It sounds like science fiction to make a living brain transparent and watch neurons fire without interfering with its function. But the solution may already exist within our own bodies.
In a study published in nature method On March 12, 2026, a research team led by Kyushu University introduced a new reagent called SeeDB-Live. Albumin, a common protein in serum, is used to remove tissue while preserving cellular function. This technique allows scientists to see deeper and brighter structures in both brain slices in dishes and in living mice, allowing them to access previously invisible neural activity.
This is the first time that tissue removal has been achieved without altering biology. ”
Takeshi Imai, lead study author, professor at Kyushu University Graduate School of Medical Science
“SeeDB-Live can pave the way for live imaging of deep tissue. ex vivo and alive”, added Shigenori Inagaki, assistant professor at the same department and lead author of the study.
How can we look deeper into the living brain?
Complex functions such as memory and thinking arise from real-time communication between cells deep in the brain. Although some activity is preserved in the slice, we need to image the living brain to understand normal brain dynamics.
Making the opaque brain transparent is one solution, and it starts with optics.
Consider a glass ball. It is clearly visible in air, but becomes almost invisible in oil. This is because light refracts and scatters when it passes between substances with different refractive indexes, and brain tissue behaves similarly. Lipids and other cellular components create small mismatches that scatter light and hide deeper structures. When you reduce them, the light travels evenly.
Through systematic experiments, Professor Imai’s team discovered that living cells are most transparent when the refractive index of the extracellular solution is adjusted to between 1.36 and 1.37.
With a precise target in hand, the team needed a non-toxic way to reach it while maintaining osmotic balance so that the cells did not swell or shrink. They had previously tried natural substances such as sugar, but they required high concentrations that increased osmotic pressure and dehydrated cells.
Because osmotic pressure depends on the number of molecules, the researchers focused on large spherical polymers. The larger size means less material is needed to increase the refractive index, allowing for tuning of optical performance without stressing the cell. But despite screening nearly 100 compounds, they didn’t get an answer.
Blood proteins are the surprising key to brain transparency
The turning point came unexpectedly.
Late one night, Inagaki returned to the simple idea that proteins are polymers. He picked up a bottle of bovine serum albumin (BSA), a common blood-based laboratory reagent. Surprisingly, this reagent exhibited the lowest osmolality at the desired refractive index.
“I tested it three or four times before I believed it,” Inagaki recalls. That night, alone in his laboratory, he let out an excited scream. “More than anything, I never expected something like this to happen.”
By adding albumin to the culture medium to match the refractive index within cells, the research team developed a live tissue clearing solution, which they named SeeDB-Live.
“During the development of SeeDB-Live, we discovered that neurons are very sensitive to ion concentration, and it took a lot of effort to achieve the right formulation. Thanks to a lucky night spent alone in the lab, we were able to obtain on our own an expensive and highly pure BSA that we normally wouldn’t have the courage to use,” Inagaki adds with a laugh.
SeeDB-Live renders mouse brain slices transparent within 1 hour of immersion. When combined with a calcium indicator, normal neuron firing deep within the tissue was illuminated in transparent brain slices. When applied to the brain of a living mouse, the fluorescent signal from deep neurons became three times brighter.
This opens a clear view of layer 5 of the cerebral cortex, where richly branched neurons help reveal how the brain processes information and converts neural activity into action. Before SeeDB-Live, it was difficult to obtain clear images at this depth using traditional methods.
Furthermore, within a few hours, extracellular fluid washes away SeeDB-Live and the tissue transparency returns to its original state. Because this method does not produce permanent changes, the same mouse can be imaged repeatedly to track brain activity over time.
“Albumin is abundant in blood and has high solubility, so it is suitable for purification,” Professor Imai points out. “This was a serendipitous discovery, but looking back, it feels almost natural. What evolution has shaped over millions of years is truly impressive.”
10 years since I said “impossible”
SeeDB-Live demonstrates the first non-invasive optical clearing that significantly increases imaging depth and allows observation of whole tissue dynamics.
The researchers hope to enhance deep fluorescence imaging for understanding the brain’s integrated functions. It may also be useful for evaluating 3D tissues and brain organoids for drug discovery research.
The researchers note that although SeeDB-Live works well in brain tissue, biological barriers limit delivery to other organs, and access to the brain still requires a surgical window, which can cause stress and reduce efficiency.
“We feel that we have yet to fully realize that potential,” Inagaki said, adding that future efforts will focus on less invasive delivery methods to improve the penetrance for deeper imaging and better functional analysis of brain activity.
For Imai, this result is the culmination of more than 10 years of work. After developing SeeDB for fixed tissue in 2013 and SeeDB2 in 2016, he was repeatedly asked whether removal of living tissue was possible.
“I was asked that question about 100 times, and each time I answered, “It’s impossible,”” Imai recalls. “But 10 years later, here we are. When something seems unattainable, if you keep thinking about it, you might eventually find a way.”
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Reference magazines:
Inagaki, S., Others. (2026). Isotonic, minimally invasive optical clearing medium for ex vivo and in vivo live cell imaging. nature method. DOI: 10.1038/s41592-026-03023-y. https://www.nature.com/articles/s41592-026-03023-y.
