Professor William E. Moerner, along with Stefan W. Hell and Eric Betzig, received the 2014 Nobel Prize in Chemistry. Moerner, currently a Stanford professor, was awarded the prize for his work on single molecule microscopy.

Harker Aquila reporter Praveen Batra interviewed Professor Moerner at Stanford University on Oct. 21.

Praveen Batra: Congratulations on being named for the prize, and so the first question I have for you is just how has your perception of the Nobel Prize changed now that you are a laureate?

Professor William E. Moerner: Okay, so one of the things that changed a bit is that I’m really just stunned by how overnight all of a sudden people seem to want to congratulate you or think they know you or something even though they don’t know you at all. And I was just at a conference yesterday down in Tucson, and this is [an] optics conference, and so there are students at the optics conference […] After I made some remarks to the leadership forum, then they basically mobbed the stage. And there were a hundred students there, graduate students mostly, all wanting to quickly get selfies. So everybody wants to get a selfie now. So that’s a bit of a change, and I knew there would be a lot of recognition, but […] people on airplanes and all [that] sort of thing seem to immediately recognize the importance of the Nobel Prize. That’s very exciting.

PB: Have you done any research with or about single [molecule] microscopy recently and do you plan to continue research on the subject in the future?

WEM: Well, we work on single molecule microscopy, spectroscopy and microscopy […] and we’ve been doing that for 25 years. We’re continuing to do that, and we’re going to continue to do that, so yes. We’ve been working on this and have continued to work on it for really a very long time, ever since the first demonstration of this in 1989. […] We started at low temperatures. We started at a liquid helium temperature cryostat where the sample is […] frozen and looked at single molecules there first. But then the field switched to room temperature, in the mid 90s. We’ve been doing this in cells, even in living cells, in the most recent work.

PB: If [single molecule microscopy] requires that you take multiple images over time, then how do you study cell activities involving moving molecules?

WEM: Okay, that’s a great question. So you want to remember, or maybe recognize, that the prize is recognizing single molecule imaging and super resolution microscopy […] Super resolution microscopy is the thing that you were talking about that requires taking multiple images over time. So, yes, it can take some finite time and so it’s not so suited for things that are changing very, very fast. Some researchers have pushed the speed to make it go faster and faster from minutes down to, you know, tens of seconds even down to, maybe, some images can be taken in the time of a second. That means that all of those individual images were taken in milliseconds to get enough information to give you a full image by a second or ten seconds. So anyway, it’s already moving faster. It’s already running faster, but if you want to look at dynamical processes and that’s your primary interest, you can also use single molecules, it’s just that you don’t try to get a full structure. […] We’ve followed single molecules doing a bunch of things in cells.

PB: So this is not taking multiple images of different molecules and piecing them together, it is just the one molecule?

WEM: Right, right. So you can see molecules that sometimes […] appear to move randomly, and then sometimes they will move in a line because they’re being driven by a motor. Sometimes they’ll sit somewhere because they’re bound to something, and so from all these changes in the motion we can infer what’s going on in a really, really interesting way.

PB: Do you think that right now in the field research is currently focused on refining the techniques or on actually applying them?

WEM: The answer is both. […] In my lab, and in many other places around the world, people are both applying and working very hard to develop new methods to enhance and refine the method. Now, what do I mean by enhance and refine? Well, you want to get more and more information out of the system. You want to improve the resolution even more. The resolution is now maybe five times better than the diffraction limit, but wouldn’t it be great if we could make it be ten times better than the diffraction limit? And so that requires more photons, it requires new labels, it requires improved optics, and so forth. So in the area of improved optics, a major area that we are working on, and others, is three dimensional imaging. So the three dimensional imaging is a way to get information about not just x and y […] but also going in depth, in the z direction. […] Nature is three dimensional, so we want to have not only x [and] y, but also z, so there’s a huge effort adding the third dimension in the most optimal way, and that’s something that we’re working on right now.

PB: But as for the two-dimensional, is it currently being used in its form for research or is it being used right now in the form that it is?

WEM: Yes, yes, absolutely. So there’s scores to hundreds of groups all over the world using this super resolution with single molecules to look at behavior and structures in cells now. And some new things have been observed. In my group, we have used it to study bacteria. Bacteria are already very small. They’re only a micron, couple of microns long and half a micron across. They’re kind of close to the diffraction limit, so they’re very hard to image by conventional methods, but using the super-resolution methods, we can now see some structures inside the bacteria. We can see that certain proteins are localized to one end of the pole or the other or have patterns inside the bacterium. All of these things weren’t really detectable before.

PB: And so you can see the proteins. You can not only see the bacterium, you can also see the proteins. How much detail do you get on those?

WEM: We get detail down to regularly 40 nanometers or so […] You have to remember that before this advance everything was totally fuzzy. […] But using these new approaches, we now see five times better focus, that is, from 250 nanometers down to 50 nanometers or 200 nanometers down to 40 nanometers. So that means that things get sharper and sharper, and you can begin to see structures [because] it becomes, so to speak, in focus, but it’s not just as trivial as just turning a focus knob […] Because it is changing, circumventing this physical law, we have to use these special methods.

PB: So when you are studying bacteria, do you work primarily with just single molecule or […] superimposing different images?

WEM: Super-resolution. It’s mostly super-resolution, but we combine them. We can do one or the other. We can switch back and forth. The same setup works for both of them.

WEM: By the way, you mentioned electron microscopy earlier. […] Electron microscopy has extremely high resolution, but it doesn’t tell you which spot is which. It doesn’t tell you which things you’re observing. You see black and white. Everything you see is shades of gray. And so if there’s only one thing there, you can get detail. But if you’re in a cell or even if it’s a frozen cell, they all look like little blobs and you have to infer what they might be, but with visible light, and fluorescence, we’re able to label a specific structure and have it light up with these single molecule emitters. And so it’s telling us that that light is coming from that particular kind of protein inside the cell. In other words, we fuse the labels to the proteins of interest.

PB: How much overlap between different fields of science did you encounter in your research and do you think there is more or less overlap today than when you started it?

WEM: Well, these days, there’s a lot of exciting science that goes on at the boundaries between disciplines. And I love that, because that’s exactly the way my science is designed. So I started out as an electrical engineer going to college as an engineering student and then morphed into a physicist, and my graduate degree was in physics, and then I joined […] IBM, and this company allowed me to learn a lot of chemistry and become a physical chemist, and we’re now applying it to biology and biophysics. So even now there’s aspects of the work that we do here in this lab that combine all of those […] I have engineering students in my group, I have physics students in my group, I have chemistry students in my group, and we work with collaborators usually for [biology], to add the biology to the problem. So it is unbelievably interdisciplinary.

PB: Do you have any advice for high school students interested in research?

WEM: Sure. I mean, the thing to do is to, you know, study hard is an obvious thing, but let me just say that more carefully by noting that you want to be passionate about science. Remember that this is the way to answer how things work, and I believe that people ought to still be asking this kind of a question. How does this work? How does the world work? How does nature work? How do we understand [the] behavior of things that happen around us in as much detail as we possibly can? And so the advice I would have is to, you know, even though it takes a long time to achieve something really large, you have to–you want to have fun along the way. Each new thing that you learn is something fun and exciting to add to your collection of tools and so, enjoy it at every stage. But it is a big process of delayed gratification, that’s for sure.

PB: That is for basic or applied [research] or for both?

WEM: Well, […] whenever people want to work on something that’s new, that hasn’t been studied before, it’s not going to be easy at the start. There’s going to be mistakes, there’s going to be false starts, there’s going to be heading down one path and then having to change direction and head back on another path, and so that has happened many times in my career, specifically related to single molecules and issues around that, and so you want to have the ability to change directions and try another way and so forth. It takes quite a lot of motivation and determination, but that’s sort of the process of trying to learn things new about the world, is the thing that makes it exciting all the way along.