LEFT: Interacting with biologists helps Eric Betzig (right) and Thomas Planchon improve design of their microscopes. RIGHT: Three-dimensional imaging of live cells by the Bessel sheet microscope reveals remarkable detail, such as a cell’s ruffled edges and internal vacuoles.

So when Chen, Gao, and their microscope parts reached Woods Hole at the end of June, they wasted no time. They were greeted by Jim and Cathy Galbraith, a husband and wife team who have taught in the neurobiology course for seven years, and a small crew ready to help maneuver an 800-pound optical table, on loan from Thorlabs, into a tiny, windowless room in the basement microscope facility. The top of the table went in first, suspended on a scissor lift until its vibration-eliminating supports were positioned underneath. From there, the team followed Gao’s lead. Modular segments of the microscope were unwrapped and bolted to threaded holes in the tabletop. A tower of electronic equipment—the control panel—was erected in the cramped room’s remaining space. Cables were connected; alignment measured; blue, green, violet, and infrared lasers tested.

Gao knew what he was doing: he’d built this version of the microscope—a second-generation version, more compact and portable than the original built by Planchon at Janelia. And last summer, he and Planchon had accompanied the Bessel sheet on its first trip to Woods Hole, when it was so new Betzig was calling it “bleeding-edge.” That visit had been grueling: two weeks of 18-hour days, imaging the very first living cells to be viewed with the microscope, save one quick run-through back at Janelia Farm with the Galbraiths. But the benefits were enormous. During the rapid-fire days, the team tested a panoply of samples and introduced the microscope to a range of users. The Bessel sheet’s early successes at Woods Hole became the vivid movies the team published in its Nature Methods paper, which is coauthored by the Galbraiths, whose own labs are at the National Institutes of Health (NIH). And throughout the following year, the Betzig lab hosted collaborators at Janelia Farm to advance projects initiated during those fervent weeks.

So when Betzig suggested they repeat the experience this past summer, Gao’s first thought was the challenge of transferring the delicate equipment to its temporary home. “It’s almost like starting a new lab,” he says. But he knew it would be worth the long drive and the long days that would follow, particularly if they extended their stay to work with a wider group of biologists.

		Skin Development in C. elegans An unprecedented view of roundworm embryo skin cells arising, making junctions, and then forming a sheet. Dividing Chromosomes Chromosome sorting during cell division in a cancerous osteosarcoma cell. Surface of a HeLa Cell On the ever-changing surface of a HeLa cell, thin projections called filopodia continually extend and retract.

They chose a four-week period during which their microscope could be integrated into two courses. Gao and Planchon made plans to helm the microscope in two-week shifts, while Chen would stay the entire four weeks to learn the intricacies of the Bessel sheet and become familiar with the language of its users. Betzig would join the team for the weeks in the middle.

During the first two weeks, the Bessel sheet would help physiology students working with Jennifer Lippincott-Schwartz from the NIH watch cells migrate or break down their unwanted parts; in the second half of the microscope’s stay, neurobiology students working with the Galbraiths could use it to visualize the processes that drive nerve cell function. Spare moments would be tightly scheduled with MBL faculty curious to see what the Bessel sheet might reveal about their own samples.

The Photon Budget

The Bessel sheet was the newest imaging technology at Loeb Laboratory, MBL’s educational hub, but it was not the only one. The basement and first-floor hallways were crowded with bulky crates emptied of sophisticated microscopes on loan for the summer. Course directors had collected commercial instruments for super-resolution imaging (including Zeiss’s ELYRA, based on the concept of photo-activated localization microscopy (PALM), invented by Betzig and Janelia Farm colleague Harald Hess), microscopes designed to peer deep into tissue, and high-resolution methods for three-dimensional imaging of fixed tissue to offer their students new perspectives on biological complexity.

According to Cathy Galbraith, the two-week imaging section of the neurobiology course is designed not just to expose students to cutting-edge technology, but also to help them understand which tools are best suited for particular questions, as well as how the technologies are complementary. Likewise, physiology students experience firsthand how each tool has its strengths—but none can do it all.

Photo: Betzig and Planchon: Jared Leeds; Science image: Betzig lab

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