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In H.G. Wells's 1897 science fiction novel The Invisible Man, the protagonist develops a serum that makes the cells in his body transparent by affecting how they bend light.
More than 100 years later, scientists have discovered a real-life version of the substance: A commonly used food dye can temporarily make a mouse's skin transparent, allowing scientists to watch the mouse's organs function, according to a new study published Thursday in the journal Science.
This breakthrough could revolutionize biomedical research and, if successfully tested in humans, could have broad applications in medicine and healthcare, such as making veins more visible for drawing blood.
Researchers made the skin on the skulls and bellies of living mice transparent by applying a mixture of water and a yellow food dye called tartrazine. Washing away the remaining solution reversed the process, which did not harm the animals. The mice's fur was removed before the solution was applied.
"For those who understand the fundamental physics behind this, it makes sense; but if you're not familiar with it, it looks like a magic trick," the study's first author, Zihao Ou, an assistant professor of physics at the University of Texas at Dallas, said in a statement.
Light-absorbing dye molecules
The "magic" uses insights from the field of optics. Light-absorbing dye molecules improve the transmission of light through the skin by suppressing the tissue's ability to scatter light.
The dye, mixed with water, changes the refractive index - a measure of how a substance bends light - of the watery part of the tissue to better match the index of proteins and fats in the tissue. The process is similar to a cloud of fog lifting.
"We combined the yellow dye, a molecule that absorbs most light, especially blue and ultraviolet light, with the skin, a scattering medium," said Ou, who conducted the study as a postdoctoral researcher at Stanford University in California.
"Individually, these two things block most of the light from getting through," he said. "But when we put them together, we were able to achieve transparency of the mouse skin."
Once the dye had completely penetrated the skin, the skin became transparent.
"It takes a few minutes for the transparency to appear," Ou said. "It's similar to how a face cream or mask works: the time it takes depends on how quickly the molecules diffuse into the skin."
The team experimented with chicken fillets before moving on to live animals.
In mice, the researchers could see blood vessels directly on the surface of the brain through the transparent skin of the skull. The mice's internal organs were visible in the abdomen, as were the muscle contractions that move food through the digestive tract.
The transparent parts turn an orange color, Ou said, similar to the color of food coloring.
The dye used in the solution is commonly known as FD&C Yellow No. 5, certified for use by the U.S. Food and Drug Administration. The synthetic dye is commonly used in orange- or yellow-colored snack chips, candy coatings, ice cream and baked goods. However, a 2021 study by the California Office of Environmental Health Hazard Assessment linked the coloring to behavioral problems and decreased attention in children. A state bill, if passed into law, would ban the use of the dye in food served in California public schools.
Ou said it was important that the dye be biocompatible - safe for living organisms. "Also, it's very cheap and efficient; we don't need a lot of it to work," he said.
Potential biomedical applications for humans
The researchers have not tested the process on humans, and it is not clear what dosage of dye or method of administration would be required. According to the researchers, human skin is about 10 times thicker than that of a mouse.
"In the future, this technology could make veins more visible, making the process of drawing blood or administering fluids through a needle easier, especially for older patients whose veins are hard to find," lead author Guosong Hong, an assistant professor of materials science at Stanford, said via email.
"In addition, this innovation could aid in the early detection of skin cancer, improve light penetration for deep tissue treatments such as photodynamic and photothermal therapies, and make tattoo removal using lasers easier."
Christopher Rowlands, a senior lecturer in the department of bioengineering at Imperial College London, said he was "kissing himself" for not coming up with the same insight as the Stanford-led team, which is based on the widely studied and long-standing physics principle called Kramers-Kronig relations: when a material absorbs a lot of light at one colour, it will bend light at other colours more.
"It's obvious when someone notices it, but no one had thought about it for over 100 years," said Rowlands, who was not involved in the study but co-authored a commentary published alongside the research.
Rowlands, co-author with Jon Gorecki, an experimental optical physicist at the same institution who was also not involved in the study, said the approach offered a new way to visualize the structure and activity of deep tissues and organs in a living animal in a safe, temporary and noninvasive way.
"It just works. You rub it on a mouse and you see what it had for breakfast. It's that powerful," he added.
Rowlands and Gorecki said existing methods of making tissue transparent use solutions that have side effects such as drying and swelling and can alter the structure of the tissue. However, tartrazine was used at a low concentration and its effects were easily reversed, potentially allowing for long-term study of biological processes in living animals, they wrote.
The duo noted that the discovery was an example of life imitating art, with the dye solution resembling the serum from 'The Invisible Man'.
"The main character (in the story) invents a serum that makes the cells in his body transparent by precisely controlling their refractive index to match that of the surrounding medium, the air," they wrote.
"One hundred and twenty-seven years later... biocompatible dyes make living tissues transparent by matching the refractive index of the surrounding medium to that of the cells."
However, Ou and Hong said that a mouse that was completely invisible would go too far: current approaches cannot make bones transparent.
"So far, we have only tested soft tissues, including brain, muscle and skin. We have not done much research with hard tissues such as bone, so I am not sure if we can make the mouse completely invisible," Ou said via email.
"However, a partially transparent (mouse) will already offer numerous research opportunities to answer questions regarding development, regeneration and aging."
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