From left to right: Eric Betzig, Stefan Hell, and William Moerner.

From left to right: Eric Betzig, Stefan Hell, and William Moerner.

N. Elmehed/Nobel Media/Wikimedia Commons.

Updated: Barrier-breaking microscopy methods that revealed cell's inner life win Nobel

Three scientists who overcame the diffraction limit of light to take optical microscopy down to the molecular level have won this year’s Nobel Prize in chemistry. Eric Betzig of the Howard Hughes Medical Institute in Ashburn, Virginia; Stefan Hell of the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany; and William Moerner of Stanford University in Palo Alto, California, share the prize equally “for the development of super-resolved fluorescence microscopy,” the Nobel Committee announced earlier today.

For more than 100 years, microscopists trying to view very small objects ran up into what was thought to be a fundamental physical limit: that resolution could get no better than half a wavelength of light. Known as the Abbe diffraction limit, it meant that a researcher using visible light—the best method for studying biological samples—couldn’t hope to see things smaller than about 0.2 micrometers, or millionths of a meter. With that restriction, bacteria, cells, and viruses looked either blurry and indistinct or like featureless blobs.

The three new Nobelists overcame that limit using fluorescence, getting the objects under the microscope to emit light themselves to reveal their details. Hell developed a technique called stimulated emission depletion microscopy in 2000. It uses a laser beam to excite molecules to glow, and a second beam to cancel out all fluorescence except that in a small nanometer-scale (billionths of a meter) volume.

Betzig and Moerner, working separately, developed a different method known as single-molecule localization microscopy. It relies on the ability to stimulate different types of molecules to turn on or off selectively. By causing molecules of a particular type—which are widely spaced in a sample—to fluoresce, researchers can image the molecules and precisely determine their locations. Other molecules are then imaged separately, and the separate images are finally superimposed to build up a picture of the structure in the whole sample. Betzig demonstrated the method for the first time in 2006. He published a paper in Science; click here for a news story about the research.

Hell told the Nobel press conference on 8 October by phone from Germany that he began working on the problem when he became bored by the conventional problems of microscopy and wondered if this seemingly unbreakable limit could be breached. “I was attracted to the problem. I eventually realized there was a way by playing with the molecules. Turning molecules on and off allows you to see things.” At first, Hell said, other scientists couldn’t believe his new approach had cracked a problem that had vexed researchers since Abbe’s work in 1873. “I realized you don’t overcome the limit by changing the waves of light; you overcome it by playing with the molecules.”

Being able to reach a resolution of tens of nanometers with visible light meant that biological molecules could be observed while still alive, not under the harsh conditions necessary for an electron microscope. “This doesn’t just tell us where, but when and how. That’s the greatness of this development,” inorganic chemist Sven Lidin of Lund University in Sweden, chair of the Nobel chemistry committee, told the press conference.

Microscopists told Science they are delighted about the award. “It’s very well deserved,” says cell biologist Michelle Peckham of the University of Leeds in the United Kingdom, a council member of the Royal Microscopical Society. “It’s opened up the horizons of microscopy to new techniques, especially in the biological sciences.”

“I am thrilled by this. It’s an area that has caught a lot of attention from biologists,” says Catherine Lewis, director of the cell biology and biophysics division at the National Institute of General Medical Sciences in Bethesda, Maryland. “For the first time, it allows biologists to look inside the cell and see things we could not see before. … We can see the behavior of molecules in real time. Because these techniques allow researchers to monitor molecular movements over time, they are becoming very important for understanding things such as metastasis in cancer, and the way viruses enter cells and where they go.”

But there was some surprise that Nobel honors had come so soon after the discovery of these techniques. “It’s still quite new. It’s only just starting to be adopted in the lab,” Peckham says. Susan Cox, a biologist at King’s College London, agrees. “These three people are very worthy recipients,” she says. “It’s clear it would be very important. But we’re still at the start. It’s a little messy, and the technological development is happening as the scientific results are coming in.” Cox says it took a while for biologists to realize that the techniques would work with biological samples.

Once they did, related techniques with a bewildering array of acronyms began springing up: SPDM, SPDMphymod, STORM, PALM, dSTORM, fPALM, and SOFI. The cost of the techniques and the expertise in optics that some of them required put them out of reach of some biology labs. But in recent years, major optics manufacturers have begun producing off-the-shelf systems. “That’s the critical thing: being able to push the button, and it just works,” Cox says.

With reporting by Robert F. Service.

For more on Nobels in science, click here.

*Update, 9 October, 5:05 p.m.: The updated version of this story adds four paragraphs of comments from other researchers at the end. It also adds details to the descriptions of the microscopy techniques for which the Nobel was awarded.