BreakthroughThree-dimensional clusters of living neurons that can be grown in a lab from human stem cells.
Why it mattersResearchers need new ways of understanding brain disorders and testing possible treatments.
Key playersMadeline Lancaster and Jürgen Knoblich, Institute of Molecular Biotechnology; Rudolph Tanzi and Doo Yeon Kim, Massachusetts General Hospital
As Madeline Lancaster lifts a clear plastic dish into the light, roughly a dozen clumps of tissue the size of small baroque pearls bob in a peach-colored liquid. These are cerebral organoids, which possess certain features of a human brain in the first trimester of development—including lobes of cortex. The bundles of human tissue are not exactly “brains growing in a dish,” as they’re sometimes called. But they do open a new window into how neurons grow and function, and they could change our understanding of everything from basic brain activities to the causes of schizophrenia and autism.
Before it grows in one of Lancaster’s dishes, a brain organoid begins as a single skin cell taken from an adult. With the right biochemical prodding, that cell can be turned into an induced pluripotent stem cell (the kind that can mature into one of several types of cells) and then into a neuron. This makes it possible to do things that were impossible before. Now scientists can directly see how networks of living human brain cells develop and function, and how they’re affected by various drug compounds or genetic modifications. And because these mini-brains can be grown from a specific person’s cells, organoids could serve as unprecedentedly accurate models for a wide range of diseases. What goes wrong, for example, in neurons derived directly from someone with Alzheimer’s disease?
The prospect of finding answers to such questions is leading pharmaceutical companies and academic researchers to seek collaborations with Lancaster and Jürgen Knoblich, whose lab at the Institute of Molecular Biotechnology (IMBA) in Vienna, Austria, is where Lancaster developed the organoids as a postdoc. The first of these collaborations was an investigation of microcephaly, a disorder characterized by small brain size, with Andrew Jackson of the University of Edinburgh. Using cells derived from a patient with microcephaly, the team cultured organoids that shared characteristics with the patient’s brain. Then the researchers replaced a defective protein associated with the disorder and were able to culture organoids that appeared partially cured.
This is just the beginning, says Lancaster. Researchers such as Rudolph Jaenisch at MIT and Guo-li Ming at Johns Hopkins are beginning to use brain organoids to investigate autism, schizophrenia, and epilepsy. What makes cerebral organoids particularly useful is that their growth mirrors aspects of human brain development. The cells divide, take on the characteristics of, say, the cerebellum, cluster together in layers, and start to look like the discrete three-dimensional structures of a brain. If something goes wrong along the way—which is observable as the organoids grow—scientists can look for potential causes, mechanisms, and even drug treatments.
The breakthrough in creating these organoids happened as part of a side project. Other researchers had grown neurons in a dish before, and like them, Lancaster started by using a flat plate to “play” with neural stem cells—the kind that form into neurons and other cells in the nervous system. Sometimes, she says, “I’d get neural stem cells that wouldn’t really stay in 2-D, and they would kind of fall off the plate and they’d make 3-D clumps—and rather than ignoring them or throwing them away, I thought, ‘Those are cool—let’s see what happens if I let them keep growing.’” But there was a major challenge: how to keep the tissue at the center of the organoids fed without the benefit of veins. Lancaster’s solution was to encapsulate each organoid in a matrix known to nurture cells, put a dozen of these blobs in a nutritious bath, and shake or spin it all to keep the organoids awash in cellular food.
Since publishing her method, Lancaster has pushed the brain tissue to further levels of complexity with neurons at later stages of development. The number of possible applications grows with each advance. Most tantalizing to Lancaster herself is the prospect that cerebral organoids might solve the deepest of mysteries: what happens in our brains to set us apart from other animals? “I’m mainly interested,” she says, “in figuring out what it is that makes us human.”
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