Way back in 1896, the Swiss scientist Rudolf Albert von Koelliker coined the term “axon” to describe the thin cable of a nerve cell that transmits electrical pulses away from the body of the cell. Even further back, however, in 1781, Italian microscopist Felice Fontana already described nerve cells as having “uniform and simple cylinders,” which is the basis for how axons have been described and drawn in textbooks for decades. However, researchers at Johns Hopkins University have conducted experiments with mice showing that brain cells aren’t actually shaped quite like we thought. Their study, published in 2024, and a subsequent one published in 2025, reveal that axons have an endearingly named pearls-on-a-string shape. Instead of just cylindrical tubes, they are like very thin strings with balls arranged along them — all at the nanoscale, of course. The “nonsynaptic varicosities,” which is what the scientists have termed the pearls, are about 200 nanometers across. This is 500 times thinner than the average human hair.
One key question is how they discovered this structure after it has flown under the radar for so long. The important step they took was their high-pressure freezing method, applied to preserve the cells before observing them with electron microscopy. This method preserves the shape of the membranes that make up the axons much better than previously used standard methods of chemically fixing and dehydrating tissues. The experiments were performed on mouse neurons cultured in the laboratory from tissue removed directly from both adult and embryonic mouse brains. Then, the freezing process was applied after the cells were grown. The researchers used a multi-step process that involved liquid nitrogen, acetone at -90°C, and even prechilled tweezers to move specimens between stages. Importantly, the liquid in the tissues is preserved throughout the freezing process. This was demonstrated to produce different results than just chemically fixing the specimens; axons in the chemically fixed cells appeared smoothly cylindrical, as they had in previous experiments.
Gaining a better understanding of what axons look like allows us to better understand their behavior and their role in memory and learning. The observation of pearling in axons allows them to be represented using mathematical models for membrane mechanics, which is already a much-studied field. This could lead to further advances in understanding brain cell signaling and the differences between healthy and diseased neurons. It could contribute to understanding Parkinson’s disease and to modeling the dynamics of brain signals via a better understanding of the biophysical mechanisms that determine the shape of axons. As our understanding of cellular structures progresses and changes, textbooks will need to be redrawn—not for the first time in the history of science—and the field of medicine will continue to deepen and evolve.
