Human–animal chimeras: ethical issues about farming chimeric animals bearing human organs

Bourret et al. Stem Cell Research & Therapy (2016) 7:87 DOI 10.1186/s13287-016-0345-9 REVIEW Open Access Human–animal chimeras: ethical issues about farming chimeric animals bearing human organs Rodolphe Bourret1, Eric Martinez1, François Vialla2, Chloé Giquel1, Aurélie Thonnat-Marin1 and John De Vos3,4,5* Abstract Recent advances in stem cells and gene engineering have paved the way for the generation of interspecies chimeras, such as animals bearing an organ from another species. The production of a rat pancreas by a mouse has demonstrated the feasibility of this approach. The next step will be the generation of larger chimeric animals, such as pigs bearing human organs. Because of the dramatic organ shortage for transplantation, the medical needs for such a transgressive practice are indisputable. However, there are serious technical barriers and complex ethical issues that must be discussed and solved before producing human organs in animals. The main ethical issues are the risks of consciousness and of human features in the chimeric animal due to a too high contribution of human cells to the brain, in the first case, or for instance to limbs, in the second. Another critical point concerns the production of human gametes by such chimeric animals. These worst-case scenarios are obviously unacceptable and must be strictly monitored by careful risk assessment, and, if necessary, technically prevented. The public must be associated with this ethical debate. Scientists and physicians have a critical role in explaining the medical needs, the advantages and limits of this potential medical procedure, and the ethical boundaries that must not be trespassed. If these prerequisites are met, acceptance of such a new, borderline medical procedure may prevail, as happened before for in-vitro fertilization or preimplantation genetic diagnosis. Keywords: Human organs, Animals, Chimera, Interspecies chimera, Animals Containing Human Material, Induced pluripotent stem cells Background The idea of chimeras can be traced back to Antiquity. In Greek mythology the Minotaur had a man’s body and a bull’s head, and Pan was half man, half goat. Similarly, many Egyptian gods had a human body and a beast head, such as Sobek, Anubis, and Horus. The concept of “chimera” has gone through a semantic shift since Antiquity. Originally, “Chimera” was a proper noun designating a fabulous creature, whereas in modern medicine “chimera” describes a living organism that contains cells or tissues with different genotypes. Nevertheless, there are variations to the exact meaning of this word, depending on the field. In embryology, “chimera” refers to a combination of cells from different individuals. * Correspondence: 3 INSERM, U1183, Montpellier F34000, France 4 Université de Montpellier, UFR de Médecine, Montpellier F34000, France Full list of author information is available at the end of the article In molecular genetics, “chimera” describes the combination of two DNA molecules from different individuals, or from different chromosomes of the same individual. Conversely, in genetics, “chimera” refers to interspecies hybrids, such as the mule (the cross of a female horse with a male donkey) [1]. “Chimera” may even refer to the grafting in a postimplantation embryo of cells or tissues from another individual or species, such as the injection of hematopoietic stem cells intraperitoneally into a sheep fetus to produce a chimeric sheep that expresses human myeloid and lymphoid lineages [2]. In the rest of this article, “chimera” will refer to the meaning used in embryology. One of the first embryological chimeras created by scientists was the result of landmark experiments carried out by Hans Spemann and Hilde Mangold, who grafted part of one amphibian (Triturus) embryo into another with a different degree of pigmentation [3]. Later, Nicole Le Douarin et al. [3] used chimeric embryos from © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Bourret et al. Stem Cell Research & Therapy (2016) 7:87 chicken and quails for cell lineage tracking analyses during early vertebrate development. Alongside these manmade chimeras, natural chimeras have also been described. For instance, mothers might retain some of their fetus cells after pregnancy, a phenomenon called fetal microchimerism [4]. Recent technological progress (described in the following) accomplished in the field of chimera research could now allow the production of human organs in animals and thus the generation of human–animal chimeras. The medical needs are undeniable, particularly for organ transplantation, due to the severe organ shortage [5]. Nevertheless, such a perspective raises major legal and ethical questions. This review will describe briefly the technology that allows the creation of chimeric animals bearing human organs. The review will then discuss the ethical issues raised by this possibility. Chimeric animals bearing human organs Pluripotent cells The idea of producing human organs in animals originates from the discovery of pluripotent stem cells (PSC). Such cells can differentiate into any cell types of the organism, for instance skin, liver, or heart cells. Pluripotency is a key property of very specific human embryonic cells found in the inner cell mass (ICM) of the early embryo and that can be derived in vitro into lines of embryonic stem cells (ESC) [6, 7]. As human ESC retain the pluripotency property of ICM cells, they are particularly interesting for studying human embryo development in vitro and for regenerative medicine. Nevertheless, the origin of human ESC has raised important ethical questions because their production involves the destruction of human embryos [8]. Another source of PSC are induced pluripotent stem cells (iPSC) that result from reprogramming differentiated cells into pluripotent cells by transitionally forcing the expression of four transcription factors [9, 10]. These iPSC have the same properties as ESC. The possibility to produce pluripotent cells from adult cells and not from ICM cells has many medical and scientific applications. For example, it would be possible to produce autologous medicinal cells for regenerative medicine, or to derive iPSC from patients with a genetic disease to model the disease in Petri dishes. In 2012 Shinya Yamanaka, who invented induced pluripotent stem technology, was awarded the Nobel Prize in Medicine for this discove (...truncated)