Are Cerebral Organoids the Key to Future Neuropsychological Research?

Neuroscience is a major discipline of psychology and provides a biological perspective for psychologists to reference. This connection allows psychology to enter the realm of “hard science,” that is based on empirical evidence rather than speculation. Other disciplines of psychology have entered this realm as well, but neuroscience provides an indisputable concrete perspective. Some of the more closely applicable fields of neuroscience within psychology involve various brain scans to identify correlations between behavior and brain activity. However, one major shortcoming of the field is the lack of access to human brain tissue for analysis, to identify mechanisms of pathology, and to investigate the neuroanatomy that allows for complex cognitive functioning. Researchers have been asking mechanistic questions for decades related to the source of cognitive function, pathology of psychotic illness, and many other questions that have alluded scientists to the present day.

In the past 20 years, there have been breakthroughs in the field of neuroscience that allow for novel research methods that could provide insight into the aforementioned questions. In 2006, Shinya Yamanaka won a Nobel Prize for discovering the use of Induced Pluripotent Stem Cells(iPSCs) to be manipulated to differentiate into any cell (Takahashi & Yamanaka, 2006). The use of these iPSCs allows for new cell culture research methods that permit researchers to examine human brain tissue in a new light. By 2013, this research led to the development of a new model called Organoids, which are 3D in-vitro models that contain organic human brain tissue that contains genetic information from the source of the iPSCs. These Organoids can be adapted to represent various human organs that depend on procedural elements and the maintenance of the iPSCs that allow them to differentiate into models of different organs. Among these models are Cerebral organoids, which demonstrate the ability to differentiate into the actual layers of the cerebral cortex and provide a new method of investigating certain neurological components of diseases (Chiaradia, & Lancaster, 2020).

Concerning the field of psychology, researchers are using these models to investigate the biological processes behind disorders like schizophrenia. Dr. Dilek Colak, at Weill Cornell, was the Principal Investigator on a project that investigated transcriptional differences in cerebral organoids modeling Schizophrenia (Scz). These Scz organoids were analyzed to determine whether there were “four GWAS factors (PTN, COMT, PLCL1, and PODXL)” that were altered in Scz organoid models compared to controls; as well as “peptide fragments belonging to the POU-domain transcription factor family (e.g., POU3F2/ BRN2)” were altered (Notaras et al., 2022). The authors concluded that Scz organoids differed in their “proteomic diversity, specifically in their total quantity of disease and neurodevelopmental factors at the molecular level” (Notaras et al., 2022). Based on these findings the authors were able to determine that the developmental neuropathology of Schizophrenia is more complex than what is currently accepted within the academic community. Furthermore, the authors were able to uncover several biomarkers of Schizophrenia that would be otherwise unable to be confirmed without access to human brain tissue. The use of these cerebral organoid models has allowed access to human brain tissue and the ability to study specific genetic differences that have allowed researchers to investigate neural mechanisms to better understand mechanisms behind neurodevelopmental disorders. This further understanding can allow clinical psychologists to use these bio-markers to establish clinical differences in behavior and potentially allow for a better course of treatment. Additionally, these organoid models were used to assess developmental pathology in Autism. In a 2023 article, published in Brain, researchers generated cerebral organoids, derived from a patient with Autism that exhibited significant neurological impairment and intellectual disability. These organoids were shown to have deficits in growth and in neural progenitor cell (NPC) proliferation. However, the researchers then used gene-editing software (CRISPER-CAS9) to knock out the AUTS2 gene, which resulted in the reversal of some of the developmental deficits in the organoids (Fair et al., 2023). This shows the wide range of potential this model has for establishing mechanisms behind neuropsychopathology and the potential for establishing therapeutic treatment.

These organoids are a revolutionary in-vitro methodology that allows a study of the brain that has never been possible before. Studying organic, human brain tissue would require open neurosurgery of a live participant, which would put any participant at considerable risk and would potentially put someone at risk of death. Cerebral organoids allow for the study of this same brain tissue and the analysis of genetic components of pathology, but there are still ethical concerns that accompany it. In 2022, a study published Neuron examined the sentience of these cerebral organoids. The cerebral cortex is crucial for decision-making and complex cognitive ability, and these organoids make up the same layers of the cortex on a cellular level. This study embedded a cerebral organoid, derived from a “typical” human, into a game world via a “high-density multielectrode array” (Kagan et al., 2022). In other words, they connected the organoid to a video game. The game was Pong, the first arcade video game. The organoid was probed with an electrode to measure the electrical signal. The results indicated that neural signals were being sent within the organoid and it played the game against a computerized bot (Kagan et al., 2022). So now the question exists, are these organoids sentient and conscious? Are they the key to understanding complex brain mechanisms that can change how we approach psychology and biology? If these creations are conscious, are they ethical to use without their consent? These are the questions being asked, and the world of academia is searching for the answers.        

Works Cited

Chiaradia, I., & Lancaster, M. A. (2020). Brain organoids for the study of human neurobiology at the interface of in vitro and in vivo. Nature Neuroscience, 23(12), 1496–1508. https://doi.org/10.1038/s41593-020-00730-3

Fair, S. R., Schwind, W., Julian, D. L., Biel, A., Guo, G., Rutherford, R., Ramadesikan, S., Westfall, J., Miller, K. E., Kararoudi, M. N., Hickey, S. E., Mosher, T. M., McBride, K. L., Neinast, R., Fitch, J., Lee, D. A., White, P., Wilson, R. K., Bedrosian, T. A., Koboldt, D. C., Hester, M. E. (2023). Cerebral organoids containing an AUTS2 missense variant model microcephaly. Brain: a journal of neurology, 146(1), 387–404. https://doi.org/10.1093/brain/awac244 

Kagan, B. J., Kitchen, A. C., Tran, N. T., Habibollahi, F., Khajehnejad, M., Parker, B. J., Bhat, A., Rollo, B., Razi, A., & Friston, K. J. (2022). In vitro neurons learn and exhibit sentience when embodied in a simulated game-world. Neuron, 110(23), 3952-3969.e8. https://doi.org/10.1016/j.neuron.2022.09.001

Kathuria, A., Lopez-Lengowski, K., Jagtap, S. S., McPhie, D., Perlis, R. H., Cohen, B. M., & Karmacharya, R. (2020). Transcriptomic Landscape and Functional Characterization of Induced Pluripotent Stem Cell–Derived Cerebral Organoids in Schizophrenia. JAMA Psychiatry, 77(7), 745. https://doi.org/10.1001/jamapsychiatry.2020.0196

Notaras, M., Lodhi, A., Dündar, F., Collier, P., Sayles, N. M., Tilgner, H., Greening, D., & Colak, D. (2022). Schizophrenia is defined by cell-specific neuropathology and multiple neurodevelopmental mechanisms in patient-derived cerebral organoids. Molecular Psychiatry, 27(3), 1416–1434. https://doi.org/10.1038/s41380-021-01316-6

Takahashi, K., & Yamanaka, S. (2006). Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell, 126(4), 663–676. https://doi.org/10.1016/j.cell.2006.07.024