The brain remains famously remains one of the of the human body. The challenges of neuroscience are among the most daunting in the medical field. Expansion microscopy is a crucial element of that study, a chemical technique that expands a small specimen to make it more observable at the molecular level. A new technique allows scientists to expand microscopy so that instead of focusing on a single cell, it can explore full neural circuits, at a speed around 1,000 times faster than before.
A struggle in studying live cells is watching them without altering their actions. Scientists work around this problem by using thin sheets of light to illuminate cells with a piece of complex technology called a . By combining this microscope with expansion microscopy, scientists at the Howard Hughes Medical Institute (HHMI) were able to expand the possibility of how they could study insect brains.
“I thought they were full of it,” says Eric Betzig, now an HHMI investigator at the University of California, Berkeley, in a . "They" refers to Ruixuan Gao and Shoh Asano of MIT, who wanted to use Betzig's lab to attempt their combining of the two practices. A complex procedure involving high-end scientific equipment, at its heart “the idea does sound a bit crude,” Gao says. “We’re stretching tissues apart."
When the experiment was over, Betzig says, “I couldn’t believe the quality of the data I was seeing. You could have knocked me over with a feather.”
Years earlier, the MIT lab had started using swellable gels, similar to what's found in baby diapers, to expand tissues to study them further. But it can be difficult to study these enlarged tissues or cells, especially when a scientist wants to focus only on a specific region. Adding too much light can risk what's known as "photobleaching," rendering the cell or tissue useless to study.
The lattice microscope uses an ultrathin sheet of light on whatever specimen it's studying, allowing a scientist to study only a specific part of a cell or a tissue. When it came to mouse tissues, Gao and Asano were able to study what are known as dendritic spines. These dendritic spines look like mushrooms with rounded heads and skinny, tiny necks. But with the lattice telescope, they were able to study “the smallest necks possible,” says Asano.
Their combined method has allowed them to image the fly brain in multiple colors in 62.5 hours, or roughly two and a half days. To put that in context, it would have taken years to perform the same procedure with a traditional electron microscope.
“I can see us getting to the point of imaging at least 10 fly brains per day,” says Betzig. That performance ability would allow scientists to ask completely new questions about insect brains, including the differences between male and female flies and even how brain circuits vary.
“We’ve crossed a threshold in imaging performance,” says Eric Boyden, who ran Gao and Asho's lab at MIT and was selected as an HHMI investigator in 2018. “That’s why we’re so excited. We’re not just scanning incrementally more brain tissue, we’re scanning entire brains.”
“Our hope is to rapidly make maps of entire nervous systems,” Boyden says. Being able to capture a full nervous system would be a "holy grail for neuroscience,” he says, allowing scientists to spot where brain diseases originate or even the basics of how behavior works.
Last year, scientists were able to record a mouse's brain in real time. The faster science can capture brains, the closer we'll be to figuring out one of the human body's great mysteries.