primates’ rights? One could make the argument that some primate species possess more rationality than certain humans (such as children and those who are mentally impaired). Should they be given the same right to consent that human donors have? One last point against the use of primates is their conservation status. As all great apes are listed as at least endangered by the IUCN (2013), their use in any scientific manner is highly controversial, not to mention illegal in many countries.
Due to the numerous health and ethical issues with using primates as donors, the primary focus for xenotransplantation has turned to pigs. Pigs share many anatomical and physiological similarities with humans, and importantly have similar sized organs (Klymiuk et al., 2010). However, we are different enough that over the course of our long history with pigs we have not acquired many serious infections (one notable exception being swine flu) (Daar & Phil, 1997). Pigs are also much less expensive to acquire and rear than primates, they have a relatively large litter size, and carry a lower risk of zoonotic infection (Hansen et al., 2004; Health Canada, 2010).
Donor Animal Integrity
The biggest problem facing xenotransplantation is the same one we have with human-to-human transplants – rejection (Einsiedel & Ross, 2002; Klymiuk et al., 2010). In order to overcome this risk, pig DNA is being altered to include human elements (Dahl et al., 2003). These changes are being made to ensure that the transplanted organs are more likely to be accepted by the human recipient. The genomes of source animals now carry the genes necessary to express human complement regulatory factors (CRF) on their tissues (Hansen et al., 2004). After the transplant, the human immune system recognizes these CRFs as being “human” and doesn’t attack the animal tissue. It is important that the source animal still expresses its own species specific CRFs in addition to the human ones so that they don’t reject their own organs (Hansen et al., 2004).
Is this genetic engineering a violation of the animal’s telos? Bernard Rollins advocates for an animal’s right to live as nature dictates, but by changing a pig’s genetic structure, are we changing what it means to be a “pig”? Some may argue that the few genes it requires to achieve immunosuppression won’t be significant enough to impact the make-up of a pig. But at what point do we stop?
Donor Animal Welfare & Housing
There are already strict regimes in place for pig production to limit the potential for pathogen transfer between handlers and animals (Hansen et al. 2004). These include handler hygiene, facility maintenance and porcine housing. In order to use pigs for medical purposes, even more drastic measures would need to be taken to ensure human safety.
It is likely that the pigs intended for xenotransplantation would need to be reared in isolation to limit the spread of disease between individuals (Bach & Ivinson, 2001). Not only this, but piglets may need to be delivered via caesarean section directly into a sterilized incubator (Steering Committee on Bioethics, 2003). Pigs are naturally social animals and confining them in such a way would be unnatural. Ruis et al. (2003) found that gilts raised in social isolation showed long term stress responses to being housed in such a way. Pigs are also natural rooters and foragers, but to prevent the transmission of bacterial infection they likely won’t have access to any soil in which to express these behaviours.
The Canadian Council on Animal Care (CCAC) (1997) specifically outlines in their guidelines on animal use “if animals must be used, they must be maintained in a manner that provides for the physical comfort and socio-behavioral well-being.” It would appear that socially isolating an animal, especially one with a complex social structure like a pig, violates the CCAC’s guidelines. As such it is questionable whether this practice should be accepted in Canada for xenotransplantation.
The United States takes a different approach. The Food and Drug Administration has put forward some extreme recommendations for source animal housing. First, the FDA (2003) specifically recommends against using free-range animals for xenotransplantation, stating that these animals have a higher likelihood of harbouring harmful pathogens due to exposure to other animals and uncontrolled environmental factors. While this is certainly a valid risk, steps should be taken towards ensuring that the donor animals are being raised in a safe environment, rather than isolating them from the world. Second, the FDA (2003) advises screening donor animals’ feces for any pathogens, including normal flora, which may be harmful to an immunosuppressed individual, and avoiding the use of these animals. This test may result in a lot of unnecessary animal rejections and subsequent waste, as normal bacteria are deemed “dangerous”. Lastly, the FDA (2003) recommends quarantining source animals for a minimum of three weeks prior to tissue harvesting.
While considering these recommendations, it must be kept in mind that the FDA is primarily concerned with human health and safety. They are not an animal welfare and ethics body like the CCAC and their stance on animal housing reflects this. While the FDA (2003) recommends housing animals meant for xenotransplantation in facilities operated in accordance with the National Research Council’s Guide for the Care and Use of Laboratory Animals and accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International, I wonder if their strict regulations would meet the criteria of an overseeing animal ethics body.
Despite the harshness of their housing situation, animals raised as organ sources may receive a higher standard of medical care due to their economic value. But if this care entails completely changing their natural way of life, one must question the appropriateness of such a decision. A utilitarian may argue that the animal will be in peak health, and its growth will result in great happiness for a human, thus justifying such a way of life. However, someone arguing from Bernard Rollin’s “animal nature” point of view would likely decide that such a tremendous deviation from a pig’s nature is not acceptable, no matter the potential benefits.
There is already much controversy over the use of gestation crates in pig production. The measures put in place to ensure medical practices can safely occur may be too extreme for the public to accept. But at what point does human life outweigh pig welfare? Is there a case in which the possible benefit to a human is more important than the negative impact on a pig?
Risks to Donor Animal Health
As described above, future donor animals will need to have their genes modified in an attempt to prevent activation of the human immune system. Specifically, there is a marker called the alpha-gal epitope found on the surface of all proteins. Rejection of transplanted organs is thought to be at least partially due to natural human antibodies binding to porcine alpha-gal antigens on the donor tissue and activating the immune system. Therefore it becomes necessary to genetically alter the donor alpha-gal antigens so that the human recipients antibodies will recognize them as their own.
One problem with this alteration is that it appears as though alpha-gal antibodies are capable of binding to bacteria expressing the alpha-gal epitope. This protects the bacteria from the immune system, preventing them from being lysed (Hansen et al., 2004). As a result, pigs with circulating alpha-gal antibodies may be more susceptible to infections caused by bacteria such as Escherichia coli. If in fact the alpha-gal antibodies can protect Enterobacteriaceae species such as E. coli, this would be a major health and welfare concern as blood poisoning caused by these bacteria is one of the most common causes of death in pig herds (Hansen et al., 2004).
Another potential porcine health issue is related to a human health problem. Porcine endogenous retrovirus (PERV) is of concern because it may be transmitted from the host pigs to humans via xenotransplantation. However there is also the possibility that these viruses could not affect humans at all, but mutate in their human host and be transmitted back to the pig population. The new mutation could turn a virus that was previously not harmful to pigs into a catastrophic disease (Hansen et al., 2004).
It is possible to deal with issues regarding animal health in the production phase, and management here could occur in one of two ways (Hansen et al. 2004). The first solution is to reduce possible risk factors within the current system framework. This may involve practices such as decreasing stocking density and reducing post-weaning stress. Such changes would help decrease the risk of disease transmission without severely impacting pig welfare. Alternatively, the donor pigs could to be bred in isolation away from human handlers, other pigs and the external environment. As discussed above, this route would likely have a large negative welfare effect on the pig. It would also be much more time consuming and costly on behalf of the producer. However, isolation will likely be more effective in limiting disease spread.
Risks to Human Health
The potential risks to human health are the main reasons why so many aspects of the donor animal’s livelihood are being called into question. The first risk is of course transplant rejection. This can cause the recipient’s immune system to go into overdrive, severely taxing their body and possibly resulting in death. To prevent this outcome, the porcine genome is being altered as discussed above.
The next concern is the risk of xenozoonosis, or disease that can be passed between animals and humans (Einsiedel & Ross, 2002). HIV, ebola, west-nile, H1N1; each of these viruses have had significant impacts on society and have originated from non-human animal sources. These viruses may not manifest themselves in their natural hosts, but have been shown to be capable of crossing the species boundary and infecting humans. As a result society has become very wary of animal born pathogens. Specifically regarding xenotransplantation, porcine endogenous retrovirus (PERV) is currently the biggest concern (Bach & Ivinson, 2001; Hansen et al., 2004; Klymiuk et al., 2010; Scobie et al., 2013). Retroviruses, like HIV and PERV, are potentially capable of infecting a host and inserting itself into the host genome and causing huge health problems. It has been found that PERVs can infect immunosuppressed mice (Health Canada, 2001); however, there is no evidence that a human xenograft recipient has ever been infected (Hammer et al. 1998; Health Canada 2001; Skyes et al. 2003). Paradis et al. (1991) found that in the follow-up of 160 patients 12 years after their xenotransplantation, there was no evidence of a PERV infection in any of them. In fact, thus far in xenotransplantation experimentation there has been no evidence of PERV transmission, or of PERV antibodies in patients receiving xenografts (Scobie et al., 2013).
Other types of disease transfer such as bacterial and viral infections are also possible. Examples of pathogens carried by pigs include Salmonella species of bacteria and influenza viruses (Hansen et al., 2004). Especially in countries where pig production is a major part of the agriculture industry it may be very difficult, if not impossible, to be completely rid of any kind of porcine infections. Agriculturalists have lots of contact with pigs and pig products so it is still possible for diseases to be exchanged between species, despite stringent regulations on safe work procedures. The transfer of actual living tissue from pigs to humans will only exacerbate this issue if appropriate production and maintenance procedures are not carefully planned and implemented
Ethical Arguments
One may argue that because raising pigs for meat is already an acceptable practice, their use for lifesaving medical procedures should also be acceptable in today’s society. In fact, xenotransplantation should be even more widely practiced because it has the potential direct effect of saving a human life. However this argument does not take into consideration the implications for animal welfare and health. For instance, is transgenesis an acceptable practice to undertake in order increase human happiness? The creation of GM products such as corn and tomatoes is already coming under fire. The EnviroPig project was scrapped because people weren’t comfortable eating a GM animal. Will society be more open to genetic modification if it can save a human life? Or is xenotransplantation research all a waste of time and resources?
There are also questions about whether or not introducing new material into a genome violates an animal’s integrity or nature. Likely the changes that are necessary for xenotransplantation will not affect a pig’s physical appearance or characteristics, but their fundamental makeup will have been altered. The Nuffield Report (1995) argues that for successful xenotransplantation no more than one or two human genes need be inserted into the pig genome, itself consisting of 50,000-100,000 genes. As this is proportionally a minor change (0.001-0.004% of the genome) they don’t consider the pig to be any part human. However, not everyone is going to agree with this position, and many opponents of GM products consider any change to be substantial and unacceptable. They argue that there is no way of knowing how genetic modification will affect society in the future, and therefore we should not be doing it. Furthermore, if an animal’s genome has been changed to include human DNA, can it acquire enough that it ought to have human rights; for example the right to consent?
In addition to the fundamental problems with transgenesis, there are also logistical issues. For instance, t here is no guarantee that every piglet born in a litter will have the proper transgenic genes required for xenotransplantation. In these cases, leftover animals will be surplus and unsuitable for meat, release into the environment, or as organ sources (Steering Committee on Bioethics, 2003). They will have to be euthanized and essentially wasted. Such a practice would go in direct conflict with the CCAC who advocates for the three Rs in science: replace, reduce, and refine. Having to euthanize surplus animals is certainly not reducing the number of animals used in research.
We also need to consider the potential repercussions to humans in the process using transgenic pigs. Of course the issues brought up in Risks to Human Health are important, but as are human rights to privacy and consent. Because of the unknown potential for disease transmission, patients may need to be monitored for years following a xenotransplantation (Laderoute, 2001). They will need to be continually screened for potential pathogens, and will likely have their freedom reduced. As the xenotransplant patient could be harbouring some unknown disease, they would need to stay away from immunosuppressed people to avoid infecting them with potentially fatal diseases. The patient would also have to avoid areas of pig production to prevent the possible transfer of disease back to the source animal.
It will likely be many years before a xenotransplantation clinical study is approved in Canada, if ever. There are many ethical and welfare concerns to address before then, only some of which have been discussed here. Ultimately it needs to be decided how much of an animal’s nature we are willing to put at risk in order to elongate human life.
References
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