Mouse kidneys, liver, and pancreas imaged after treatment with a variety of protocols: a saline solution, Scale, SeeDB, CUBIC, and CB-Perfusion used in the study. (Courtesy: Riken Institute)

Japanese Scientists Succeed to Make Mice Transparent; Invisibility Next?

A Japanese research team has succeeded in turning mice transparent by administering them with special chemicals, a process the scientists say allows the observation of organs without dissection or inserting pipes inside for detecting ulcers or cancer and to study diabetes. The acievement may be said to half-way through to achieve the next phase which is making the mice invisible.

The team from the Riken Institute and the University of Tokyo have achieved the amazing feat and the result will be published in the US scientific journal Cell.

The process involves perfusion of the mice’s organs with a chemical cocktail, dubbed CUBIC, which decolorises blood efficiently. By subjecting the organs to CUBIC through blood vessels, the team was able to turn entire adult mice as well as specific organs transparent in 10-14 days.

While the technology existed to make mouse fetuses and the brains of adult mice transparent, turning adult mice and internal organs containing large amounts of blood colorless had been difficult, said researchers.

transparent miceThe process can also be used to mark particular types of cells to observe parts of the body in 3D. By marking the insulin-producing cell masses in the pancreas of a diabetic mouse and making the rest of the pancreas transparent, the team could observe the cell masses reduce in number.

Kazuki Tainaka, a researcher at the University of Tokyo who co-authored the paper, said the findings “will have uses in many fields, such as research into the progression of cancer in organs.”

Researchers at the RIKEN Quantitative Biology Center and the University of Tokyo, have jointly developed tissue decolorization and light-sheet fluorescent microscopy to take extremely detailed images of the interior of individual organs.

The work opens new possibilities for understanding the way life works—the ultimate dream of systems biology—by allowing scientists to make tissues and whole organisms transparent and then image them at extremely precise, single-cell resolution.

To achieve this feat, the researchers, led by Hiroki Ueda, began with a method called CUBIC (Clear, Unobstructed Brain Imaging Cocktails and Computational Analysis), which they had previously used to image brains. Now, the group decided to focus on this issue and discovered to its surprise, the aminoalcohols included in the CUBIC reagent could elute the heme from the hemoglobin and by doing so make other organs dramatically more transparent.

Using the method, they took images of mouse brains, hearts, lungs, kidneys, and livers, and then went on to attempt the method on infant and adult mice, and found that in all cases they could get clear tissues.

With the technique of light-sheet fluorescent microscopy, which involves taking “slices” of tissues without having to actually cut into it, to gain 3D images of the organs, they examined the pancreases of diabetic and non-diabetic mice, and found clear differences in the isles of Langerhans, the structures in the pancreas that produce insulin.

Kazuki Tainaka, the first author of the paper,  said, “We were very surprised that the entire body of infant and adult mice could be made nearly transparent by a direct transcardial CUBIC perfusion coupled with a two-week clearing protocol. It allowed us to see cellular networks inside tissues, which is one of the fundamental challenges in biology and medicine.”

According to Hiroki Ueda, who led the research team, “This new method could be used for 3D pathology, anatomical studies, and immunohistochemistry of entire organisms. For example, it could be used to study how embryos develop or how cancer and autoimmune diseases develop at the cellular level, leading to a deeper understanding of such diseases and perhaps to new therapeutic strategies. It could lead to the achievement of one of our great dreams, organism-level systems biology based on whole-body imaging at single-cell resolution.”

In the future, the group plans to make improvements to the microscopy method to allow for the rapid imaging of whole bodies of adult mice or larger samples such as human brains, and to apply this technology to further our understanding of autoimmune and psychiatric diseases.

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