How to Build a Mini Brain
According to Dr. Knoblich, the researchers began their work with established human embryonic stem cell lines and then induced microcephalic patient-derived cells to turn into pluripotent stem (iPS) cells to generate organoids. “We wanted to compare the organoids to healthy cells,” he said.
Intrinsic cues from the stem cells guided the development toward different interdependent brain tissues. Using the mini brains, the scientists were able to model the development of a human neuronal disorder (i.e., microcephaly) and identify its origin.
“A normal developing brain has a stem cell population that undergoes rounds of division at specific times to make more stem cells and eventually neurons,” noted Dr. Lancaster. “But the microcephalic patient-derived stem cells made neurons too early in the process. This led to a depletion of the stem cell population, which resulted in fewer neurons being made.”
Putting it another way, Dr. Knoblich explained that this finding led to the hypothesis that, during brain development of patients with microcephaly, the neural differentiation happens prematurely at the expense of stem and progenitor cells, which would otherwise contribute to a more pronounced growth in brain size. “Further experiments also revealed that a change in the direction in which the stem cells divide might be causal for the disorder,” he continued.
The mini brains had reached their maximum size after two months, but they could survive indefinitely (currently up to 10 months) in the spinning bioreactor, according to the scientists. Further growth, however, was not achieved, most likely due to the lack of a circulation system and hence a lack of nutrients and oxygen at the core of the mini brains. “In normal brain cells the vasculature brings in essential nutrients,” explained Dr. Knoblich.