What if we had a glass window into the brain that lets us look inside? For the first time ever, a team of physicists, chemists and biologists has done just that. Led by a microscopy pioneer, they peered into a living mouse's brain using powerful technology.
"You can look into the brain and see a true neuron in action," said physicist Stefan Hell, who leads the Max Planck Institute of Biophysical Chemistry's Department of NanoBiophotonics. His team's achievement is described in the latest issue of the journal Science.
Hell is well-known in the field for inventing a super-resolution "stimulated emission depletion" or STED microscope in the 1990s that can distinguish among features in living samples on a scale so small that general wisdom said it would be impossible.
With that microscope, Hell and his colleagues at Max Planck can discern features down to 70 nanometers in the living brain — four times beyond what had been the physical limit.
An electron microscope can show powerful levels of detail, but only on dead cells mounted and prepared just so. Recently Hell's team took a live mouse that had been genetically modified so its neurons produce a fluorescent agent. They placed the mouse under anesthesia, opened its skull, and replaced part of the bone with a glass window.
Then, the STED microscope lens was attached to the window so light could be focused on an upper layer of the live mouse's brain. Operating almost like an ultra-precise spotlight, the microscope illuminated only individual neurons carrying the fluorescent marker. All the other cells were dark, letting the neurons shine. (The mouse survived the procedure.)
The resulting images from the live brain have an unprecedented level of clarity, Hell said. Little protrusions with thin necks and a cup-like shape at the end can be seen on the neurons. These "dendritic spines" are the input, the place where a neuron receives signals from a synapse.
Since their technique requires a transgenic animal whose neurons fluoresce, Hell said the plan isn't to make such a window for any human brains. However, there is potential to use this approach for research into treating or even preventing certain neurological diseases.
"I think we can learn a lot about what's going wrong, for example, at a synapse in certain cases," Hell said. "That door is now slammed wide open because one can access a level of functionality, a level of detail that is really critical."
Next, Hell said, he and his colleagues want to help neuroscientists use their method to learn about brain functions that are still poorly understood. They would also like scientists to advance research into potential treatments by studying malfunctioning synapses in live animal brains. As physicists, he added, his team will work on producing sharper images.
Neurobiologist Bill Betz is a professor and chair of physiology and biophysics at the University of Colorado School of Medicine who uses microscopes to synapses.
Electron microscopes are great, Betz continued, but increasingly people want to know what live cells are doing, especially since nearly all psychiatric drugs used in medicine work on synapses.
"Then along came Stefan Hell. 'Hell,' by the way, in German means 'bright,'" Betz said. "He built a microscope that broke a fundamental law of physics."
Hell's technique fills the gap where scientists couldn't view anything smaller than about a quarter of a micrometer in size, he added. "With the STED microscope, there are just many — probably thousands — of different types of structures that this opens a window on to see."
Columbia University biology professor Rafael Yuste's lab researches the cerebral cortex, the part of the brain responsible for perception, memory and imagination. Together with Andrew Matus' group, his lab was the first to discover how dendritic spines actually move in 1999. The reason for those precise movements remains a scientific mystery.
"The main significance is the technical tour de force, not the scientific discovery," Yuste said of Hell's research. He added that one potential challenge is that the technique can currently only be applied to the top 1 percent of the brain.
He knows Stefan Hell and called the physicist resilient. "Although it may seem impossible to solve the problem of imaging deeper, I have confidence that they will come up with an answer."