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Highlight: Disease-in-a-Dish

Healthy mouse neurons are compared to mouse neurons with Timothy syndrome, showing fewer developed dendrites in the neurons with mutation.

In a mouse model of Timothy syndrome, branched extensions of neurons, called dendrites, failed to develop normally in animals with the mutation (right; TS) versus control animals (left; WT).

Source: Ricardo Dolmetsch, Ph.D., Stanford University

The developmental events within the brain that lead to heightened risk for illnesses such as autism and schizophrenia occur long before symptoms appear. How might we learn what these events are, and how to prevent and treat them? A technology called induced pluripotent stem cells (iPSC) holds promise. The iPSC process first alters a person’s skin cells to resemble the stem cells from which they were originally derived. These cells are then induced to differentiate into neurons or glial cells bearing the person’s same genetic signature, thus mimicking an affected brain cell—a veritable disease in a dish! Potentially, researchers can discover the neurodevelopmental secrets of that person’s illness by experimenting with the cells growing in culture. In the future of precision medicine, this information might even lead to engineering a specific treatment for a person’s unique illness. In the meantime, the iPSC technique has become a boon to discovery.

My Neurons—Fast!

Until recently, methods used to coax induced stem cells to differentiate into neurons were comparatively slow and inefficient, resulting in hobbled neurons with diminished capacity to form connections, or synapses. Nobel Laureate Thomas Südhof, M.D., of Stanford University and his colleagues have developed a shortcut to rapidly convert induced human stem cells into viable neurons. The breakthrough method opens the way to large-scale production of induced human neurons for studying the causes of mental illnesses, screening potential treatments, and developing regenerative therapies. This new method readily yields functional, pure neurons in less than 2 weeks—with nearly 100 percent success. To understand how these neurons function, they need to be integrated into a system of neurons—a neural circuit. Researchers are now growing circuits in cultures and transplanting the new human neurons into mouse brains, promising rapid turnaround between new knowledge of mechanisms and translation into practical applications. The new method is based on tweaking a single pivotal regulator of gene expression.15 Using this iPSC approach, Ricardo Dolmetsch, Ph.D., and colleagues at Stanford University discovered the molecular workings of Timothy syndrome and another genetic syndrome related to autism by pinpointing the molecular defects and correcting them in cultured neurons grown from patients’ own skin cells.16

“The brain works by neurons communicating via synapses. We’d like to understand how synapse communication leads to learning on a larger scale. How are the specific connections established? How do they form? And what happens in schizophrenia and autism when these connections are compromised?”

Thomas Südhof, M.D., Stanford University

Highlight from Strategic Objective 1