Researchers from a newly created Nanomedicine Development Center at UC Berkeley and Lawrence Berkeley National Laboratory (LBNL) are trying to develop cellular photoswitches for retinal cells in blind patients. The aim is to make these blind cells see:
“We’re asking the question, ‘Can you control biological nanomolecules – in other words, proteins – with light?'” said center director and neurobiologist Ehud Y. Isacoff, professor of molecular and cell biology and chair of the Graduate Group in Biophysics at UC Berkeley. “If we can control them by light, then we could develop treatments for eye or skin diseases, even blood diseases, that can be activated by light. This challenge lies at the frontier of nanomedicine…”
The chemistry at the core of the photoswitch is a molecule – an azobenzene compound – that changes its shape when illuminated by light of different colors. Kramer, Trauner and Isacoff created a channel called SPARK, for Synthetic Photoisomerizable Azobenzene-Regulated K (potassium) channel, by attaching the azobenzene compound to a broken potassium channel, which is a valve found in nerve cells. When attached, one end of the compound sticks in the channel pore and blocks it like a drain plug. When hit with UV light, the molecule kinks and pulls the plug, allowing ions to flow through the channel and activate the nerve cell. Green light unkinks it and replugs the channel, blocking ion flow.
Isacoff said that this same photoswitch could be attached to a variety of proteins to push or pull them into various shapes, even making a protein bend in half like a tweezer.
In 2006, in a cover article in the new journal Nature Chemical Biology, the researchers described for the first time a re-engineered glutamate receptor that is sensitive to light, which complements the SPARK channel because the same color of light will turn one on while turning the other off.
“Now we have photochemical tools for an on switch and an off switch for nerve cells,” Kramer said. “This will allow us to simulate the natural activity of the healthy retina, which has on cells and off cells that respond to light in opposite ways.”
Isacoff, Kramer, Trauner and their colleagues are experimenting with other molecules that can force shape changes, looking for improved ways to attach shape-changing molecules to proteins, developing means to shuttle these photoswitches into cells, building artificial genes that can be inserted into a cell’s DNA to express the photoswitches in the correct cell, and searching for ways to get light into areas of the body not possible to illuminate directly.