Process unveils interior of brain

An image, from Karl Deisseroth’s lab, shows a three- dimensional rendering of clarified mouse brain seen from below. The process has also been used on a human brain.
associated Press
An image, from Karl Deisseroth’s lab, shows a three- dimensional rendering of clarified mouse brain seen from below. The process has also been used on a human brain.

NEW YORK — Scientists, in a development that could eventually allow doctors to uncover the physical underpinnings of devastating mental disorders, have created a way to peer into the inner workings of the brain by making it transparent, researchers at Stanford University said Wednesday.

With the process, scientists said, they had made a whole mouse brain, and part of a human brain, transparent, so that networks of neurons that receive and send information can be highlighted in stunning color and viewed in all their three-dimensional complexity without slicing up the organ.

Called Clarity by its inventors, the process preserves the biochemistry of the brain so well that researchers can test it over and over again with chemicals that highlight specific structures within a brain and provide clues to its past activity. The researchers say this process might help unlock some of the mysteries of such disorders as schizophrenia, autism, and post-traumatic stress disorder.


The work, reported Wednesday in the journal Nature, is not part of the Obama administration’s recently announced initiative to probe the secrets of the brain, although the senior author on the paper, Dr. Karl Deisseroth at Stanford, was one of those involved in creating the initiative and is involved in planning its future.

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Dr. Thomas Insel, director of the National Institute of Mental Health, which helped fund the research, described the new work as helping to build an anatomical ‘‘foundation’’ for the Obama initiative, which is meant to look at ongoing activity in the brain.

Insel said the technique works in a human brain that has been in formalin, a preservative, for years, which means that long-saved human brains might be studied.

‘‘Frankly,’’ he said, ‘‘that is spectacular.’’

Kwanghun Chung, the primary author on the paper, and Deisseroth worked with a team at Stanford for years to get the technique right.


Deisseroth, known for developing another powerful technique, called optogenetics, that allows the use of light to switch specific brain activity on and off, said Clarity could have a broader impact than optogenetics.

“It’s really one of the most exciting things we’ve done,’’ he said.

‘‘I think it’s great,’’ said Dr. Clay Reid, a senior investigator at the Allen Institute for Brain Science in Seattle, who was not involved in the work. ‘‘One of the very difficult challenges has been making the brain, which is opaque, clear enough so that you can see deep into it.’’

This technique, he said, makes brains ‘‘extremely clear’’ and preserves most of the brain chemistry. ‘‘It has it all,’’ he said.

In the mid-2000s, Reid was part of a team led by Dr. Jeff Lichtman at Harvard University that developed a process called Brainbow to breed mice that are genetically altered to make their brain neurons fluoresce in many colors.


That technique would allow whole brains of those mice with their rainbow neurons to be preserved and studied.

The process keeps the biochemistry of the brain intact, so it can be tested over and over.

“I’m quite excited to try this,’’ Lichtman said.

There are several ways to make tissue transparent. The key to the new technique is a substance called a hydrogel, a material that is mostly water held together by larger molecules to give it some solidity.

Chung said the hydrogel formed a kind of mesh that permeates the brain and connects to most of the molecules, but not to the lipids, which include fats and some other substances.

The brain is then put into a soapy solution and an electric current is applied, which drives the solution through the brain, washing out the lipids. Once they are out, the brain is transparent, and its biochemistry is intact, so it may be infused with chemicals, like antibody molecules that also have a dye attached, that show fine details of its structure and previous activity.

Techniques like this, said Insel, ‘‘should give us a much more precise picture of what is happening in the brains of people who have schizophrenia, autism, post-traumatic stress disorder, bipolar disorder, and depression.’’

Chung said he planned to refine the technology. But he pointed out it works on all tissue, not just brains, and can be used to look for structures other than nerve cells.

On his laboratory bench, he said, ‘‘I have a transparent liver, lungs, and heart.’’

Reid agreed that Clarity had applications in many fields.

“It could permeate biology,’’ he said.