Author: Melanie Bonyadi
Artist: Emily Vialls
Editor: Rachel Nguyen
“Mini brains,” or brain organoids, are a 3D multicellular tissue generated from human-derived pluripotent stem cells that have been reprogrammed to resemble the human brain. To do this, human cells, such as skin cells, are taken from a patient and reprogrammed by specific transcription factors into induced pluripotent stem cells, which can differentiate into any cell type. These stem cells are then induced to differentiate into neural stem cells, which can produce many of the cell types found in the brain and can then be aggregated together to form 3D structures that can physiologically respond to signals in a similar way to the human brain. At this point, the organoids can also form structures such as neurons that can be representative of specific brain regions.
Given the structural and functional complexity of the brain, the extent to which brain organoids can develop structures in the same way as a human brain remains elusive. A study by Trujillo and colleagues reported electrophysiological waves of activity in brain organoids and found alternating periods of quiescence (inactivity) and synchronised oscillatory activity. Even though this pattern of activity does not demonstrate the full complexity of adult brain activity, it does resemble electrical activity observed in preterm human infants, hence demonstrating the potential for brain organoids to exhibit human-like electrical activity. Furthermore, these synchronous waves of activity could possibly indicate a functional neuronal network and given that this type of activity is important for the flow of information between different brain regions, these results seem promising.
Subsequently, this leads us to question whether these brain organoids could be conscious. This is a difficult question to answer as there is often ambiguity concerning the definition of consciousness. One approach for assessing consciousness in brain organoids would involve stimulating them with a pulse of energy. In theory, if the organoids are “conscious,” they should produce an electrical “echo”; an unconscious organoid would remain unresponsive to this stimulation. However, this type of experiment has not been conducted in brain organoids to date. Another way to evaluate consciousness in brain organoids could be to measure their responsiveness to light stimuli. For example, Quadrato and colleagues found that brain organoids cultured for an extended period of time generated photoreceptor-like cells that have proteins that are required to respond to light. These organoids also showed signs of neuron firing, which normally indicates communication between neurons, following light exposure. Although these results may seem promising, there is still insufficient evidence to ascertain whether brain organoids can be deemed as “conscious,” as the organoids would be unlikely to be able to process visual information from the light. Therefore, many neurobiologists do not currently think that brain organoids are capable of being conscious.
Overall, human-derived brain organoids can be a more useful model for studying diseases than using animal models or 2D human brain models, as organoids more closely resemble human brain development. Organoids can therefore be used to study diseases, such as for identifying how risk factors of a disease are linked to cellular phenotypes, understanding how pathogenic mutations can affect tissues, and screening potential therapies. For example, Mohamed and colleagues found that midbrain organoids derived from human cells in patients with a mutation in the SNCA gene (which is known to be a risk factor for Parkinson’s disease) had increased levels of aggregates that are normally seen in human Parkinson’s patients. This suggests that using brain organoids as a model for Parkinson’s disease could be vital for studying the pathogenesis of the disease. Having said this, there are still ethical implications that should be considered when using brain organoids in research. For example, using human cells to create organoids can be an ethical issue as it is important that the donors give consent and know what research their cells are being used in. In addition, the consequences of transplanting organoids into humans or animals would need to be considered. For example, one experiment found that brain organoids implanted in rats led to their integration into the rat’s brain and appeared to affect its cognitive abilities, which raises issues about humanising animal brains.
Therefore, despite these potential shortcomings, brain organoids the size of a sesame seed could revolutionise research and understanding of brain diseases and provide a platform for testing potential treatments for such diseases in the future.
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