Transparent mice? Scientists see potential in “tissue cleaning”

When a dye called tartrazine is added to food, it creates a bright yellow hue often associated with lemon drops. However, when the dye is mixed with a little water and rubbed onto the skin of mice, it turns their skin almost transparent.

Researchers reported the new use of the common food coloring today in the journal Science. The technique opens up new ways for researchers to understand what is happening beneath the skin of a living animal. This could eventually allow them to study how large organs work or how the body changes due to disease.

“The application here is definitely for living samples. The tissue purification methods that we currently have at our disposal largely don't work with living samples,” said Douglas Richardson, a senior scientist at Harvard's Center for Biological Imaging who was not involved in the new work. “So this really opens up a new avenue.”

The idea of ​​tissue cleaning is not new. As early as 1914, researchers mixed chemicals to make tissue transparent. Until now, however, researchers could only work with dead tissue samples because the chemicals – usually various acids and alcohols – were not safe for living organisms.

The key to tissue whitening is changing the way light passes through tissue. Tissue is not normally transparent because light moves through water, lipids and proteins – the three main components of tissue – at different speeds. Tissue whitening works by making the light pass through all the different tissue components at similar speeds, allowing it to pass right through them. Combined with high-powered microscopes, scientists can look at deep tissue in more detail than with other imaging techniques such as CT scans or MRIs.

The new method, the researchers say, may seem counterintuitive. “Normally, we expect dye molecules to make things less transparent,” says Guosong Hong, a professor of materials science at Stanford University and lead author of the study. “If we dissolve tartrazine in an opaque material like muscle or skin, which normally scatters light, the more tartrazine we add, the clearer the material becomes.”

The researchers started from a theoretical framework that suggested that molecules that absorb light of a certain wavelength “could actually change some of the optical properties of the tissue, resulting in improved transparency,” said Zihao Ou, an assistant professor of physics at the University of Texas at Dallas and lead author of the study. The team was skeptical that the method would work, so Ou set out to test their theory by applying different dyes to chicken breasts. “I brought my knife and my cutting board to the lab,” he said. “And I marinated chicken breasts in different dye solutions.”

Hong and Ou's team chose tartrazine because it made tissue transparent in the visible spectrum. Within five minutes of massaging the solution into mice, they could see through them with the naked eye.. However, their technique could be used with different dyes to make tissue transparent in different light spectra.

The technology has potential, says Ali Ertürk, director of the Institute for Tissue Engineering & Regenerative Medicine at the Helmholtz Association in Munich, who has developed other methods for cleaning tissue and was not involved in the study. But “significant further research is needed to prove its safety, effectiveness and practical benefits.” Concerns are particularly raised about how deeply the dye is absorbed by the body and what long-term effects contact with the dye could have.

The method is noninvasive and reversible: It simply requires rubbing a dye solution onto the surface of a tissue, and can then be washed off when scientists are finished imaging. For these reasons, researchers say it could open up new areas of research — for example, observing the inner workings of an animal over longer periods of time. (For thicker and less permeable skin, like that of humans, the dye, if proven safe, could be injected to reach deeper layers of tissue.)

“It's been really exciting to watch this field over the last decade,” Richardson said. “All biology is three-dimensional, and this allows you to better understand the three-dimensional anatomy of a tissue.”