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Bioethics Forum Essay

Xenotransplantation: Three Areas of Concern

News of the first  transplant of a pig’s heart into a human was widely reported last week, raising hope that the procedure could one day help alleviate the shortage of organs. In decades of experimentation with xenotransplantation, the transplantation of organs from one species to another, no human recipient of a nonhuman organ has survived for more than a few months. Most have died within hours or days from  rejection, infection, or both. Like the recipient of the pig’s heart, many previous patients were dying and were not eligible for an organ transplant through conventional channels. But before we forge ahead with clinical trials of xenotransplantation we should be concerned about several issues: the potential to spread pathogens, exploitation of human research participants, and animal welfare.

Early research on xenotransplantation used organs from monkeys and chimpanzees, who are the closest phylogenetic and evolutionary relatives to humans. That research ended because of concerns about the transmission of pathogens, including retroviruses, some of which are readily transmitted from nonhuman primates to humans. The U.S. Food and Drug Administration  effectively banned the use of nonhuman primates for xenotransplantation in 1999, citing the unacceptably high risk of zoonotic infection. In recent years, with the availability of genetic technologies like CRISPR-Cas-9, scientists have sought to genetically modify pigs to grow human-compatible organs for transplant. The genetic modifications are intended to reduce the risk of rejection and to inactivate or eliminate pathogens harbored in pig cells. The ultimate goal of this research is to turn pigs into a ready source of organs for transplant, as part of the effort to address the chronic shortage of organs. As scientist Claus Hammer has described it, for xenotransplantation to succeed, “we need to ‘outwit’ the 180 million years of evolution.”

 We are in the third year of a global pandemic that has killed millions of people worldwide and sickened many millions more. SARS-CoV-2 is a zoonotic virus that has been identified in many wild, captive, and domestic animal species. The potential dangers of known and unknown pathogens unleashed through xenotransplantation are impossible to quantify or predict, but heightened concern is warranted.

Xenotransplantation remains experimental, and potential recipients of xenografts are research subjects whose consent and safety are governed by human subjects research regulations and guidance. Several regulatory and advisory organizations  have concluded that it is imperative for xenotransplant recipients to submit to extended, possibly lifelong surveillance for zoonotic infectious diseases. The U.S. Public Health Service calls for lifelong surveillance of recipients to monitor for infectious agents. The Nuffield Council on Bioethics in the U.K. notes that the xenotransplant recipient, their close contacts, family, and sexual partners, and the transplant and health care teams should all be monitored for unexplained illness. “Patients consenting to xenotransplantation should be informed that post-operative monitoring for infectious organisms is an integral part of the procedure, and that their consent to the operation includes consent to this monitoring,” Nuffield states.

Requiring lifelong surveillance and submission to monitoring as a condition of research participation in xenotransplantation trials is in tension with the right of research subjects to withdraw from research at any time, for any reason. This right is endorsed worldwide in ethical guidelines governing human subjects research and is a critical component of voluntary informed consent. The U.S. Common Rule states that research “participation is voluntary . . . and the subject may discontinue participation at any time without penalty or loss of benefits.” Requiring lifelong surveillance effectively denies research subjects their fundamental right to withdraw, and violates international norms and ethical guidance. Surveillance and notification of close contacts impinge on the right to privacy and confidentiality of patients and research subjects.

There are also novel ethical concerns about the use of pigs to grow organs. While pigs are farmed and killed in the millions for meat, the pigs used for xenotransplantation are categorically different animals, and their use in research is governed by different welfare considerations. These pigs are genetically modified and cloned, and must be bred and housed using infection-control measures like artificial insemination, embryo transfer, Caesarian births, and isolation in sterile environments without contact with other animals, preventing the expression of their natural behaviors. Their use would require frequent blood and tissue sampling, which in pigs requires restraint, including drug-induced restraint. If pigs are used for multiple tissue and organ transplants, they could be subjected to repeated surgeries, causing these highly intelligent and social animals pain and distress.  Additionally, although nonhuman primates have been ruled out as organ sources, they are still used in xenotransplantation research as experimental recipients of organs from pigs, raising similar welfare concerns. Using pigs and nonhuman primates for xenotransplantation research, or to grow organs, violates established best practices for animal care and welfare, which include providing ethologically appropriate environments that meet the animals’ behavioral and physiological needs.

The organ shortage is a formidable problem. More than 100,000 people in the U.S. are on waiting lists for organ and tissue transplants, and 17 people die each day while waiting. But using pigs to grow organs is only one of many possible solutions to the shortage. Access to basic health care and therapies to treat common diseases like hypertension, diabetes, and heart disease can prevent organ failure. Using expanded criteria organs, such as those from older donors and donors with chronic diseases, has already increased the supply of organs. Other promising solutions include the use of stem cells to grow human organs and possibly 3D bioprinting to repair organs. Low-tech social engineering, such as improving communication about organ donation, and implementing opt-out organ donor registration, should be used to encourage more people to become organ donors. At a time of growing public concern about animal welfare, a genuine commitment to reducing the numbers of animals killed for research and other purposes favors seeking out and developing alternatives. As the SARS-CoV-2 pandemic has demonstrated, the health and well-being of humans and animals are entangled. Zoonotic pandemics are a grave threat both to humanity and to other creatures, and a compelling reason to reevaluate the risks and reconsider xenotransplantation as a path forward.

L. Syd M Johnson, PhD, (@LSydMJohnson) is an associate professor at the Center for Bioethics and Humanities and a clinical ethics consultant at Upstate Medical University in Syracuse, N.Y.

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    L. Syd M. Johnson notes reflections in three lines of great importance. He mentions, regarding the intimate surveillance to which those undergoing xenotransplantation will be subjected, the violations of Informed Consent and Good Clinical Practices and it is the least that those of us in Research Ethics Committees could demand of respect. The experience of this pandemic has wreaked havoc on many families due to the loss of loved ones, but also due to economic losses and family breakups caused by long isolations, so taking new risks for another zoonosis is not something that many of us want.
    The border in this field is a very fine border that must keep the integrity of the subject safe. It would be worth asking if the person who receives a pig’s heart agrees to “give up” the rights to it in exchange for living a few more days. That I myself would respond to the question is idle, because only those who live those last moments over and over and over again while waiting for an organ can answer.
    The reflections help us, the Ethics Committees, to give a voice to those who do not have a voice: the research subjects.

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