Scientist Stories: Eric Betzig, New Approaches to Microscopy

Hi, I'm Eric Betzig. I make microscopes for a living. Uh, one of the microscopes for some reason won the Nobel Prize in Chemistry. I'm a lucky guy. I get to work for Howard Hughes Medical Institute. Um, they have a freestanding research facility near D.C. Um, there I again work on developing new microscopes. It's a nice environment. It was modeled after Bell Labs where I had been as well. And it gives us the freedom to work 100% of the time in the lab. So there's no teaching or grant writing or other responsibilities, so it's a lot of fun. I think that ability to focus has really been key to my success, is that even if the time to write a grant or the time to teach a course or sit on a committee isn't in the integral all that much, it's the breaking up of the momentum, the research and mental momentum when you're really focused on a project that's really detrimental., and we're fortunate at the places I've been that that hasn't been a problem. By the standards of many Nobels, this one came real quick, right? Because the modern forms of super-resolution, the STED that Stefan developed and then the PALM that I developed based on the single molecule work at WE, all of those things are really, I'd say, real tools only in the last decade. So they're babies by Nobel standards. In some ways, I honestly think this prize was really premature in that and that super-resolution still has a lot to prove. So in 2008, I realized the limitations of super-resolution fluorescence in the same way that I understood the limitations in near-field back in '94, and I got frustrated for many of the same reasons. And I decided that— plus many people jump into the field by this time, and I don't like to work in a field where I'm bumping elbows with everybody else. I like to I'd like to have my own space. And so I dropped super-resolution at that point and started working on another idea that I had pitched before Harold and I latched onto the PALM, and that's developed into a very fast 3D imaging system for living cells that increases the speed of live imaging by about the same order of magnitude in the time dimension that PALM did increase the resolution in the spatial dimension. And so that's my latest toy. We published that paper in October, and now I'm basically— view that in the rearview mirror, and one of our big areas now is adaptive optics for microscopy. That steal as much as we can from the astronomers and learn how to take cells away from the coverslip, because they didn't evolve there, and be able to apply these high-speed tools and these super-resolution tools inside whole living organisms, but we need adaptive optics to make that work. Just as the atmosphere has differing refractive indices that scramble the light rays from distant astronomical objects and create an aberrated image in the telescope, the fact that you have to have heterogeneity in biology, that mitochondria and nuclei and proteins and lipids and all these things have different refractive indices and scramble the light like the water on your car windshield before you turn on the wipers. And if you can measure how that stuff is scrambled, and in astronomy they use something called a laser-induced guide star, we use a similar principle in transparent specimens, then you can look at that aberrated image of that little laser spot and use that and deform the shape of a mirror to exactly balance it and recover diffraction-limited resolution. I think in terms of basic science usually, I mean, I'm, I'm too far removed from the translational side of research to really know what tools to develop or how to go there, but I think the first step in the pipeline is just making better tools for live imaging, both at the single-cell level and at the model organism level. And at a certain level, I really feel like we are on the cusp of really being able to get a real quantitative grip on cell biology because we have not only now the optical tools to be able to see fast and to see at very high resolution, We also have genetic tools, this CRISPR-Cas9 system that allows you to have expression of fluorescent proteins at levels that are equal to what they are in the normal wild-type state. Before, we were looking at highly overexpressed cells, and we were looking at them with damaging techniques like confocal and two-photon. But now we can finally see the cell on its own terms, and I think this is going to really change our understanding of cell biology. And this plus The missing link in all of this is bioinformatics, is that the modern microscopes like the light sheet lattice microscope or high-speed imaging scope generates data so fast that we have 300 terabytes stored on drives, and most of it unanalyzed. In a week, it's easy to get 10 to 20 terabytes. And so the problem of even navigating the data, leastwise quantifying it, is, I think, still the missing link that the research community has to figure out. I feel that if we just publish a paper on the technology, that that in itself is fairly useless. The only way that you have a real impact is if these things get used by biologists and can answer real questions. So it's critical to me to try to find ways of getting over that valley of death from an initial technical concept to something that can be broadly used in a turnkey fashion by many biologists. That's not an easy problem, but we're trying a number of solutions. One at Janelia is we've actually developed an advanced imaging center inside of Janelia so biologists can do a very simple two-page application, apply, come for a week or two at a time, and do their experiments at Janelia with these advanced scopes. For people who have the technical chops to build their own, we supply all the drawings, all the code, all the wiring diagrams, etc., alignment guides, so that they can build their own. And then commercialization. So the lattice light sheet's been licensed, but one small company offers clones of what we have now, and another company will in a few years offer more turnkey. And the palm has been commercialized for years. There's at least a dozen vendors that offer some flavor of palm that you can get. But that's really critical. I feel I will be a failure still, Nobel Prize or not, if I can't, on my deathbed, take a look and say, "Hey, there were these sorts of discoveries or these sorts of uses that came out of those tools," because otherwise it was a waste of time. I agree that my story is unusual, and people sometimes resonate with that and get inspired by that, and I'm happy to see that happen. It may not may not be, you know, this is not the way you should do it at home, kids, kind of way to follow your career. But I do think that people should primarily follow what they're passionate about, and I hope I can convey that message. If the work they're doing doesn't really excite them a lot, they should look somewhere else for something that does.