Correction: An earlier version of this article incorrectly identified Eric Betzig’s advisers at Cornell University. They were Aaron Lewis and Michael Isaacson, not Erin Lewis and Mike Isaacs. This version has been corrected.

As a child in Ann Arbor, Mich., Eric Betzig told his family over and over that by the time he was 40 he’d have a billion dollars and a Nobel Prize.

But Betzig was being a bit optimistic. He’s no billionaire and he didn’t win a Nobel prize until Wednesday, at the age of 54. “I failed on both fronts, more spectacularly on one front than the other,” he joked by phone from Munich, where he learned the news about the prize while attending a conference.

The Royal Swedish Academy of Sciences awarded the 2014 Nobel Prize in chemistry to Betzig, a research group leader at Howard Hughes Medical Institute’s Janelia Research Campus in Ashburn, Va., for contributions to modern-day microscopes. He shares the award with Stefan W. Hell of the Max Planck Institute for Biophysical Chemistry in Germany and William E. Moerner of Stanford University.

The three are credited with using fluorescent molecules to give microscopes higher resolutions — turning microscopy into nanoscopy, and looking at living cells in detail.

Betzig made something of a comeback: He received the award despite being estranged from academia and the sciences for seven years during the middle of his career. He owes his success to a super-powerful microscope he built on a friend’s living room floor.

Growing up as the son of an engineer, he was particularly captivated by the space race and had dreams of becoming an astronaut.

“I can still tell you the names of the astronauts on every flight from Mercury to Apollo,” he said. He studied physics at the California Institute of Technology but, by the time he graduated in 1983, felt that the space craze was over. “My timing was just bad,” he said.

Betzig went on to earn an MS and a PhD from Cornell University, where he studied applied and engineering physics. When he went looking for advisers and thesis topics, he found most of the topics too boring, he said. Then he found Aaron Lewis and Michael Isaacson, who were trying to create high-resolution images of cells too small for available microscopes to spot. Scientists believed that microscopes using light would never be able to clearly show objects less than 0.2 micrometers, and other types of microscopes required killing the specimen. “Now, that [research] sounded interesting, and useful too,” he said.

Betzig was hired by Bell Labs in 1988. In 1989, Moerner (now his fellow Nobel laureate) became the first person to detect the light absorption of a single molecule. Then Betzig showed that it was possible to do so at room temperature — instead of near absolute zero. That opened the door for more practical study of the properties of single biological molecules.

Working with his Bell Labs colleague Harald Hess — who is now at Janelia and to whom Betzig says he owes his career and Nobel achievement — Betzig came up with the seeds of his award-
winning idea. He theorized that optical microscopes could be made to detect single molecules in isolation and put the images together to make a high-
resolution shot. But at the time, the technology to tell one molecule from thousands of others in one place didn’t exist.

Betzig felt restless. Even the advanced work he was doing had obvious dead-ends, and the roadblocks frustrated him.

“Science goes through fads, and there are big ups and crashes,” Betzig said. “[The] microscopy we were using was going through one of those fad phases, which disturbed me. It was being grossly oversold.”

This video shows an adaptive optics microscope operating in two-photon excitation 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 and deconvolution turned on, and for comparison's sake, AO turned off. (Howard Hughes Medical Institute)

Meanwhile, Betzig’s father had been trying for years to get the young scientist to work at his machine tool company in Michigan. In 1994, Betzig left Bell Labs “in a huff,” he said, and spent nearly a decade working on the large-scale production of machine parts. While Betzig felt he was an engineer at heart and didn’t care for many aspects of academia, he found that he started to miss science itself.

“I missed the basic curiosity of being in the lab,” he said. But with a seven-year gap on his résumé, he knew he needed to make a splash to get back into science academia.

Hess had entered industry too, and was “pining” for science, according to Betzig. The two men worked on pitching a new idea, but a visit to the labs of Florida State University’s Mike Davidson changed that.

Davidson had fluorescent proteins — ones that Betzig and Hess could use to make their theoretical microscope a reality.

“We were sitting in the airport and just looked at each other and said, ‘That’s the missing link!’ and we had to do it,” Betzig said. These new fluorescent proteins came from the lab of Jennifer Lippincott-Schwartz­ at the National Institutes of Health’s National Institute of Child Health and Human Development. Swearing her to secrecy, Betzig begged her for the use of her proteins — and she readily agreed.

In September 2005, the two men set up shop in Hess’s living room. “Hess wasn’t married, and it was more comfortable than working in the garage like Jobs and Wozniak,” he explained, referring to Apple’s cofounders. With some equipment that Hess had kept from his days at Bell Labs and about $25,000 apiece, they built their prototype — a hand-built microscope about the size of an easy chair — in two months.

The work quickly garnered attention. By October, Betzig was offered a job at Janelia — but because his new lab was still under construction, the groundbreaking microscope went to a cramped old photoplate darkroom deep in NIH headquarters. Their work now had a major lab behind it, but they had moved from a living room to a windowless box. The men took turns sleeping on the concrete floor while they collected data.

The microscope represented a new approach to microscope technology — photoactivated localization microscopy (PALM). The microscope, used successfully for the first time in 2006, allows scientists to distinguish individual molecules that are only two nanometers apart. Because the microscope doesn’t harm the specimen, it can be used to watch biological processes in real time.

The Nobel announcement was an exciting surprise to Betzig, but he has moved on from PALM. In fact, he hasn’t really done anything with the technology since 2008.

Now he has returned to the concept he and Hess abandoned in favor of the photoactivated scope. This one, which will be described in a forthcoming paper, will allow scientists to produce high-speed images of whole cells in three dimensions, noninvasively.

“There’s always something that an engineer can do to make microscopes better,” Betzig said.

The Howard Hughes Medical Institute, based in Chevy Chase, Md., describes its mission as efforts “to advance biomedical research and science education for the benefit of humanity” and employs 3,000 people nationwide. The institute’s Janelia Research Campus uses small groups of interdisciplinary researchers to tackle science’s most challenging problems.

Dana Hedgpeth contributed to this report.