The GFP That Blinked Sent W.E. Moerner On a Path from Physics to Cell Biology and on to a Nobel in Chemistry

ASCB member W.E. Moerner won the 2014 Nobel Prize in Chemistry for his work that set the stage for super-resolution imaging. Photo credit: L.A. Cicero, Stanford University

ASCB member W.E. Moerner won the 2014 Nobel Prize in Chemistry for his work that set the stage for super-resolution imaging.
Photo credit: L.A. Cicero, Stanford University

Winners of a Nobel Prize typically get a private call from a member of the selection committee shortly before the news breaks to the public. But this year the Nobel committee couldn’t reach W.E. Moerner, a professor of chemistry at Stanford University and an ASCB member. Moerner was in Recife, Brazil, on the morning of October 8, attending the Third International Workshop on Fundamentals of Light-Matter Interactions. Moerner had his cell phone turned off to save international roaming charges. So when it was announced that he was one of the three winners of the 2014 Nobel Prize in Chemistry it fell to the Associated Press to reach his wife, Sharon, at home with the news. She turned to WhatsApp to send him the message to turn on his phone. Moerner was thrilled to share his excitement with family, friends, and colleagues. His first call was to his son, Daniel, who is working toward a PhD in philosophy at Yale University.

There was no time for celebration in Brazil as the conference was ending that day. But when Moerner arrived home at the San Francisco airport, he was startled to be met in the terminal by a large contingent of his students and postdocs, cheering, holding balloons, and pouring champagne. Later that evening, he and his wife celebrated the prize with a seafood dinner.

For Moerner, the chemistry Nobel represents recognition for an unusual scientific career that began in physics and embraced a long stretch at IBM in basic industrial R&D before he moved on to biological applications of this new super-resolution technology. He joined ASCB in 2008 because “it seemed the reasonable thing to join since we were doing more and more cell biology,” Moerner said.

Moerner won the chemistry Nobel along with Eric Betzig of HHMI and Stefan Hell of the Max Planck Institute in Germany for his breakthrough work in laying the fundamentals for circumventing the diffraction limit with single molecules in a new technique known as super-resolution imaging. A normal light microscopes’ resolution is limited to 200 nanometers, which is a hundred times too large to see proteins at their native size. In 1873, the German physicist Ernst Abbé calculated this limit of light microscopy based on the wavelength of light that became known as the “Abbé limit.” Over time, new microscopes were developed to image smaller structures using electron and x-ray techniques, but these methods could only be used on dead, somewhat beat-up cells. Moerner and his two fellow Nobel laureates opened the way for super-resolution microscopy that can work around the Abbé limit in live cells.

“In many instances Nobel prizes are given for breakthroughs in technology that are so incredibly enabling that many realms are impacted by their discovery,” said Lucy Shapiro, an ASCB member who is also at Stanford who has collaborated with Moerner for over 15 years. “Single molecule visualization in a living cell enables experiments and results that break the diffraction barrier. We can now visualize single molecules in live cells revealing a multitude of unexpected behaviors. We always thought that light microscopy would be limiting; well, that’s been broken,” she said.

Described by Shapiro as a “smart, analytical, thorough person,” Moerner is called “W.E” by friends and colleagues. It’s a name that he’s had since childhood to distinguish him from his father and grandfather, also named William. Moerner grew up in San Antonio, Texas. After earning bachelor’s degrees in physics, electrical engineering, and math from Washington University in St. Louis, he went on to earn his master’s and doctoral degrees in physics at Cornell in 1978 and 1982. In 1981 he joined the research staff at the IBM Almaden Research Center in San Jose, California.

“The initial interest was not to break the diffraction limit, but to do some quite fundamental science,” Moerner said. “I was working at IBM research and we were working on optical storage, that is, ways that we could record digital information at different laser wavelengths or laser colors using molecules… It was as a result of looking at the fundamental limits of that optical storage scheme that I decided to look for spectral features that represented information from single molecules, and ultimately detected individual molecules,” Moerner explained.

“It’s this imaging of molecules that’s one of the central features of super resolution, going beyond the diffraction limit, because you’re measuring an image of a single nano-scale object. A molecule is a nanometer or two on a side. My part of all this is observation of key fundamental elements for the first time,” Moerner said.

In 1995 Moerner left IBM to study biological systems at the University of California, San Diego. It was there that he and Robert Dickson recorded an image of a single green fluorescent protein (GFP) variant that they got from Roger Tsien, who later won his Nobel in chemistry in 2008 for his part in the discovery of GFP. But in their experiment, Moerner and Dickson noticed something surprising. They saw GFP blinking on and off. “[GFP] was going into dark states then coming back and starting to emit [light] again. We were able to optically control it. We can turn on a different wavelength of light and then restore the molecule from a long-lived dark state,” Moerner recalled. “This sets the stage for Eric Betzig and his colleagues, including Harald Hess and the current president of ASCB Jennifer Lippincott-Schwartz working with photoactivatable GFP, to demonstrate you can do super-resolution when you image single molecules and turn them on or off to keep the emitting concentration low.” In 1998 Moerner was recruited to Stanford, in part, by Shapiro.

The path to the Nobel wasn’t easy, according to Moerner. Getting funding has been a challenge at times since he left IBM in 1995, but he said pursuing basic research is worthwhile for its unforeseen advances. He hopes young scientists will not be discouraged by the current funding climate. “The message to young people is to keep trying because we fundamentally believe in the value of basic science,” Moerner said.

“We have to work harder to convince our constituents and legislators that it’s important to support this kind of work to maintain the strength of the research enterprise, to develop new ideas that will turn into great advances in the future. This whole story is a great example of that. The single-molecule detection and imaging was all done as part of a piece of IBM that was interested in basic research. We didn’t know what the final applications would be, but we were exploring matter and exploring nature,” Moerner said.

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Christina Szalinski is a science writer with a PhD in Cell Biology from the University of Pittsburgh.