Pushing in Different Directions
Among a very small community of liquid-phase TEM researchers, Qian Chen is creating new methods that expand the limits of electron microscopy.
Professor Qian Chen describes herself and her team as “filmmakers,” taking advantage of a technique called liquid-phase transmission electron microscopy (TEM) to capture movies of nanomaterials and living cells as they move and interact. She uses that artistic phrase, but it is still a refreshing surprise when she leads off a description of her work with a story about Vincent Van Gogh.
In 1888, Van Gogh moved to Arles, France. His time there was prolific but troubled. He would famously cut off his own ear in a manic episode late that year. In October, he described his bedroom in Arles to his brother in a letter. “The walls are pale violet. The floor is of red tiles. The wood of the bed and chairs is the yellow of fresh butter, the sheets and pillows very light greenish-citron,” he wrote. “The squareness of the furniture…Portraits on the walls, and a mirror and a towel and some clothes.”
Chen continued the story: “He used words to detail the shape and position of everything. But he also painted it. The painting has direct spatial information. It gave him the opportunity to show the interplay between light, color, and shadow. Based on this inspiration, our scientific vision is to collect experimental data with spatial and temporal information and to capture it in a way that can be revisited and reinterpreted. We want to build something that will stand the test of time. We focus on cinematography because we are fascinated by the power of that direct imaging.”
Direct imaging using liquid-phase TEM is a relatively new and uncommon technique.
All over the world, there aren’t many people doing liquid-phase TEM. Maybe 10 to 20 people talking with each other in this community and at our conferences,” said Chen, who is a Racheff Faculty Scholar in the Department of Materials Science & Engineering and the Materials Research Laboratory at The Grainger College of Engineering. Because it’s a young field, there’s ample room to explore. “Everyone is trying to find the good application areas. [T]here are so many possibilities. There are different fields and techniques for image processing, so you have lots of variety in scientific backgrounds. Everyone can push the technique in different directions.”
Being an early-adopter and innovator has translated into support from some of the most prestigious programs in her field. “Qian’s won an NSF CAREER award, an Air Force Young Investigator Research Program award, a Sloan Fellowship, a Defense University Research Instrumentation Program award, and a Multidisciplinary University Research Initiative award from the Office of Naval Research. All in the last five years!” said Professor Paul Braun, a Grainger Distinguished Chair in Engineering and director of the Materials Research Lab.
“We have great young faculty around here. They secure wins like this pretty frequently. But to rack up all of these? That’s exceptional.”
Professor Qian Chen is a Racheff Faculty Scholar in the Department of Materials Science & Engineering and the Materials Research Laboratory. She joined the Grainger Engineering faculty in 2015 and has already earned an NSF CAREER award, an Air Force Young Investigator Research Program award, and a Sloan Fellowship.
Protecting the Body and Imaging What’s Inside
Many of the Chen team’s projects look at traditional areas of materials science. They watch particles dance in a solution and form highly crystalline structures, getting a moving picture of how the particles change shape, interact, and self-assemble at the nanoscale. The liquid-phase TEM technique captures details that can’t be found in the static images of cryogenic electron microscopy or the approximations of movement created by fluorescence-based optical microscopy. These projects allow the team to improve their still-developing field of liquid-phase TEM. What the team learns is used in applications like increasing batteries’ storage capabilities or building better military armor.
As part of their Multidisciplinary University Research Initiative project, for example, they are creating new topological mechanical metamaterials.
“That’s a long name, but that’s how we can design materials with very fast mechanical response,” Chen explained. “One of the many ultimate applications will be a very good helmet, essentially, that can quickly absorb the mechanical impact without being made of very heavy materials. The absorption of the mechanical energy will be achieved by the reconfiguration of a material...built from nanosized building blocks that a synthetic chemist can synthesize in very large quantity. Our movies allow us to watch how those materials’ building blocks come together so we can control them.”
Electron microscopy is typically used to image hard materials like metals, ceramics, and oxides. But Chen also takes movies of biomolecular dynamics — movements of small cellular machinery made of proteins. Chen studied colloids and polymers as a graduate student, so soft, biological materials are familiar. But that’s not so for many of her students and colleagues in materials science.
“It’s an exciting adventure at this phase,” she said. “I tell them, ‘Anything we’re going to get out of it will be for the first time ever. Any insights we get will be brand new.’”
She also shared her excitement at getting support on this high-risk, high-return research direction at a very early stage of her career, “We were fortunate that the idea was recognized and encouraged four years ago by Dr. Sofi Bin-Salamon, the manager of the Biophysics Program of the Air Force Office of Scientific Research. Not only has the program supported this project ever since, she also has this management magic to build a nurturing and interactive community of biophysicists, which is greatly beneficial for us newcomers.”
The First Work of its Kind
Chen’s partner in exploring this largely uncharted territory is Professor Aditi Das, a membrane protein biochemist who is part of the Department of Comparative Biosciences at the University of Illinois Urbana-Champaign. Together, they are investigating a cardiovascular enzyme that’s involved in synthesizing lipid molecules. These small lipid molecules control our heart rate and keep our blood vessels open. By using liquid-phase TEM, they can get a look at these enzymes without destroying them or perturbing the system unnecessarily.
“If you have a cardiovascular condition, if you have too much cholesterol or lipids, then they hang around with particular proteins and form small chunks. With this method, we’re actually able to see some of those things happening in real time,” Das said. “People have simulated lots of these things, but nobody has really experimentally shown them to be true. That’s the exciting part. This is the first work of its kind. The first step — proof of concept — and we have a huge plan for doing many, many things." For imaging, the biomolecules that the team studies are embedded in a nanodisc. Das said to think of the nanodisc like a piece of sushi. “The proteins [you want to image] are floating in a suspension in the middle with some lipids around it. Then the seaweed is another protein meant to keep it all together.”
That roll of protein surrounded by lipids is placed in a vacuum chamber. A 200-kilovolt electron beam is fired through it. Because those electrons have much shorter wavelengths than visible light, they can capture much higher-resolution images of much smaller objects than an optical microscope. The sample is sandwiched — more food metaphors — between two pieces of graphene. This setup prevents the sample from being influenced by the heat and electrical charge that the beam generates.
Once the movies are taken, there’s still more to be done. The images are filled with background signals, what Chen called “a sea of outliers and noise.” Chen’s team is developing a machine learning workflow to avoid drowning in that sea. It allows them to automatically extract quantified characteristics like a protein’s modulus of elasticity or level of interfacial tension. That helps materials scientists, chemists, drug designers, and the like more easily make sense of what they’re looking at and its impact on their work. “To take movies of these things, to learn all of these things, is almost too wild a dream,” Chen said. “It’s a difficult project, and it requires initiative from all sides to keep pushing on it.”
Like Van Gogh — who painted five versions of his bedroom in Arles — a simple description and a single image aren’t enough. Chen and her colleagues keep pushing, as they refine the picture they paint and their understanding of nanoparticles and biomolecules.