Ethically Advancing Pediatric Cardiac Xenotransplant.

This Viewpoint examines how pediatrics should prepare for the prospect of cardiac xenotransplant, including its ethical implications.

Are we ready for pig-to-human clinical xenotransplantation trials? / Estamos prontos para ensaios clínicos de xenotransplante porco-para-humanos? / ¿Estamos listos para ensayos clínicos de xenotrasplante del cerdo al humano?

Abstract: The invention and widely use of organ allotransplantation provides effective treatment of some originally fetal diseases such as liver/kidney failure and has saved million of lives around the globe. However, the scarcity of human organs has caused many patients, who could have been treated, to die while waiting for suitable organs around the world. Pig-to human xenotransplantation provides a potential solution to solve this tough problem. Pig organs have been considered as major sources of xenotransplantation because of the sufficient number of donors, the sizes of organs, and physiologically structural similarities. However, xenotransplantation also has some problems, such as the possibility of spreading animal diseases to human, the interspecies immunological barrier, organs of animal origin challenging human nature, and potential informed consent issues. This article will discuss these potential issues and to see whether it is the suitable time to conduct clinical xenotransplantation trials in humans.

Resumen: La invención y el amplio uso de trasplantes alógenos proporciona tratamiento efectivo de algunas enfermedades de origen fetal, como la insuficiencia renal y hepática, y ha salvado a millones de pacientes en el mundo. Sin embargo, la escasez de órganos humanos ha causado que muchos pacientes en el mundo, que podrían haber sido tratados, murieran por esperar un órgano adecuado. El xenotrasplante del cerdo al humano proporciona una solución potencial para resolver este difícil problema. Los órganos de cerdo han sido considerados como fuentes mayores para xenotrasplantes debido al suficiente número de donantes, el tamaño de los órganos y estructuras fisiológicas similares. No obstante, el xenotrasplante también tiene algunos problemas, como la posibilidad de expandir enfermedades animales a humanos, la barrera inmunológica entre especies, el desafío para la naturaleza humana de tener órganos de origen animal y problemas potenciales de consentimiento informado. Este artículo discute estos temas potenciales y plantea si estamos en un momento apropiado para realizar ensayos clínicos de xenotrasplantes en humanos.

Resumo: A invenção e amplo uso de alotransplante de órgãos propicia tratamento efetivo para algumas doenças originalmente fetais tais como falência hepática/renal e tem salvo milhões de vidas em todo o globo. Entretanto, a escassez de órgãos humanos tem causado a morte de muitos pacientes que poderiam ter sido tratados - aguardando por órgãos apropriados em todo o globo. Xenotransplante porco-para-humanos propicia uma solução potencial para resolver este difícil problema. Órgãos de porco tem sido considerados como as principais fontes de xenotransplante por causa do número suficiente de doadores, do tamanho dos órgãos e de similaridades estruturais fisiológicas. Entretanto, xenotransplante também tem alguns problemas, tais como a possibilidade de disseminar doenças animais aos humanos, a barreira imunológica entre espécies, órgão de origem animal desafiando a natureza humana e aspectos potenciais de consentimento informado. Esse artigo discutirá esses aspectos potenciais e verificará se é o momento adequado para conduzir ensaios clínicos de xenotransplante em humanos.

"You cannot stay in the laboratory forever"*: Taking pig kidney xenotransplantation from the laboratory to the clinic.

Progress in life-supporting kidney transplantation in the genetically-engineered pig-to-nonhuman primate model has been encouraging, with pig kidneys sometimes supporting life for > 1 year. What steps need to be taken by (i) the laboratory team, and (ii) the clinical team to prepare for the first clinical trial? The major topics include (i) what currently-available genetic modifications are optimal to reduce the possibility of graft rejection, (ii) what immunosuppressive therapeutic regimen is optimal, and (iii) what steps need to be taken to minimize the risk of transfer of an infectious microorganism with the graft. We suggest that patients who are unlikely to live long enough to receive a kidney from a deceased human donor would benefit from the opportunity of a period of dialysis-free support by a pig kidney, and the experience gained would enable xenotransplantation to progress much more rapidly than if we remain in the laboratory.

What does it take to consent to islet cell xenotransplantation?: Insights from an interview study with type 1 diabetes patients and review of the literature.

BACKGROUND: The transplantation of porcine islet cells provides a new potential therapy to treat patients with type 1 diabetes mellitus (T1DM). Compared to other biomedical technologies, xenotransplantation stands out in terms of its involvement of animals as graft sources, as well as the possible transmission of infectious diseases. As these aspects are especially relevant for potential xenotransplantation recipients, it is important to assess their opinion regarding this technology, in particular in terms of the requirements that should be met in the informed consent process for xenotransplantation. METHODS: We conducted qualitative interviews with seven T1DM patients to assess their information needs prior to xenotransplantation. Before the interview, the participants received a model informed consent form for a clinical trial with porcine islet cells transplantation. The interviews were transcribed and analysed using qualitative content analysis. RESULTS: In the interviews, we identified several requirements that are crucial for patients with T1DM in order to consider xenotransplantation as a potential treatment option: therapy-related requirements, professional care and supervision, successful behaviour and attitude management, improving quality of life, and managing control/self-determination challenges. Regarding the informed consent form, several of the participants' questions remained open and should be addressed in more detail. The interviewees stressed the importance of personal consultations. CONCLUSIONS: To become a sustainable therapeutic option, patients especially expected an improved diabetes control and a reduction of diabetes-related burdens. Health-related aspects prove to be pivotal for diabetic patients when considering porcine islet cell transplantation. The use of pigs as source for organ retrievals was not considered as problematic.

Ethical considerations in xenotransplantation: a review.

PURPOSE OF REVIEW: The purpose of this review is to present and analyse recent literature on the patterns, trends, and developments of ethical considerations concerning xenotransplantation by appraising normative aspects within a coherent framework. RECENT FINDINGS: Developments within xenotransplantation may soon allow for pig-to-human xenotransplantation to take place. Ethical analysis of xenotransplantation commonly follows an anthropocentric cost-benefit analysis, which may imprecisely measure costs. Xenotransplantation should not merely be approached from an anthropocentric perspective. Rather, the potential risks presented to human and nonhuman donors, recipients, and third parties should all be thoroughly considered. SUMMARY: The range of feasible alternatives to xenotransplantation to increase organ supply should be examined before resorting to xenotransplantation because of the moral distinction between imposing certain risks on others before, or after, alternative solutions have been exhausted.

'It's not worse than eating them': the limits of analogy in bioethics.

Bioethicists often defend novel practices by drawing analogies with practices that we are already familiar with and currently tolerate. If some novel practice is less bad than some widely-accepted practice, then (it is argued) we cannot rightly reject it. Using the bioethics literature on xenotransplantation and interspecies blastocyst complementation as a case study, I show how this style of argument can go awry. The key problem is that our moral intuitions about familiar practices can be distorted by their seeming normality. When considering the ethics of emerging technologies and novel practices, we should remain open to the possibility that our moral views about familiar practices are mistaken.

Leo Fabian: A Life of Accomplishment.

Leo Fabian played a role in many anesthesia firsts: the first halothane anesthetics in the United States, the first American electrical anesthetic, the first lung allotransplant, and the first heart xenotransplant. As was common for men of his generation, Fabian's first taste of medicine came during World War II, as a pharmacist's mate aboard the U.S.S. Bountiful. Afterward, he pursued his medical education before joining Dr. C. Ronald Stephen and the anesthesiology department at Duke. There he helped to create one of the first inhalers for halothane, the Fabian Newton Stephen (F-N-S) Fluothane Vaporizer. Fabian left Duke for the University of Mississippi Medical Center, where he consistently worked with the chair of surgery, Dr. James Hardy. Together they performed the first American electrical anesthetic, the first lung allotransplant, and the first heart xenotransplant. By the end of his time at Mississippi, Fabian and Hardy had several philosophical disagreements, and Fabian ultimately left for Washington University in St. Louis, where he rejoined Dr. Stephen. He served as Stephen's right-hand man and would oversee the department when Stephen was away. Fabian spent the final years of his career as chair of the department before his own health forced him to step down.

How the COVID-19 pandemic may impact public support for clinical xenotransplantation in the United States?

Many patients who would undergo organ transplantation cannot proceed due to the inability of human organ donation to satisfy medical needs. Xenotransplantation has the potential to offer unlimited availability of pig organs for transplantation, and pig-to-non-human primate models have demonstrated outcomes that may soon justify clinical trials. However, one of the unique ethical challenges faced by xenotransplantation is that the risk of introducing potential zoonotic disease into the community must be weighed along with the benefit to the patient. While most experts believe that zoonosis is manageable, apprehension over disease transmission from animal donors to human recipients remains a frequent concern of many who are undecided or opposed to clinical xenotransplantation. The COVID-19 pandemic represents a scenario (rapid worldwide spread of a highly contagious novel zoonotic disease with no natural defense in humans) that would seem to justify apprehension, especially in the United States, which has largely avoided previous pandemic outbreaks. However, there are many differences between zoonosis found in the wild or after xenotransplantation that favor the safety of the latter. Still, these differences, as well as the benefits of xenotransplantation, are not widely understood outside of the field. We must therefore ask what impact the COVID-19 pandemic will have on attitudes toward xenotransplantation.

Regulatory changes in China on xenotransplantation and related products.

BACKGROUND: Given the persistence and the worldwide shortage of organs from both the deceased and living donors for clinical transplantation, pig organs or tissues hold immense promises for the patients on the waiting list, and xenotransplantation is deemed as one of the solutions to the organ shortage crisis. Indeed, the emerging gene editing technologies, such as CRISPR/Cas9, have led to tremendous progress in the generation of genetically modified pigs to overcome many barriers associated. METHOD: We presented a description of the xenotransplantation regulations in China and the related products. RESULT: Several groups in China have successfully generated transgenic pigs with the elimination of immune rejection or coagulation-related genes, and both pre-clinical and clinical studies have been reported. However, the pre-clinical evaluation and clinical application of porcine xenotransplantation raises ethical and regulatory considerations. Herein, in this review, we will summarize and discuss the progress in xenotransplantation in China and xenotransplantation-related products from the regulatory perspective. CONCLUSION: There has been remarkable progress in both the genetically modified pigs and pre-clinical studies in China, and China will be the first country to successfully fulfill the xenotransplantation from pig organ to human in the near future.

Regulation of Clinical Xenotransplantation: A Reappraisal of the Legal, Ethical, and Social Aspects Involved.

Clinical trials of encapsulated pig islet transplantation are underway and are showing promising results. In addition, better immunosuppressant drug regimens and a wealth of new gene-edited pig varieties are raising new hopes in this field. Thus, consideration is also being given to the selection of patients for initial clinical trials of pig solid organ xenotransplantation. It seems likely that clinical trials of pig organ will be initiated within the next couple of years. For the moment, transplanting porcine islets to treat type 1 diabetes is generally viewed as the most likely to reach the clinical first. Further advances will hopefully make this approach a treatment choice for patients with this condition. Regulatory framework for this type of xenotransplantation is now available in several countries, and there is also a wider awareness of the importance of developing an internationally harmonized regulatory framework. For now, xenotransplantation is mainly conceived and regulated as a pharmaceutical product. The reframing of this emerging technology as cell therapy has redefined the normative landscape. Countries should be cautious about allowing xenotransplantation clinical trials to develop. But the original meaning of precaution, referred to safety measures in order to control risks of infection, is no longer seen as requiring restrictive limitations on fundamental rights. As with any new medicinal product, safety is certainly a crucial topic in research. Specific to xenotransplantation is the safety of porcine product. In this regard, regulatory frameworks should contain specific conditions about the safety of the source animals, of the xenotransplantation product, and of the manufacturing process. In turn, these frameworks should ensure that preclinical studies indicate safety and efficacy of the procedure and that risk management protocols are in place to identify, contain, and combat any outbreak of infection in a timely manner. The fragile balance between individual and collective rights and the tensions of globalization make necessary a coordinated international action to harmonize global practices in this field. Xenotransplantation clinical trials should be carried out in a context in which specific safety and ethical issues are addressed and in an environment in which specific practices that facilitate public engagement as a form of shared responsibility for regulatory decision-making are promoted as well.

Translational Research-For the Individual and the Community.

The potential for translational research to improve human health is unprecedented, as the integration of genetic health risks with other data influencing health provides substantial opportunities for improvement. However, how integrating these data sources in a fair, unbiased and appropriate way without reinforcing pre-existing assumptions requires thoughtful implementation. Furthermore, integration of new technologies requires assessment of needs and benefits for the individual balanced with community needs and goals. Thus, examination of values, goals and implicit assumptions through transparent, authentic engagement of individuals and communities is essential.

Bodies in Transition: Ethics in Xenotransplantation Research.

Xenotransplantation, or the grafting of organs from one species to another, may seem at first a far cry from brain death, but there is rising hope in some quarters of the biomedical community that such transplants may reduce, even obviate, the need to harvest human organs-and hence eliminate the primary reason for needing an unambiguous definition of brain death. As with all research on the frontiers of biomedicine, xenotransplantation raises its own ethical quandaries. One concern that has long occupied ethical thought is the degree to which advances in science and technology should control the boundaries between the human and the nonhuman. Might the dimming of a previously entrenched bright line between species entail negative consequences for concepts, such as human dignity and bodily integrity, that historically anchored the protection of both human and animal subjects in biomedical treatment and research? To date, ethical thinking about xenotransplantation, and about gene editing, has largely been left in the hands of scientists, subject only to loose supervision by institutional review boards and animal welfare committees whose remit may be too narrow to address age-old moral concerns.

200 Years After Frankenstein.

Mary Shelley's Frankenstein is 200 years old and remains relevant to 21st-century scientific experimentation. Molecular biologists today have become especially bold in their attempts to cure diseases while remaining mindful of the real dangers of their research. Scientists presumably share an abiding concern about producing uncontrollable mutations in people, animals, and the wider environment, yet a sense of urgency appears to inform the current scientific willingness to take risks, especially in the realm of embryology and germ-line modification. This willingness to go more boldly than before could be influenced by the unprecedented ability of such gene-cutting technologies as CRISPR to make immediate and lasting improvements to persons suffering from certain diseases and other physical malignancies, but also by an acculturated sense that such persons deserve to participate more fully in broader society.

Ethical issues surrounding the transplantation of organs from animals into humans.

In this paper, the authors provide an analysis of the ethical issues surrounding the transplantation of organs from animals into humans. The main objections to xenotransplantation relate to safety concerns for the recipient; public health concerns about new viruses spreading from animals to humans; the possibility of animals developing human features; concerns about human dignity; and the fact that animals must be sacrificed so humans can benefit from their organs. Despite these objections, the urgency of the organ shortage situation is such that xenotransplantation may be justified, if further advances make it a realistic possibility.

Les auteurs analysent les questions éthiques suscitées par la transplantation chez l'homme d'organes provenant d'animaux. Les principales objections contre la xénotransplantation se réfèrent aux risques pour la santé du receveur, aux problèmes de santé publique liés à une éventuelle propagation chez l'homme de virus émergents d'origine animale, au risque que des animaux acquièrent des caractéristiques humaines, au respect de la dignité humaine et à la nécessité de sacrifier des animaux pour que des êtres humains puissent bénéficier de leurs organes. Malgré ces objections, le déficit d'organes est tel que la xénotransplantation pourrait se justifier à condition que les avancées scientifiques en garantissent la faisabilité à l'avenir.

Los autores proponen un análisis de las cuestiones éticas que rodean el trasplante de órganos animales al ser humano. Las principales objeciones que suscita el xenotrasplante tienen que ver con: la preocupación por la seguridad del receptor; la problemática de salud pública ligada a la eventual propagación de nuevos virus que pasen de los animales al ser humano; la posibilidad de que los animales adquieran atributos humanos; consideraciones vinculadas a la dignidad humana; y el hecho de que haya que sacrificar a animales para que los humanos se beneficien de sus órganos. Pese a todas estas objeciones, la urgencia de la situación de penuria de órganos es de tal magnitud que los xenotrasplantes podrían estar justificados si se sigue progresando lo bastante como para hacer de ellos una perspectiva realista.