Neuro Primer: Cerebral Organoids

[dropcap]I[/dropcap]t may sound like something Dr. Frankenstein himself would be envious of, but scientists can now create miniature “brain” organoids in a dish. This technique was perfected by Madeline Lancaster and her colleagues in 2013, who published their findings in Nature. The researchers start with human stem cells, which are cells that have the capacity to develop into multiple other types of cells. They are self-renewing, meaning that they can also divide to increase their number without differentiating into a different cell type. This quality allows the researchers to culture stem cells in a petri dish. 

To trigger these cells to differentiate into neurons, the scientists add just the right cocktail of nutrients. These molecules turn on the cell signaling cascades that tell the cell to become a neuron. They then incubate these cells with a scaffold to grow on in a spinning chamber that promotes nutrient absorption. By 8-10 days, neural cells have formed, and by 1-2 months, the cells have turned into a cerebral organoid, about the size of a pea.

Unlike regular cultured cells, cerebral organoids possess several characteristics that take them a step closer toward “brains in a dish.” Like a true human brain, the neurons in cerebral organoids organize themselves into discrete regions with characteristics of specific parts of the brain. These regions can take on the identity of forebrain, hindbrain, retina, and other neural tissue types. As in real tissue, diverse types of neurons make up each region, and the neurons in different regions can form connections to communicate with each other. 

To test whether this technique is relevant to human disorders, the researchers created a cerebral organoid from a patient with microcephaly, a disability that causes the brain to be abnormally small and typically causes cognitive impairment. They were pleased to find that the organoid made from this patient was much smaller than an organoid made from a control of the same age. Comparing the two “mini-brains” revealed that the patient-derived organoid was more disorganized than the control, and the neural stem cells exited the cell cycle (meaning they can no longer divide to increase their number) too soon. Other scientists are now using cerebral organoids to make progress on solving other threats to human health, such as microcephaly caused by Zika virus.

The capacity to grow “brains-in-a-dish” has spurred debate among bioethicists as well. Currently the organoids are very simple models of the human brain, approximating that of a nine-week-old fetus. However, organoids are becoming increasingly complex, and that raises some concerns. This past April, 17 prominent neuroscientists published a comment in Nature outlining the issues that will need to be considered as we progress into the future. These include the need to assess how “sentient” cultured brains are and the risk of making animal-human chimeras that are too “human-like.” Although these issues may sound like the stuff of science fiction, scientists have already shown that cerebral organoids thrive when transplanted into a rodent brain, suggesting that the ethical issues in the rearview mirror may be closer than they appear.

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Written by Caitlin Aamodt

Illustrated by Kayleen Schreiber

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References

Lancaster, M. A., Renner, M., Martin, C. A., Wenzel, D., Bicknell, L. S., Hurles, M. E., … & Knoblich, J. A. (2013). Cerebral organoids model human brain development and microcephaly. Nature, 501(7467), 373.