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The noise knows

Scrutinizing differences in single-cell behavior, Philippe Cluzel characterizes biology in terms of variation.

Just as a driver listening to the car radio gets annoyed when static overpowers the music, biologists studying a group of organisms may view “noise”—any variation from the norm—as distracting. They often eliminate it by calculating average behaviors. Not Philippe Cluzel, assistant professor of physics. Noise matters to Cluzel because it provides insight into a system’s design. Noise isn’t always a nuisance,” he says. Deviations in E. coli bacteria, for example, carry information useful for understanding the network that controls cell division and whose breakdown in higher organisms can cause cancers. “Decisions on the single-cell level are crucial for life or death,” he notes. “At the beginning of the story, it’s a single-cell decision.”

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Photo by Dan Dry
Philippe Cluzel, assistant professor of physics, projects E. coli on a screen.

But what makes cells face different fates? After all, the standard theory is that genes and environment determine behavior, so identical cells in the same setting should act alike. But Cluzel and his group have shown that such cells don’t always follow suit. Analyzing E. coli’s chemotaxis system, whose biochemical signals direct locomotion, the team immobilized cloned bacteria on microscope slides. Next the researchers tracked how the E. coli rotated their flagella, recording when the arms switched direction from clockwise to counter-clockwise, and vice versa. Individual bacteria, they found, produced different rotation patterns, as seen through variations, or noise. Calculating average behaviors would have masked the variations.

The team’s findings, published in the April 1 Nature, goes far beyond E. coli: the bacteria’s chemotaxis system serves as a model for studying signaling networks across species. “It’s cool,” says Cluzel, 37. “It means that even if you and I are clones, because of this randomness we would exhibit some variability. So you have some evolutionary advantage. It’s a source of richness.” The findings also suggest that measurements of variability in more complex organisms, including humans, may elicit information previously lost through averaging. More broadly still, focusing on single-cell behavior forms the basis for an emerging field of biology—a field so new that scientists haven’t agreed on a name. Cluzel calls it “single-cell biology,” while others prefer “systems biology” or “computational biology.” Whatever term they apply, the field’s practitioners use an interdisciplinary approach to examine what happens within a cell in real time and to model how it functions as an integrated system.

“We are witnessing some kind of revolution in biology, which is now trying to characterize biology in terms of variability, or probability,” says Cluzel, who joined the University in 2000. “Our ultimate goal is to understand the origin of cell-fate variability.” In cancer, for instance, a determinist view would suggest that a particular gene causes a particular cancer. “But it’s a disease that you can also describe in terms of probability,” he explains. Thus, breaking down the signaling network that governs E. coli’s flagella movements could shed light on why some cells mutate and others don’t. “The division of our cells is controlled by a signal transduction network, and its malfunction causes cancers,” Cluzel says. To better understand the malfunction, his group has partnered with a team led by Marsha R. Rosner, director of the University’s Ben May Institute for Cancer Research.

The collaboration exemplifies the interdisciplinary nature of the single-cell approach. In fact, Cluzel thinks it’s because he’s a physicist—an outsider—that he recognized the importance of biological noise. Because E. coli is probably the world’s most-studied microorganism, first described three centuries ago by van Leeuwenhoek, Cluzel characterizes it as “an old dish—overworked, almost.” A Paris native who planned on becoming a chef, then shifted his focus and studied physics at the Institut Marie Curie, he compares scientific discovery to culinary innovation. Like new recipes, scientific insights can arise from taking a fresh look at the familiar.

The single-cell approach constitutes a revolution in the literal sense: a circling back. Traditionally, Cluzel says, “biology was very fond of concepts, asking, What are the design principles of biological systems?” But “researchers didn’t have access to all the molecular details, and they had to rely on philosophical hypotheses.” With molecular biology’s emergence and the human genome’s decoding, biologists turned to “this open book of life. Now it’s time to sit down and ask what we can learn from all these data,” he continues. “Biologists are really excited” by the prospect of finding out these design principles.

Trying to uncover those principles is quite different from grasping their individual components, says Cluzel’s colleague, University research scientist Thierry Emonet, co-lead author of the Nature study (along with Chicago chemistry graduate student Ekaterina Korobkova). “Imagine if you have a list of the parts of a car. It doesn’t tell you how a car works,” Emonet explains. “You have to understand how the different parts work together.” But knowing how each part works remains indispensable, Cluzel notes. “The way we do science, you need a scientific Babel team. You need engineers, you need biologists, you need physicists, you need chemists, you need computer scientists—because living matter is very complex.” (His team has not only multidisciplinary but also multinational origins, with members from six countries, including France, Vietnam, Russia, Korea, China, and Switzerland.)

The University’s interdisciplinary Institute for Biophysical Dynamics (IBD), which next spring will move into the under-construction Interdivisional Research Building, first attracted Cluzel to Chicago. “I wanted my lab among the biologists,” he says. Chicago “already understood it was important to mix cultural backgrounds to solve complex problems in biology.”

Universities increasingly recognize that “the most interesting problems people want to study don’t fit easily into departmental labels,” agrees Stephen B. H. Kent, who directs the IBD. Cluzel, Kent notes, offers a good example of a researcher who crosses boundaries: “a card-carrying physicist who does cutting-edge biology.”

Single-cell biology interests Cluzel partly because it has implications beyond the individual cell. “Once you understand how one little unit works on its own,” he says, “then you want to understand the role of an organism embedded in a larger population of cells,” just as researchers study an individual ant and then its role in a colony. “You can consider a population of single-cell bacteria as a multicellular organism because they also have some collective behavior. You always need to think across scales.”—Cathy Shufro



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