Researchers crowd around a microscope as part of a microscopy training workshop

Ru-ching Hsia, Ph.D., heard the same concern from colleagues across the country: There is a dearth of electron microscopy training opportunities in the United States, and it’s limiting biological sciences.  

Hsia, who heads the Electron Microscopy Laboratory at the Frederick National Laboratory (FNL), realized that FNL could help fill this need and train the next generation of researchers, so she decided to pilot an ultramicrotomy mini-course.  

Ultramicrotomy is the method for cutting specimens into ultra-thin sections (less than 100 nanometers), for analysis, typically done with a diamond knife. This technique enables the microscopist to capture the specimen’s internal structures at an extremely high resolution. 

Twelve students participated in the pilot course held earlier this year. They listened to presentations by experts in the field, watched technique demonstration, and engaged in hands-on practice at the ultramicrotomes in the Electron Microscopy Laboratory.  

The need for training 

Several researchers crowd around a microscope in a lab during a training workshop

Hsia said preparing electron microscopy specimens requires special skills, and the lack of training opportunities for these essential techniques in the United States is hindering biomedical research. She explained that there are electron microscopy courses in Europe, and there are plenty of intensive confocal microscopy training opportunities in the United States, but there has been limited investment in electron microscopy training specifically designed for biological sciences.  

The reason, she said, is that these are challenging programs to run.  

“The instruments are expensive and require space,” Hsia said. “Not many institutions can afford them. The FNL is unique.” 

Currently, the FNL has six ultramicrotomes, four in one room, making it an ideal setting to conduct small group trainings. Furthermore, FNL has more than 15 electron microscopes and many leading-edge electron microscopy sample preparation instruments. And FNL has a high number  of experienced microscopists to lend their expertise.  

Hsia said the lack of formal training means many microscopists acquire their skills on the job, so they learn in an environment where the focus is on contributing to the productivity of the laboratory rather than learning the principles and theories. 

“Like driving a car, to use a microscope, you do not need to know how it works,” Hsia said. “But you cannot troubleshoot issues if you do not understand the principles behind it.”  

Learning microscopy techniques  

2024 electron microscopy mini-course participants

The pilot course offered two sets of two-day classes, one for beginners—including those who had never used an ultramicrotome before—and one for more advanced users looking to hone their skills.  

Although the FNL has deep internal content expertise in this technology, Hsia brought in outside experts as well. Of note, Helmut Gnaegi, research director of Diatome, travelled from Switzerland. With more than 40 years of experience, Gnaegi is a leading expert on diamond knives for ultramicrotomy.  

Hsia said there are many misconceptions about diamond knife handling techniques which can result in expensive mistakes, given that resharpening a knife costs thousands of dollars.  

“The knife is strong, but the edge is fragile,” she explained. “The edge is only as thick as an eyelash, and a bump to the knife edge will easily break it.”  

Gnaegi demonstrated correct techniques to use and care for diamond knives, then turned the ultramicrotome over to the trainees for practice. 

Attendees from across the biosciences  

Attendees came from several institutes within the National Institutes of Health: the National Institute on Drug Abuse, National Eye Institute, National Institute on Deafness and Other Communication Disorders, and National Cancer Institute, showcasing the value of electron microscopy across a range of biomedical research areas. Participants also hailed from universities and medical schools along the East Coast. Representatives from the microscope company Leica Microsystems also sat in to observe how the ultramicrotomes are being used and to learn best practices.  

“Everyone sees the need for this training,” Hsia said. “The classes filled rapidly, and everyone who attended said they would recommend the course to their colleagues.” 

Future steps 

Hsia hopes to offer the class again in the future. She noted that this training followed in the footsteps of the cryo-electron microscopy training program that FNL offered in 2022. She sees sharing FNL’s microscopy resources as an important part of the FNL’s mission to serve as a national resource and place to advance biomedical research.  

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