Lim can imagine using light to orchestrate new organizations of cells, perhaps even for making neuron-based logic components for biological computers or to help reconstruct damaged nerve tissue.

To demonstrate the utility of the approach in fine cell sculpting, Lim's group used a digital micromirror array device to project a minuscule “game of life” movie onto mammalian cells containing the phytochrome module. Each movie frame displays a pattern of dark and light boxes. The pattern evolves in a systematic way from frame to frame—dark boxes become light and vice versa, according to simple mathematical rules. By projecting these changing patterns of light and dark boxes (pixels) onto a cell, the researchers induced the cell surface to embody the same morphing patterns.

In a paper in the September 13, 2009, issue of Nature, Lim and several UCSF colleagues at the Cell Propulsion Lab say they should be able to link the phytochrome light switch to many other cell signaling pathways that involve the recruitment of protein players. Lim refers to the system as a “universal remote control” for experimentally dictating when and where in a cell to activate a pathway of interest. He can also imagine expanding the toolkit.

		Beyond Light As researchers just begin to get comfortable with the first generations of optogenetics tools, some can't help but imagine how the overall strategy might expand into new territories. “We have focused so far on light for lots of reasons, but there are other physical inputs that might be better for some applications,” says synthetic biologist and HHMI investigator Wendell Lim of the University of California, San Francisco. The blue, yellow, and red lights that optogeneticists have been using in their experiments represent only a tiny portion of the available electromagnetic spectrum. There are other wavelengths that can penetrate skin and bone, Lim says, and thereby potentially bypass the need to feed optical fibers into internal tissues through, say, holes in a creature's head. In April in the journal Cell, Karl Deisseroth, an HHMI early career scientist at Stanford University, and his team described new approaches that combine optogenetic silencing with light sensitivity that extends to the infrared border. These wavelengths can penetrate tissue more deeply, enabling safer optogenetics-based experimental and therapeutic procedures in larger animals. The researchers also describe versatile strategies for targeting cells based only on their connections within the brain, rather than their genetic identity. It's empowering, Deisseroth notes, because it means researchers can apply the technique to cells whose connections within the brain interest them but that they are unable to target by strictly genetic means. Another approach that comes to mind, Lim says, is to find “adapters,” things like magnetic nanoparticles or molecules that would act like minuscule microwave antennae. These adapters, which might be attached to receptors, channels, and other cellular features, may render a cell responsive to magnetic fields, radio-frequency electromagnetic waves, and other controlling signals.

“We are learning how to dissect biological systems the way electronics engineers dissect circuits,” Lim says. Elegant, precise interventions in neural circuitry, the kind that optogenetics researchers are exploring, stand a chance of eventually taking the place of blunt instruments like surgery, electrodes, and the present generation of pharmaceuticals.

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