Team Science at the Allen Institute: The Synapse Biology Team

January 22, 2015

How do the individual cells in our brains communicate? This seemingly simple question is in fact enormously complex. To address this  fundamentally challenging topic, the Allen Institute recently welcomed renowned neuroscientist Stephen Smith from Stanford University to lead a team to understand how human brain cells relay and store information.

Long before he studied the human brain, Smith’s career began by investigating more humble neural systems. “I studied neural computation in just about any animal you can imagine—slugs, snails, squid, frogs, fish, rats, mice,” says Smith. “My motivation all along was to understand the human brain: something that I had almost given up hope would happen in my lifetime.”

This quest to understand the human brain has led Smith to investigate synapses: the tiny gaps between brain cells where chemical signals are sent and received. Each of the brain’s roughly 100 billion neurons can have up to ten thousand synaptic connections to other cells. No two of these connections are exactly alike. “We are only just beginning to understand the immense diversity of synapses,” says Smith.

But if neurons are challenging photographic subjects, synapses are so incredibly small that Smith and the team he has assembled are inventing new technologies to capture them.

A synapse may have anywhere from 10 to 2,000 molecules on either side of its gap. To identify them, Linnaea Ostroff, who joined the Institute from New York University, takes small pieces of brain tissue and freezes them down to liquid nitrogen temperatures in a fraction of a second in order to outrun dangerous ice crystals. She then replaces all the water in the brain tissue with hard plastic, making it easier to slice the brain into sheets less than a thousandth of the thickness of a sheet of paper. The plasticized slices are washed in fluorescent chemicals that identify individual molecules before being imaged in a fluorescent microscope, where the molecules Ostroff labeled glow eerie colors. For a more detailed view, the same slices can be viewed in an electron microscope, where even the tiniest synapses can be seen clearly.

But the picture is not complete. Next, the many thousands of slices need to be digitally reassembled in three dimensions. Forrest Collman, who also recently joined the Institute from Stanford, has been charged with taking this painstaking process and making it automatic enough that computers can do the reassembly for us. The images need to be not only stitched together like a patchwork quilt horizontally and vertically, but also stacked to recreate the three-dimensional brain. And because those impossibly thin slices of brain often warp, shrink or stretch, computers need to be especially smart about reconstructing them.

Studying synapses poses challenging technical problems for biochemists as well as computer scientists, which is why Smith’s multidisciplinary team is so crucial to success. Smith hopes that his team will make valuable contributions to the understanding of how human brains can process vast amounts of information, with synapses as the main stage for all that signal processing.

“The way that networks of neurons process information is fundamental to who we are as humans,” says Smith. “Not only can a better understanding of synapses help us create preventions and cures for many diseases, but it can give us insight into the nature of humanity.”