Human-animal Chimeras Research Articles

Transplantation of Human Brain Organoids: Revisiting the Science and Ethics of Brain Chimeras.

Recent demonstrations of human brain organoid transplantation in rodents have accentuated ethical concerns associated with these entities, especially as they relate to potential "humanization" of host animals. Consideration of established scientific principles can help define the realistic range of expected outcomes in such transplantation studies. This practical approach suggests that augmentation of discrete brain functions in transplant hosts is a more relevant ethical question in the near term than the possibility of "conscious" chimeric animals. We hope that this framework contributes to a balanced approach for proceeding with studies involving brain organoid transplantation and other forms of human-animal brain chimeras.

The Moral Status of Human-Animal Chimeras with Human Brain Cells.

While there is not unanimity (across time or cultures), almost all who read this commentary will think that both they and a toddler have a moral status higher than that of a rat. For instance, they will think that a third party who has to choose whom to save from death should choose them over the rat, and the toddler over the rat. But what is it about humans that gives us this greater moral status? This question is particularly pressing when considering that scientists have begun creating human-animal chimeras with brains composed partly or wholly of human cells. In "Human-Animal Chimeras: The Moral Insignificance of Uniquely Human Capacities," Julian Koplin focuses on the moral implications of such experiments and those that use (or plan to use) these chimeras to study diseases and treatments. How should we understand the concerns about moral status that have been raised about such chimeras? In this commentary, I interpret these concerns differently from Koplin and respond to his suggestion that the greater one's ability to draw value from certain kinds of conscious experiences, the greater one's moral status.

Human-Animal Chimeras: The Moral Insignificance of Uniquely Human Capacities.

Human-animal chimeras-creatures composed of a mix of animal and human cells-have come to play an important role in biomedical research, and they raise ethical questions. This article focuses on one particularly difficult set of questions-those related to the moral status of human-animal chimeras with brains that are partly or wholly composed of human cells. Given the uncertain effects of human-animal chimera research on chimeric animals' cognition, it would be prudent to ensure we do not overlook or underestimate their moral status. However, to assess moral status, we first need to determine what kinds of capacities are morally relevant. The standard view holds that it matters, morally, if chimeric animals develop uniquely human cognitive capacities. I argue that this view is mistaken, highlighting three problems with it: that we can think of examples of uniquely human cognitive capacities that are not morally significant, that we can think of examples of morally significant cognitive capacities that are not uniquely human, and that evidence that some cognitive capacity is shared with nonhuman animals does not undermine claims that this capacity is morally significant. We need a better framework for thinking about the moral status of part-human beings.

Animals with Human Cells in Their Brains: Implications for Research.

In "Human-Animal Chimeras: The Moral Insignificance of Uniquely Human Capacities," Julian Koplin argues against the views that all uniquely human traits have moral significance or that all the traits humans have in common with other animals "are morally insignificant." He recommends instead the adoption of "a better framework for thinking about the moral status of part-human beings," one that emphasizes the "phenomenal value (or disvalue)" chimeric animals are likely "to enjoy (or suffer)." If the moral status of these chimeric animals is grounded in the phenomenal value of their interests-that is, their interests as nonhuman animals-current protections for animals used in research may be inadequate to protect those interests.

Human-Animal Chimeras, "Human" Cognitive Capacities, and Moral Status.

In "Human-Animal Chimeras: The Moral Insignificance of Uniquely Human Capacities," Julian Koplin explores a promising way of thinking about moral status. Without attempting to develop a model in any detail, Koplin picks up Joshua Shepherd's interesting proposal that we think about moral status in terms of the value of different kinds of conscious experience. For example, a being with the most basic sort of consciousness and sentience would have interests that matter morally, while a being whose consciousness featured the riches of loving affection, say, might have greater moral status and therefore deserve some sort of priority if the interests of the two beings conflicted. This approach represents an improvement over the more common, transparently anthropocentric habits of thinking about moral status, whether in connection with evaluating human-animal chimera research, deciding what one can ethically eat, or pursuing some other moral inquiry.

Hurdles to Generating Human Islets in Animals via Blastocyst Complementation

To clarify the hurdles to generation of human islets via blastocyst complementation and to identify techniques to overcome them. Blastocyst complementation is a promising method for generating functional islets from pluripotent stem cells which are identical to in vivo islets. Studies have reported successful generation of mouse pancreas in rats and rat pancreas in mice via interspecies blastocyst complementation and have shown the possibility for generation of human organs in xenogeneic animals. However, there remain hurdles to generating human islets in animals. The major hurdles to generating human islets include difficulty in engineering human-animal chimeras due to the cellular status of human pluripotent stem cells, immunological rejection of donor tissue in xenogeneic animals, and ethical concerns.

The Pluripotency Continuum and Interspecies Chimeras.

Pluripotency refers to the capacity of single cells to form derivatives of the three germ layers-ectoderm, mesoderm, and endoderm. Pluripotency can be captured in vitro as a spectrum of pluripotent stem cell states stabilized in specialized laboratory conditions. The recent discovery that pluripotent stem cells can colonize the embryos of distantly related animal organisms could, with further refinement, enable the generation of chimeric embryos composed of cells of human and animal origin. If achievable, the production of human-animal chimeras will open up new opportunities for regenerative medicine, facilitating human disease modeling and human organ generation inside large animals. However, the generation of human-animal interspecies chimeras is anticipated to require human chimera-competent pluripotent stem cells. Thus, it remains imperative to examine the pluripotency continuum more closely in light of advances that will facilitate the production of human-animal chimeras. This piece will review the current understanding of the pluripotency continuum and interspecies chimeras. © 2019 by John Wiley & Sons, Inc.

Generation of ERK-Independent Human and Non-Human Primate Pluripotent Stem Cells.

The production of human organs inside human-animal interspecies chimeras might one day comprise a viable strategy for generating patient-specific organs, but such experiments will require human chimera-competent pluripotent stem (PS) cells. The stabilization of PS cell self-renewal in serum-free medium and ERK blockade might be critical for capturing primate chimera-competent pluripotency. It has recently been shown that shielding primate cells from the activation of ERK, WNT, and PKC signaling is crucial for deriving African green monkey ERK-independent PS cells. Here, I show that this principle is generalizable to human cells. In this chapter, methods are provided to reset conventional human PS cells to ERK-independence using histone deacetylase inhibitors and PGCX media comprised of N2B27 medium supplemented with LIF, PD0325901, Go6983, CHIR99021, and XAV939. The novel stem cells exhibit higher levels of KLF4 and manifest increased mitochondrial membrane depolarization. However, the author observed that not all PS cell lines are amenable to small molecule-mediated resetting. The ERK-independent PS cells described herein will provide a useful resource for testing interspecies organogenesis strategies. © 2019 by John Wiley & Sons, Inc.

Social Acceptance of Ethically Controversed Innovative Techniques Related to or Derived from Assisted Reproductive Technologies – A Review of Literature

In vitro fertilization (IVF) is the most widely known assisted reproductive technique (ART). Due to IVF, a number of medical practices have emerged, such as surrogate motherhood or cryopreservation of human embryos, which gives the possibility to have children not only to infertile heterosexual couples at the normal age of procreation, but also to homosexual or lesbian couples or to people who are past the biological age when they could naturally procreate. IVF makes it possible to create embryos outside the human body, and therefore opens the door for the possibility of physical and moral augmentation of the future child prior to implanting the embryo in uterus, as well as for embryonic stem cell research, in order to find the causality of diseases and treat them, but also for experiments that today do not seem so futuristic anymore, such as tcreating human-animal chimeras or hybrids, or cloning. This article aims to analyze the relevant literature on the mechanism of achieving social acceptability for these controversial techniques.

ERK-independent African Green monkey pluripotent stem cells in a putative chimera-competent state

Generating human organs inside interspecies chimeras might one day produce patient-specific organs for clinical applications, but further advances in identifying human chimera-competent pluripotent stem (PS) cells are needed. Moreover, the potential for human PS cells to contribute to the brains in human-animal chimeras raises ethical questions. The use of non-human primate (NHP) chimera-competent PS cells would allow one to test interspecies organogenesis strategies while also bypassing such ethical concerns. Here, we provide the first evidence for a putative chimera-competent pluripotent state in NHPs. Using histone deacetylase (HDAC) and selective kinase inhibition, we converted the PS cells of an Old World monkey, the African Green monkey (aGM), to an ERK-independent cellular state that can be propagated in culture conditions similar to those that sustain chimera-competency in rodent cells. The obtained stem cell lines indefinitely self-renew in MEK inhibitor-containing culture media lacking serum replacement and FGF. Compared to conventional PS cells, the novel stem cells express elevated levels of KLF4, exhibit more intense nuclear staining for TFE3, and manifest increased mitochondrial membrane depolarization. These data are preliminary but indicate that the key to deriving primate chimera-competent PS cells is to shield cells from the activation of ERK, PKC, and WNT signaling. Because of the similarity of aGMs to humans, the more ethically palatable use of NHP cells, and the more similar gestation length between aGMs and large animals such as sheep, the aGM cell lines described herein will serve as a useful tool for evaluating the efficacy and safety of interspecies organogenesis strategies. Future studies will examine chimera-competency and generalizability to human cells.

The Ethics of Chimera Creation in Stem Cell Research

To summarize and clarify the main ethical issues surrounding the generation and use of human-animal chimeras in stem cell research. US federal funding remains restricted for certain forms of human-animal chimera research despite the widespread promulgation and acceptance of national and international stem cell-specific research guidelines. Stem cell-based human-animal chimera research can promote advances in basic human developmental biology, disease modeling, and new drug discoveries. National and international guidelines for this form of stem cell research have been developed over the past several years but ethical concerns persist around human dignity and the possible moral humanization of chimeric animals. These concerns can be defused and ought to be replaced with a more tractable focus on animal welfare.

The Legal Lacunae of Human-Animal Hybrids and Chimeras within Patent Law

Abstract This article compares and contrasts the patenting of animals, humans, and biotechnological inventions in the United States, at the European Patent Office, and within the European Union. It shows that morality is not a concern of U.S. legislative instruments or courts and patents have been granted liberally on living organisms, from microorganisms to mammals, in North America since the 1980s. By way of contrast, both European legislative instruments enshrine a morality bar that must be employed to deny patentability. Their implementation, however, is unpredictable due to a lack of detailed guidance on what morality means. The remit of the morality bar extends principally to humans, but the interests of animals must now also be factored into the equation. The manner in which this is done is unclear and patents on plants, although controversial among the public in general, do not unduly trouble lawmakers now that a significant time has elapsed since this Rubicon was crossed. This article explains and critically assesses these systems while identifying some of the ethical problems that are likely to emerge in due course focusing on the ad hoc regard paid to animals and the lack of a structured approach to considering their rights or welfare.

Human-Animal Chimeras and Hybrids: An Ethical Paradox behind Moral Confusion?

The prospect of creating and using human-animal chimeras and hybrids (HACHs) that are significantly human-like in their composition, phenotype, cognition, or behavior meets with divergent moral judgments: on the one side, it is claimed that such beings might be candidates for human-analogous rights to protection and care; on the other side, it is supposed that their existence might disturb fundamental natural and social orders. This paper tries to show that both positions are paradoxically intertwined: they rely on two kinds of species arguments, "individual species arguments" and "group species arguments," which formulate opposing demands but are conceptually interdependent. As a consequence, the existence of HACHs may challenge exactly those normative standards on which the protection of HACHs may eventually be based. This ethical paradox could constitute the ultimate source of the "moral confusion" that some authors have suspected HACHs to provoke.

Ethical and Safety Issues of Stem Cell-Based Therapy.

Results obtained from completed and on-going clinical studies indicate huge therapeutic potential of stem cell-based therapy in the treatment of degenerative, autoimmune and genetic disorders. However, clinical application of stem cells raises numerous ethical and safety concerns.In this review, we provide an overview of the most important ethical issues in stem cell therapy, as a contribution to the controversial debate about their clinical usage in regenerative and transplantation medicine.We describe ethical challenges regarding human embryonic stem cell (hESC) research, emphasizing that ethical dilemma involving the destruction of a human embryo is a major factor that may have limited the development of hESC-based clinical therapies. With previous derivation of induced pluripotent stem cells (iPSCs) this problem has been overcome, however current perspectives regarding clinical translation of iPSCs still remain. Unlimited differentiation potential of iPSCs which can be used in human reproductive cloning, as a risk for generation of genetically engineered human embryos and human-animal chimeras, is major ethical issue, while undesired differentiation and malignant transformation are major safety issues.Although clinical application of mesenchymal stem cells (MSCs) has shown beneficial effects in the therapy of autoimmune and chronic inflammatory diseases, the ability to promote tumor growth and metastasis and overestimated therapeutic potential of MSCs still provide concerns for the field of regenerative medicine.This review offers stem cell scientists, clinicians and patient's useful information and could be used as a starting point for more in-depth analysis of ethical and safety issues related to clinical application of stem cells.

A Preliminary Study Exploring Japanese Public Attitudes Toward the Creation and Utilization of Human-Animal Chimeras: a New Perspective on Animals Containing “Human Material” (ACHM)

Ongoing research on making “human-animal chimeras” or “animals containing human material” (ACHM) to solve the shortage of organs available for transplantation has raised many ethical issues regarding the creation and utilization of such constructs, including cultural views regarding the status of those creations. A pilot study was conducted to explore Japanese public attitudes toward human-animal chimeras or ACHM. The February 2012 study consisted of focus group interviews (FGIs) with citizens from the Greater Tokyo Area, aged between 20 and 54. The 24 participants were divided into four groups. Transcripts of the interviews were analyzed and participants’ attitudes categorized. Five categories of participant attitudes were identified: (1) resistance to the unnatural, (2) concerns about animal welfare, (3) concerns about controlling human-animal chimeras, (4) concerns about the possible birth of intermediate entities, and (5) resistance to creating and utilizing animals containing my material or my child’s material. Our FGI results showed a broader and greater variety of public concerns than those reported in previous studies. While researchers have tried to establish new methods to avoid creating intermediate entities, our participants expressed concerns about not only intermediate entities but also animals containing their own material or their child’s material. Based upon their responses in the interviews, we are introducing a new ethical concern: “animals containing my material/my child’s material.”

Regulating Estrangement: Human–Animal Chimeras in Postgenomic Biology

Why do laws and regulations marking boundaries between humans and other animals proliferate amid widespread proclamations of the waning of the species concept and the consensus that life is a continuum? Here I consider a recent spate of new guidelines and regulations in the United Kingdom and United States that work to estrange human bodies from other animals in biomedicine. Using the idea of a bioconstitutional moment to understand how state institutions deliberate over “human–animal chimeras,” I address how nations differently establish separations between humans and other animals. New chimeric entities, containing human hereditary material, have consecrated regulatory ground and signify increased attention to fields of research that have long used interspecies mixing. Regulators and policy makers now find themselves in a curious position. On the one hand, they continue to regulate the estrangement between humans and other animals, but on the other, they support the creation of chimeric life––a form of life that draws into question the very basis of such separations.

NIH to Lift Moratorium on Chimera Research Funding.

“The AJT Report” reviews proposed changes to the NIH's polices regarding human–animal chimera research and talks to several experts about how they may impact the field of transplantation if put into practice. Also this issue, we report on an advertising company in Japan using stuffed animals to generate awareness of child organ donation. “The AJT Report” reviews proposed changes to the NIH's polices regarding human–animal chimera research and talks to several experts about how they may impact the field of transplantation if put into practice. Also this issue, we report on an advertising company in Japan using stuffed animals to generate awareness of child organ donation.

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

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.

On recent advances in human engineering.

Advances in embryology, genetics, and regenerative medicine regularly attract attention from scientists, scholars, journalists, and policymakers, yet implications of these advances may be broader than commonly supposed. Laboratories culturing human embryos, editing human genes, and creating human-animal chimeras have been working along lines that are now becoming intertwined. Embryogenic methods are weaving traditional in vivo and in vitro distinctions into a new “in vivitro” (in life in glass) fabric. These and other methods known to be in use or thought to be in development promise soon to bring society to startling choices and discomfiting predicaments, all in a global effort to supply reliably rejuvenating stem cells, to grow immunologically non-provocative replacement organs, and to prevent, treat, cure, or even someday eradicate diseases having genetic or epigenetic mechanisms. With humanity's human-engineering era now begun, procedural prohibitions, funding restrictions, institutional controls, and transparency rules are proving ineffective, and business incentives are migrating into the most basic life-sciences inquiries, wherein lie huge biomedical potentials and bioethical risks. Rights, health, and heritage are coming into play with bioethical presumptions and formal protections urgently needing reassessment.

Interspecific in vitro assay for the chimera-forming ability of human pluripotent stem cells.

Functional assay limitations are an emerging issue in characterizing human pluripotent stem cells (PSCs). With rodent PSCs, chimera formation using pre-implantation embryos is the gold-standard assay of pluripotency (competence of progeny to differentiate into all three germ layers). In human PSCs (hPSCs), however, this can only be monitored via teratoma formation or in vitro differentiation, as ethical concerns preclude generation of human-human or human-animal chimeras. To circumvent this issue, we developed a functional assay utilizing interspecific blastocyst injection and in vitro culture (interspecies in vitro chimera assay) that enables the development and observation of embryos up to headfold stage. The assay uses mouse pre-implantation embryos and rat, monkey and human PSCs to create interspecies chimeras cultured in vitro to the early egg-cylinder stage. Intra- and interspecific chimera assays with rodent PSC lines were performed to confirm the consistency of results in vitro and in vivo. The behavior of chimeras developed in vitro appeared to recapitulate that of chimeras developed in vivo; that is, PSC-derived cells survived and were integrated into the epiblast of egg-cylinder-stage embryos. This indicates that the interspecific in vitro chimera assay is useful in evaluating the chimera-forming ability of rodent PSCs. However, when human induced PSCs (both conventional and naïve-like types) were injected into mouse embryos and cultured, some human cells survived but were segregated; unlike epiblast-stage rodent PSCs, they never integrated into the epiblast of egg-cylinder-stage embryos. These data suggest that the mouse-human interspecies in vitro chimera assay does not accurately reflect the early developmental potential/process of hPSCs. The use of evolutionarily more closely related species as host embryos might be necessary to evaluate the developmental potency of hPSCs.