Prof. Betzig: My work on super-resolution dates back to 1982, when I was in graduate school at Cornell University. At the time, a few professors were working on the theory of passing light through holes in a black screen that were smaller than the wavelength of light. The holes would act like nano-flashlights. This is now called a near-field scanning optical microscope. I worked on this in graduate school and when I joined Bell Labs in 1988, with a lot of success. In 1989, William E. Morner, who would later win my Nobel Prize in spectroscopy, and I did experiments using absorption spectroscopy to look at the spectral properties of single molecules in crystals at near absolute zero, a few Kelvins. So researchers began to wonder if we could do the same thing at room temperature. With my near-field technique, it was very easy to see fluorescent molecules that were a fraction of the wavelength of light, and I published a paper on that in 2004. ScienceI started thinking about single molecules, and as my techniques became more prevalent in the field over the years, I also learned that this super-resolution technique had a major limitation: the light coming out of that tiny hole spreads rapidly with distance, so the hole needed to be about 20 nanometers or closer to the specimen. This was a big problem for samples that weren't perfectly flat on the nanometer scale. I was getting frustrated because I was trying to eventually build a light microscope that could look at living cells with electron microscope resolution, because living cells are not flat at the 20 nanometer level.
Eric and collaborator Rob Chichester holding a near-field microscope at Bell Labs in 1993.
Near-field optical image of a magnetic recording bit
Top: High density bits (black) written with super-resolution near-field microscopy
Bottom: Low-density bits (white) written with a conventional diffraction-limited microscope.
I also grew frustrated with a trend I see in the scientific world. I think academic science in general is largely trapped in bubbles, and people find a bubble of like-minded people. And everyone is happy in this little bubble, everyone acts the same, everyone gets along. But that leads to mediocrity. It doesn't lead to really radical ideas or people that push in new directions. Moreover, these bubbles generally have a very limited perspective; they're focused on their own problems. But I think scientific breakthroughs happen when people interact at the interface of very different disciplines that don't necessarily have a clear connection. To date, all my successes in science have been about getting out of my comfort zone and learning more about a field that is completely unrelated to optics, and how optics can be applied to that field.
Plus, once near-field microscopy became a hot field, a lot of people with no experience or knowledge of the limitations got in, which created so much noise that the signal of good research got drowned out. Eventually I got very frustrated and left Bell Labs, and basically stayed home to help raise our first baby. And then one day I had this idea that if a single molecule was all glowing in different colors, you could find its center just by fitting a point spread function, and make a super-resolution map of its location, and then make a super-resolution image in the far field. Of course, at the time I had no idea how to dye molecules in different colors, so I published the idea and forgot about it. Then I started working for my dad's machine tool company, but after six years I missed doing research so much that I decided to go back to science.
Eric, unemployed and living at a lakeside cottage, is relearning science for the first time in ten years.
I started reading the scientific literature and came across Martin Chalfie's paper on something called Green Fluorescent Protein (GFP). It talked about hijacking DNA from a glowing jellyfish to splice into a protein you wanted to see, and hijacking the cellular machinery to make copies of that protein with tags already glowing. This was revolutionary and elegant. They completely revolutionized cell biology and, rightly so, won a Nobel Prize in 2008. Based on that technology, I came up with the idea of using plane wave illumination from discrete directions to create a massively parallel array of foci that I called the Light Lattice Microscope, and contacted my good friend Harald Hess at Bell Labs to ask if he could help me find a lab where I could work. Together we visited Mike Davidson at Florida State University, where he was building one of the largest libraries of different fluorescent proteins. There he told me about Photoactivated Green Fluorescent Protein (PAGFP), a fluorescent protein that can be turned on and off with light.Harald and I realized that this protein fit with my idea for achieving super-resolution, not by dyeing molecules different colors, but by simply making them fluoresce at different times. So we pooled together some money and spent two months building a microscope in Harald's living room, and testing it with Jennifer Lippincott Schwartz and George Patterson at the NIH, who developed PAGFP. Then we published a paper. Science And the rest is history: I returned to science and won a Nobel Prize.
The original PALM microscope in Harald's living room
Eric is seen blowing a kiss to his wife from the stage in Stockholm, holding his Nobel Prize medal and diploma.
Escorting Crown Princess Victoria to the Nobel Banquet
