On a biological level, there are dynamics happening on all time scales, from the femtosecond to the many, many tens of seconds. There's a whole continuum of processes happening, and you want to be able to study as many as you can. So the second goal is to increase the dynamics.

The reason we do optical microscopy (as opposed to electron microscopy)—despite the limited resolution—is that we want to be able to look at living cells without pumping in so much energy that we perturb them. But the more energy you pump into trying to interrogate your sample, the greater the chance of perturbing it. The third goal, then, is to achieve the greatest dynamics possible so that we can look at things in real time, yet do so noninvasively.

Of course, the fourth area would be high resolution: trying to get to the diffraction limit and push beyond it. And finally, deep-tissue imaging: We need to do better than diffraction-limited resolution, which confines us to really thin and idealized samples, and actually push into the brain and other areas. Those are the five main issues that I see people working on in the field of optics.

HHMI: IS THERE AN IDEAL GOAL?

EB: In terms of resolution, once you get to the molecular level, that's pretty much it; there's not much more to do there. But in terms of dynamics, you can always ask for more. In terms of slicing and dicing your signal and getting different contrast, you can always ask for more. In terms of how deep you can go, you can always ask for more. There's loads of room for improvement.

HHMI: DO YOU HAVE THOUGHTS ON HOW TO SPEED UP PROGRESS?

EB: Well, that gets into the wider philosophical issues of how research is done, which Janelia will try to address in some ways. In particular, I'm hopeful that the innovative engineering group within Janelia will help, at least for stuff we start to develop internally.

The problem with the near-field microscope—a device I was using fairly successfully—was that there was no mechanism for turning it into a good turnkey instrument. And it's still too embryonic for most biologists to consider using. There are hundreds, if not thousands, of examples in science and technology of good ideas that just languish because of the gulf that exists between the conception/demonstration of an idea and something that's economically viable.

My hope is that Janelia will be a step in the right direction, because mechanisms will be in place there to take ideas that have been shown to work from a proof-of-principle standpoint to the point where they might be broadly applied. Right now, that's pretty damn rare.

Interview by Jennifer Michalowski

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