important for sensation, cognition,

same exact state happening in a human being. That’s now guiding our ongoing clinical work, including the clinical trial that I mentioned. So it really works both ways. The science enhances the patient work. The patient work enhances the science. I wouldn’t do it any other way now.

Speaking of the connection between clinical work and science, have there been any clinically relevant applications of optogenetics?

DEISSEROTH: Optogenetics, first and foremost is a discovery tool. It lets us understand what actually matters in the brain—which cells, which activity, and which connections are important for sensation, cognition, and action, whether healthy and adaptive, or maladaptive. This is so powerful because once you understand at that level, then any kind of treatment becomes much more grounded. It could be a pill. It could be a brain stimulation treatment: Now you can target specific? components. That would be the broadest and biggest impact, you could call it indirect application, guiding treatment. But my colleague and friend, Botond Roska in Switzerland, just published the first direct application of optogenetics in the human central nervous system this past year, in Nature Medicine. It was used to treat someone who was blind, and he was able to confer new light sensitivity onto the retina of this person with optogenetics. It’s pretty amazing. You can see videos of this on the journal site: A person sitting at a table who had been unable to see objects was now able to reach for them in a directed way.

Are there any clinical trials under way?

DEISSEROTH: There are a bunch involving the retina. There’s some work percolating, exploring pain treatment. And then there are a lot of optogenetics-guided clinical trials—where people have discovered something using optogenetics and are using that to design brainstimulation therapies, medication therapies, and so on.

What are your thoughts about the immediate or intermediate-term future of optogenetics?

DEISSEROTH: Thousands of discoveries have been made with optogenetics, all over the world. It’s been applied in essentially every experimental animal system, to many different kinds of cells and questions. And just in the past couple of years it’s made this leap from the level of cell types to the level of single cells. That’s very exciting— mammalian behavior controllable at the single-cell level. And so the future will be understanding how many cells are needed for a sensation, or a cognition, or an action.

Which cells, and which regions, work together? What’s essential, what’s not at the single cell level?

The other development is all the way at the other end of the scale—at the whole, intact-brain level. Getting to all the cells. We can now do this in the zebra fish, which is a small, transparent vertebrate. It’s small enough and transparent enough that we can see all the way through it, see all the cells during behavior, and during optogenetic control.

Of course, there’s a huge amount of data. Basically, the people in the lab have to become near-professional data scientists. But it’s got the appeal of not missing anything. We can take global, unbiased perspectives, which we definitely need in neuroscience because there are so many unknowns. In many cases, we can’t even frame hypotheses well. We want to take the big picture. We want to play the role of an astronomer centuries ago who built a new telescope and was pointing it at part of the sky to see what could be seen.

And this is already bearing fruit, this approach. The dissociation question I mentioned earlier: nobody really knew—we certainly didn’t—how dissociation might be implemented in the brain. What it actually is, physically, materially. And by taking that very broad, unbiased approach, we were able to see a signal that nobody anticipated. It popped out at us and turned out to be really important, both in mouse and in human for dissociation.

How did you do this?

DEISSEROTH: We used what we call wide-field imaging, where you can see almost across the entire brain. We gave a range of different strong, psychoactive drugs, including dissociative agents. We saw an amazing pattern that we hadn’t predicted: a rhythm in one part of the brain that all the dissociative drugs elicited, but none of the non-dissociative drugs. And then optogenetics came in, because then we could say “does it matter?” We provided that rhythm to those cells, and we saw if it caused the dissociative behavior. And it did. Then we were able to go and look for the same rhythm in human beings who were dissociating, and we found it.

Final thoughts about optogenetics?

After a study abroad experience, Perry switched her focus from neuroscience to microbiology.

DEISSEROTH: It highlights how important basic, curiositydriven research is. The deepest roots of optogenetics are in botany, 150 years ago. If people weren’t poking around with weird microorganisms a century or more ago, we wouldn’t be where we are today. l