Cell Biology, Microbiology
Dr. Theriot is also a professor in the Department of Biochemistry and the Department of Microbiology & Immunology at the Stanford University School of Medicine.
How to Build a Cell
How is a cell created from its molecular constituents? Individual proteins are typically only a few nanometers in size. Without a blueprint or an architect, these tiny molecular parts are able to organize themselves in a dynamic and self-correcting manner to form precise cellular structures that may be four or five orders of magnitude larger. Understanding the proper spatial and temporal arrangement of macromolecules in cells, the large-scale coordination of their functions, and the choreography of their movements requires the discovery of organizational principles and mechanisms that work at a cellular scale, over the rapid time-frames consistent with life processes.
Julie Theriot explores the mechanics and dynamics of cell self-organization and movement in a variety of cell types ranging from bacteria to fish skin cells. Her team's current work focuses on three areas: 1) the actin-based motility of intracellular bacterial pathogens such as Listeria monocytogenes, 2) the whole-cell crawling of epithelial cells and leukocytes, and 3) the dynamics of cellular organization in bacteria and diatoms. Their work is highly interdisciplinary in nature, bridging cell biology, microbiology, and biophysics. By studying diverse questions in diverse biological systems, using both bottom-up approaches (biochemical reconstitution, single-molecule force measurements, mathematical modeling) and top-down approaches (genetic and pharmacological perturbations, quantitative video-based analysis of cell movement, shape, and mechanical coupling), the researchers aim to develop a broad conceptual understanding of the organizational rules that give rise to large-scale cell structure and coordinated movement.
Scuba divers enter a weightless world filled with fantastic creatures, where light and sound behave in strange ways. Yet, when Julie Theriot first went scuba diving, the sensation felt wholly familiar—it was like the first time she looked down a microscope as an undergraduate. "Scuba diving is like going into outer space—it's a totally different world," says Theriot, who studies cell organization and movement at Stanford University. "When I'm peering down a microscope, I get transported in the same way. I love what I get to see. Looking at muscle cell development is gorgeous in its intricate complexity—it's beautifully ordered."
Her original path to the microscope wasn't quite as orderly. Theriot started out as a physics major at the Massachusetts Institute of Technology (MIT), following indirectly in her father's footsteps. She was born in Switzerland while her father, Dennis, was a postdoctoral fellow at the European Organization for Nuclear Research (CERN), the international center for nuclear and high-energy physics. But by the time she went to MIT, her father thought biology would be a better career.
"My dad was trying to encourage me not to go into high-energy physics," Theriot recalls. "At the time I was entering college, physics experiments were large group efforts, and it was really hard to do a satisfying experiment on your own." In the end, she completed a dual physics and biology major—not to assuage her father but because she was hooked. "I loved doing microscopy, and it became pretty clear that I was interested in biology."
In graduate school at the University of California, San Francisco, where she was an HHMI predoctoral fellow, Theriot began studying how pathogenic bacteria move using actin, a protein in the cellular scaffolding of the human host cell. In the intervening 15 years, she has taken an interdisciplinary approach to this question, combining cell biology, bacterial genetics, mathematical modeling, videomicroscopy, and large-scale computational image analysis to describe how bacterial pathogens use actin "comet tails" to steer themselves through cells in our bodies.
"I tell people that a lot of my work is just an excuse to make movies," Theriot laughs. However, to understand how actin comet tails drive movement of pathogenic bacteria in our cells, she visualizes that activity by using fluorescent beads and time-lapse microscopy that can be quantified. Her work established the physical forces underpinning actin-based movement. "Our work has really helped us understand actin-based motility of bacterial pathogens moving in host cells. Fifteen years ago it was a really hard problem," Theriot says. "I've been lucky enough to make fundamental discoveries. But now I'm ready to move on to something different."
Theriot is still interested in how cells move. She is working on using cells from fish scales to create an artificial cell capable of crawling, which will help her understand the biochemistry and biomechanics of whole-cell movement. As an HHMI investigator, she also hopes to branch out in an attempt to explain the universal rules dictating how all cells ranging from bacteria to multicellular eukaryotes, like animals and humans, organize their internal structure, called their cytoskeleton. Recent discoveries that overturned prevailing wisdom fueled Theriot's interest. For decades, researchers thought bacterial cells remained small, relative to plant and animal cells, because they lacked a complex cytoskeleton. New research has shown that they do have proteins similar to those found in the major eukaryotic cytoskeletal proteins actin and tubulin, and they may have a constantly changing cytoskeleton similar to larger, more complex cells.
Her research has already contributed to this revolution in thinking. Theriot's lab has shown that different bacteria take different approaches to one important task of the cytoskeleton: maintaining polarity. Polarity means that the distribution of proteins and other internal cellular components within a cell is uneven, so one side has a higher concentration of some charged components than the other. Cells need to maintain polarity to move and to divide correctly. "All cells have to organize," Theriot says. "Looking at bacteria, they are so small, and lack the familiar protein-sorting apparatus of eukaryotic cells. How do they set up polarity? When they are dividing, how do they get their replicated chromosomes to go into the two new daughters? And, if they do have a cytoskeleton just like eukaryotic cells, why have they remained so small and simple in their shapes?"
Theriot intends to use her biochemical and video techniques to study these questions and others as she looks for the common rules governing cellular structure. "Bacteria are much simpler systems than plant and animal cells, and that makes them better organisms to explore fundamental cellular design," she says.
Theriot's ability to explain how to think about science has made her a widely sought after teacher and textbook author. As a guest instructor she will participate in a summer course at the Marine Biology Laboratory at Woods Hole and has been a "bootcamp biologist" at Caltech's Physical Biology Bootcamp in the past. Theriot has also contributed chapters to some of the most important texts in molecular and physical biology, including Molecular Biology of the Cell; she even narrates the book's accompanying CD. Along with two coauthors, she recently completed a textbook, Physical Biology of the Cell, to appear in fall 2008.
The medical students she teaches also benefit from her broad approach to science. "They have to absorb so much information, so I really have to make sure that what I am teaching is important for them to learn," says Theriot, explaining that she enjoys the challenge of deciding what information from her field is relevant to teach medical students, who are focused on learning to treat patients in the clinic. "Any particular thing that they learn in my class is likely to be outdated in a few years because science is changing so quickly. The most important thing that I can teach them is how to read the literature and how to think about science." At Stanford, Theriot has won teaching awards from both the medical students and the graduate students in her classes.
Her research and teaching efforts leave her wanting more time to accomplish her goals. At the same time, she is quite clear about why she pushes so hard. "It's been fun combining physics and biology," Theriot says. "And I am hoping that the next generation of scientists who train in biology will be more quantitative in their approach."