Monthly Meeting Report
June 2015 Monthly Meeting Report
Professor W. E. Moerner-2014 Nobel Prize Winner in Chemistry Lectures at NESACS
Report by Jack Driscoll, NESACS Public Relations Chair
Photos by Morton Z. Hoffman
The information for this article was taken from an interview with Prof. Moerner on March 28, 2014, the Stanford University website, the website of the Thomas Jefferson High School Alumni Association, Internet articles, the Nobel Prize website and his visit to Waltham, Massachusetts for the NESACS Monthly Meeting on June 11, 2015.
Nobel Prize Background
Moerner was at a conference in Brazil when his wife called him last October. “I had this feeling of incredible excitement, and my heart was racing, because you don’t know if this is real or not,” he said. “You never expect such things, because there are lots of scientists doing exciting research all over the world. This prize is possible because of the incredible work by my group of students and postdocs over a long period of time.”
Moerner shared the $1.1-million Nobel Prize in chemistry with Eric Betzig of Howard Hughes Medical Institute in VA and Stefan W. Hell of the Max Planck Institute for Biophysical Chemistry in Germany “for the development of super-resolved fluores- cence microscopy”. His research is praised for making it possible for researchers “to view the toxic protein accumulations in the brain cells of patients with deadly Alzheimer’s and Huntington’s diseases.” Because of his work, researchers “can also study how biomolecules—such as DNA and enzymes—work in cells to carry out the processes that are critical to life.” Moerner and Betzig were recognized for work done separately to advance super-resolution microscopy with single molecules, while Hell was recognized for developing a technique that uses patterned laser beams to achieve similar high-resolution imaging results.
The research into super-resolution microscopy has enabled researchers to effectively image and resolve objects that are smaller than a wavelength of light. That size had previously been accepted as the limit of microscopy’s ability because optical microscopes by definition cannot resolve objects smaller than about half a micron. They would appear somewhat blurry. Although electron microscopy and X- ray technologies can surpass this level of detail, these techniques required scientists to kill the cell inorder to make the observation.
To perform super-resolution microscopy, a researcher must first label the molecule of interest with a fluorescent molecule that is switchable (ability to turn the fluorescence on and off). While at UC-San Diego in the 90s, Moerner discovered just such an effect for a green fluorescent protein (GFP), which was sweeping the world at that time as a genetically encoded label in cells. Once the molecule of interest is labeled, reading light as well as control light are provided while capturing images of the cell. Not every GFP tag emits at the same time, so researchers can distinguish individual molecules labeled with GFP as spots of light, and these spots provide the key information about the locations of the molecules of interest.
While these spots appear much larger than the molecules themselves due to diffraction, an approximation of the spot’s center provides the location of the labeled molecule. To build a full image, simply superimpose all of the locations of centers onto one image. The uncertainty present in approximating the spot’s center is the uncertainty of the blurriness due to diffraction, resulting in a potential tenfold increase in resolution.
This image of a specialized brain cell was captured using a structured illumination super-resolution micro- scope — the kind of equipment made possible because of W.E. Moerner’s work. By keying in on fluorescent light, however, Moerner and his co-winners were suddenly able to see much smaller molecular structures. “With light, you can’t observe details smaller than half a micron,” he said. “But with the new methods, you can go to factors of 10 or more below that level using super-res-olution.”
 
Early Years
Moerner was born on June 24, 1953, at Parks Air Force Base in Pleasanton, California. He grew up in Texas, where he attended Thomas Jefferson High School in San Antonio. His activities during high school included becoming an Eagle Scout.
Beyond the truly critical role of his parents, he was encouraged to excel by Mrs. Gates in the Math department at Longfellow Junior High. At Jefferson, he had many favorite teachers, but per- haps the most important was Mrs. Blanche Rodriguez, the counselor who encouraged him to apply for a Langsdorf Fellowship to attend Washington University in St. Louis for college - and it was central to his f uture development to go to another state.
W.E. offers the following advice to fellow Jefferson Mustangs: “Explore your passions and live life to its fullest — it takes practice and persistence to be “good” at something, but it is well worth the effort. The work you do now lays the foundation for the rest of your life, so don’t be afraid to study hard or to be a geek!”
Moerner joins Robert Floyd Curl Jr. ‘50 as the second Thomas Jefferson graduate to win a Nobel Prize in Chemistry. Dr. Curl won the Nobel Prize in Chemistry in 1996 with Sir Harry W. Kroto and Dr. Richard E. Smalley for the discovery of fullerenes. Curl became interested in chemistry after he received a chemistry set for Christmas at age 9. The chemistry teacher at Thomas Jefferson High School, Mrs. Lorena Davis, encouraged his interest in chemistry. Dr. Curl credits her for leading him to under- stand that chemistry is an intellectual subject rather than a hobby.
 
College
Moerner attended Washington University in St. Louis for undergraduate studies as an Alexander S. Langsdorf Engineering Fellow, and obtained three degrees: a B.S. in physics with Final Honors, a B.S. in electrical engineering with Final Honors, and an A.B. in mathematics summa cum laude in 1975. Talk about a total Science Technology Engineering & Math (STEM) career. He had mastered all the STEM fields just in his undergraduate career.
This was followed by graduate study in solid state and chemical physics, partially supported by a National Science Foundation Graduate Fellowship at Cornell University in the group of Albert J. Sievers III. Here he received an M.S. degree and a Ph.D. degree in physics in 1978 and 1982, respectively.
 
Industrial & Academic Career
After college, Moerner was interested in doing research at one of the major industrial labs and was offered positions both at Bell Labs and at IBM in San Jose, He chose IBM: http:// www.research.ibm.com/articles/2014n obel.shtml.
There he was able to join a team of talented chemists, physicists, and engineers to follwo the motto of the lab at the time: "Be famous for your science and technology." It was at IBM that he made the first of two major discoveries that were key to his role in the Nobel prize recognition. Moerner was investigating the potential for high-density optical data storage at IBM, both by physical effects known as spectral hole-burning and hologram formation by photorefractivity.
During the course of his research to determine fundamental limits to optical storage, he and his postdoc, Lothar Kador, became the first people to optically detect and image a single molecule.
Moerner was awarded the Nobel Prize in Chemistry for work contribut- ing to the development of super-resolution microscopy – work that all started with that discovery at the IBM lab. Throughout the 1990s’ researchers all over the world completed a wide variety of optical studies of single molecules. Moerner spent 13 years at IBM, but in 1993 everything changed. IBM sales had been lagging for years, with sales lost to PCs and networking systems. They decided to write off $8B, lay off 10,000 employees http:// prospect.org/article/system-crash, and rethink their role in the marketplace. Moerner took a sabbatical from IBM to work as a Visiting Guest Professor at ETH Zurich, and continued explorations of single molecules while laying the groundwork for a jump to academia.
Moerner joined the chemistry faculty at the University of California, San Diego, in 1995, and there began research on single molecules at room temperature. The freedom of the academic environment allowed him to explore the broader realm of biological applications of single molecules in collaboration with biochemists and biophysicists. It was at UCSD that he made the second major discovery, albeit somewhat by accident.
He and a postdoctoral researcher, Robert Dickson, were interested in determining if single copies of GFP could be optically detected and imaged. (As a side note, Osamu Shi- momura of the Marine Biological Laboratory in Woods Hole, MA, was one of the discoverers to isolate the GFP from deep water jellyfish. Shimomura won the Nobel Prize in 2008 along with Roger Y. Tsien of UCSD and Martin Chalfie of Columbia University. Shimomura spoke at the January 2012 NESACS meeting). Roger Tsien’s postdoc, Andy Cubitt, happily provided samples of a yellow variant of GFP for the experiments. Indeed, they could image single copies of GFP, but instead of staying brightly lit, the tags turned on and off in a random stochastic pattern. This property is essential to being able to use single copies of GFP to achieve super-resolution. Moerner said “They are like little beacons, or flashlights, telling us where the structure is and in precise detail going far beyond the optical limit of diffraction,” This has led to an entirely new way of looking at structures in fixed and living cells.
Moerner joined the Stanford faculty in 1998, attracted by the opportunity to apply his work to new fields. “I knew that Stanford was an incredibly exciting multidisciplinary environment with so many experts that it would be highly stimulating to my science over time, and indeed it has,” he said. “We use light to probe molecules, and that involves physics and chemistry. We apply this to biology and biomedical systems. But it’s very important to do precise measurement and extract as much information as possible from a single object, and we do that with concepts from electrical engineering.”
Through collaborations with colleagues in medicine, biology, applied physics and electrical engineering, Moerner has helped reveal key details of how Huntington’s disease proteins form tiny subwavelength aggregates that can damage the brain, how bacterial proteins regulate DNA replication and cellular division in time and space, and the precise structures and behavior of the cellular antennae that, if mutated, can trigger various diseases in humans. This is the prototype of a STEM team that is needed to keep the USA competitive in the future, and government funding of R&D is a necessary part of this research.
 
Family & Researchers
Moerner and his wife, Sharon, have one son, Daniel, who is working for a doctoral degree in philosophy at Yale University. Prof. Moerner has been a thesis advisor for 26 graduate students and has mentored more than 45 postdoctoral researchers. Stanford professors, a graduate student and post-doctoral scholar reflect on the work of Professor W.E. Moerner in the following video: http://news.stanford.edu/features/2014/nobel/.
Moerner noted that throughout his career, much of the Nobel-winning work has been funded in part by the Office of Naval Research, the National Institutes of Health, the National Science Foundation, the Department of Energy, and several other federal granting agencies. “The support of this type of fundamental research from federal funding sources needs to continue and increase,” he said.
"The path-breaking work of Professor Moerner and his colleagues has made a major contribution to our ability to observe molecules at the smallest scales, opening up new possibilities for discovery in areas ranging from disease management to drug development,” Stanford President John L. Hennessy said. “The Nobel Prize recognizes this remarkable work, of which all of us in the Stanford community are immensely proud.” This is the fifth Nobel Prize awarded to Stanford faculty in the past three years.
We were pleased to have Prof. Moerner talk to our group at NESACS on June 11, 2015 at Nova Biomedical Corp. in Waltham, MA,
Jennifer and I picked up W.E at his hotel and drove him to Nova Biomedical. We discussed a number of topics like my new red sports car, climate change, why groups like the ACS don’t have a Nobel Laureate symposium for their members, his work on the Nobel prize, some background on PID Analyzers, Nova and NESACS. We spent a very enjoyable hour ride to Nova but it was entirely too short. Jen and I found W. E. to be very personable and easy to talk to.
After arriving at Nova, Prof. Moerner had a discussion with the Nova principals about medical technology and critical clinical measurements. We had a tour of Nova’s manufacturing operations in Waltham. All of Nova’s instrumentation and diabetes strips are monaufactured in the USA.
Following the tour, we went to the reception area. There were about 90 people for the reception, dinner, and lecture. There was an air of excitement and a real buzz in the air. His hand must have been sore because everyone wanted to meet him and shake his hand.
 
The Story of Light and Single Molecules, from Early Spectroscopy in Solids, to Super-Resolution Nanoscopy in Cells and Beyond
Prof. Moerner began with a description of the early days and initial discovery of single molecules, which occurred in 1989 at IBM Research. This was a story of high resolution spectroscopy at low temperatures, exploration of fundamental limits, and optimization of signal-to-noise ratio to achieve the ultimate limit. He then described how room temperature optical detection of single fluorescent molecules is accomplished today. Imaging of single copies of labeled proteins at low concentration in cells enables researchers to see the diffusional motion in membranes, to observe cell walls under construction, and even to detect defects in crystals.
To achieve super-resolution imaging, one must combine single-molecule imaging with two additional steps: First, the image of a single molecule, which looks a bit like a mountain when displayed in 3D, is used to find the position of the molecule with very high precision. Second, the experimenter must choose a method to force the emitting concentration to be low for every imaging frame. This can be accomplished by photochemistry, by natural blinking, by binding to fixed sites or membrane receptors, or by enzymatic reactions. Then, by recording a movie of sparse single molecules, the positions of all of them can be put together to create a pointillist reconstruction with detail far below the diffraction limit. This approach has now been used to discover many previously hidden mysteries of cell biology, such as bands of proteins in the axons of neurons, as well as the examples mentioned above. We now stand on a frontier of using single-molecule emitters to show nanoscale structures in a variety of complex cellular and materials environments.
I had about twenty emails from our NESACS members after W.E.’s excellent talk thanking me for bringing him to our NESACS monthly meeting. I never had such a response before. The NESACS younger chemists were very impressed and asked us for a contact at Woods Hole Oceanographic Institution so that they could bring a group down during the National Meeting in Boston. The areas that interested them were optical microscopy and imaging.