Master of microscopy
Fei Chen admits the idea behind the microscopy technique he co-invented as an MIT grad student was “pretty outlandish.” But by pursuing that seemingly wild idea, he pushed the limits of what can be visualized with a light microscope.
Chen and fellow Ph.D. student Paul Tillberg came up with the new technique when they were struggling to look at synapses, the tiny spaces between neurons where signals are transmitted. A typical light microscope can’t resolve anything smaller than about 200 nanometers — synapses are often only about a tenth of that. Chen and Tillberg built a complex, high-resolution microscope, but they still couldn’t see synapses clearly. That’s when the idea for expansion microscopy struck: “What if instead of building a better microscope you could just make your sample bigger?” Chen said. He remembers picturing in his mind the little foam dinosaurs that he used to put in water and watch grow as a child.
The two students began tinkering with the idea. Late one night they started an experiment where they introduced polyacrylate, an expandable polymer gel commonly used in diapers, into a few cells from a human cell line and added water. “We put it under the microscope and then there it was before our eyes getting bigger,” said Chen. “We just kept watching it for hours until it was like 2am.” Though the attempt wasn’t perfect — structures in the cells became distorted — they knew their idea could work, and after some more experimenting, they perfected the process for expansion microscopy.
The technique involves labeling cellular components of interest with fluorescent tags, adding polyacrylate, and heating the sample so that the polymer forms a gel. Enzymes are then added to digest the proteins that hold the specimen together so that everything can grow uniformly. Then, add water, and watch cells expand 100-fold. The expansion enlarges cellular components, making it possible for ordinary light microscopes to distinguish them.
“The cool thing is that anyone can buy these chemicals and go and do it with any microscope,” Chen said.
Inventing expansion microscopy, which was published in Science in 2015, was an early example of how Chen brings an engineering mindset to biology. An avid science fiction reader (Isaac Asimov and Neal Stephenson are his favorite authors), Chen embraces innovative approaches and impresses the postdocs in his lab at the Broad Institute with his creativity and enthusiasm, especially when talking about new results. He moved to the Broad as a Schmidt Fellow in 2017, and his collaborators say that his microscopy expertise has elevated several research projects here.
“Nobody knows microscopy in this community like Fei does,” said Evan Macosko, an associate member at the Broad who collaborates closely with Chen. “Having him here really has transformed a lot of projects.”
Today, Chen is combining microscopy and single-cell RNA analysis, allowing researchers to learn more about the context of specific cell types in addition to their gene expression. This work has already earned Chen multiple honors, including a National Institutes of Health Director’s Early Independence Award, an Allen Distinguished Investigator Award, and a place on the 2019 Forbes 30 Under 30 - Healthcare list.
From circuits to genomics
Raised by parents who were trained as biologists, Chen grew up interested in science, but he was initially drawn more to engineering, particularly space flight, than biology. “If I wasn’t doing this right now, I think I would probably want to go work at SpaceX,” said Chen. He decided to major in electrical engineering at the California Institute of Technology, but while there he began using DNA to build circuits as part of a research project. “At the time there was this big push to do the same kind of computations you could do in an electrical circuit but in DNA,” Chen explained.
One of his undergrad projects was building a control circuit — the type of circuit in a thermostat that keeps temperature within a set range — out of DNA. These were more engineering experiments than biological ones, but they changed Chen’s career trajectory. “I quickly realized that what I actually wanted to do was engineering in service of biology, to learn new things about biology,” said Chen. A senior year research project using DNA to detect RNA in cells exposed Chen to cells, tissues, and microscopy, opening the door to studying bioengineering in graduate school.
(Credit: Casey Atkins)
While pursuing his Ph.D. at MIT, Chen focused on microscopy research. Ed Boyden, a professor of biological engineering and brain and cognitive sciences at MIT and Chen’s Ph.D. advisor, says Chen showed creativity and flexibility in learning new skills and thinking about problems from different angles. “Very often when we were trying to solve problems with expansion microscopy, we would delve into chemistry ideas and then we would talk about biological ideas and he was also building microscopes,” Boyden said. “This multidisciplinary approach that Fei has is very powerful and played a key role, I think, in how we were able to make that project a reality.”
While in Boyden’s lab, Chen also worked on combining expansion microscopy with fluorescence sequencing, a way of visualizing which genes are active in a particular cell. “I really wanted to bridge these two worlds, the world of microscopy and the world of genomics,” he said. He wanted to come to the Broad because it seemed like an ideal place to do that — scientists at the institute had just developed a new technique to read the RNA of individual cells. Single cell analysis reveals a cell’s identity and activity, but not where it came from, Chen said. “With the microscope you always know where the cell comes from.”
The stories of single cells
Toward the end of his graduate work, in 2017, Chen was selected as a Schmidt Fellow at the Broad. The Schmidt Fellows Program, founded with a generous gift from Eric and Wendy Schmidt, enables extraordinary early-career scientists from the mathematical, computational, or physical sciences to develop their own independent labs before pursuing faculty positions.
Shortly after arriving at Broad, Chen had lunch with Evan Macosko, a neuroscientist who was also starting his own lab at the institute, and they quickly found common research interests. “Evan was coming from the single-cell world and I was coming from the microscopy world but we both wanted to put these things together,” Chen said. While still eating, the two hatched a plan to do single-cell sequencing in a way that preserved information about the location of individual cells within a tissue. They called the technology Slide-seq.
Early this year, the Chen and Macosko labs published the first paper on Slide-seq in Science. The technique involves covering a rubber-coated glass slide with tiny beads about the size of an individual cell. Each bead is tagged with a unique DNA address label and those addresses are mapped. Then, a piece of fresh-frozen tissue is dissolved on the slide, leaving mRNA transcripts bound to the beads. Researchers then sequence the RNA and feed the results, along with the DNA address labels for each of the transcripts, into software. The resulting high-resolution maps show the location of specific cell types or cells expressing certain genes in the sample.
A three-dimensional reconstruction of nine cubic millimeters of mouse hippocampus profiled with Slide-seq (colors indicate different cell types). (Credit: Chen and Macosko labs)
So far, Chen and Macosko have used Slide-seq to look at brain development and neurodegenerative diseases. The Human Cell Atlas is also using the technology to help them map the multitude of cell types in the human body.
Chen has collaborated with other scientists at the Broad as well. He’s working with Anna Greka’s lab to apply Slide-seq to kidney cells, examining cell type changes and spatial gene expression changes that take place in diabetic kidney disease. In addition, Chen has been working with Jason Buenrostro for several years using imaging techniques to define the structure of the genome at high resolution.
From space to time
Chen is looking forward to applying Slide-seq to developmental processes and studying how they’re affected by genetic mutations. Just recently, his lab began collecting data on early stage mouse embryos, which can fit on a single slide.
One of the other primary projects in Chen’s lab is creating tools to track and analyze what happens to individual cells over time. “We’re working on ways where you can build basically flight recorders, black boxes, for the cell, where the cell keeps track of some of the information about what it’s been doing,” Chen said. He hopes to do this by engineering a way for particular events in the cell to create changes in DNA or RNA, since those are the two forms of cellular information that are easiest to read.
Eventually, Chen would like to use this kind of “black box” tool to see how the brain grows and how cell types are formed, but he’s still searching for a good way to encode past events in DNA or RNA. “We’re trying a lot of really out-there stuff to tackle this temporal problem and it’s exciting,” said Chen. “It’s very high risk and most of them probably won’t work, but it’s going to be cool to see what happens.”
These bold, new ideas make the Chen lab an exhilarating place to be, says Tongtong Zhao, a postdoctoral researcher in Chen’s lab. “For us to realize those ideas, we need to constantly learn new things and gather new skills, and that is just very, very fun.”
Chen’s enthusiasm is infectious, says Haiqi Chen, another postdoctoral researcher in the lab. “Whenever we have very exciting results he’s even more excited than we are, and it feels great to see someone who’s so passionate about science.”