#WhyIScience Q&A: A mechanical engineer builds microscopes to give new spatial views of cells and tissues

At some point during her education, self-described “space nerd” Lindsey Erion-Barner traded gazing through telescopes for peering into microscopes. “There are many commonalities between astronomy and microscopy, they’re just at different scales,” she explained. The computational algorithms for correcting distortions are often the same, she added, whether you’re examining a star far away or small spots within a tissue.

During her childhood in Gaithersburg, Maryland, Erion-Barner enjoyed building erector sets with her father, an engineer, and joining him in the backyard to view the night sky through the family’s telescope. During her undergraduate years, she studied mechanical engineering at Messiah College, aligned X-ray telescopes at NASA’s Goddard Space Flight Center as a student researcher, and helped test cosmic ray detectors at Fermilab. However, many of her siblings and extended family members had instead pursued medical careers, and their dinnertime chatter about clinical work inspired Erion-Barner to shift focus to a career that could impact human health.

At the University of Washington, she applied her optics expertise to graduate research aimed at building light sheet microscopes that could view tissues in 3D for cancer diagnostics. She later worked at the Allen Institute for Neurodynamics building a new 3D light sheet microscope for imaging mouse brains. The team planned to one day use it to observe and spatially map gene expression in tissue, known as spatial transcriptomic analysis.

Erion-Barner joined the Broad Institute in 2023 as a scientist and microscope builder in the Spatial Technology Platform, where she leads the development and implementation of imaging-based spatial transcriptomics and proteomic profiling technology.

We spoke with Erion-Barner about her career in microscope building and the challenges of working in the fast-advancing field of spatial biology in this #WhyIScience Q&A.

 

What is your role in the Spatial Technology Platform, and how are you helping advance the platform’s goals?

Our mission in the platform is to help disseminate different spatial profiling and imaging transcriptomics technologies — including those invented by Broad scientists — to the scientific community. We also want to develop innovative tools and imaging techniques, and then eventually benchmark many of the different tools to help our collaborators understand which ones are best to use in their experiments.

I lead a group within the platform that develops new ways to image transcriptomics in three dimensions, and I specialize in optical microscopy techniques and hardware development. One goal is to employ light sheet microscopy, which uses “sheets” or planes of light to illuminate samples, to image thick tissues in 3D. Our dream is to one day do it in whole brains at low resolution. We’ve been focused on techniques that might increase the thickness of sections that we can image and that would allow us to measure expression of more genes at a time at low magnification. We rely on a barcoding approach that allows us to measure hundreds of genes with a small number of fluorescent labels, but it requires many cycles of labeling and washing, so we’re working on new labeling and computational methods to reduce the time involved for thick tissue.

I also work closely with the lab of Adam Granger in the Stanley Center for Psychiatric Research. We’re using spatial technology to understand the role of the AKAP11 gene, a risk factor for bipolar disorder and schizophrenia, by observing how brain cells and their connections are altered when the gene is turned off.

What are some of the biggest challenges in your work?

Spatial technologies are advancing so fast. In the platform, we strive to not only keep up with the field, but to develop imaging technologies that can be implemented and keep pace. Sure, we can develop cool research tools that enable innovative experiments, but there’s a trade-off if they’re not as easy to implement as commercially available instruments.

In addition, my personal challenge as a microscope builder without the same expertise in genetics as many of our collaborators is to educate myself so that I can engage them in an intelligent way, so that our combined efforts can be as successful as possible.

What is the most rewarding part of your role as a microscope builder?

My favorite thing to do in the lab is to see a need, come up with a solution, put it together, and see if it works, which it often does. Even more rewarding than that is having that thing I’ve built actually meet a user’s needs.

I love being able to work closely with our collaborators and feel like I’m being helpful. It’s incredible to be next to the biologist who’s getting a brand-new view of the thing they’ve studied for so long, and to watch their “Aha” moment happen because of my instrument. I once stood next to a biologist who, while we were imaging her protein labels throughout an organ in 3D, stopped my chit-chat and said, “Hold on, I’m having an emotional moment here,” as we were panning through the live feed. 

How have mentors influenced your academic and professional journey?

My college physics professor used to sit with me for hours to explain the biggest concepts in particle physics. Although I was just a student researcher, he never made me feel like I wasn’t worth his time, and that helped me stay curious about physics. I’d also say my dad was a great mentor to me — we shared an interest in space science, and he taught me so many of the hardware skills that I still use today.

What advice would you offer young aspiring scientists?

Lean into the things you’re curious about, the things that you like doing. I really enjoy building stuff and jerry-rigging stuff, and that interest and those skills have become part of my career now. So I’d tell those young scientists to find the things they enjoy doing and stay curious about them.