In 2011, a biologist named Madeline Lancaster was working on growing 2D neural rosettes. Neural rosettes are columnar cells that form a radial structure and express proteins that are also expressed in neuroepithelial cells of a neural tube (Wilson & Stice, 2006). In an interesting turn of events, the cells instead started growing into a self-organized 3D structure. When she grew them over time, these structures began to seem slightly similar to brain tissue. We call these structures brain organoids. This breakthrough has significantly changed the way we understand and study the human brain, including the evolution and development of the brain, brain cancer, brain disorders and many other possibilities (Nowogrodzki, 2018). It provides us with a more efficient alternative to how we study the brain today.

Studying the brain is quite difficult due to ethical and practical limitations. The methods we use have helped us advance in the study of human brains; however, there are many disadvantages as well. For example, brains that are surgically removed from the body are not sufficient in tissue preservation or tissue processing. Observing the brain tissue of live humans is also difficult and involves many ethical complications. Instead, scientists study neurons in dishes that are kept alive, but this method was also not sufficient enough for thorough observation. Due to these complications, we observe animal brains; however, this is insufficient as the overall composition of an animal’s brain and a human’s brain differ considerably (Koo et al., 2019).

Brain organoids are comprised of progenitor, neuronal and glial cell types. They are produced from human stem cells that, when grown, self-structure themselves into a model that has resemblance to a very small fetus brain and consist of electrically active neurons. A depiction of the neurons within a brain organoid structure can be seen in Figure 1. As of now, they have a diameter of about 4mm. They recapitulate the development trajectory and tissue structure of a brain, providing us with the opportunity to study the evolution of the brain (Qian, Song & Ming, 2019).

During the early development of brain organoids, the cells seem to form in an organized manner (Figure 2), although after a considerable period of development, the cells begin to form in a disorganized manner. Though these models consist of the major functional and neuroanatomical structures, they lack the diversity of cell subtypes. Diversity within cell subtype is crucial for the neural circuits to function appropriately. These models also exhibit an unusually high amount of cellular stress genes. Cellular stress can be caused by various factors, including environmental conditions, such as heat, damage within the cell, etc. (Fulda, et al., 2010). For these reasons, over time, brain organoids begin to form in a disorganized manner (Figure 3). Researchers hypothesize that the cellular stress experienced by these models may be the reason the models are unable to develop into appropriate neural cell types, and are currently looking into the ways we can reduce the cellular stress experienced by a model (Weiler, 2020).

Brain organoids have great potential in the field of science, particularly neuroscience. With more research and experimentation, we may be able to form a standard experimental model that resembles the complex organization of the human brain, so as to be able to efficiently study the brain. Furthermore, this may allow for further study of the brain without the limitations that restrict us today.

References:

Fulda, S., Gorman, A.M, Hori, O., Samali, A., 2010. Cellular Stress Responses: Cell Survival and Cell Death. International Journal of Cell Biology, 2010(214074), p.23. https://doi.org/10.1155/2010/214074

Koo, B., Choi, B., Park, H., and Yoon, K., 2019. Past, present, and future of brain organoid technology. Molecules and Cells, 42(9), pp.617-627. https://doi.org/10.14348/molcells.2019.0162

Nowogrodzki, A., 2018. How cerebral organoids are guiding brain-cancer research and therapies. Nature, 561, pp.S48-S49. https://doi.org/10.1038/d41586-018-06708-3

Qian, X., Song, H., and Ming, G., 2019. Brain Organoids: Advances, Applications and Challenges. The Company of Biologists, 146(8): dev166074. https://doi.org/10.1242/dev.166074

Velasco, S., Kedaigle, A.J., Simmons, S.K., Nash, A., Rocha, M., Quadrato, G., Paulsen, B., Nguyen, L., Adiconis, X., Regev, A., Levin, J.Z., and Arlotta, P., 2019. Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature, 570, pp.523–527. https://doi.org/10.1038/s41586-019-1289-x

Weiler, N., 2020. Not ‘Brains in a Dish’: Cerebral Organoids Flunk Comparison to Developing Nervous System. University of California San Francisco [online]. Available at: <https://www.ucsf.edu/news/2020/01/416526/not-brains-dish-cerebral-organoids-flunk-comparison-developing-nervous-system> [Accessed 13 Nov. 2020]

Wilson, P.G., and Stice, S.S., 2006. Development and differentiation of neural rosettes derived from human embryonic stem cells. National Library of Medicine 2(1), pp.67-77. https://doi.org/10.1007/s12015-006-0011-1