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Ethical concerns about embodied brain organoids shaped by foundational distinctions and perceptions of consciousness.
Human brain organoids embodied within virtual learning environments provide a novel experimental system for mechanistic studies of learning and memory. Yet these forms of synthetic biological or organoid intelligence raise moral and ethical concerns. Bioethicists argue that if biocomputers become conscious, they have ‘moral status’, which places limits on permissible research. Yet previous empirical studies of public opinion suggest that creation of conscious brain organoids may be essential to modeling features of the human brain relevant to medical advancement. We conducted a nationally representative experimental study that investigated factors that shape public attitudes toward brain organoids integrated with computer hardware and software, herein referred to as embodied brain organoids or ‘biocomputers’. We report several key findings. First, the public’s tendency to attribute consciousness to biocomputers is positively correlated with attribution of other cognitive traits and increased ethical concerns, but also the perceived benefits and overall support for research. Second, support for research is largely unaffected by applications of biocomputers to medicine or development of information technology. Third, support is highest for biocomputers that are described as having moral status-conferring abilities, such as awareness of other biocomputers. Finally, attribution of consciousness to biocomputers and support for research are lowest among people who endorse a ‘foundational distinction’ between humans and embodied organoid systems. The negative impact of these foundational distinctions on perceived benefits can be mitigated, however, by how the technology is applied toward societal benefit. Our findings provide key insights into factors that shape moral judgements about brain organoids integrated with conventional computing systems to perform cognitive-like tasks.
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Integrating adult neurogenesis and human brain organoid models to advance epilepsy and associated behavioral research.
Epilepsy is a chronic neurological disorder characterized by recurring, unprovoked seizures, asymmetrical electroencephalogram patterns, and other pathological abnormalities. The hippocampus plays a pivotal role in learning, memory consolidation, attentional control, and pattern separation. Impairment of hippocampal network circuitry can induce long-term cognitive and memory dysfunction. In this review, we discuss how aberrant adult neurogenesis and plasticity collectively alter the network balance for information processing within the hippocampal neural network. Subsequently, we explore the potential of human brain organoids integrated into microelectrode array technology as an electrophysiological tool. We also discuss the utilization of a closed-loop platform that connects the brain organoid to a mobile robot in a virtual environment. While in vivo models provide valuable insights into some aspects of epileptogenesis, such as the impact of adult neurogenesis on hippocampal function, brain organoids are indispensable for comprehensively studying epileptogenesis involving genetic mutations that underlie human epilepsy. More importantly, a combinational approach using brain organoids on MEA paves the way for studying impaired plasticity and abnormal information processing within epileptic neural networks. This innovative in vitro approach may provide a new pathway for investigating the behavioral outcomes of aberrant neural networks when integrated with a mobile robot, closing the loop between the neural network in brain organoids and the mobile robot. In this review, we aim to discuss the use of each model to study the behavioral changes in epilepsy and highlight the benefits of both in vivo and in vitro models for understanding the behavioral aspects of epilepsy.
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Multiscale 3D phenotyping of human cerebral organoids.
Brain organoids grown from human pluripotent stem cells self-organize into cytoarchitectures resembling the developing human brain. These three-dimensional models offer an unprecedented opportunity to study human brain development and dysfunction. Characterization currently sacrifices spatial information for single-cell or histological analysis leaving whole-tissue analysis mostly unexplored. Here, we present the SCOUT pipeline for automated multiscale comparative analysis of intact cerebral organoids. Our integrated technology platform can rapidly clear, label, and image intact organoids. Algorithmic- and convolutional neural network-based image analysis extract hundreds of features characterizing molecular, cellular, spatial, cytoarchitectural, and organoid-wide properties from fluorescence microscopy datasets. Comprehensive analysis of 46 intact organoids and ~ 100 million cells reveals quantitative multiscale "phenotypes" for organoid development, culture protocols and Zika virus infection. SCOUT provides a much-needed framework for comparative analysis of emerging 3D in vitro models using fluorescence microscopy.
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Single-cell analysis reveals shared and distinct molecular signatures in brain organoid models of neurodegeneration and neuroinflammation.
BACKGROUND: Alzheimer’s disease (AD) and Parkinson’s disease (PD) are complex neurodegenerative disorders with common pathological features, but the molecular mechanisms underlying their early stages remain poorly understood. This study aims to elucidate common and divergent changes in cellular processes in the early stages of neurodegeneration and neuroinflammation using brain organoid models. METHODS: We performed a multi-level comparative analysis of single-cell RNA sequencing data from brain organoid models previously designed to mimic specific features of PD- and AD-like pathology, by integrating gene expression, pathway enrichment, molecular network, and cell-cell communication analyses. Given the critical role of neuroinflammation in neurodegenerative disorders, we particularly focused on inflammatory signaling pathways and alterations in cell-cell communication that might drive disease progression. RESULTS: Our results reveal both common and contrasting changes between the different organoid models, including a common dysregulation of apoptotic pathways in astrocytes, a common upregulation of energy metabolism pathways in neurons, and opposing trends in ribosome-related pathways. Notably, our multi-level analysis identified key inflammatory alterations, including contrasting changes mediated by HMGB1 and shared dysregulation in the MDK signaling pathway. Finally, comparison with post-mortem brain tissue and GWAS data revealed a small set of overlapping significant genes, showing robust shared patterns across different stages of pathology and tissue sources. CONCLUSIONS: These findings provide new insights into the molecular basis of neurodegeneration and neuroinflammation, highlighting diverging and shared alterations between different organoid models and post-mortem brain tissues that may inform follow-up validation and preclinical intervention studies for neurodegenerative disorders.
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Modelling amoebic brain infection caused by Balamuthia mandrillaris using a human cerebral organoid.
The lack of disease models adequately resembling human tissue has hindered our understanding of amoebic brain infection. Three-dimensional structured organoids provide a microenvironment similar to human tissue. This study demonstrates the use of cerebral organoids to model a rare brain infection caused by the highly lethal amoeba Balamuthia mandrillaris. Cerebral organoids were generated from human pluripotent stem cells and infected with clinically isolated B. mandrillaris trophozoites. Histological examination showed amoebic invasion and neuron damage following coculture with the trophozoites. The transcript profile suggested an alteration in neuron growth and a proinflammatory response. The release of intracellular proteins specific to neuronal bodies and astrocytes was detected at higher levels postinfection. The amoebicidal effect of the repurposed drug nitroxoline was examined using the human cerebral organoids. Overall, the use of human cerebral organoids was important for understanding the mechanism of amoeba pathogenicity, identify biomarkers for brain injury, and in the testing of a potential amoebicidal drug in a context similar to the human brain.
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A Material Transfer Agreement between Glioblastoma and Normal Brain Cells.
Tumor cells communicate with normal cells in various ways, typically leading to the exploitation of resources of the normal cells by tumor cells for their benefit. In this issue, Mangena and colleagues use three-dimensional organoid models to show the transfer of GFP and mRNA from malignant glioblastoma to nonmalignant cells in cerebral organoid models; this transfer is facilitated by extracellular vesicles and possibly tunneling nanotubes, demonstrating how nonmalignant cells in the tumor microenvironment can be exploited by neighboring malignant cells. See related article by Mangena et al., p. 299.
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Organoid-microglia system for modeling the immune microenvironment of the brain and retina.
Glial cells play a critical role in neural development, function, and immune regulation, with microglia serving as the principal immune cells of the central nervous system and retina. Although microglia are central to neuroinflammation and disease progression, progress in understanding human microglial biology has been limited by the lack of physiologically relevant in vitro models. Stem cell-derived brain and retinal organoids provide three-dimensional systems that recapitulate human tissue architecture and developmental trajectories, offering new opportunities to study neuroimmune interactions. This review summarizes strategies for integrating microglia into neural organoids through co-differentiation and transplantation, and outlines methodologies for establishing humanized immune microenvironments and assessing microglial maturation, migration, phagocytic function, and inflammatory activation. We highlight applications of organoid-microglia models in neurodevelopmental and neurodegenerative disorders, including autism spectrum disorder, Alzheimer's disease, and retinal diseases, as well as their potential in drug screening and microglia-targeted interventions. Additionally, emerging technologies-such as organ-on-a-chip platforms, spatial transcriptomics, and multi-omics analyses-are enhancing the physiological relevance and analytical power of these systems. Overall, organoid-microglia platforms bridge a critical gap between conventional cell culture and in vivo models, enabling deeper insights into neuroimmune interactions and accelerating the development of precise immunomodulatory therapies.
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Generating Cerebral Organoids from Human Pluripotent Stem Cells.
3D brain organoids derived from human pluripotent stem cells (hPSCs) possess the remarkable ability to self-organize and differentiate into tissue resembling the early human fetal brain. Brain organoids provide a powerful tool for studying human brain development and disease in an in vitro system. Here we describe a protocol for the differentiation of hPSCs to human cerebral organoids using a commercially available kit (STEMdiff™ Cerebral Organoid Kit) and discuss methods to scale up the protocol in a high-throughput manner.
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Reconstructing human corticogenesis: Insights from cerebral organoids into neurodevelopment and disease modeling.
Understanding the neurodevelopmental biology of the human brain remains a major challenge, primarily due to the lack of model systems that accurately reflect the evolutionary innovations underlying human-specific cell-type diversification, cortical expansion, and higher-order cognition. Cerebral organoids have emerged as powerful stem-cell-derived systems that offer unique opportunities to investigate these processes. Here, we discuss the cellular and molecular features that define human telencephalic development, evaluate how faithfully organoid models mirror in vivo developmental programs, and explore their potential for modeling neurodevelopmental disorders and for therapeutic discovery. We also critically assess the current limitations of cerebral organoids and highlight emerging strategies to enhance their fidelity and translational utility.
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Targeted Microinjection and Electroporation of Primate Cerebral Organoids for Genetic Modification.
The cerebral cortex is the outermost brain structure and is responsible for the processing of sensory input and motor output; it is seen as the seat of higher-order cognitive abilities in mammals, in particular, primates. Studying gene functions in primate brains is challenging due to technical and ethical reasons, but the establishment of the brain organoid technology has enabled the study of brain development in traditional primate models (e.g., rhesus macaque and common marmoset), as well as in previously experimentally inaccessible primate species (e.g., great apes), in an ethically justifiable and less technically demanding system. Moreover, human brain organoids allow the advanced investigation of neurodevelopmental and neurological disorders. As brain organoids recapitulate many processes of brain development, they also represent a powerful tool to identify differences in, and to functionally compare, the genetic determinants underlying the brain development of various species in an evolutionary context. A great advantage of using organoids is the possibility to introduce genetic modifications, which permits the testing of gene functions. However, the introduction of such modifications is laborious and expensive. This paper describes a fast and cost-efficient approach to genetically modify cell populations within the ventricle-like structures of primate cerebral organoids, a subtype of brain organoids. This method combines a modified protocol for the reliable generation of cerebral organoids from human-, chimpanzee-, rhesus macaque-, and common marmoset-derived induced pluripotent stem cells (iPSCs) with a microinjection and electroporation approach. This provides an effective tool for the study of neurodevelopmental and evolutionary processes that can also be applied for disease modeling.