Advances is modern biological science has provided the world with copious amounts of cutting-edge human models and drastic improvements to the level of knowledge in multiple different pathologies. Although, despite the spectacular improvement of modern medicine throughout history, we as a species have still only scraped the surface of potential discoveries and own much more room for improvement. One recent advancement in the field of biological science is the utilization of 3-D cerebral organoid technologies, which despite its novelty, has allowed researchers to make substantial discoveries in many different fields. One current study titled, “Dynamic Characterization of Structural, Molecular, and Electrophysiological Phenotypes of Human-Induced Pluripotent Stem Cell-Derived Cerebral Organoids, and Comparison with Fetal and Adult Gene Profiles”, composed by Sarah Logan et al., the researchers propose a novel experiment, where they aim to uncover further understanding of the relatively new 3D cerebral organoid technology, utilizing pluripotent stem cells (iPSCs) (Logan et al., 2020). More generally, an article from Scientific America, authored by Simon Makin, titled “’Organoids’ Reveal How Human Forebrain Develops”, attempts to summarize the methodology and different uses of 3-D cerebral organoid technology, as well as introduce a different use of these organoids, specifically to better understand how the human forebrain develops (Makin, 2020). Together, these studies offer a glimpse into the workings and implications of this novel organoid technology, and how the discovery of one piece of technology can be utilized to study countless questions in the field of neuroscience.
In the initial study, the researchers were curious on certain properties of these organoids, attempting to understand the molecular and cellular electrophysiology, as few studies have been done in this area. The authors analyzed the possibility of comparison between the lab organoid and human organoids, by utilizing gene expression profiles of cerebral organoids, being either from fetus or adult brains (Logan et al., 2020). This is significant, as comparison between in-vivo models and human models has been historically difficult to dissertate, though the human-induced pluripotent stem cell-derived cerebral organoid has been sufficient in its tasks to model the human brain. After their experimentation was completed, the data was thoroughly analyzed and the researchers concluded that these cerebral organoids held the ability to produce and increase heterogeneous expression of genes of many different types of neuronal cells, (astrocyte, glial, etc.) (Logan et al., 2020). This substantial finding suggests the 3-D cerebral organoid technology may mimic the process of neurogenesis, meaning the production of new functional neurons from adult neuronal precursors (Ming & Song, 2011). In addition, the neuronal cells produced by the cerebral organoids were dosed in the anesthetic agent propofol and showed the expected electrophysiological responses, as well as the evidence of action potentials and activity in various channels, and through bioinformatical analysis, the researchers discovered the gene profiles in the cerebral organoids showed close to an equidistance length apart from each other in all the brain tissues sampled (Logan et al., 2020). Also, in the analysis, the Ingenuity Pathway Analysis (IPA) performed by the researchers suggested that synaptogenesis signaling, glutamate receptor binding, cyclic adenosine monophosphate (cAMP) binding protein CREB signaling, and calcium signaling exclusively were downregulated in the fetal samples, whereas all the phenotypic pathways were suggested to be shown in the adult samples (Logan et al., 2020). This analysis suggests that the pluripotent stem cells (iPSCs) were in-fact performing in the expected fashion, where the neurochemical molecules the researchers were observing were affected by the 3-D cerebral organoid. Overall, the researchers found that electrophysiological drug response closely resembles what occurs in-vivo, specifically the neuronal attributes of the cerebral organoid are closely related to human function, which is beneficial to possible application of these organoids in future models of disease and overall health in the human brain (Logan et al., 2020). This study serves as a glimpse into the many potential implications of this 3-D cerebral organoid technology, where the authors effectively paved a path for future researchers to continue improvement on their human model, hopefully allowing for a better understanding of the human brain overall.
The second study further illustrates the implications of 3-D cerebral organoids, where author Simon Makin explores the work of psychiatrist Sergiu Paca of Stanford University, and his use of 3-D cerebral organoids to develop a more accurate understanding of how human forebrain develops (Makin, 2020). Furthermore, the researchers utilized the same human induced pluripotent stem cells used in the study by Logan, though in the current study they are utilized to mimic the development of the earliest two sections of the forebrain (Makin, 2020). In doing so, the authors utilize a technique known as ATAC-seq, which is a genetic sequencing tool that determined which genes were available for generating proteins, if they are active, current stage of the cell cycle, and what type of neuronal cell it will make (Makin, 2020). Following this, the authors implemented the 3-D cerebral organoids for approximately twenty months, where they observed both the prenatal and postnatal stages of development (Makin, 2020). Most excitedly, once the researchers compared their findings to previous literature, they suggested that the changes they were observing during this twenty month process actually closely mimicked the development of a human brain (Makin, 2020), which effectively adds to the power of this technology, given the first study also happened to make this claim. Following the results of this study, the researchers utilized their findings on this 3-D cerebral organoid technology and found that they can utilize it to find when genes that are linked to autism and schizophrenia (Makin, 2020). Overall, this study provides future researchers with a functional resource when determining if a certain genetic disease may be playing a role in its development, effectively allowing researchers to know what stage to observe when genetic manipulation takes place (Makin, 2020). The study provides sufficient evidence to the use of 3-D cerebral organoid technology, as well as providing resource to future researchers that aim at decoding the mechanisms that develop the human brain.
Thus, these two studies, both equally important, shed light into the vast potential applications and uses of this cutting-edge 3-D cerebral organoid technology. Whether 3-D cerebral organoid technology is aiding researchers in understanding the molecular and cellular electrophysiology, or functionally allowing researchers to better understand the development process of the human forebrain, the development of this technology has been shown to greatly aid researchers in developing more accurate models of disease and function. Despite this technology’s great benefits, both studies discussed here have noted the requirement for more research into 3-D cerebral organoids. As more research is conducted, the potential discovery of different medicines and therapeutics to combat these pathologies is important and crucial to society.
References
Makin, S. (2020, January 24). “Organoids” Reveal How Human Forebrain Develops. Scientific American.https://www.scientificamerican.com/article/organoids-reveal-how-human-forebrain-develops/
Ming, G. L., & Song, H. (2011). Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron, 70(4), 687–702. https://doi.org/10.1016/j.neuron.2011.05.001
Logan, S., Arzua, T., Yan, Y., Jiang, C., Liu, X., Yu, L. K., Liu, Q. S., & Bai, X. (2020). Dynamic Characterization of Structural, Molecular, and Electrophysiological Phenotypes of Human-Induced Pluripotent Stem Cell-Derived Cerebral Organoids, and Comparison with Fetal and Adult Gene Profiles. Cells, 9(5), 1301. https://doi.org/10.3390/cells9051301
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