Pushing cells to the extreme
When Hawa Racine Thiam looks at a cell, she sees more than a living thing responsible for carrying out the processes that allow us to move our muscles, digest our food, and fight off infections. She sees a physical object that interacts with other cells and tissues that are soft or stiff, goes through channels that are wide or narrow, and experiences and exerts forces.
Born and raised in Senegal, Thiam was fascinated by numbers from a young age. Her curiosity brought her from physics to biology to immunology. She earned her BS in Physics and her MS in Physics for Biological systems at Paris Diderot University, and later her PhD in Biophysics from the Institut Curie, where she studied what happens to immune cell nuclei as they squeeze through small passages while patrolling the body.
During her postdoctoral training at the National Institutes of Health, she began studying a process called NETosis in which a certain immune cell, called a neutrophil, self-destructs, releasing its DNA outside the cell to form networks that trap invading pathogens.
Thiam, an Institute Scholar at Sarafan ChEM-H, joined Stanford in May 2022 as an assistant professor of bioengineering and of microbiology and immunology. Here, she shares her fascination with extreme cell behaviors, the connection between immune cells and elite athletes, and the importance of mentorship in science.
You have an undergraduate degree in physics and now you are leading a bioengineering lab that focuses on immunology. How did that transition happen?
I’ve always really loved math; I love the freedom of thinking about abstract concepts governed by numbers and equations. But eventually I felt the need to transfer these abstract concepts to concrete problems, and I moved to physics because it was a way to apply math. And then I got curious about applying physical concepts to living systems and learning the new physics that comes with biology. Then I found physical biology, the field I was looking for! I became fascinated with understanding how living systems are built and how they work. And for me, it all started with the nucleus.
The nucleus, of course, contains DNA, your genetic material. A lot of people study the nucleus for its biochemical properties, like discovering the molecules involved in gene expression or cellular replication. But the nucleus is also an object with physical properties. It has a certain size and shape and stiffness, and it contains this mega-long, compacted DNA inside of it. They are dense spheres. And if you ignore the physics of the nucleus, you are completely underestimating the beauty of biology.
So how did studying the nucleus lead you to immunology?
When I discovered the immune system, it was a complete “Oh my God” moment. I think of immune cells as free, in a way. They deviate a lot from other “normal” cell functions, which is really reflected in the nucleus.
We can think of immune cells as having at least two key functions: migration and pathogen killing. They have different ways of moving through and interacting with different parts of the body, and different methods of attacking and neutralizing foreign invaders.
For migration to work, immune cells—and their nuclei—have to squeeze through tight spaces. During My PhD work in the lab of Mathieu Piel, I designed devices that allowed me to watch what happens to immune cell nuclei under confinement, and I discovered how otherwise stiff nuclei can deform to accommodate narrow channels.
Are there any links between the physical properties, like shape and size, of the nucleus and diseases?
In most cells, the nucleus is a round, ovoid shape, and when you look in a textbook, a cell’s nucleus will usually be depicted as a circle with some genes in it. But sometimes, cells deviate from that. When a cancer patient gets a biopsy, for example, one of the first things a pathologist will look at is the shape of the nucleus. If it’s not ovoid anymore, that’s an indication that the cells have become malignant.
But that transition from round to not-round nuclei is perfectly normal in immune cells. Immune cells naturally differentiate, or evolve, in our bodies to become different cells with different functions. In one of these lineages, a cell evolves from one with a round nucleus to one with a kidney-shaped nucleus, to one with a multi-lobed nucleus that in some species resembles a doughnut!
So there’s this behavior--changing the nuclear shape--that might seem extreme but is totally normal in immune cells. And this is just one example of extreme immune cell behavior.
Can you give me another example of this “extreme” behavior?
I study NETosis, a pathogen-killing process undergone by neutrophils, which are those multi-lobed nucleus cells. During NETosis, chromatin, a cell’s genetic material that is usually compacted in the nucleus, is decompacted and eventually released into the extracellular environment. That DNA then forms these antimicrobial “NETs” outside the cell that capture and neutralize pathogens.
If you think about it, it’s crazy that a cell would do that, right? It’s releasing its own genetic material! But this really happens. And what’s more interesting is that it can be helpful in combating things like bacterial or viral infections, but it appears that NETosis can also be detrimental in diseases like diabetes, rheumatoid arthritis, and cancer.
Once we better understand how NETosis, nuclear shape transitions, and other extreme behaviors happen, we can then understand why these processes occur. Not all cells can do these things, and it would be so cool if we could convince any cell to perform these extreme behaviors to benefit human health!
It sounds like these cells are kind of like elite athletes.
Exactly! It’s like the question: could anyone become an elite athlete? If placed in the right situation, could any cell adapt like an immune cell? And that cancer cells go through this immune cell-like nuclear shape transition might just be one example of how other cells can adopt the extreme behavior we see in immune cells.
When you find one cell that does something, it doesn’t tell you that every cell does this, of course. But it does tell you something about what is possible. It means that maybe, in the right environment, they can move towards that behavior. And that’s beautiful.
The next step after seeing what’s possible is figuring out what pushes the cells in that direction and then, eventually, how we can engineer that behavior to get cells to do things they wouldn’t ordinarily do.
What other kinds of extreme cellular behavior are you interested in?
I’ve recently been fascinated by what happens to your cells in space. We know that astronauts who return from space travel tend to have recurring infections. And it turns out that most scientists who have looked at this have focused on the adaptive immune system, which is the part of your immune system that responds to pathogens that your body has already encountered. There is less work in the innate system, the part that is responsible for initial pathogen response. I want to know what happens to neutrophils, which are part of the innate immune system.
We also know that when you put immune cells in zero gravity conditions, some of the chemical pathways in the cell change. To me, this is completely crazy, because a classical physicist will tell you that gravity has a strong dependence on the mass of an object, and cells are tiny, so there shouldn’t be this big effect. What are we missing? Are we missing something in our understanding of gravitational force? Or in our understanding of biology?
These questions all go back to my global interest in the interactions between physics and biology, how physical forces impact biological function.
What excites you about being a professor?
A big part of what excites me is, of course, research and getting to ask interesting questions. I’m really excited to be here at Stanford because I strongly believe in immersing myself in places where people think and do things differently than I because that has been my way of learning and of growing. My transitions from physics to cell biology to immunology have been the best things that ever happened to me as a scientist. In bioengineering and in Sarafan ChEM-H I’m surrounded by people who think about problems differently than I do, and I am excited to bring those perspectives to my work.
I’m most excited, though, to be a mentor. I really believe that if you have a passion for science and can go through the ups and downs of it, anyone can do research. But, of course, you also need privilege. For me, that privilege was the support of my parents. Neither of them finished high school but they believed that if you study, anything is possible. I loved to read, and they bought me so many books as a kid. That may not seem like much, but I don’t know where I would be today without that.
I can’t overstate the impact they and my other mentors have had, and I really want to be a supportive mentor to other scientists. I hope that through teaching and mentoring, I can help break this preconceived notion that you have to be a certain way or come from a certain background to do research. I want my lab to be a place not only for people who know they want to do science but also a place where people can have doubts and wonder whether this is for them. And hopefully, they will find that this is for them.
Thiam is a member of Stanford Bio-X and a Chan-Zuckerberg Biohub Investigator.