This biophysicist’s work could one day let doctors control immune cells

But that’s only possible by demystifying the mechanics of cell movement. “We need to understand how cells work if we want to manipulate them,” Thiam says.

This is “unquestionably an important area of research,” says Clifford Brangwynne, a bioengineer at Princeton University. People sometimes have the misconception that biology is this mysterious universe that somehow operates outside the laws of physics, he says. But the same kinds of physical rules that govern the inanimate world are also at play in living systems. 

It’s a topic that keeps Thiam’s curiosity whirring. This past summer, she submitted three grant applications, and her potential projects can lead in some surprising directions. In one, Thiam proposed collaborating with a biologist who studies ant behavior. Yes, the insects. That may sound out of the blue for someone who studies immune cells.

But Thiam says the cells her lab studies — a type of white blood cell called neutrophils that seek out and destroy dangerous microbes — have something in common with ants. Neither have a central control system telling them how to do their job. Instead, the first wave of ant hunters finds a food source and then leaves a trail of chemical breadcrumbs for other ants to follow. Similarly, neutrophils leave a chemical trail for their reinforcements. This type of collective behavior, where interactions between individuals influence group action has been well-studied in ants, Thiam says. “We can learn a lot from that.”

Now, she wants to know if what a neutrophil ends up doing with a microbe it discovers — eat it, poison it, trap it — influences the search behavior of subsequent cells.

That undercurrent of desire to learn and ask questions — about science and herself — has flowed throughout her career. Thiam grew up in Senegal and moved to France for her undergraduate and graduate degrees. Her Ph.D. work revolved around understanding how the nucleus influences a cell’s ability to move. At the time, conventional wisdom on cell migration for the most part ignored the nucleus, Thiam says. Scientists thought crawling cells took three basic steps. They extend a “foot,” attach it to a nearby surface, then retract the rear, pulling the cell body forward. (Imagine Batman whisked up the side of a building by his retractable grappling hook.)

But that largely two-dimensional view overlooked cells’ 3-D environment, Thiam says. Sure, cells can crawl along flat surfaces, but what about when they need to cram through tight spots? From experiments that had cells moving through smaller and smaller pores, Thiam’s team reported in Nature Communications in 2016 that the nucleus helps determine whether immune cells can migrate in confining environments. Compare cell movement to passing a plastic bag through a small hole. If the bag contains a kiwi, it probably won’t fit.

Thiam and her colleagues discovered that cells have a way to deform their nuclei, up to a point. Cells rupture the membrane surrounding the nucleus and extrude some of its guts, making the whole thing more able to ooze through a constriction. It’s like crushing that kiwi until the fuzzy skin breaks and the fruit is floppy rather than firm. Now it can squeeze through a smaller space. Until this work, no one had shown that nuclei behave like that, Thiam says.

Later, during her postdoctoral work in Clare Waterman’s lab at the National Institutes of Health in Bethesda, Md., Thiam continued her investigations of cell nuclei. In a 2020 paper in Proceedings of the National Academy of Sciences, she and her colleagues reported on one of the weirder aspects of biology, a cellular defense mechanism called NETosis. It’s a way for neutrophils to physically trap invading bacteria, fungi or viruses. Pathogens creep into the body and — BOOM — suddenly they’re ensnared, like dolphins caught in a fishing net. But this net is made of DNA: The immune cell blasts out its own genetic material to capture microbes. “It’s this crazy phenomenon,” Thiam says.

Scientists had first reported NETosis in 2004, but they didn’t really know how it worked. That’s what Thiam’s team took on. Using cutting-edge microscopy and gene-editing techniques, the researchers outlined the sequence of events that begin with a cell’s DNA packed inside the nucleus and end with it blown outside the cell.

“She has this fearlessness in coming at these really very challenging problems in cell biology,” says Brangwynne, who is also a Howard Hughes Medical Institute investigator. He thinks that fearlessness stems from her background. Thiam has crossed boundaries between nations, different fields of science and languages (she speaks four). “I think she’s really not afraid of much of anything,” he says.

But Thiam says she still asks herself if she’s smart enough, works hard enough and is capable of being a good scientist and mentor. “I think it’s OK to have doubts,” Thiam says. She acknowledges them, tries not to let them overpower her and thinks about how she can improve. And whenever Thiam’s questioning herself, she tries to remember that she and others believe in her — and then she forges onward with her work, writing grants, doing science and training students. “I just try to keep pushing,” she says.