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Before he moved to the Janelia Research Campus, Eric Betzig—physicist, inventor, and engineer—didn't have a lab. There was an office in his Michigan cottage where he did most of his work, but some days he packed it all up and took his boat out on Hiland Lake, finding a secluded spot to serve as his workspace. The tools of his trade, which he says amounted to "a laptop and a couple of really good ideas," packed easily, after all.

But now Betzig's ideas have outgrown the laptop and the cottage. After two and a half years of theoretical research, he has taken his theories into the lab, where he can apply them to one of the major technological challenges of biological research. As a JFRC lab head, Betzig will work to develop a microscope that will allow biologists to peer inside living cells with unprecedented resolution.

Betzig is trained as an experimental physicist, and he made waves in that field early on by helping to develop a technique known as near-field microscopy, which brought into focus structures that scientists had long considered too small to see with a light microscope. As a graduate student at Cornell University, and then during six years at Bell Labs, he advanced the technology to make it more practical for biologists, allowing powerful imaging of dead cells.

The size of a typical protein is about one or two nanometers—some 200 times smaller than what can be seen with an ordinary light microscope. Near-field microscopes, on the other hand, can discriminate structures as small as 30 nanometers. That's much larger than a protein, but according to Betzig, "there's still a lot you can learn." He was frustrated, however, when he realized the limitations inherent in the overall approach meant it would probably never be useful for imaging living cells. Sensing he'd taken the technology as far as it could go, Betzig decided it was time to move on.

Betzig turned his back on Bell Labs, and the world of science altogether, to join his father Robert's machine tool company in Chelsea, Michigan. He spent seven years at the Ann Arbor Machine Company, tackling the automated high-volume production of machine parts. The problem, he explains, is that a multi-ton machine and its tools must be moved to many points in order to cut a single part. "So more time is spent moving the machine," he says, "than actually cutting metal." Betzig used his engineering savvy to create a method to move machines with extraordinary speed without sacrificing the necessary precision, greatly reducing the time devoted to that aspect of manufacturing.

Once he'd seen his latest invention through development and marketing, Betzig says, he became restless, and started to think about returning to science. But with no scientific publications for the past ten years, "there was this big gap on my résumé. So I knew I had to come up with some intellectual capital to get people to listen to me again."

"So I holed up in my cottage, and just started thinking. Eventually those thoughts brought me back to microscopy," he recalls. Progress in the imaging field, such as the development of fluorescent proteins, makes the need for advanced microscopy even more critical today than when he worked in science a decade ago, Betzig says. "We can at least dream now about being able to see within the cell on the molecular level, which is where all the action is. If we can do that, and study dynamics at that level, our understanding of cell biology and molecular biology should skyrocket."

However, his experience with the near-field microscope made him keenly aware of the trade off between spatial resolution and signal strength, which normally would doom any possibility of studying macromolecular dynamics in real time. "That led to a theoretical development of mine," he says—an approach to microscopy that relies on a massive three-dimensional array light foci. By collecting light from all these foci at once, he believes he can compensate for the rapid loss of signal that made the earlier technique unsuitable for imaging living cells. He expects the new technique, which he calls optical lattice microscopy, will have further advantages over conventional methods, such as improved sensitivity to single fluorescent molecules and less damage to cells.

Betzig has filed a patent for his design, and has already begun preliminary experiments to demonstrate that the approach is feasible. At Janelia, he will continue testing his theories and work toward translating them into a functional instrument. His initial approach should enable rapid imaging of the dynamic changes within living cells, but the spatial resolution will still be limited, Betzig says. "So from there you need to do various types of tricks to try to get beyond the diffraction limit to super-high resolution. And that's another thrust of what I'll be doing at Janelia."

Janelia is the ideal environment for this work, he says, largely because of the opportunity to interact with people who will ultimately use the tool he creates. "I learned from my business experience that there is nothing more important than constant contact with the customer as you're developing new products," he says. "And that's exactly what we have at Janelia. The people who will use the microscope will be right there; they'll guide the design."

Equally important, Betzig says, are the mechanisms Janelia has in place to "take this rubber band-and-bubblegum thing that a physicist can get to work, and take it through the development phase to turn it into something that biologists are really going to be able to use."

"Ultimately," he says, "it comes down to impact. You want to create an instrument that's going to have an impact." And, by bringing his ideas to Janelia, he expects to do just that.