Nature Methods has picked optogenetics, a biological-research technology largely pioneered at Stanford, as its designated “method of the year” for 2010. Karl Deisseroth, MD, PhD, who’s also written a commentary appearing in the same issue, was and is the leading force in this new tool’s development.
If there’s anyone who understands the meaning of the admonition, “Get the right tool for the job,” it’s neuroscientists. Trying to make sense of the 100 billion neurons and 250 trillion nerve-cell-to-nerve-cell connections that dot the human brain is a huge headache.
But the payoff is big, too: Understanding exactly which circuits in the brain go awry in autism, schizophrenia, depression and other mental diseases – not to mention Parkinson’s disease and stroke, which are brain disorders, too – is the surefire way to developing treatments and perhaps cures.
Until recently, though, the only tools researchers had available for dissecting the brain’s circuitry were pretty rusty knives.
There’s electrophysiology, in which investigators place an electrode near a nerve cluster of interest, flip on the juice, and observe the change in an experimental animal’s (or in some surgical procedures, a person’s) behavior. That can cause a nerve to fire, but it can’t keep it from firing, which is sometimes what you’d like to do. And it may excite other nerves in the vicinity that the investigator didn’t intend to affect and doesn’t even know have been affected.
And there’s drugs. They tend to ooze all over (at least in terms of the microscopic scale you’re working at). They also can be pretty imprecise as to which circuits they affect as well as with respect to both how and how much they affect those circuits, and in any case they do whatever they do rather slowly compared with the speed an impulse of information moves along a nerve.
And there’s genetic approaches – mutate a particular gene, see what happens. These approaches have the advantages of working in a very specific way and in a highly reproducible manner. But genetic manipulations are tedious, take a ton of time and mouse food, and are usually irreversible. No quick-and-easy on/off switch here.
And then, wham!! Along came optogenetics, which as the name implies is a blend of optics and genetics (but also of several other disciplines from microbiology to animal care). Deisseroth and his colleagues succeeded in bioengineering mice so that long-known photosensitive molecules called opsins, ordinarily found only in various one-celled creatures, would turn up on the surfaces of mice’s nerve cells. And not just any nerve cells, only the nerve cells forming the circuits that researchers want to manipulate.
Once they figured out how to do that, Deisseroth and his team figured out how to deliver laser bursts of light, at just the right frequency, via a long, flexible optical fiber, to just the right place in a mouse’s brain, then at the flick of a switch turn the circuits on, turn them off, or deliver patterns of on/off repetitions to see how the circuits respond to waves of impulses coming in at various frequencies.
Armed with optogenetics, Deisseroth and his collaborators both at Stanford and elsewhere have identified circuits whose defective operation may be behind sleep disorders, schizophrenia, cocaine addiction, and Parkinson’s disease. This experimental technique has now spread to some 800 labs (and climbing) around the world, and holds promise for understanding how not just the brain but the heart, pancreas, and immune system do what they do, and what’s going on when they’re not doing well.
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