From the Deputy Director for Intramural Research

Eric Betzig's Nobel Prize: A Homegrown Success

BY MICHAEL GOTTESMAN

The NIH intramural program has placed its mark on another Nobel prize. You likely heard that Eric Betzig of the Howard Hughes Medical Institute’s Janelia Farm Research Campus (Ashburn, Virginia) will share the 2014 Nobel Prize in Chemistry “for the development of super-resolved fluorescence microscopy” with Stefan Hell (Max Planck Institute for Biophysical Chemistry, Göttingen, Germany) and NIH grantee William Moerner (Stanford University, Stanford, California).

What you may not know is that Eric’s key experiment came to life right here at the NIH, in the lab of Jennifer Lippincott-Schwartz.

In fact, Eric’s story is quite remarkable and highlights the key strengths of our intramural program: freedom to pursue high-risk research; opportunities to collaborate; and availability of funds to kick-start such a project.

Eric was “homeless” from a scientist’s viewpoint. He was unemployed and working out of a cottage in rural Michigan with no way of turning a theory into reality. He had a brilliant idea to isolate individual fluorescent molecules by a unique optical feature to overcome the diffraction limit of light microscopes, which is about 0.2 micrometers. He thought that if green fluorescent proteins (GFPs) could be switched on and off a few molecules at a time, it might be possible using Gaussian fitting to synthesize a series of images based on point localization that, when stacked, provide extraordinary resolution.

Eric chanced to meet Jennifer, who heads the Section on Organelle Biology in the National Institute of Child Health and Human Development (NICHD). She and George Patterson, then a postdoc in her lab and now a senior investigator in the National Institute of Biomedical Imaging and Bioengineering, had developed a photoactivatable version of GFP with these capabilities, which they were already applying to the study of organelles. Jennifer latched onto Eric’s idea immediately; she was among the first to understand its significance and saw that her laboratory had just the tool that Eric needed.

So, in mid-2005, Jennifer offered to host Eric and his friend and colleague Harald Hess so that they could collaborate on building a super-resolution microscope based on the use of photoactivatable GFP. The two had constructed key elements of this microscope in Harald’s living room out of their personal funds.

Jennifer located a small space in her lab in Building 32. She and Juan Bonifacino, also in NICHD, then secured some centralized Intramural AIDS Targeted Antiviral Program funds for microscope parts to supplement the resources that Eric and Harald brought to the lab. Owen Rennert, then the NICHD scientific director, provided matching funds. By October 2005, Eric and Harald had become affiliated with HHMI, which also contributed funds to the project.

Eric and Harald quickly got to work with their new NICHD colleagues in their adopted NIH home. The end result was a fully operational microscope, married to GFP technology, capable of producing super-resolution images of intact cells for the first time. Called photoactivated localization microscopy (PALM), the new technique provided 10 times the resolution of conventional light microscopy.

Another postdoc in Jennifer’s lab, Rachid Sougrat, now at King Abdullah University of Science and Technology in Thuwal, Saudi Arabia, correlated the PALM images of cell organelles to electron micrographs to validate the new technique, yet another important contribution.

Upon hearing of Eric’s Nobel prize, Jennifer said, “We didn’t imagine at the time how quickly the point-localization imaging would become such an amazing enabling technology, but it caught on like wildfire, expanding throughout many fields of biology.”

That it did! PALM and all its manifestations are at the heart of extraordinary discoveries. We think this is a quintessential intramural story. We see the elements of high-risk, high-reward research and the importance of collaboration and the freedom to pursue ideas, as well as NIH scientists with the vision to encourage and support this research.

Read the landmark 2006 Science article by Eric, Harald, and the NICHD team, “Imaging Intracellular Fluorescent Proteins at Nanometer Resolution,” at http://www.sciencemag.org/content/313/5793/1642.long (Science 313:1642–1645, 2006).

The story of the origins of Eric Betzig’s Nobel prize in Jennifer Lippincott-Schwartz’s lab is one that needs to be told. I feel proud to work for an organization that can attract such talent and enable such remarkable science to happen.

Kudos to Eric and to Jennifer and her crew.