“I tested it three or four times before I believed it,” said Shigenori Inagaki of the discovery that enabled the breakthrough.
It might sound like something out of a piece of gothic sci-fi, but researchers have managed to turn a living brain transparent without interfering with its function—allowing them to observe brain activity down to watching individual neurons fire.
Making Dr. Frankenstein eat his heart out are scientists from Japan’s Kyushu University, who have developed an impressive new chemical tool they have dubbed “SeeDB-Live.” The reagent uses albumin—a protein found in blood serum—to make tissue see through while maintaining normal cellular function.Paper co-author and neurophysiologist professor Shigenori Inagaki added that “SeeDB-Live can pave the way for deep-tissue live imaging” in both tissue samples and live animals. This, the team explains, could not only shine fresh light on how the brain works, but also help researchers to evaluate lab-grown tissues and organoids for use in drug discovery research.Major brain functions like memory and thought are the result of communication between cells deep with the brain—meaning that, to understand brain dynamics, methods of imaging deep into living One approach is to make the brain tissue itself transparent. Key to this is a property of materials known as the “refractive index," which determines how much light bends when it enters a material. There’s a fun scientific"magic trick"—if you place glass marbles into oil, they seem to almost disappear. This is because the refractive index of glass and oil is roughly the same, reducing the amount that light is scattered as it crosses the surfaces where the two meet. The contents of the brain behave in the same way. Ordinarily, the difference in refractive indices of the various cellular components causes light to scatter, obscuring our view of deep brain structures. But if you could reduce these differences, the brain would become more see-through. Through experimentation, the researchers determined that living cells become most transparent to light when the refractive index of the extracellular solution is adjusted to between 1.36 and 1.37. Of course, identifying this value is one thing—reaching it is another. Any solution would need to be non-toxic, but also maintain"osmotic balance" so that the brain cells neither swell nor shrink. Case in point: one of the substances that the researchers initially experimented with to change the refractive index of the extracellular solution was sugar. Unfortunately, the concentration of sugar needed to achieve the desired effect was so high that it ended up dehydrating the brain cells. The researchers’ next gambit involved experimenting with large, spherical polymers—under the rationale that, as osmotic pressure is dependent on molecular size, larger molecules might sufficiently raise the refractive index without compromising cellular water levels. But after screening nearly 100 such polymers, the team had still failed to find one that worked successfully. The breakthrough came when Inagaki returned to a simple idea one night alone in the lab—the notion that proteins are biological polymers. He grabbed a bottle of bovine serum albumin — a common laboratory reagent, derived from cows’ blood—which he discovered had the lowest osmotic pressure at the desired refractive index. “I tested it three or four times before I believed it,” Inagaki said. “Of all things, we never expected it would come down to this.” Adding albumin to the culture medium allowed the team to match the refractive index inside cells, producing their live-tissue clearing solution, SeeDB-Live. “During the development of SeeDB-Live, we found that neurons are extremely sensitive to ion concentrations—and it took us enormous effort to get the formulation right. “Thanks to that fortunate night alone in the lab, I helped myself to an expensive, high-purity BSA I wouldn’t normally dare use,” Inagaki quipped.According to the team, SeeDB-Live renders mouse brain slices transparent within just an hour of immersion. When the team combined the clearing solution with a calcium indicator, it allowed the team to illuminate the activity of neurons firing within tissue samples. Applied to live mouse brains, the fluorescence signals from the neurons became three times brighter, the team said. In fact, the team were able to see as far into the mouse brains as the fifth—and penultimate—layer of the cerebral cortex, the part of the brain thought responsible for high-level cognitive functions. Previously, good images from this depth were difficult to obtain; with SeeDB-Live, however, the branching neurons could be seen clearly. The researchers explained that SeeDB-Live is washed out by the extracellular fluid within hours of being administered, after which the tissue turns back to its normal, opaque state. “Albumin is abundant in blood and highly soluble, which makes it well-suited for clearing,” said Imai. “It was an accidental discovery, but looking back it feels almost natural. What evolution has shaped over millions of years is truly impressive.” While SeeDB-Live successfully makes brain tissue see-through, biological barriers impede its application to other organs. Furthermore, its use in the brain still requires a surgical window to access the organ. In the future, the team plan to explore less invasive delivery methods to enable deeper views inside the brain, along with work to improve functional analysis of brain activity.For Imai, the breakthrough is the culmination of more than a decade of work—and the triumphant settling of the question as to whether live clearing was even feasible.“But 10 years later, here we are. When something seems unachievable, if you keep thinking about it, you may eventually find a way.”Mousati, I., Vermeersch, P., & Meyten, N. . Left Atrial Myxoma as a Rare Cause of Acute Coronary Syndrome: A Case Report.Politics
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