Hawa Racine Thiam in her lab at Stanford University. (Credit: Kurt Hickman/Stanford University)

CZ Biohub San Francisco Investigator Hawa Racine Thiam’s new Stanford lab applies physics to the study of cells and their nuclei

Hawa Racine Thiam was 22 years old when her obsession with cell nuclei began.

It was early in her master’s studies, at a poster session hosted by her university, that Thiam first learned that certain cells can contort their bodies to travel through tiny passages within our tissue. One poster included an image of an immune cell squeezing through a narrow laboratory-constructed constriction in much the same way you’d expect a gel-filled stress ball to behave if you tried to shove it through a napkin ring. 

As she examined the photographed cell — which was bulging on either side of the constriction but nothing more than a skinny tendril within it — a thought struck her.

There was a problem, she realized. While these cells are mostly watery entities surrounded by flexible membranes, the nuclei carried inside them are rigid and — as Thiam knew — substantially bigger than the narrow constriction this cell was easily traversing. It would be as if you put a large rock inside your stress ball and then tried to get it through that napkin ring. It shouldn’t be possible.

No one else seemed to have given much thought to this puzzle, but Thiam — whose master’s program centered on applying physics to biological systems — couldn’t get it out of her head. Soon, she had convinced the researcher presenting the poster to take her on as a graduate student and let her dig into the mystery through a thesis project in his lab. That project eventually formed the basis for her Ph.D. and by the time she’d finished her doctorate, she’d shown that certain cells employ a complex mechanism to temporarily soften their nuclei before passing through small openings — allowing the whole cell to slip right through. 

Today, Thiam is a Chan Zuckerberg Biohub San Francisco Investigator celebrating the recent launch of her lab at Stanford University, and she is continuing to investigate the physics behind how cells — and their nuclei — move and behave. Thanks to Biohub support, she’s designing new ways to experimentally replicate the physical forces cells encounter in the body and has plugged into the growing regional “physics of life” community the Biohub is working to foster. 

Immune cells often have to travel long distances and navigate varied obstacles to perform their roles in the body. Here, an immune cell squeezes through a man-made constriction in a laboratory. (Credit: Hawa Racine Thiam)

“I’m very lucky to be developing my lab from scratch with the support of not just my university but also the Biohub, which creates additional opportunities to learn from people who are working on things that are completely new to me,” she says.

The path to science

As a child, Thiam never expected to be a scientist. Raised in Kaolack, Senegal by parents who didn’t graduate high school, “I had no one in my environment who would have inspired me to go into research,” she says. 

But despite not having the opportunity to study themselves, Thiam’s parents were dedicated to making sure their children did, equipping their home with study stations to make sure all the kids in their large family had a quiet space to work. And Thiam’s father made a practice of accompanying her to every school exam — sometimes making a four-hour drive from his furniture shop in Dakar, Senegal’s capital, to ask her how she fared as she emerged from a test.

“I think that’s what made a huge difference and ensured people in my family studied while many others with the exact same socioeconomic struggles didn’t,”  Thiam says. “I had the kind of moral support that let me push through.”

High marks won Thiam a fellowship to attend college in France. There, she worked as a server at McDonald’s to help pay for her eventual degree in physics from Paris Diderot University. By then she was getting curious about research, but she wasn’t sure if it was for her. She hadn’t had much of a chance to see what the work of a researcher might look like and a well-meaning relative’s warning that science was “just for rich kids” gave her doubts. 

She decided she would take the decision step-by-step, testing the waters with the master’s that eventually expanded into Ph.D research at Paris’s Curie Institute and a doctorate degree  conferred by Paris Descartes University. At that point, she was still feeling somewhat cautious and credits her Ph.D. advisor, Matthieu Piel, with encouraging her to stay in science and go on to a postdoc at the U.S. National Institutes of Health in Maryland. That eventually led to her current position as an assistant professor of bioengineering at Stanford. Though she had concerns at each juncture, it was curiosity — especially unanswered questions about the cell nucleus — that kept pulling her forward.

“Knowing that I wanted to be an academic — that came much later in my career,” she says. “But I did know that I wanted to keep learning. And I couldn’t stay away from the nucleus.” 

Biology through a physical lens

The idea of using physical principles to predict cellular movement was captivating to Thiam. While physicists had long ago mastered the art of applying the basic concepts of force, mass, and acceleration to make predictions about the movement of objects in the macroscopic world of cars, people, and planets, Thiam saw that scientists didn’t have the same grasp on such problems when it came to the microscopic world of the cell. 

“If you have a car that’s moving at a certain speed, we can predict when it needs to start braking in order to stop at a given point,” she points out. “We cannot do that with a cell.” 

While most cellular nuclei are spherical, immune cell nuclei (displayed here in purple) come in various shapes and sizes. Researchers suspect this diversity is due to the specific mobility needs of different immune cells throughout the body. (Credit: Regina Sanchez Flores)

To Thiam, questions about the physics of how cells move and behave are particularly interesting in the case of immune cells, which — as the body’s scouts and soldiers — must often travel long distances within our tissues, braving varied terrain and obstacles along the way, all the while juggling their stiff, bulky nuclei. 

Physics, it turns out, is critical to understanding many other other immune cell actions as well. As a postdoc, Thiam took on a project investigating NETosis, an unusual process by which certain white blood cells unwind their DNA, pepper it with microbe-killing proteins, and then hurl the entire toxic mesh at nearby pathogens — typically killing themselves in the process. By taking thousands of microscope photos of this bizarre behavior, she characterized the steps through which NETosis occurs, and she’s still investigating just how DNA manages to burst through the rigid nucleus to make its way outside the cell.

“These are processes that can’t be fully understood just through the lens of biochemistry,”  Thiam says. “We don’t know enough about the physical nature of these important functions, which are fundamental for our health.”

Building something new 

At Stanford, Thiam is continuing to dig into questions of physical biology that have so far been largely overlooked, from the mechanisms behind NETosis to why astronauts’ immune systems seem to weaken when they experience zero gravity. And she sees great potential for new approaches to designing immune therapies if scientists can learn to tweak certain physical properties of cells.

NETosis can be triggered by the presence of a pathogen (shown here as a blue blob “eaten” at the video’s start) and results in a neutrophil ejecting its DNA (apparent here in the burst of green at the video’s end). (Credit: Hawa Racine Thiam)

In preparing her team to investigate these and other subjects, she’s equipped her bright new lab with state-of-the-art equipment. Her microscope room sports a “spinning disk” microscope, which rapidly sweeps thousands of individual light beams across a specimen to capture ultrafast cellular processes without damaging living cells. And a device called an optical tweezer lets her team grab and manipulate precise points within a cell using a highly focused laser beam. Thiam’s team is also working to establish a unique system that will mimic environments that an immune cell encounters in the body.

Thanks to CZ Biohub SF funding, Thiam’s lab includes an extra teammate: postdoctoral scholar Manasi Sawant, whose background in molecular biology and epigenetics is helping the team dig into questions of how physical factors and the molecular inner-workings of cells, together, lead to certain cell behaviors. 

“Manasi brings us expertise in an area that I have never worked in, and we can leverage this expertise to ask questions about the interplay between the physical world and the molecular world,” Hawa says. “Her complementary background has allowed me to address research questions that I wouldn’t otherwise have been able to work on this early in my career.” 

But pushing innovative research initiatives isn’t Thiam’s only vision for her new lab. She’s also determined to establish a research culture that helps promote diversity in science and encourages collaborations among people with differing backgrounds. As an immigrant scientist (in both France and the U.S.) for her entire career, Thiam notes that she couldn’t be where she is today without having had the opportunity to cross borders and work with colleagues who welcomed diverse perspectives and experiences. Now she wants to support similar opportunities for others. 

Thiam is also a new parent, and over the past few months, has been setting up her lab with her infant daughter in tow. It’s something she feels both privileged and proud to be able to do, as she hopes she’s sending a message that institutions have to create space for researchers to be both scientists and parents. It’s another opportunity to demonstrate that science shouldn’t be accessible only to certain kinds of people. 

“My dream,” she says, “is that, by the end of my career, I can look back and see that I’ve trained people that look very different from one another, and regardless of what they end up doing with their careers, have transmitted this perspective of adopting a quantitative mindset when trying to solve problems in biology.”