When Claudia López, Ph.D., first arrived at Oregon Health & Science University in 2003 as a postdoctoral fellow, she never imagined the trajectory her career would take. Originally trained in biology and biophysics, Claudia's curiosity about microscopy technology and her deep commitment to research would lead her to pivotal leadership roles in two of OHSU’s most groundbreaking initiatives: the Pacific Northwest Center for Cryo-EM and the Multiscale Microscopy Core.
“I came to OHSU for a short-term postdoc and ended up staying,” she said. “My journey started with electron microscopy and it’s been a fascinating path of learning and growth ever since.”
Today, López leads the OHSU Multiscale Microscopy Core and is co-director of the Pacific Northwest Cryo-EM Center, which together form an unmatched resource for researchers studying everything from molecular biology to cancer and infectious diseases. Both centers are located in OHSU’s Robertson Life Science Building, which has a specialized basement with a 5,000 square-foot concrete pad, supported by more than 70 pylons, each 200 feet long, to hold the heavy and sensitive microscopes.
In January, the team will launch a new microscopy suite for the Multiscale Microscopy core that will expand by an additional 1,600 square feet the space OHSU is dedicating to high-end microscopy.
Building the local facility
In 2013, OHSU established the Multiscale Microscopy Core, an initiative sparked by a vision from Joe Gray, Ph.D., professor emeritus of biomedical engineering in the OHSU School of Medicine, who recognized the need for a diverse set of imaging tools that could span cellular, molecular and even atomic-level analysis. López was there at the beginning, managing a small but growing facility with just a couple of electron microscopes.
“It started small, with very old equipment,” she said. “But it grew rapidly, thanks to collaborations with vendors and industry partners, as well as grants from places like the M.J. Murdock Charitable Trust. The relationships we built were key to expanding the facility.”
The Multiscale Microscopy Core is now home to five electron microscopes, each of which can examine specimens with incredible precision — from entire cells down to individual molecules. The core also includes crucial training opportunities, helping scientists from a variety of fields acquire the skills to operate the high-end equipment. As a university-shared service, the Core is available to any OHSU researcher through a fee-for-service model.
Sarah Andres, Ph.D., assistant professor of pediatrics in the OHSU School of Medicine, relies on the Multiscale Microscopy Core in her work studying human milk and its interaction with infant intestines. Her lab focuses on extracellular vesicles — tiny nanoparticles in milk that can potentially be leveraged for therapeutic purposes.
“The component of milk that my lab studies primarily is extracellular vesicles, which are best imaged using electron microscopy,” Andres said. “We’re interested in how these vesicles carry different components and how they could help infants at risk of intestinal inflammation and diseases.”
Without access to cutting-edge electron microscopes at the Multiscale Microscopy Core, her research would be much more challenging.
“The skill set required to process electron microscopy specimens is very specific,” she said. Without this facility and the staff, I would either have to hire someone with those skills or collaborate with others. Having a core facility to submit my samples and get back the processed data is invaluable.”
A critical technique used in Andres’ lab is immunoelectron microscopy (immunoEM), which combines antibodies with electron microscopy to study proteins within extracellular vesicles.
“ImmunoEM is a method used to see where proteins are located in tiny packages called vesicles,” she said. “We've used this technique in studies on RNA-binding proteins that play a role in gene regulation, like one focused on colon cancer. In that study, we showed that a protein called IMP1 enters extracellular vesicles and affects their contents. Without using electron microscopy, we wouldn't have been able to prove this.”
Carmem Pfeifer, D.D.S., Ph.D., Weight Professor of Restorative Dentistry in the OHSU School of Dentistry, also used the Multiscale Microscopy Core for her research. Her research focuses on developing materials that will make dental fillings less prone to re-infection, making them last longer and reducing the need for repeated treatments.
“We use the core to obtain images of our material reinforcing particles, which can only be visualized in the nanoscale,” she said. “We can then analyze the fractured surfaces of materials to study how cracks spread, so we can then optimize the reinforcement given by the particles. We can also analyze the interface of simulated dental restorations to evaluate the effectiveness of bonding agents that keep the materials connected to the tooth, at the microscale.”
Like Andres, Pfeifer emphasized the importance of not only having access to the lab, but the staff’s training and knowledge as a crucial component of her research.
“In our line of work, images are incredibly important to assess the effectiveness of the materials we make, and that needs to be done with precision at a very small scale,” she said. “The core is excellent not only because of the really advanced microscopes with a whole host of capabilities, but also because the core personnel are extremely experienced in sample preparation, and that allows for even challenging imaging projects to be completed.”
Cryo-EM — a game-changer for research
In 2018, López expanded her leadership role as she became part of the team behind the Pacific Northwest Cryo-EM Center, or PNCC, one of only three National Institutes of Health-funded national centers for cryogenic electron microscopy in the United States. Located at OHSU, this center complements the Multiscale Microscopy Core by specializing exclusively in high-resolution imaging of isolated proteins and molecular structures.
“There’s a significant difference between what we do at the local facility and what happens at the national center,” López said. “The national center focuses solely on cryo-electron microscopy, allowing us to analyze molecular structures with unprecedented resolution.”
The PNCC is operated jointly by OHSU and Pacific Northwest National Laboratory. The center is a resource not only to OHSU researchers, but also to thousands of scientists nationwide and even internationally. In addition to PNCC, the NIH funds two other centers with complementary facilities: the National Center for CryoEM Access and Training, known as NCCAT, is in New York, and the Stanford-SLAC Cryo-EM Center is in California. PNCC is free for scientists to use through competitive peer review of user proposals.
Cryo-EM has emerged as a transformative technique in structural biology, allowing researchers to visualize proteins, viruses and other molecular structures in detail. Unlike traditional methods, such as X-ray crystallography, Cryo-EM captures images of molecules frozen in their natural states, offering a more dynamic view of how proteins fold, interact and function.
“Understanding protein structure is key to understanding function, and protein function is the basis of life,” said Craig Yoshioka, Ph.D., co-director of the national center. “If you want to understand how something works, you first must understand how it’s built and how it moves.”
Yoshioka’s journey into Cryo-EM started with X-ray crystallography in the early 2000s. But his fascination with the technical side of science, particularly working with machines and software, led him toward the rapidly developing field of Cryo-EM.
“It was the wild west of science at the time,” he said. “There was so much still to be done, and I loved the idea of being at the cutting edge of something new.”
The PNCC serves not only as a hub for cutting-edge science, but also as a training ground for the next generation of structural biologists.
“We’re not just doing science,” Yoshioka said. “We’re helping graduate students graduate, postdocs get faculty positions and faculty secure tenure.”
Steve Reichow, Ph.D., associate professor of chemical physiology and biochemistry in the OHSU School of Medicine and the Vollum Institute at OHSU, uses the center regularly for his work. He also is a principal investigator in the PNCC. His research, which revolves around molecular structural biology, directly benefits from the high-powered microscopes.
“As structural biologists, we study the three-dimensional structures of molecules to understand their function, and how those functions may go awry in disease states,” he said.
At the molecular level, Reichow’s team builds three-dimensional models of molecules, often using computer simulations.
“For example, a molecule may have a hole running through its center, which is crucial for transporting signals between cells,” he said. “By studying these structures, we can infer how the molecule functions and how it may malfunction in various diseases.”
The need for high-resolution imaging is paramount in Reichow’s field. “Visible light just doesn’t have the resolution to see these small molecules,” he said. “That's where electron microscopes come in — they provide the angstrom-level resolution necessary to capture these tiny structures and turn them into 3D models that we can study and manipulate.”
As a principal investigator in the PNCC, Reichow uses the cutting-edge tools available to him to push the boundaries of molecular research.
“Our work wouldn’t be possible without the electron microscopes here,” he said. “These microscopes enable us to see the tiny molecular details that are essential for understanding the fundamental processes of life.”
Yoshioka said that the next frontier of Cryo-EM research is tomography, which allows for imaging of entire cells or tissue sections at extremely high magnifications. He and López are committed to keeping the center at the forefront of advanced technology.
“Tomography lets us see how individual proteins are positioned relative to other structures within the cell, providing a more comprehensive understanding of cellular function,” he said. “This transition marks a significant leap toward understanding not just isolated molecules, but also how they work together in the complex environments of living organisms.”
Training the next generation of scientists
A significant part of the mission at both the local and national centers is education. López, Yoshioka and their teams offer hands-on training, helping researchers learn how to prepare samples, operate the microscopes and interpret their results. They say one of the most rewarding aspects of this work is the opportunity to mentor the next generation of scientists.
“This year, we had the pleasure of training students from Clark College for the first time,” López said. “The excitement on their faces when they get to operate these microscopes is contagious. It’s a powerful experience for them — and for us.”
Beyond OHSU, researchers from across Oregon, including those from the University of Oregon and Oregon State University, also use the centers.
“We’re not just having an impact at OHSU; we’re reaching out to the broader state and national community,” López said. “Our work is strengthening the research ecosystem in Oregon, and it’s inspiring to see young people get excited about these technologies.”
The center also hosts trainees from across the United States and has seen numerous postdoctoral fellows return to the facility as independent researchers.
A vision for the future
Both Yoshioka and López see exciting developments on the horizon. The combination of their teams, the resources at OHSU and PNNL and the collaborations with both industry and academic partners will continue to drive innovation in electron microscopy.
“The technology we offer is not only advancing research, but it’s also attracting attention from donors and industry partners who see the value in centralizing these powerful tools,” López said. “Having everything in one location and providing expert support makes a difference.”
Being able to adapt to a quickly changing technological landscape is part of the reason both microscopy centers have flourished. For example, even before the COVID-19 pandemic, Yoshioka and team had already set up the PNCC for remote operation and data analysis anywhere in the U.S.
“We already had the infrastructure to work remotely, so when the pandemic hit, we just had to show our new staff how to use it,” Yoshioka said. “We more than doubled the size of the team during those challenging years, which was no small feat.”
Yoshioka is proud of how the team has come together.
“The center’s success goes beyond just producing results. It’s about the people we’ve helped — researchers whose careers have been accelerated or even saved because of the work we’ve done here.”
López said the collaborative nature of both centers — students, faculty, staff and researchers coming together to advance scientific discoveries — is one of the reasons for its success.
“Our work is about the bigger picture,” she said. “Yes, we provide the technology, but it’s the researchers who push the boundaries of what we can achieve with it.”
The Pacific Northwest Center for Cryo-EM is supported by funding from the National Institutes of Health’s Common Fund and administered by the National Institute of General Medical Sciences under Award Number U24GM129547.