The issue of xenotransplantation has raised serious interdisciplinary concerns. Many have called for a continued public debate on the issue of xenotransplantation, especially genetically modified pig kidneys for human transplants, that would examine all aspects of it including the crucial ethical and moral implications. These issues include the safety of the technology, animal welfare issues and the claim by some that genetic engineering is a technology that should not be advanced by humans. However, some have warned that the agenda of the debate, especially the moral debate, should not be wholly framed within the aspirations of the practitioners. All parties need to be consulted—clinicians, recipients and society as a whole. The surgeons involved are still talking in terms of how we should proceed rather than should we proceed. If this is going to be an open debate with all parties participating, then all options must be placed on the table, including the option that we should not proceed with xenotransplantations and in particular, genetically modified pig kidneys in humans. To determine if this procedure is ethical, the principles of respect for persons, beneficence, nonmaleficence and justice will be applied to this procedure and its consequences.
Respect for persons refers to the right of a person to exercise self-determination and to be treated with dignity and respect. Proponents argue that genetically modified pig kidneys have the potential to save hundreds of lives. We know that the current wait time to receive a human kidney from a deceased donor is approximately 10 years and that 240 people die each day on dialysis while waiting for a kidney transplant.[1] The two experiments at the University of Alabama and NYU Langone Health “suggest that major barriers to human xenotransplantation have been surmounted and identifies where new knowledge is needed to optimize xenotransplantation outcome in humans.”[2] Opponents argue that there is not enough information available for recipients to give informed consent. Safety concerns exist in regards to porcine endogenous retroviruses (PERVs) carried by pigs that could transfer to the recipient and be not only detrimental to the recipient but possibly become a public health crisis, immunosuppressants have serious side effects and genetic modifications pose serious concerns medically and ethically. Proponents argue that respect for persons is protected because any participant in this experimental surgery would give their informed consent and be made well aware of the animal trials and previous human trials that have preceded this surgery and the potential risks, benefits and alternatives. In addition, they would know that the surgery has met the conditions of being ethically justified research by the local Institutional Review Board (IRB). The problem is that in the United States and many European countries a new surgical technique requires no formal regulatory approach and is controlled primarily through surgeons’ self-regulation that is sometimes, but not always supplemented by local control over research including peer review and IRB approval of a formal protocol[3]. The conditions for approval by an IRB are: 1) a reasonable prospect that the research will generate the knowledge that is sought; 2) the necessity of using human subjects; 3) a favorable balance of potential benefits over risks to the subject; and 4) a fair selection of subjects.[4] Proponents argue that the duty of the IRB is to check that researchers have not overestimated the potential success and underestimated the possible risks. Their duty is also to ensure that the risk-benefit ratio of undergoing this surgery is reasonable. [5] Approval by the IRB would be an added assurance to potential recipients and to society as a whole.
To give valid informed consent to be a subject in an experimental surgery, two conditions must be met: the consent must be freely obtained from a competent person and the individual must be adequately informed regarding all aspects of the experimental surgery.[6] First, from the recipient’s perspective, the option open to patients with severe end stage renal disease (ESRD) is dialysis until a human kidney becomes available for transplant. “Dialysis is a form of renal replacement therapy. It’s the clinical process of replacing the filtration functions of the normal kidneys. In hemodialysis, this is done by using a machine to filter the circulating blood in the vessels through an artificial membrane. Metabolites and excess fluid are removed from the blood. The blood is filtered through diffusion across a semipermeable membrane. This works by microscopic openings in the filter and concentration gradient. Concentration gradient means that the concentration of molecules is lower in the dialysate, causing unwanted molecules from the blood to naturally move into the ‘less crowded’ solution. Which molecules are filtered out of the blood can be controlled by the contents of the dialysate solution. The membrane also filters molecules by size, keeping larger molecules like proteins in the blood. In hemodialysis, the blood vessel can be accessed several ways. In emergent or temporary dialysis (after trauma or acute illness) a dual lumen dialysis catheter is placed into a large vein above the heart. These catheters are easy to place and can be used immediately, but carry risk of infection and clotting. For chronic hemodialysis, an arteriovenous fistula or graft is created, connecting the vein and artery in the forearm, and the vein accessed by two needles. With a fistula, a surgical anastomosis, or connection, is created and must mature before use. In an arteriovenous graft, a synthetic material is implanted connecting the vein and artery. While it can be used immediately, the artificial graft carries risk for infection. The ideal approach depends on urgency and the quality of the patient’s vessels.”[7] Hemodialysis is done three times and week and usually takes four hours per day. It is relatively painless but there are side effects—low blood pressure, muscle cramps, anemia, hypertension, fluid overload. Patients can survive on dialysis for over 10 years but one’s quality of life is lessened. As stated above, 240 people died each day on dialysis while waiting for a kidney transplant.
To give informed consent, recipients would have to be made aware of the risks, benefits and alternatives available to them. They would need to understand and comprehend that the pig kidney has ten genetic modifications. Four genes were inactivated, including one that encodes a molecule that causes an aggressive human reaction response. Another gene is genetically tweaked to prevent any donated organs responding to human growth hormones and growing out of control. Another key alteration removes a sugary molecule, called alpha-GAL, which sticks to the surface of pig cells and acts like a gigantic flashing neon sign marking the tissue as absolutely alien. Two other neon signs will be genetically removed and six human ones added in, acting like a camouflage net over the pig cells to help hide them from the immune system. The resulting 10-gene pigs are then raised in sterile conditions so they are suitable for transplant.[8]
The problem is that besides the risk of rejection, which would mean removal of the kidney, the patient would also have to be on immunosuppressant drugs for the remainder of his or her life, which are expensive and have serious side-effects such as increased chances of serious infections.
This is still an experimental procedure with serious risks, but with additional research, genetically modified pig kidneys for humans has the potential to be lifesaving and to give individuals with ESRD a far better quality of life. Under these circumstances, it is questionable whether the recipient is really free to give consent for such a procedure. Research has shown that whenever a new form of surgery is proposed that patients tend to dwell more on the benefits than the risks. “If potential patients are desperate for a procedure, the question arises whether it is feasible for them to assess if possible improvements in quality of life outweigh the potential morbidity and mortality caused by long-term immunosuppression.”[9] It is very difficult to determine if informed consent can be freely obtained with the way the media has sensationalized this surgery and the hype by various surgeons about its potential benefits. The consent may appear to be free but unfortunately, it may be based upon unrealistic expectations. At the present time, what this procedure realistically offers these patients is the possibility of improvement in the quality of their life.
Second, for a patient to give informed consent, he or she must have the necessary information to make such a decision. The basic elements of informed consent are:
- A fair explanation of the procedures to be followed, including an identification of those which are experimental;
- A description of the attendant discomforts and risks;
- A description of the benefits to be expected;
- A disclosure of appropriate alternative procedures that would be advantageous for the subjects;
- An offer to answer any inquiries concerning the procedures;
- An instruction that the subject is free to discontinue participation in the project or activity at any time. [10]
In a specific sense, the surgeons who want to transplant genetically modified pig kidneys into humans have an ethical obligation to give an objective, non-biased assessment of all materially relevant information pertaining to the animal studies and the human trials so that the patient can give informed consent. In addition, the rates of rejection, the costs and side-effects of the immunosuppressant drugs, the psycho-social issues, and other risks must be clearly stated and explained to the patient. The surgeons are also responsible to verify, to the best of their ability, that the patient can comprehend and has comprehended the information and has not engaged in “selective hearing.” This means, surgeons should explain the risks, benefits and alternatives at a 5th grade level so that all patients can comprehend the information. Under the circumstances, it is not uncommon for patients to engage in “selective hearing,” that is, taking in all information about potential benefits and filtering out all information about potential risks. To overcome “selective hearing” the surgeon should invoke the “teach-back method,” which means the patient repeats back to the surgeon what he/she heard and understands. In addition to this, surgeons must be vigilant against their influence over subjects, who may unwarily treat the surgeon with the same deference as they treat their primary care physicians. Dr. Robert Levine, professor of Medicine at Yale University, describes the surgeon/researcher’s obligation as one of “forthright disclosure.” This includes preliminary evidence and data from animal studies and previous human clinical trials that indicate the risks and benefits as well as the safety and efficacy of these controlled studies. [11] Patients need to have information that a reasonably prudent person would require to make well-reasoned decisions that will protect their personal interest.
The problem is determining what sort of knowledge translates to what degree of risk to patients. This is a value judgment that must be made by the surgeons. The concern is that the judgment of some surgeons may be biased by considerations of career self-interest and even financial gains.[12] “The potential for coercion can be difficult for surgeons. On the one hand, most accept that the final choice for surgery should be left to the patient. On the other hand, surgeons want what they believe to be best for their patients. Therefore, there is ample room for unintentional coercion through selecting information for disclosure that overtly reinforces the surgeon’s beliefs.” [13] There is also the problem of forming an “innovative alliance.” Patients may encourage their surgeons to try any new and promising technique to improve their quality of life or prospects for survival and surgeons also may be eager to apply a promising new technique for the same reasons. It is the duty of the surgeons to decide whether responsible behavior lies in attempting an innovative technique or in concluding that the background research is not sufficient to warrant its use, even when the patient consents.[14] The surgeon has the responsibility to act in the best interest of the patient. The belief that this experimental surgical procedure will not cause too much harm to too many people or that society will benefit at the possible expense of particular individuals violates the duty of the surgeon/researcher to act in the best interest of the patient. To determine whether that duty has been breached, a surgeon/researcher’s actions should be measured against the accepted practice as set by professional norms. Those researchers whose treatments fall below the professional standards and cause harm to patients may be held civilly liable for that failure.[15] Various ways have been proposed that ensure individuals going into research protocols are giving informed consent, these include: written and oral forms of consent so that the patient has time to read and reflect on the risks and benefits; someone other than a member of the surgical team obtains the informed consent; obtaining second opinions from other knowledgeable physicians regarding the feasibility of such a procedure; and appointing an objective advocate who would accompany the patient during the decision-making process. These advocates would ensure that the patient is capable of understanding the information and comprehends all the information, that researchers do not overestimate potential benefits and underestimate potential risks, and that all viable options are given, even the option of no transplant. These are not only excellent ideas; they should be implemented with every research protocol.
The complexity of this experimental surgery and its multileveled physical, psychological and social dimensions, make informed consent very complex. Since this surgery has been performed on a limited basis, it would be hard for surgeons to evaluate the potential risks and then adequately inform the patient of them to satisfy informed consent. Therefore, information that is necessary for informed consent is limited at the present time. In fact, the obstacles to informed consent in this situation seem almost insurmountable. In addition to weighing the risks and benefits, we are also asking individuals considering a transplant from a genetically modified pig to weigh just as many psychologically demanding variables. These issues only highlight the complexity of a patient giving informed consent under the circumstances. However, if the previous mentioned safeguards are enacted, it may be possible for patients to give informed consent, but this must be done objectively, comprehensively and honestly by a team of medical profesisonals.
Beneficence involves the obligation to prevent and remove harm and to promote the good of the person by minimizing the possible harms or risks and maximizing the potential benefits. Beneficence includes nonmaleficence, which prohibits the infliction of harm, injury, or death upon others. In medical ethics this principle has been closely associated with the maxim Primum non nocere: “Above all do no harm.”
Proponents argue that xenotransplantation and in particular, transplant of a genetically modified pig kidney into a human has the potential to save thousands of lives. Proponents contend that the risks are present as they are with any form of transplantation, but that if a patient comprehends the risks, benefits and alternatives and consents freely and knowingly to the surgery, then that individual should be given the right to make that informed decision. To delay the inevitable when the knowledge, technology and skills are available and when patients believe this surgery is in their best interest, is not only standing in the way of scientific advancement but is failing to promote the good of the patient and the good of society as a whole.
Opponents argue that the safety concerns regarding xenotransplantation are a major factor. The most significant concern is the immunological rejection of the organ by humans. The human system will recognize the organ as foreign and correlatively reject it. To date the 10 genetic modifications have been successful, on a limited clinical trial basis of avoiding the hyper-acute rejection. The use of immune-system-suppressing drugs has also reduced the probability of rejection. The immunosuppressant drugs do have serious side-effects, but the patient would need to weigh the side-effects against the potential of a lifesaving transplant. The costs of the drugs must also be factored into the patients consent process.
Second, there are safety concern for endogenous retroviruses carried by pigs, which could be capable of making humans very ill. This is not only a recipient concern but also a public health concern. Porcine endogenous retroviruses (PERVs) could impact the common good of society. Proponents will argue that the pigs used in xenotransplantation are not raised under the traditional husbandry conditions. “Rather they are kept much in a manner of laboratory animals, under confined, sterile conditions that minimize the risk of pathogen proliferation and keep the animals sufficiently healthy to provide a (relatively) safe source for transplantation. Although such conditions are far better than agricultural conditions in terms of animal health, they are equally deficient in accommodating the animal’s biological and psychological natures.”[16] Most ethicists would argue that the good of humanity would take priority in this regard. Another ethical issue concerns the limited privacy of recipients of a genetically modified pig kidney. These patients would need to be monitored for pathogens dangerous to them and others for extended lengths of time, which in turn would impact on the privacy of the patient but also the patients’ family, friends, work associates and others who are in contact with the patient. Due to the experimental nature of these transplants, it would be difficult to protect the anonymity and confidentiality of the recipient and their respective families from the public and the press. These patients may be looked upon as “freaks of nature.”[17] Critics fear the large amount of publicity will place unrealistic expectations on the recipient thus creating additional psychological stress and pressure. This could result in discrimination, alienation and exploitation of the patient and his/her family. To imagine or even calculate the psychological impact on the recipient and his or her family seems almost impossible.
The final issue regarding the risk/benefit ration has to do with the genetic modification of the pigs with human stem cells. To date the process seems very regulated and controlled but some critics raise the issue of the human stem cells migrating to the brain of the pig and creating medical and ethical concerns. This is an issue that has been advanced in regards to all genetic engineering in regard to xenotransplantation. This is a valid concern, but it is not enough of a concern to limit all genetic engineering technology. Researchers are also moral agents and we must respect their integrity in regards to following proper human research protocols. There are also many safeguards in place to verify this integrity.
No one will dispute that balancing the benefits and risks is difficult. Some will say that the value of life will take precedence over potential risks. After reviewing the facts concerning the state of our knowledge regarding xenotransplantation, the effects of immunosuppressant drugs and the inevitable psychological impact on the recipient and the recipient’s family, it seems reasonable to argue that the transplant of a genetically modified pig kidney into a human person could maximize the benefits and minimize the risks incurred by these patients. This is still an experimental surgery and more research in this area will need to be done. Unless more research is done, we will never know conclusively if the benefits outweigh the burdens. Arguably, this form of xenotransplantation has the potential to not only pass the test of beneficence, but also pass the test of nonmaleficence.
Finally, justice recognizes that each person should be treated fairly and equitably, and be given his or her due. The principle of justice can be applied to this situation in two ways. First, questions of justice have been raised about whether those patients who are desperate for kidney transplants might be classified as vulnerable individuals and whether this type of experimental surgery is a form of exploitation. No one seems to dispute that surgeons have the skills and techniques needed to perform this experimental xenotransplantation. However, there also seems to be a competition present among the various transplant teams examining this form of xenotransplantation. This debate cannot and must not be framed within the aspirations of the surgeons. There must be equality between the surgeons and the possible recipients. To allow these charismatic surgeons to present this form of transplantation in the media in such a way that seems to trivialize the side-effects and downplays the possibility of rejection and even death, is to exploit these recipients and use them as a means to an end. At the present time the debate among the transplant surgeons is on how they should proceed. Most transplant surgeons see no need for a delay in increasing the surgery because there is nothing to be learned during this time of delay. With this attitude, how objective and unbiased will the information about the surgery and its possible benefits and risks be that will be disclosed to potential recipients? How will surgeons know when the potential vulnerability of some patients is unduly influencing their willingness to consent? These transplant surgeons have suggested ways they believe will ensure informed consent however, since many of these potential recipients have no other viable options, one could say it is unjust to place these vulnerable individuals in this position now. However, if the safeguards to informed consent are enacted, and recipients clearly comprehend the benefits and risks of the xenotransplantation, then it would be just to allow these individuals to become involved in further research protocols.
Second, the issue of justice pertains to genetically modified pig transplants into humans specifically in regards to distributive justice, which concerns the fair and equitable allocation of medical resources. The main issue here is research priorities. Should funds be used to support xenotransplantation surgery now when the potential risks seem unreasonable and even deadly? The amount of money spent on these surgeries could certainly be invested in new ways to tolerate immunosuppressant drugs and primate experimentation to lessen the rejection rates. This would help to minimize the risks and maximize the benefits not only for recipients of xenotransplantation but for all transplant patients. Also, immunosuppressant drugs cost tens of thousands of dollars a year. Will this not limit the individuals who would qualify for this surgery? If so, this now becomes a social justice issue, because those who would have access to this technique would logically be those who are privileged. The poor, the uninsured, the underinsured, and many middle-class individuals would never be viable candidates for this surgery, because they could not afford the cost of a life-time supply of immunosuppressant drugs. As a matter of social justice, who this surgery would benefit and whether it is a fair and equitable allocation of medical resources is an important ethical issue. Medical professionals have an ethical obligation to use available resources fairly and to distribute them equitably.
In conclusion, transplanting genetically modified pig kidneys into humans could be considered ethically and morally acceptable under certain circumstances. If there is a standardization of outcomes and comprehensive inclusion/exclusion criteria for xenotransplantation and guidelines and safeguards for informed consent, then and only then would this surgery be ethically permissible. To make xenotransplantation a reality, physicians have an ethical obligation to perfect the safety and efficacy of this technique. This will entail additional research to overcome the unknow long-term prospects.
[1] Porrett et al. 2022.
[2] Porrett et al. 2022.
[3]Siegler M: Ethical Issues In Innovative Surgery: Should We Attempt A Cadaveric Hand Transplantation In A Human Subject? Transplantation Proceedings, 1998; 30: 2279–82
[4] Faden R, Beauchamp T: A History And Theory Of Informed Consent (New York): Oxford University Press; 1986, at 287–94
[5] Siegler M: Ethical Issues In Innovative Surgery: Should We Attempt A Cadaveric Hand Transplantation In A Human Subject? Transplantation Proceedings, 1998; 30: 2279–82
[6] Appelbaum PS, Loiz CW, Meisel A: Informed Consent: Legal
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[7] Study.com. “Hemodialysis: Indications and Patient Management,” 2022. https://study.com/academy/lesson/hemodialysis-indications-patient-management.html?src=ppc_adwords_nonbrand&rcntxt=aws&crt=519972749261&…
[8] Gallagher, James. “Xenotransplantation: Are Pigs the Future of Organ Transplants?” BBC BBC, 3/14/2022. https://www.bbc.com/news/health-60708120
[9] Jones J: Concerns About Human Hand Transplantation In The 21st Century. The Journal of Hand Surgery, 2002; 27A: 771–87
[10] Department of Health, Education and Welfare: On the Protection of Human Subjects: U.S. Department of Health, Education and Welfare’s Institutional Guide. in Source Book in Bioethics, eds. Jonsen A, Veatch R and Walters L (Washington, D.C.): Georgetown University Press; 1998; 16–21, at 19–20
[11] Levine RJ: The Use of Placebos in Randomized Clinical Trials. IRB: A Review of Human Subjects Research, 1985; 7: 1–4
[12] Schafer A: The Randomized Clinical Trial: For Whose Benefit? IRB: A Review of Human Subject, Research, 1985; 7: 4–6
[13] Working Party Report-The Royal College of Surgeons of England Face Transplantation. 2003; 1–24
[14] Siegler M: Ethical Issues In Innovative Surgery: Should We Attempt A Cadaveric Hand Transplantation In A Human Subject? Transplantation Proceedings, 1998; 30: 2279–82
[15] Freedman B, Glass KC, Weijer C: Placebo Orthodoxy in Clinical Research II: Ethical, Legal and Regulatory Myth. Journal of Law, Medicine and Ethics, 1996; 24: 252–59
[16] Rollin, Bernard. “Ethical and Societal Issues Occasioned by Xenotransplantation,” Animals10 (9): 2020:1695. DOI: 10.3390/ani10091695
[17] Rollin, Bernard. “Ethical and Societal Issues Occasioned by Xenotransplantation,” Animals10 (9): 2020:1695. DOI: 10.3390/ani10091695