In 2005, few neuroscientists would have bet that electron microscopy could map entire neural circuits in three dimensions. The technique was slow and cumbersome, offering only thin slices of brain tissue rather than a view of the complex web of connections underlying thought and memory. Two decades later, the improbable has become reality. In 2025, Nature Methods named electron microscopy (EM)–based connectomics its Method of the Year, recognizing how the technology has transformed the way researchers study the brain.

Among the scientists who helped drive that transformation is Rainer Friedrich, one of the pioneers of EM-based connectomics. At the Friedrich Miescher Institute for Biomedical Research (FMI) in Basel, his lab has helped turn what was once a speculative idea into a powerful experimental approach, producing landmark studies that link neural wiring to brain function.

The technique reconstructs neural circuits at nanometer resolution using three-dimensional electron microscopy, allowing scientists to trace individual neurons and map every synapse connecting them.

“It’s in the connectivity where the function lies,” Friedrich says. For decades, neuroscientists tried to understand brain computation without seeing the full wiring—like reverse-engineering a machine while blind to its circuitry, he says. EM-based connectomics now allows researchers to test theoretical models directly against biological reality.

Pioneering path
Friedrich’s journey into EM connectomics began early in his career at the Max Planck Institute for Medical Research in Heidelberg, where his next-door neighbor was EM-connectomics pioneer Winfried Denk.

“Winfried Denk was developing this new electron microscopy technique, and we would try it out together to answer neuroscience questions, often doing experiments late at night” Friedrich says. “Those were the heydays when things started to work, but it was far from obvious that the method would ever scale.”

Working with Denk made the potential clear. When Friedrich later moved to FMI, he decided to fully invest in the approach. With access to specialized equipment and close collaboration with experts in the EM center, which the FMI shares with Novartis, the method soon evolved beyond what he had imagined. The FMI also provided an environment where neurophysiology, computational neuroscience, and advanced electron microscopy could come together in one place, he says.

Friedrich’s group investigates how networks of neurons give rise to intelligence, memory, and perception. Working in zebrafish, the team focuses on the sense of smell and on how the brain builds internal maps of the surrounding environment. In an early study, the researchers showed how a network of more than a thousand neurons in the olfactory bulb — the brain’s first processing station for smells — turns very similar sensory signals into distinct patterns of neural activity. This process allows the fish to learn and to tell apart smells that would otherwise seem almost identical.

“This is a fundamental computation involved in many learning processes,” Friedrich says. “But it was impossible to understand how it works without detailed information about the connectivity between neurons.”

Theory suggested the computation depended on precise connectivity, but proving that remained out of reach until EM connectomics matured. Using the technique, the team reconstructed more than a thousand neurons in a zebrafish larva’s olfactory bulb and mapped every connection, revealing wiring patterns that explain how the computation emerges from the network.

“That was a breakthrough,” Friedrich says. “It showed that understanding connectivity allows researchers to take a step toward understanding mechanisms of neural computation.”

Inside connectomics
Yet advances in connectomics are rarely the work of a single lab. At the FMI, neuroscientists rely on specialists who design, prepare, and run the complex imaging workflows behind the research. Research associate Alexandra Graff Meyer is one of the experts at the technical heart of connectomics. She prepares samples, supports imaging experiments, trains researchers, and develops protocols that make mapping neural circuits possible.

In EM connectomics, brain tissue is imaged layer by layer at extremely high resolution. Thousands of images are then stacked to reconstruct a three-dimensional map of neural connections. But the process begins long before tissue ever enters an electron microscope. In Friedrich’s lab, experiments start with behavioral training of zebrafish larvae and live calcium imaging, which allows the researchers to record the activity of thousands of neurons as the animals process odors and learn to distinguish between them. These recordings reveal how neural populations respond during behavior and identify the circuits researchers want to examine in detail.

Only then does the preparation for electron microscopy begin. Preparing tissue can take a full week: first, it is fixed to preserve ultrastructure, then stained to create contrast for electrons, and finally embedded in resin to turn delicate biological material into a hardened block that can withstand ultrathin cutting.

Inside a microtome, a diamond knife shaves sections just 25 nanometers thick—about 4,000 times thinner than a human hair. “It’s like cutting carpaccio,” Graff Meyer says. Lose even one slice, and months of work can be ruined, because the continuity of neural wiring is broken.

To make the process reliable at scale, scientists in Friedrich’s group developed SBEMimage, an open-source program that automates serial block-face electron microscopy, where tissue is cut and imaged layer by layer to build a three-dimensional view of neural circuits. The software allows acquisitions to run for days or even weeks.

Imaging is only the beginning. Millions of images must be aligned, reconstructed, and analyzed through computational pipelines that transform raw data into navigable 3D maps of neural circuits. Every step—from sample preparation to image analysis—is tightly connected, requiring close collaboration among neuroscientists, engineers, microscopists, and computational experts.

At the FMI, Tomas Gancarcik, an EM application specialist in Friedrich’s lab, oversees imaging and early computational steps, ensuring each dataset meets the quality needed for accurate 3D reconstruction and turning EM images into full 3D volumes.

The meticulous work of tracing and reconstructing the brain’s circuitry from the processed data falls onto neuroscientists in Friedrich’s team. “You bring together different strands of expertise and focus them on a common project,” Friedrich says. “That’s what generates breakthroughs.”

For Graff Meyer, applying technical skill to answer biological questions is what makes the work rewarding. With the right preparation and imaging, she says, researchers can finally begin to uncover how the brain works.

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