Building a powerhouse microscope

Like many physics students, Joerg Bewersdorf, PhD, professor of cell biology and biomedical engineering, was first drawn to the great theoretical heights of the field: the study of cosmology, and the origins of the universe. “As a high school student, I admired Einstein,” he says, “but then, in college, I decided I wanted to do something more applied. Something that not only the colleagues in my field would be interested in. Something with an impact beyond our immediate neighborhood.” He thought he would pursue medical physics, and imaging techniques such as MRI.

Then Bewersdorf stumbled onto an optics class at the University of Heidelberg, in his native country, Germany. He recalls that studying the properties of light and its transmission seemed “pretty boring,“ to him, but was a necessary step in a well-rounded education. “I took a crash course, and I thought, oh good, after a week it will be over.”

That crash course was taught by a young assistant professor named Stefan Hell. Hell, a physicist and a current director of the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany, went on to win the 2014 Nobel Prize in Chemistry for his work in super-resolution fluorescence microscopy. “It's funny how life works,” Bewersdorf says. Hell’s take on what Bewersdorf had thought was a dull topic inspired him to pursue an internship with him.

Bewersdorf was drawn in by how Hell could connect the centuries-old laws of optics with modern research. “That’s the beauty of optics: you can have these really fundamental, basic principles and still discover something new.” Bewersdorf completed his PhD with Hell as his advisor, and was one of the first people to be hired when Hell started his first lab in Germany.

From that auspicious beginning, Bewersdorf embarked on a career in super-resolution microscopy. Now, within the School of Medicine’s Cell Biology Department, Bewersdorf and his lab continually push the limits of these techniques to develop bespoke, cutting-edge microscopes both for scientists at Yale and collaborators around the world.

Super-resolution microscopy elevates the resolution of light microscopy to the scale of nanometers. “Light microscopes are an absolutely essential tool for biomedical research because you can look at living cells or organisms, and not just in a fixed manner like electron microscopy,” says Bewersdorf. “To understand how a cell functions, you need to understand how proteins interact with each other.” This should take place, ideally, at the scale of proteins, or about ten nanometers. Using this technique, researchers can apply a color stain to a protein or organelle and observe it in real time to understand how it behaves, or interacts with other structures around it.

While these techniques have come a long way in the past twenty-five years, for Bewersdorf, advancing the field means finding new research applications for them. Up until now, most studies have provided proof of concept, he says. “They all showed ‘Look! We can do it!’ But that’s not really enough. We actually want to be able to use them for something of biomedical relevance.”

To do so, Bewersdorf’s lab seeks to increase the resolution of these already very sensitive instruments, and enable them to see deeper and deeper into the tiniest parts of cells. The frontiers of development in the field, he says, also include better live cell imaging, better multicolor imaging, and better 3D resolution. He and his lab are well-positioned, he says, to push those frontiers further into the horizon. “There might be maybe 100 labs in the world that refine these techniques, and make them more useable, and we are one of these labs.”

Bewersdorf finds that his lab’s location at the School of Medicine is an advantage. With his lab located in the Cell Biology Department, “we are at the heart of the medical school,” he says. “That guides our development. Our colleagues can tell us what they need, and what the limitations are, and what is still missing. They also challenge us.”

More practical, applied use also means making these delicate machines more reliable, and less temperamental. “If our collaborators arrive with a sample that maybe took two weeks to prepare, well, the microscope better work when they are here,” he says. “It can’t only work on a good day.” Bewersdorf and his colleagues are currently in the process of publishing a paper on increasing microscope throughput, an important factor with bearing on reliability. Until recently, he says, a sophisticated light microscope had the capacity to image ten cells in a day. But for more complicated biomedical research, in which one study alone might seek to examine thousands of cells under different conditions, more is needed. “We have now built a microscope where we can automatically provide super-resolution images of 10,000 cells instead of ten in 24 hours,” he says, as well as automatically analyze the data collected.

Bewersdorf and his lab patent and license their ideas, as well as collaborate with labs all over the world who wish to use the microscopes created here in New Haven. Currently, labs in Oxford, Cambridge, and Heidelberg are working on reproducing their own versions of Bewersdorf’s microscopes. “It’s more like a collaboration,” he says. “They are in a sense paying back by refining these instruments; they are writing software, for example. This helps us build a better next generation of these instruments.”

As his ideas and instruments reach further across the globe, Bewersdorf is, as he has been since his student days, motivated by having an impact, both on his field, and on biomedical research in general. “I’m not doing the stuff just for my own curiosity,” although it is clear that his fascination for this centuries-old field, and its constant capacity for new applications, is boundless.