Animal Chimeras Research Articles

A Political and ethical landscape of brain organoid research

Human cerebral organoids (hCOs), produced in labs through directed cell culture of embryonic or induced pluripotent stem cells, closely replicate the 3-dimensional architecture of the human brain on a micro scale. This technology has been used to model neurological disease and shows promise to complement or supplant animal subjects in preclinical therapeutic investigation. However, attention must be paid by researchers and institutions to the various ethical concerns associated with hCO development. Human-animal chimeras produced through the grafting of hCOs have shown integration of neurological function, calling into question the moral status of both the animal chimeras and the organoid itself. Sensationalist reporting on such acts may also prompt public backlash, potentially jeopardizing hCO research and the promised benefits thereof. Moreover, concerns arise over privacy and consent for past and prospective donors of stem cells used to produce organoids. Genetic information may be considered privileged to the public domain and disrupted trust can reduce the supply of willing donors. Though hCOs are believed thus far to lack the capacity for consciousness and cognitive function, consideration must be given to their potential status as moral agents with further development or enhancement. Boundaries concerning organoids adhered to by researchers have been largely voluntary and informal to this point. By edict or by the power of the purse, governmental regulatory agencies ought to formalize necessary guidelines to ensure compliance with ethical principles and the adequate representation of all affected stakeholders in future decisions.

Political and ethical landscape of brain organoid research

Human cerebral organoids (hCOs), produced in labs through directed cell culture of embryonic or induced pluripotent stem cells, closely replicate the 3-dimensional architecture of the human brain on a micro scale. This technology has been used to model neurological disease and shows promise to complement or supplant animal subjects in preclinical therapeutic investigation. However, attention must be paid by researchers and institutions to the various ethical concerns associated with hCO development. Human-animal chimeras produced through the grafting of hCOs have shown integration of neurological function, calling into question the moral status of both the animal chimeras and the organoid itself. Sensationalist reporting on such acts may also prompt public backlash, potentially jeopardizing hCO research and the promised benefits thereof. Moreover, concerns arise over privacy and consent for past and prospective donors of stem cells used to produce organoids. Genetic information may be considered privileged to the public domain and disrupted trust can reduce the supply of willing donors. Though hCOs are believed thus far to lack the capacity for consciousness and cognitive function, consideration must be given to their potential status as moral agents with further development or enhancement. Boundaries concerning organoids adhered to by researchers have been largely voluntary and informal to this point. By edict or by the power of the purse, governmental regulatory agencies ought to formalize necessary guidelines to ensure compliance with ethical principles and the adequate representation of all affected stakeholders in future decisions.

What Do Chimeras Think About?

Non-human animal chimeras, containing human neurological cells, have been created in the laboratory. Despite a great deal of debate, the status of such beings has not been resolved.Under normal definitions, such a being could either be unconventionally human or abnormally animal. Practical investigations in animal sentience, artificial intelligence, and now chimera research, suggest that such beings may be assumed to have no legal rights, so philosophy could provide a different answer. In this vein, therefore, we can ask: What would a chimera, if it could think, think about? Thinking is used to capture the phenomena of a novel, chimeric being perceiving its terrible predicament as no more than a laboratory experiment. The creation of a thinking chimera therefore forces us to reconsider our assumptions about what makes human beings (potentially) unique (and other sentient animals different), because, as such, a chimera's existence bridges our social and legal expectations about definitions of human and animal. Society has often evolved new social norms based on different kinds of (ir)rational contrivances; the imperative of non-contradiction, which is defended here, therefore requires a specific philosophical response to the rights of a thinking chimeric being.

Response to the ISSCR guidelines on human-animal chimera research.

The International Society for Stem Cell Research (ISSCR) has recently released the 2021 update of its guidelines. The update includes detailed new recommendations on human-animal chimera research. This paper argues that the ISSCR recommendations fail to address the core ethical concerns raised by neurological chimeras-namely, concerns about moral status. In minimising moral status concerns, the ISSCR both breaks rank with other major reports on human-animal chimera research and rely on controversial claims about the grounds of moral status that many people will rightly reject. A more robust framework for regulating human-animal chimera research still needs to be developed.

Exclusive generation of rat spermatozoa in sterile mice utilizing blastocyst complementation with pluripotent stem cells.

SummaryBlastocyst complementation denotes a technique that aims to generate organs, tissues, or cell types in animal chimeras via injection of pluripotent stem cells (PSCs) into genetically compromised blastocyst-stage embryos. Here, we report on successful complementation of the male germline in adult chimeras following injection of mouse or rat PSCs into mouse blastocysts carrying a mutation in Tsc22d3, an essential gene for spermatozoa production. Injection of mouse PSCs into Tsc22d3-Knockout (KO) blastocysts gave rise to intraspecies chimeras exclusively embodying PSC-derived functional spermatozoa. In addition, injection of rat embryonic stem cells (rESCs) into Tsc22d3-KO embryos produced interspecies mouse-rat chimeras solely harboring rat spermatids and spermatozoa capable of fertilizing oocytes. Furthermore, using single-cell RNA sequencing, we deconstructed rat spermatogenesis occurring in a mouse-rat chimera testis. Collectively, this study details a method for exclusive xenogeneic germ cell production in vivo, with implications that may extend to rat transgenesis, or endangered animal species conservation efforts.

Streamlined and quantitative detection of chimerism using digital PCR

Animal chimeras are widely used for biomedical discoveries, from developmental biology to cancer research. However, the accurate quantitation of mixed cell types in chimeric and mosaic tissues is complicated by sample preparation bias, transgenic silencing, phenotypic similarity, and low-throughput analytical pipelines. Here, we have developed and characterized a droplet digital PCR single-nucleotide discrimination assay to detect chimerism among common albino and non-albino mouse strains. In addition, we validated that this assay is compatible with crude lysate from all solid organs, drastically streamlining sample preparation. This chimerism detection assay has many additional advantages over existing methods including its robust nature, minimal technical bias, and ability to report the total number of cells in a prepared sample. Moreover, the concepts discussed here are readily adapted to other genomic loci to accurately measure mixed cell populations in any tissue.

Visa A. J. Kurki, A Theory of Legal Personhood

In recent times, ‘personhood questions’ come up frequently in a variety of bioethical contexts. For example, consider the classic debates such as the status of embryo and abortion, questions surrounding the status of patients in persistent vegetative state and end-of-life decision-making,1 or permissibility of the scientific experimentations on or eating of animals. Then there are the relatively newer personhood discussions around the responsibility for harms caused in Artificial Intelligence-based medical treatment, or the legal status of one’s genetic materials, or of the newly emergent entities such as organoids,2 synthetic embryos,3 and human–animal chimeras.4 While in the normative discussions, arguments based on ‘personhood’ sometimes argue for increasing legal protections, the conceptual aspects and what exactly the granting of legal personhood in these contexts entails often remain unclear. Visa AJ Kurki’s A Theory of Legal Personhood aims to ‘provide a theoretical framework for understanding legal personhood in contemporary Western legal systems’,5 to address these foundational questions. It largely succeeds in doing so. The many analytic nuances and thought-provoking claims in this work make it a rich playing field for bioethical minds to indulge.

Human embryo research, stem cell-derived embryo models and invitro gametogenesis: Considerations leading to the revised ISSCR guidelines.

SummaryThe ISSCR Guidelines for Stem Cell Research and Clinical Translation were last revised in 2016. Since then, rapid progress has been made in research areas related to in vitro culture of human embryos, creation of stem cell-based embryo models, and in vitro gametogenesis. Therefore, a working group of international experts was convened to review the oversight process and provide an update to the guidelines. This report captures the discussion and summarizes the major recommendations made by this working group, with a specific emphasis on updating the categories of review and engagement with the specialized scientific and ethical oversight process.

Rethinking the oversight conditions of human-animal chimera research.

New discoveries are improving the odds of human cells surviving in host animals, prompting regulatory and funding agencies to issue calls for additional layers of ethical oversight for certain types of human-animal chimeras. Of interest are research proposals involving chimeric animals with humanized brains. But what is motivating the demand for additional oversight? I locate two, not obviously compatible, motivations, each of which provides the justificatory basis for paying special attention to different sets of human-animal chimeras. Surprisingly, the sets of animals that actually get flagged for special scrutiny by research and funding guidelines do not correlate with either of the sets of animals that arise when we think about what is motivating additional oversight. What this shows is that existing research policies and funding guidelines are disconnected from their motivation: the rationale for flagging certain types of human-animal chimeras as requiring special oversight is ignored in execution.

Recent Challenging Cases in Genetic Engineering

Genetic engineering is a rapidly evolving field of research with potentially powerful therapeutic applications. The technology CRISPR-Cas9 not only has improved the accuracy and overall feasibility of genome editing but also has increased access to users by lowering cost and increasing usability and speed. However, recent applications of genetic engineering technology have raised ethical concerns in the scientific community. An investigator in China announced the birth of twins whose genome had been edited as embryos to increase resistance to HIV. These germline genetic modifications were illicit because they both posed potential risks to the children and future progeny and used in vitro fertilization. In addition, a team of US and Spanish researchers travelled to China to perform human–animal chimera research. In light of these events, health care institutions should consider what steps can be taken to prevent or slow rogue science.

Neuroethics and Animals: Report and Recommendations From the University of Pennsylvania Animal Research Neuroethics Workshop

Growing awareness of the ethical implications of neuroscience in the early years of the 21st century led to the emergence of the new academic field of “neuroethics,” which studies the ethical implications of developments in the neurosciences. However, despite the acceleration and evolution of neuroscience research on nonhuman animals, the unique ethical issues connected with neuroscience research involving nonhuman animals remain underdiscussed. This is a significant oversight given the central place of animal models in neuroscience. To respond to these concerns, the Center for Neuroscience and Society and the Center for the Interaction of Animals and Society at the University of Pennsylvania hosted a workshop on the “Neuroethics of Animal Research” in Philadelphia, Pennsylvania. At the workshop, expert speakers and attendees discussed ethical issues arising from neuroscience research involving nonhuman animals, including the use of animal models in the study of pain and psychiatric conditions, animal brain-machine interfaces, animal–animal chimeras, cerebral organoids, and the relevance of neuroscience to debates about personhood. This paper highlights important emerging ethical issues based on the discussions at the workshop. This paper includes recommendations for research in the United States from the authors based on the discussions at the workshop, loosely following the format of the 2 Gray Matters reports on neuroethics published by the Presidential Commission for the Study of Bioethical Issues.

Crossing Phenotype Heritability and Candidate Gene Expression in Grafted Black-Lipped Pearl Oyster Pinctada margaritifera, an Animal Chimera.

Grafting mantle tissue of a donor pearl oyster into the gonad of a recipient oyster results in the formation of a chimera, the pearl sac. The phenotypic variations of this chimera are hypothesized to be the result of interactions between the donor and recipient genomes. In this study, the heritability of phenotypic variation and its association with gene expression were investigated for the first time during Pinctada margaritifera pearl production. Genetic variance was evaluated at different levels, 1) before the graft operation (expression in graft tissue), 2) after grafting (pearl sac tissue expression in chimera), and 3) on the product of the graft (pearl phenotype traits) based on controlled biparental crosses and the F1 generation. Donor-related genetic parameter estimates clearly demonstrate heritability for nacre weight and thickness, darkness and color, and surface defects and grade, which signifies a genetic basis in the donor oyster. In graft relative gene expression, the value of heritability was superior to 0.20 in for almost all genes; whereas in pearl sac, heritability estimates were low (h2 < 0.10; except for CALC1 and Aspein). Pearl sac expression seems to be more influenced by residual variance than the graft, which can be explained by environmental effects that influence pearls sac gene expression and act as a recipient additive genetic component. The interactions between donor and recipient are very complex, and further research is required to understand the role of the recipient oysters on pearl phenotypic and gene expression variances.

Endoderm Jagged induces liver and pancreas duct lineage in zebrafish

Liver duct paucity is characteristic of children born with Alagille Syndrome (ALGS), a disease associated with JAGGED1 mutations. Here, we report that zebrafish embryos with compound homozygous mutations in two Notch ligand genes, jagged1b (jag1b) and jagged2b (jag2b) exhibit a complete loss of canonical Notch activity and duct cells within the liver and exocrine pancreas, whereas hepatocyte and acinar pancreas development is not affected. Further, animal chimera studies demonstrate that wild-type endoderm cells within the liver and pancreas can rescue Notch activity and duct lineage specification in adjacent cells lacking jag1b and jag2b expression. We conclude that these two Notch ligands are directly and solely responsible for all duct lineage specification in these organs in zebrafish. Our study uncovers genes required for lineage specification of the intrahepatopancreatic duct cells, challenges the role of duct cells as progenitors, and suggests a genetic mechanism for ALGS ductal paucity.

Chimeras intended for human gamete production: an ethical alternative?

Human eggs for basic, fertility and stem-cell research are in short supply. Many experiments that require their use cannot be carried out at present, and, therefore, the benefits that could emerge from these are either delayed or never materialise. This state of affairs is problematic for scientists and patients worldwide, and it is a matter that needs our attention. Recent advances in chimera research have opened the possibility of creating human/non-human animal chimeras intended for human gamete production (chimeras-IHGP). In this paper, I examine four arguments against the creation of such chimeras and prove that all of them are found wanting. I conclude by showing that there is a strong moral reason for scientists to pursue this research avenue.

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.

Revisiting the Flight of Icarus: Making Human Organs from PSCs with Large Animal Chimeras

While cell therapies hold great potential for treating many conditions, their utility for treating patients that require whole organ replacement is unclear. To address this challenge, we propose using genetically engineered "organ niches" in large animals to generate human organs from pluripotent stem cells and discuss the hurdles facing such strategies.

Human–Animal Chimeras: Not Only Cell Origin Matters

Human–animal chimeras, mosaics, and hybrids can be obtained by different procedures and on very different levels. Depending on the applied techniques, the biological input, the outcome and ethical ...

Faith-based perspectives on the use of chimeric organisms for medical research

Efforts to advance our understanding of neurodegenerative diseases involve the creation chimeric organisms from human neural stem cells and primate embryos--known as prenatal chimeras. The existence of potential mentally complex beings with human and non-human neural apparatus raises fundamental questions as to the ethical permissibility of chimeric research and the moral status of the creatures it creates. Even as bioethicists find fewer reasons to be troubled by most types of chimeric organisms, social attitudes towards the non-human world are often influenced by religious beliefs. In this paper scholars representing eight major religious traditions provide a brief commentary on a hypothetical case concerning the development and use of prenatal human-animal chimeric primates in medical research. These commentaries reflect the plurality and complexity within and between religious discourses of our relationships with other species. Views on the moral status and permissibility of research on neural human animal chimeras vary. The authors provide an introduction to those who seek a better understanding of how faith-based perspectives might enter into biomedical ethics and public discourse towards forms of biomedical research that involves chimeric organisms.

How much longer can we create human and animal chimera for scientific research? : The agendas for discussion

How much longer can we create human and animal chimera for scientific research? : The agendas for discussion