When Harald Hess was in high school, he spent two years converting treasures from the local junk yard—refrigerator compressors and Model-T spark coils—into an electron accelerator and cloud chamber in the basement of his small-town home.
So it should come as little surprise that his latest plans to revolutionize science were cooked up in the living room of his La Jolla condo, which he transformed into a high-tech physics lab almost overnight. Hess dusted off long-idle optics equipment from his years at AT&T's Bell Labs, and his collaborator, fellow physicist and Janelia Farm group leader Eric Betzig, flew in from Michigan. The two immediately got to work, assembling a new kind of microscope right on Hess's living room optical table. The microscope they built is a prototype that enables researchers to peer inside cells with extraordinary resolution.
The project is the latest example of Hess's flair for high-impact science. During his postdoctoral research at MIT, Hess devised the method to evaporatively cool hydrogen atoms in a magnetic trap into a Bose-Einstein condensate, a new state of matter that exists close to absolute zero temperature and today is widely studied by physicists all over the world. More recently, he made significant contributions both to the data storage industry and to the semiconductor industry, where, among other achievements, he invented reflective electron beam lithography, a new nanoscale patterning method that has the potential to economically render the smaller transistors needed for the next generation of computer chips.
Hess also spent 10 years at Bell Labs developing innovative forms of microscopy—a pursuit he's returned to with the new photoactivated localization microscopy (PALM) technique he's developing with Betzig, an old colleague and collaborator from his days at Bell Labs. The approach takes advantage of a recent discovery in molecular biology: fluorescent probes that can be linked to molecules inside cells, and then switched on or off by exposing them to light. When Hess and Betzig first learned of these probes, they immediately saw the potential to dramatically improve optical imaging. "It seemed so simple and obvious we couldn't believe no one had thought of it before," Hess says.
After their initial foray into living-room physics, Hess and Betzig moved their project to an eight-by-ten-foot room at the National Institutes of Health, where they used "every square millimeter of space" to refine the technique.
The basic concepts behind their technique are simple. The researchers label the molecules they want to study with a fluorescent probe, then they expose those molecules to a small amount of blue light. The light activates fluorescence in a small percentage of molecules, and the microscope captures an image of those that are illuminated. The process is repeated approximately 10,000 times, with each repetition capturing the position of a different subset of molecules.
Because the number of molecules captured in each image is small, they are far enough apart to see each molecule individually, says Hess. This technique provides better images than the generalized, fuzzy glow seen when looking at a large number of fluorescent molecules with traditional optical microscopy. When the frames of individual snapshots are compiled, the resulting image has a resolution previously only achievable with an electron microscope. Unlike electron microscopy, however, the new technique allows for more flexibility in labeling molecules of interest.
When Hess moved to HHMI's Janelia Farm Research Campus (JFRC), both his physical workspace and his scientific focus expanded considerably. Initially he served as director of the Advanced Physics and Instrumentation Group. Hess's role was to identify areas where technological advances can benefit a broad group of Janelia researchers. He started projects on novel neural probes that leveraged technology from the semiconductor industry, and he also explored alternative electron microscope options for high-throughput imaging of neural tissue.
More recently, Hess transitioned to Group Leader, where he plans to focus on developing innovative microscopy techniques, which he calls his real passion. While working at Bell Labs in the 1980s and 1990s, Hess experimented with microscopy that could detect tiny localized electrical, magnetic, and even optical fields. That latter work led to Hess and Betzig's invention of a technique to visualize the individual spectral lines in the glow from a semiconductor—a concept the two scientists have built on in developing PALM. While PALM is already generating some striking biological images, Hess says they are "only the beginning," and talks enthusiastically about the potential to extend this to three dimensions and use new and multiple fluorescent probes for greater flexibility—work that he is pursuing at Janelia Farm.
Hess also sees opportunities in developing high-throughput methods for three-dimensional electron microscope imaging for Janelia Farm scientists. Although he confesses to being somewhat in awe of the amount of data that needs to be generated to properly resolve all circuit details of a fly brain, he is energized by the challenge—especially the implications of needing images not for a single brain, but for thousands of mutants or behavioral variants. Hess also thinks his background in industry—in particular, several years at KLA-Tencor developing techniques to quickly evaluate hard disk drive components and next generation masks for semiconductor lithography—adds a valuable perspective to research at Janelia. "Finding that one 65-nanometer shorted wire defect in a Pentium chip or that one miswired neuron in genetic variants of fruit fly brains" are fundamentally similar problems, according to Hess. "Both are nanometer-scale computers and tera- to petabyte imaging challenges," he says.
Recent upheaval in the data storage industry prompted Hess to evaluate his career plans and how he could best continue to impact science. He was drawn to JFRC, which in many ways parallels what he loved about Bell Labs: the opportunity to be surrounded and inspired by brilliant scientists and an unusual willingness to trust individuals to do the science and decide what is most relevant and important to pursue. He says that JFRC is something rare—a place for "professional scientists," referring to the freedom to be completely dedicated to research without other obligations.