It’s a window of opportunity. A chemical treatment that can turn mice transparent will allow researchers to see the body and brain in unprecedented detail.

To look at organs on a microscopic scale, researchers tend to dissect and slice them, studying each slice individually or using a computer to generate a 3D model of the organ from the slices. It’s a time-consuming process that can be inaccurate, because slices are often misaligned. It is also difficult to study cells that are sparsely distributed throughout the body, because they can end up being lost through dissection.

A better idea is to make organs transparent, allowing fragile cells and their connections to be studied in their original locations. The problem is that lipids – waxy substances that include fat – block light from passing through tissues. The lipids can’t be removed because they also give organs their structure. If you remove them, the tissue will collapse.

The almost invisible mouse (Image: Yang et al. 2014, Cell)


But in April, a group at Stanford University in California managed to get over this hurdle by making an entire mouse brain transparent. The group treated the organ with formaldehyde to halt any chemical reactions, keeping cells from moving and preserving the tissue. They then soaked the brain in acrylamide – a transparent gel that binds to proteins, and other cells to form a supportive matrix that can replace the lipids. For the final step, the brain was bathed in a detergent to dissolve the lipids and placed in an electric field, which speeded up the dissolving process. The lipids dissolve over weeks or months and the organ becomes transparent.

This approach doesn’t work for large volumes of tissue, however, because the acrylamide gel cannot reach cells deep in the organ. The electric field can also cause the tissue to heat and swell up, causing damage.

To get around these problems, Viviana Gradinaru at the California Institute of Technology in Pasadena and her colleagues adapted the technique. To start with, they removed the animal’s skin. Then, instead of using an electrical field to clear the lipids, they pumped detergent around the entire mouse through its own circulatory systems. By doing without the electric field, the team avoided tissue damage. The minimal swelling that occurred when the gel was absorbed was constrained by animal’s bones and musculature.

Using this technique, Gradinaru’s team was able to render peripheral organs transparent within two days and a whole mouse transparent within two weeks.

The team then removed any large bones that might be blocking the view of certain cells, injected fluorescent chemicals into the animal to highlight specific cells, such as kidney or intestinal cells, and visualised those cells using microscopes. The result is a beautifully clear map of the microscopic structures of the body and brain.

What’s really going on in those intestines? (Image: Cell, Bin Yang, and Viviana Gradinaru)

“Now we are working on mapping the nervous system,” says Gradinaru. Working out exactly where nerves start and stop may help inform treatments that work by stimulating the nervous system, she says. “For example, there are instances where electrical stimulation is used to help treat Parkinson’s, bladder control or pain and those electrical stimulators are applied to nerves throughout the body. Knowing exactly where those nerves run to and from, and their functions, would improve those treatments.”

A whole kidney in glorious, stained technicolour (Image: Yang et al. 2014, Cell)

Gradinaru’s group has also used the technique on human tissues. “We’ve cleared biopsies from skin cancer to identify what kind of cells are present,” she says. The team were able to identify cancer cells and other tiny molecules present in the tissue at as well as current imaging techniques.

Meanwhile, Karl Deisseroth, at Stanford University, who developed the initial transparency technique is reportedly in the process of making a whole human brain transparent.

Journal reference: Cell, DOI: 10.1016/j.cell.2014.07.017