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Janelia group leader Eric Betzig wins Nobel Prize for the development of super-resolved fluorescence microscopy.
Investigator, University of California, Berkeley
Janelia group leader Eric Betzig wins Nobel Prize for the development of super-resolved fluorescence microscopy.

High-speed imaging with the Bessel beam plane illumination microscope reveals the ever-changing surface of a HeLa cell, with long, thin projections called filopodia continually extending and retracting. Credit: Laboratory of Eric Betzig/Janelia Research Campus

The Royal Swedish Academy of Sciences announced today that Eric Betzig, a group leader at the Howard Hughes Medical Institute’s Janelia Research Campus, Stefan Hell of the Max Planck Institute for Biophysical Chemistry, and William Moerner of Stanford University are the recipients of the 2014 Nobel Prize in Chemistry for the development of super-resolved fluorescence microscopy.

For a long time optical microscopy was held back by a presumed limitation: that it would never obtain a better resolution than half the wavelength of light. Helped by fluorescent molecules the Nobel Laureates in Chemistry 2014 ingeniously circumvented this limitation. Their groundbreaking work has brought optical microscopy into the nanodimension.

Examples of methods of super-resolution imaging include photoactivated localization microscopy (PALM), developed in 2006 by Betzig and Harald Hess, scientists at Janelia and by Samuel Hess at the University of Maine; stochastic optical reconstruction microscopy (STORM), developed by HHMI investigator Xiaowei Zhuang at Harvard University; stimulated emission depletion (STED) by Stefan Hell at Max Planck; and saturated structured illumination microscopy (SSIM) by the late Mats Gustafsson at Janelia and the University of California, San Francisco.

In what has become known as nanoscopy, scientists visualize the pathways of individual molecules inside living cells. They can see how molecules create synapses between nerve cells in the brain; they can track proteins involved in Parkinson’s, Alzheimer’s and Huntington’s diseases as they aggregate; they follow individual proteins in fertilized eggs as these divide into embryos.

This video shows an adaptive optics (AO) microscope operating in two-photon excitation (TPE) mode. Imaging shows a membrane-labeled subset of neurons in the brain of a living zebrafish embryo. Portions of the video show what one would see with adaptive optics (AO) and deconvolution turned on, and for comparison’s sake, AO turned off. (Higher resolution video available on request.) Credit: Courtesy of Eric Betzig Lab, HHMI Janelia Research Campus

Before he moved to the Janelia Research Campus in 2006, 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 in Michigan, 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.

As a group leader at Janelia, Betzig and longtime collaborator Harald Hess have since developed microscopes that 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, Betzig says. 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."