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News feature: better models for brain disease
Thursday, 2016/05/19 | 07:50:37
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Helen H. Shen, Science Writer PNAS May 17, 2016 Traditional animal models have had limited success mimicking mental illnesses. Emerging technologies offer the potential for a major model upgrade.
Starting with just a tiny chunk of skin, neuroscientist Flora Vaccarino tries to unlock mysteries hidden inside the brains of people with autism. By introducing certain genes to the skin cells, the Yale University School of Medicine researcher reprograms them to an embryo-like state, turning them into induced pluripotent stem cells (iPSCs); and with two more months of nurturing and tinkering, Vaccarino can guide the cells to develop into small balls of neural tissue akin to miniature human brains.
Less than two millimeters across, these “cerebral organoids” don’t look or work exactly like full brains. But they contain many of the same cell types and undergo some of the same key developmental processes as fetal brains. Also key, the cells perfectly match the genetic makeup of the adults and children with autism who donated the original skin samples, allowing Vaccarino’s team to track the very beginnings of their disorder.
Human brain tissue usually can’t be collected and studied until after death, and by then, it can be too late to glean important insights. “You don’t get to see the same person’s cells progressing through a series of steps and time points, like we do with these organoids,” Vaccarino explains. “The organoids are a very powerful system. You can actually change things and see what the outcome is going to be.”
Predicting outcomes and, crucially, developing psychiatric drugs has proven exceedingly difficult in recent decades. Inadequate animal models have been a major stumbling block, researchers say. First developed in 2013 (1), cerebral organoids grown from human iPSCs—affectionately called minibrains by some—are one of several emerging technologies that are finally allowing researchers to make more sophisticated models of neuropsychiatric disorders. Advances in genomics are also helping to shed new light on mental illnesses by pointing researchers to new gene targets. These, in turn, can be combined with recent precision gene-editing techniques to make animal models that many researchers hope will more faithfully reproduce aspects of human diseases, such as Alzheimer’s, autism, and schizophrenia.
“It’s a very exciting time,” says Guoping Feng, a neuroscientist at the Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts. “Between the technology development and the genetic findings, this is the first time that we’ve been able to begin digging deep into the causes and neurobiology of these disorders.”
Figure: To study brain disorders in living human tissue, researchers grew this cerebral organoid from stem cells derived from a healthy donor's skin sample. In this cross-section, the neurons are green, progenitors are red, and nuclei are blue. Image courtesy of Madeline A. Lancaster and Juergen A. Knoblich. Reproduced from ref. 1, with permission from Macmillan Publishers: Nature, copyright (2013).
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