November 2019

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t m c » p u l s e | n o v e m b e r 2 0 1 9 23 W hen neuroscientist Robert Krencik figured out how to fast-track the growth of mini-brains, he shared his process with the scien- tific community. Over the past two years, his method has been adopted in labs around the world. Krencik's lab-grown 3D models— commonly known as brain organ- oids or mini-brains—incorporate star-shaped brain cells called astrocytes. He named his creations "asteroids," which seems fitting for a scientist based in Houston, a city obsessed with Astros baseball and all things NASA. For Krencik, a Ph.D. who works at Houston Methodist Research Institute, a scientific breakthrough that accelerated brain research might have been enough. But it was just the beginning. Now, he is focused on using his asteroids to uncover methods to repair the nervous system while also working to create the next genera- tion of brain organoids—with hopes of better mimicking the actual brain. "The term 'mini-brains' is misleading because they're not miniaturized versions of the human brain—they're actually small aggre- gates of cells. ... Though they do have neural activity and recapitulate some aspects of the brain, they're still lacking the multiple cell types of the brain and they're not con- nected to sensory systems," Krencik noted. Still, their potential for studying disease processes or regeneration of the nervous system is staggering. "To identify drugs to promote repair of the brain—after aging, injury, Alzheimer's disease, neuro- degenerative diseases, stroke—you need a model system that recapitu- lates the environment of the human brain. That doesn't just involve a single cell type, but it involves mul- tiple cell types including a vascula- ture, and it involves the extracellular proteins and matrix that make up the environment of the brain," he said. Krencik meets regularly with the neurosurgery department and Center for Neuroregeneration at Houston Methodist as he works to apply his research to the field of neuroregeneration. "The large structure of the organoids allows us to study things that are important in neurosurgery, which you couldn't study with traditional cell culture systems," Krencik said. "Also, the fact that we can grow these long- term allows us to study regenera- tion, because the human nervous system—during development and after injury—takes a long time to form synaptic connections." Significant benefits Krencik's lab uses a method called trans-differentiation to rapidly gen- erate neurons from stem cells, which allows the researchers to force cells, through genetic engineering, to directly differentiate into a pure population of neurons within one week—instead of waiting for them to slowly develop over several weeks, Krencik said. "By assembling neural organ- oids with both neurons and astro- cytes in specific ratios, we can reproducibly and rapidly generate a well-defined version we call 'aster- oids,' instead of waiting for them to spontaneously mature into neural networks," he said. ➟ Above: Robert Krencik, Ph.D., a neuroscientist at Houston Methodist Research Institute, holds up a 3D printed model of a human brain in his office. Facing page: Krencik captured an image of his live asteroids, floating inside a cell culture flask, in culture media, as they are typically maintained. The image was shot through a microscope with magnification. The average diameter of each asteroid is between 200 and 300 micrometers.

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