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Stanford University School of Medicine

Lightning strikes twice: Optogenetics pioneer Karl Deisseroth’s newest technique renders tissues transparent, yet structurally intact

Stanford psychiatrist and bioengineer Karl Deisseroth, MD, PhD, spent much of this century's first decade developing a revolutionary method for studying the brain: optogenetics. In 2010, Nature Methods  heralded optogenetics as its "method of the year."

It looks as though lightning has struck the Deisseroth lab again.

Suppose, just for a moment, that you're conducting espionage on a heavily guarded multi-story building strongly suspected to be an advanced nuclear-weapons facility. The building quickly proves utterly inaccesible. Fortunately, you manage (through methods too covert to be revealed here) to procure a floor plan. Nice going. Now, you know a lot about the floors themselves and a bit of cross-sectional detail on the bases of whatever's sitting on them. Better than nothing.

Now, imagine - in fantasyland, anything goes - that you can don goggles enabling you to peer right through the building's outer walls and directly observe its three-dimensional structure, including its concealed laboratories and the instruments and manufacturing machinery inside of them. Payday!

An analogous technique developed by Deisseroth promises to revolutionize cell biology. Exploring connections among, and contents within, the billions of cells in a chunk of tissue often involves slicing the chunk into ultra-thin sections, exposing each slice's top and bottom surfaces for microscopy or histochemical and electrical manipulation. Sophisticated computation can stitch the slices back together (virtually), roughly reconstructing the sample's three-dimensional structure. (That's the floor plan I mentioned earlier.)

Unfortunately, all this sawing disrupts key connections within the tissue and distorts its constitutent cells' geography. Plus, while those sections are thin, they're not infinitely thin. Light and chemicals can penetrate only so far. Volumes of valuable information about their innards remains concealed.

Deisseroth's paradigm-shifting method, called CLARITY, renders tissue transparent while leaving it structurally intact, yet accessible to large "detective" molecules scientist use to gain information about cells' surface features and genetic contents. In a study just published in Nature, a group led by Deisseroth (who discusses his work in the video above) converted an entire adult mouse brain into an optically transparent, histochemically permeable replica of itself. The position and structure of proteins embedded in the membranes of cells and their intracellular organelles remained intact.

Okay, step back with me for a minute. Essentially, all cells are liquid-filled bubbles of oil. (Nerve cells are better visualized as long, branching, liquid-filled tubes whose walls are made of fat.) These oil/fat (in science-speak, "lipid") bubbles and walls ("membranes") both house and compartmentalize their contents, so operations inside them can be carried out in relative isolation. Dotting membranes' surfaces are all kinds of proteins performing innumerable activities key to the health of the cells they enclose and the tissues those cells compose.

Evolution designed lipid membranes to be mostly impermeable to large molecules, and they happen to be opaque (or else we'd all be transparent). In a feat of chemical engineering, Deisseroth's team replaced the lipids with, for all purposes, clear plastic. With their work, you could literally read a newspaper through the mouse's brain. Formerly membrane-bound proteins remained anchored in the membranes' doppelgangers, retaining their structures (a big deal, as a protein's structure determines its function). The tissue was also nanoporous: It permitted bulky "reporter"molecules such as stain-carrying antibodies and strips of DNA to flow deep into the transformed tissue sample and out again.

Obviously you wouldn't want to try this on yourself, although Plastic Man certainly seems to have worked out the kinks.

Previously: Researchers induce social deficits associated with autism, schizophrenia in mice, Anti-anxiety circuit found in unlikely brain region and Nature Methods names optogenetics its "Method of the Year

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