DALLAS – At one of the country’s leading academic medical centers, it just became a lot easier to take a closer look.
UT Southwestern Medical Center has announced the opening of a new $17 million cryo-electron microscope (cryo-EM) facility housing a unique collection of instruments that researchers can use to view 3-D images of objects as tiny as an atom all the way up to intact cells.
“We are the only institution in the world with this configuration of instruments,” said Dr. Sandra Schmid, chair of the Department of Cell Biology and holder of the Cecil H. Green Distinguished Chair in Cellular and Molecular Biology. “It establishes UT Southwestern as one of the world’s top facilities for cryo-EM structural biology.”
The facility’s three cutting-edge instruments—a Titan Krios, a Talos Arctica, and a Scios DualBeam for thin-slice cryo-electron tomography—are expected to provide the technologies to help accelerate UT Southwestern’s biomedical investigations on everything from cancer biology to drug discovery and will run 24 hours a day, seven days a week.
These instruments will analyze specimens that have been rapidly frozen to prevent the formation of damaging ice crystals. The specimens will then be viewed in special holders under conditions that keep them at cryogenic temperatures (minus 321 degrees Fahrenheit).
The three advanced instruments and the special climate- and humidity-controlled, vibration-protected building to house them received funding from an anonymous donor, UT Southwestern, the Cancer Prevention and Research Institute of Texas (CPRIT), the UT System’s Science and Technology Acquisition and Retention program, and the Howard Hughes Medical Institute (HHMI).
Screenshot courtesy of UT Southwestern Medical Center
“This facility marks a milestone in the evolution of our structural biology research efforts at UT Southwestern. We are grateful to our supporters whose visionary generosity has helped us create this exceptional facility aimed at making fundamental basic discoveries that can be foundational for advances in medicine,” said Dr. Daniel K. Podolsky, President of UT Southwestern, who holds the Philip O’Bryan Montgomery, Jr., M.D. Distinguished Presidential Chair in Academic Administration, and the Doris and Bryan Wildenthal Distinguished Chair in Medical Science.
In April, a symposium to commemorate the opening of the cryo-EM facility brought international cryo-EM leaders to campus. Other grand opening events included tours of the facility for faculty members, staff, and students.
Cryo-EM and EM tomography allow biological specimens to be viewed in a more life-like state and environment than X-ray crystallography, the longtime gold standard of structural biology that requires assembling molecules into crystals. Many of biology’s most intriguing molecules have proved notoriously resistant to crystallization, Dr. Schmid explained.
The new facility is a joint effort of the Departments of Cell Biology and Biophysics. Dr. Schmid and Dr. Michael Rosen, chair of biophysics and an HHMI Investigator at UT Southwestern, led a team that spent four years planning and building the facility, which will be a shared resource across the academic medical center.
“In addition to the unique configuration, we are planning to use these instruments collaboratively to further research all across campus—from basic research to answer fundamental scientific questions to translational investigations in which those answers may result in potential treatments for human disease,” said Dr. Rosen, who has additional appointments in Biochemistry and in the Cecil H. and Ida Green Comprehensive Center for Molecular, Computational, and Systems Biology, and who holds the Mar Nell and F. Andrew Bell Distinguished Chair in Biochemistry. “This facility will align closely with our outstanding Structural Biology Core (SBC)—the University’s world-renowned facility for X-ray crystallography—led by Dr. Diana Tomchick, Professor of Biophysics and Biochemistry. That way, the university will provide a continuum of approaches across a spectrum of resolution ranges, from atoms to molecules,” he said.
Each microscope has its own room with many automated elements. Because temperature changes as small as those from a human body could disrupt the precision machinery, all researchers will remain in control rooms outside the microscope rooms during operation.
For example, a robotic arm inside the Titan Krios transfers frozen samples from their storage containers into the microscope for viewing, while maintaining a vacuum and cryogenic temperatures. The microscope, which is about 12½ feet tall and weighs 2 tons, can hold and precisely move 12 samples in an automated manner so that thousands of images can be recorded, processed via computers, and interpreted to generate 3-D images for study. Like the Titan Krios, the Talos Arctica is a fully automated, but less powerful instrument that will enable researchers to screen for optimal conditions before moving onto the Titan Krios. The Scios DualBeam is a molecular sand-blaster that precisely carves very thin slices of cells that can be transferred to and imaged in three dimensions on the Krios. In combination, these instruments will enable researchers at UT Southwestern to view the structure of cellular machines, which carry out bodily processes, in their native states and across scales from cells to molecules to atoms.
This imaging is facilitated by new high-tech cameras capable of directly recording electrons rather than conventional cameras that must first convert the electron’s energy to light, losing sensitivity in the process. Advances in direct electron detector technology in the past five years have been credited with what many scientists call the “resolution revolution” that enabled cryo-EM to rival X-ray crystallography. The UT Southwestern facility will have three of the advanced detectors, Dr. Schmid said.
Testing is underway on the first two instruments. The Talos Arctica, acquired by the HHMI and housed at UT Southwestern, will arrive this fall and will accelerate researchers’ access to cryo-EM, Dr. Rosen said. Scientists will be able to schedule time on the microscopes and even view their images from remote locations via computer, enabling international collaborations, he added.
The pre-opening symposium, called “The Resolution Revolution: New Windows into Cellular Structure and Function,” was held on April 25. The event, which received support from the Keith R. Porter Endowment for Cell Biology, was organized by the first new cryo-EM facility’s faculty recruit, Dr. Daniela Nicastro, associate professor of cell biology and biophysics and a CPRIT Scholar whose expertise is in cellular cryo-EM tomography.
With funding from a CPRIT grant, Dr. Nicastro will study mistakes in DNA repair that are thought to drive the development of cancer. “Before you can understand how a process goes wrong, you have to understand how it works,” she explained. “And seeing is believing!”