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Getting Under Your Skin: How a Interdisciplinary Team of Scientists Came Together to Study Epithelial Cells

The primary purpose of epithelial cells are to line things. Your skin. Your stomach. In all the places where your body needs to be “sectioned off”, there are epithelial cells creating the lining. They’re stuck together like bricks building a wall and they don’t move very much.

And if epithelial cells are bricks, then mesenchymal cells are clay. Instead of being rigid and ‘cemented’ together, they are free to move about and change shape before ‘hardening’ into a specific shape for a specific function. They’re critical during your earliest days as an embryo and, as a stem cell, can develop into a variety of different crucial structures and cell types, such as bone, cartilage, or muscle. These cells are also more proficient at moving around the body than epithelial cells. So much so, that when epithelial cells need to get around, they first turn into mesenchymal cells. This process is called the epithelial-to-mesenchymal transition (EMT).

A New Way of Moving

EMT is prevalent throughout the body occurring almost anywhere epithelial cells occur. For example, EMT is common in the lungs causing cell movement in the human bronchial epithelial (HBE) line. If cells are on the move, most textbooks would immediately say it’s EMT at work. In fact, EMT has been so well documented, it has become sort of a default for most cellular biologists. If they see epithelial cells moving, it must be EMT. This recently changed when a phenomena was discovered where epithelial cells didn’t undergo EMT to move but were able to “unjam” and move as a sort of gooey raft of cells. This process was named unjamming transition (UJT) and became a hot topic for new research. It is here at the discovery of UJT where Northeastern, Harvard and other researchers around the world began the scientific process of asking questions. Is UJT distinct from EMT, or just a special case? Does one transition type lead into the other, or can they happen independently? Northeastern researchers were keen to find out, and eventually did.

(a) Experimental image of cultured human lung epithelial cell monolayer after compression, with segmented cell boundaries; cells colored by like-orientations show formation of multiple cell packs with different orientations. Scale bar: 50 microns (b) Snapshot of simulated epithelial monolayer showing a large cell-pack (green) moving downward, arrows represent instantaneous cell velocities; inset highlights a similar cell pack (blue) in experimentally observed velocity field, scale bar: 100 microns

Greater Than the Sum of Its Parts

Max Bi and Amit Das, two researchers in the physics department at Northeastern are part of a greater team of Boston and global labs researching how UJT may be distinct from EMT. Bi would be the first to admit the biological experiments of the research weren’t his area of expertise. For that, he looked to his long-time friend, Jin-ah Park, a biologist at Harvard University. “People are trained differently, they have different mindsets. So, to bring a collaboration to finish, to be successful exploring a certain concept, or making a discovery, and eventually publishing it is not trivial,” says Bi. That’s why Bi was also pleased to have Amit Das, a post-doctoral fellow, join his team in 2018. Although a physicist, Amit comes from the National Center for Biological Sciences, the top biological institute in India. This made him crucial in bridging the gap between physics and biology in this important research project.

Being part of Northeastern made collaboration easier too, says the physics duo. Bi explained how the physics department encourages interdisciplinary collaboration. “We don’t have to do what people think of as pure physics, so we can work on various topics that are not necessarily ‘traditional aspects’ of physics. As long as we are asking interesting questions, we always have the full support of the whole institution… in terms of biological physics, applying physical concepts to biology, we are really one of the premier places to do that” says Bi.

Northeastern’s location itself plays a role in multi-institute efforts. Boston is a hub of top research institutes in the world, and in the case of this paper, Northeastern and Harvard’s proximity made communication simple. “Before the pandemic, if I needed to meet with Harvard, they were only two T-stops away,” says Das. “That proximity was instrumental in pushing this research to be done faster.”

How’d They Do It?

So where do Bi and Das and physics fit into this biological research? Computations and analysis. When trying to determine if a bunch of cells underwent EMT or UJT, a primary method of study is to see if cells remained epithelial or not. This involves categorizing the cells by size and shape. This traditionally has been a very slow process, as the cell perimeter and area is hand traced. Das was able to automate nearly 90% of this process by creating a toolkit, drastically shortening the time dedicated to cell identification. His physics-backed computing method proved so efficient that it has spread throughout the Harvard lab. Today, more than 20 people are using his method. Bi’s PhD research centers around jamming behavior of non-living matter, like sand in a bucket, or cars in traffic. Using principles from a new field of physics, active matter physics, Bi can now apply similar algorithms to model cell movement and predict where UJT might occur in the body.

Physics was also critical to simulating cell movement, and in the crunching of data after the experiments had taken place. “Our biology collaborators spend hours and hours in the lab growing cells, imaging cells, but we spend, you know, hours and weeks, and maybe I would say a month of computational time on the Discovery Cluster Lab (DCL),” says Bi “None of this would have been possible with desktop computers. It would have taken 10 years, [but with the DCL] it takes maybe several months to do what we do.”

Two Innovations for the Price of One

Through the collaboration of various minds and fields, the paper was published with the findings that UJT is a distinct process from EMT and not a type of situational side-step. This alone has major implications and opens a plethora of doors to more research. While this paper focuses on asthmatic lung cells, UJT has since been seen in cancer tumors as one way they can spread throughout the body.

While the paper was under review, Amit was invited to present its findings to the National Cancer Institute at a meeting dedicated to cancer research, where it was even honored as groundbreaking research. This is an extraordinary accomplishment considering the paper was about asthmatic cells, not cancer! If this research can someday help stop the spread of malignant tumors, it will be another piece in the holy grail of curing cancer. However, the research has important implications today. The physics models Max and Amit created can be applied to various “jamming situations” in humanity. According to Max, his active matter algorithms can simulate where to best locate a fire exit in a movie theater or to minimize congestion in a subway station.

While these applications may not be as life altering as curing cancer, they’re critical everyday benefits that could be applied now.

Biology
Physics