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Consciousness in a Rotor? Science and Ethics of Potentially Conscious Human Cerebral Organoids.
Human cerebral organoids are three-dimensional biological cultures grown in the laboratory to mimic as closely as possible the cellular composition, structure, and function of the corresponding organ, the brain. For now, cerebral organoids lack blood vessels and other characteristics of the human brain, but are also capable of having coordinated electrical activity. They have been usefully employed for the study of several diseases and the development of the nervous system in unprecedented ways. Research on human cerebral organoids is proceeding at a very fast pace and their complexity is bound to improve. This raises the question of whether cerebral organoids will also be able to develop the unique feature of the human brain, consciousness. If this is the case, some ethical issues would arise. In this article, we discuss the necessary neural correlates and constraints for the emergence of consciousness according to some of the most debated neuroscientific theories. Based on this, we consider what the moral status of a potentially conscious brain organoid might be, in light of ethical and ontological arguments. We conclude by proposing a precautionary principle and some leads for further investigation. In particular, we consider the outcomes of some very recent experiments as entities of a potential new kind.
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Donor perspectives on informed consent and use of biospecimens for brain organoid research.
Debates about the ethics of human brain organoids have proceeded without the input of individuals whose brains are being modeled. Interviews with donors of biospecimens for brain organoid research revealed overall enthusiasm for brain organoids as a tool for biomedical discovery, alongside a desire for ongoing engagement with research teams to learn the results of the research, to allow transfer of decision-making authority over time, and to ensure ethical boundaries are not crossed. Future work is needed to determine the most feasible and resource-efficient way to longitudinally engage donors participating in brain organoid research.
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Do not keep it simple: recent advances in the generation of complex organoids.
3D cell culture models which closely resemble real human tissues are of high interest for disease modelling, drug screening as well as a deeper understanding of human developmental biology. Such structures are termed organoids. Within the last years, several human organoid models were described. These are usually stem cell derived, arise by self-organization, mimic mechanisms of normal tissue development, show typical organ morphogenesis and recapitulate at least some organ specific functions. Many tissues have been reproduced in vitro such as gut, liver, lung, kidney and brain. The resulting entities can be either derived from an adult stem cell population, or generated from pluripotent stem cells using a specific differentiation protocol. However, many organoid models only recapitulate the organs parenchyma but are devoid of stromal components such as blood vessels, connective tissue and inflammatory cells. Recent studies show that the incorporation of endothelial and mesenchymal cells into organoids improved their maturation and might be required to create fully functional micro-tissues, which will allow deeper insights into human embryogenesis as well as disease development and progression. In this review article, we will summarize and discuss recent works trying to incorporate stromal components into organoids, with a special focus on neural organoid models.
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Modelling Toxoplasma gondii infection in human cerebral organoids.
Pluripotent stem cell-derived cerebral organoids have the potential to recapitulate the pathophysiology of in vivo human brain tissue, constituting a valuable resource for modelling brain disorders, including infectious diseases. Toxoplasma gondii, an intracellular protozoan parasite, infects most warm-blooded animals, including humans, causing toxoplasmosis. In immunodeficient patients and pregnant women, infection often results in severe central nervous system disease and fetal miscarriage. However, understanding the molecular pathophysiology of the disease has been challenging due to limited in vitro model systems. Here, we developed a new in vitro model system of T. gondii infection using human brain organoids. We observed that tachyzoites can infect human cerebral organoids and are transformed to bradyzoites and replicate in parasitophorous vacuoles to form cysts, indicating that the T. gondii asexual life cycle is efficiently simulated in the brain organoids. Transcriptomic analysis of T. gondii-infected organoids revealed the activation of the type I interferon immune response against infection. In addition, in brain organoids, T. gondii exhibited a changed transcriptome related to protozoan invasion and replication. This study shows cerebral organoids as physiologically relevant in vitro model systems useful for advancing the understanding of T. gondii infections and host interactions.
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Advances in neural organoids: structural organization, disease modeling, and applications in gene therapy.
Neural organoids and assembloids have emerged as advanced in vitro models that reproduce the cytoarchitecture and functional complexity of the human brain. This review focuses on recent applications of these three-dimensional systems for modeling neurodegenerative diseases and assessing the efficacy of gene therapy, particularly using adeno-associated viral vectors. The development of induced pluripotent stem cell technology enables the creation of patient-specific organoids that reflect individual genetic backgrounds and disease phenotypes. Neural organoids have been used to model Alzheimer's, Parkinson's, and Huntington's diseases, reproducing hallmark features such as protein aggregation, neuroinflammation, and synaptic dysfunction. They have also served as test systems for evaluating AAV-mediated gene delivery, revealing serotype-specific tropism and supporting optimization of vector design and gene expression. Further advances include integration of immune and vascular components and the construction of multi-regional assembloids that replicate inter-regional neuronal communication and complex network dynamics. Ongoing standardization and scalability of neural organoid systems, combined with bioengineering and analytical innovations, are expected to enhance reproducibility and translational relevance. The convergence of organoid models with gene therapy testing frameworks may accelerate preclinical validation and contribute to the development of precision approaches in neurology.
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Exploring hippocampal dysfunction in schizophrenia with pluripotent stem cell models.
Schizophrenia is a complex neurodevelopmental disorder characterized by widespread cognitive and behavioral impairments, with the hippocampus playing a critical role in its pathophysiology. While traditional approaches such as animal models and postmortem studies have provided valuable insights, they fall short in capturing the human-specific and developmental features of the disease. Human pluripotent stem cell (hPSC) models, particularly 3D brain organoids, represent a powerful new tool for investigating the cellular and circuit-level mechanisms underlying schizophrenia. Although cortical and striatal organoids have been increasingly utilized in psychiatric research, hippocampal organoid models remain underdeveloped and underused. This review outlines the developmental basis of hippocampal dysfunction in schizophrenia and discusses the emergence of hPSC-derived hippocampal organoids and assembloids as novel in vitro systems. We highlight key findings from the limited studies using hippocampal differentiations in schizophrenia, explore their potential to model region-specific circuitry (e.g., DG-CA3, cortico-hippocampal, and hippocampalstriatal networks), and identify major technical challenges such as the absence of CA1/CA2 subfields, limited vascularization, and the need for microglial integration. Finally, we propose future directions to refine these models and leverage them for mechanistic discovery and therapeutic screening. By integrating genetic, imaging, and developmental perspectives, this review positions hippocampal organoid technology as a promising yet underutilized platform for advancing our understanding of schizophrenia's neurodevelopmental origins.
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Generation of advanced cerebellar organoids for neurogenesis and neuronal network development.
Neurons within the cerebellum form temporal-spatial connections through the cerebellum, and the entire brain. Organoid models provide an opportunity to model the early differentiation of the developing human cerebellum, which is difficult to study in vivo, and affords the opportunity to study neurodegenerative and neurodevelopmental diseases of the cerebellum. Previous cerebellar organoid models focused on early neuron generation and single cell activity. Here, we modify previous protocols to generate more mature cerebellar organoids that allow for the establishment of several classes of mature neurons during cerebellar differentiation and development, including the establishment of neural networks during whole-organoid maturation. This will provide a means to study the generation of several more mature cerebellar cell types, including Purkinje cells, granule cells and interneurons expression as well as neuronal communication for biomedical, clinical and pharmaceutical applications.
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Single rosette-based generation of uniform cortical assembloids recapitulating cellular interactions between neurons and glial cells.
Despite recent advances, current brain organoid technologies face ongoing challenges in managing heterogeneity and representing the diverse structure and cell types of the human brain. Here, we develop a module-based cellular reconstitution technology to sequentially build uniform cortical assembloids with mature cortical structures and functional connectivity. The uniformity and maturity of the cortical assembloids are achieved by creating single-rosette-based organoids at the early stage, whose sizes were big and consistent with the treatment of Wnt and Hedgehog agonists, followed by spatial reconstitution with the Reelin-expressing neuronal layer and non-neuronal glial cells. The resulting single-rosette-based cortical assembloids are highly uniform and reproducible without significant batch effects, solving major heterogeneity issues caused by difficulties in controlling the number and size of rosettes in conventional multi-rosette organoids. Furthermore, these cortical assembloids structurally and functionally recapitulate the physiology of the human brain, including the six-layered cortical structure, functional connectivity, and dynamic cellular interplay between neurons and glial cells. Our study thus provides an innovative preclinical model to study a range of neurological disorders, understanding the pathogenesis of which requires an organoid system capable of representing the dynamic cellular interactions and the maturity of the human brain.
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Attachment culture of cortical organoids at the microwell air-liquid interface.
The cortical organoid is an efficient model for studying human brain neurodevelopment and neurological disease. However, its three-dimensional structure limits real-time observation of internal physiological changes. Here, we present a protocol for an air-liquid interface attachment culture for cortical organoids. We describe steps for transplanting cortical organoid slices and generating the air-liquid interface. We then detail calcium imaging on organoid external neural networks and immunohistochemical staining on confocal plates.
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Building brains in a dish: Prospects for growing cerebral organoids from stem cells.
The recent development of organoid techniques, in which embryonic brain-like tissue can be grown from human or mouse stem cells in vitro offers the potential to transform the way in which brain development is studied. In this review, we summarize key aspects of the embryonic development of mammalian forebrains, focussing in particular on the cerebral cortex and highlight significant differences between mouse and primates, including human. We discuss recent work using cerebral organoids that has revealed key similarities and differences between their development and that of the brain in vivo. Finally, we outline the ways in which cerebral organoids can be used in combination with CRISPR/Cas9 genome editing to unravel genetic mechanisms that control embryonic development of the cerebral cortex, how this can help us understand the causes of neurodevelopmental disorders and some of the key challenges which will have to be resolved before organoids can become a mainstream tool to study brain development.