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Lego-Like Brain Balls Could Build a Living Replica of Your Noggin

Lego-Like Brain Balls Could Build a Living Replica of Your Noggin
From Wired - August 12, 2017

The human brain is routinely described as the most complex object in the known universe. It might therefore seem unlikely that pea-size blobs of brain cells growing in laboratory dishes could be more than fleetingly useful to neuroscientists. Nevertheless, many investigators are now excitedly cultivating these curious biological systems, formally called cerebral organoids and less formally known as mini-brains. With organoids, researchers can run experiments on how living human brains developexperiments that would be impossible (or unthinkable) with the real thing.

The cerebral organoids in existence today fall far short of earning the brain label, mini or otherwise. But a trio of recent publications suggests that cerebral-organoid science may be turning a cornerand that the future of such brain studies may depend less on trying to create tiny perfect replicas of whole brains and more on creating highly replicable modules of developing brain parts that can be snapped together like building blocks. Just as interchangeable parts helped make mass production and the Industrial Revolution possible, organoids that have consistent qualities and can be combined as needed may help to speed a revolution in understanding how the human brain develops.

In 2013 Madeline Lancaster, then of the Austrian Academy of Sciences, created the first true cerebral organoids when she discovered that stem cells growing in a supportive gel could form small spherical masses of organized, functioning brain tissue. Veritable colleges of mini-brains were soon thriving under various protocols in laboratories around the world.

Much to the frustration of impatient experimentalists, however, the mini-brains similarity to the real thing only went so far. Their shrunken anatomies were distorted; they lacked blood vessels and layers of tissue; neurons were present but important glial cells that make up the supportive white matter of the brain were often missing.

Worst of all was the organoids inconsistency: They differed too much from one another. According to Arnold Kriegstein, director of the developmental and stem cell biology program at the University of California, San Francisco, it was difficult to get organoids to turn out uniformly even when scientists used the same growth protocol and the same starting materials. And this makes it very difficult to have a properly controlled experiment or to even make valid conclusions, he explained.

Researchers could reduce the troublesome variability by treating early-stage organoids with growth factors that would make them differentiate more consistently as a less varied set of neurons. But that consistency would come at the expense of relevance, because real brain networks are a functional quilt of cell typessome of which arise in place while others migrate from other brain regions.

For example, in the human cortex, about 20 percent of the neuronsthe ones called interneurons, which have inhibitory effectsmigrate there from a center deeper down in the brain called the medial ganglionic eminence (MGE). An oversimplified organoid model for the cortex would be missing all those interneurons and would therefore be useless for studying how the developing brain balances its excitatory and inhibitory signals.

Deliverance from those problems may have arrived with recent results from three groups. They point toward the possibility of an almost modular approach to building mini-brains, which involves growing relatively simple organoids representative of different developing brain regions and then allowing them to connect with one another.

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