How to Make a Transparent Mouse with a Few Simple Ingredients

By Veronique Greenwood | August 31, 2011 3:02 pm

On the left: A mouse embryo preserved in para-formaldehyde. On the right: A mouse embryo soaked in Scale for two weeks.

What’s the News: The trouble with brains, organs, and tissues in general, from a biologist’s perspective, is that they scatter light like nobody’s business. Shine a light into there to start snapping pictures of cells with your microscope, and bam, all those proteins and macromolecules bounce it around and turn everything to static before you’ve gotten more than a millimeter below the surface. Scientists at RIKEN in Japan, however, have just published a special recipe for a substance that makes tissue as transparent as Jell-O, making unprecedentedly deep imaging possible.

How the Heck:

  • Substances to make tissue more transparent are called clearing agents, and the ones we have now have varying degrees of penetration—in other words, they don’t always take you as deep as you’d like. To boot, they sometimes mess with the fluorescent tags that biologists splice into certain tissues to light up a particular set of blood vessels or neurons, for example.
  • This recipe clears out tissue so well that the only limitation on how deep you can see is the power of the lens of the microscope. And, as the researchers proved when they used it to image part of a mouse brain, it doesn’t diminish the glow of the fluorescent tags they’d engineered the mouse to express.
  • The clearing agent is called Scale, and, serendipitously, it’s made from odds and ends that any lab will have lying around. Urea, which most of us know as a compound in urine; Triton-X, a detergent biologists use to make cell membranes more permeable; and glycerol, which is used in antifreeze, are all it takes to whip up a batch.
  • Once the team figured out the correct proportions of each, they soaked mouse brains, mouse brain slices, and the above embryos in the stuff for two weeks and examined the results under the microscope. They were able to see at least several millimeters below the surface and, by activating fluorescent labels in neurons with a laser light, traced patterns neurons in the hippocampus and other areas of the brain.

A mouse brain soaked in Scale looks like tiny glob of jello. Turn
off the lights and shine a laser through it, and the light shoots
right through.

What’s the Context:

  • The researchers suggest that the clearing agent could be useful for drawing connectivity maps of the brain, a field known as connectomics.
  • Tracing circuits in the brain is such delicate work that it is still done by hand, and some of the most exciting new imaging methods focus on making clearer and deeper pictures of neurons for use in such cartography.
  • Scale is unusual among these, however, because instead of using algorithms to cancel out fuzz in the image or bypassing light entirely by using certain types of fMRI, it alters the tissue itself to be more amendable to viewing.

The Future Holds: Though this time the team used it to study the brain, Scale can be used in any tissue. The downside is that, like other clearing agents and treatments, Scale only works with dead tissue, so don’t expect to see barrel-fish-like mice wandering around in labs just yet. But the team is working on a milder version that they hope could be used in living creatures in the future.

Reference: Hama, et al. Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain. Nature Neuroscience (30 August 2011). doi:10.1038/nn.2928

Image courtesy of Nature Neuroscience and Hama, et al.


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