A Fierce Competitor

Credit: ® Jason varney | Varneyphoto.com Growing up in Liège, Belgium, Christine Jacobs-Wagner was ranked as the top badminton player in the country. She was planning to compete in the Olympics, when in 1993 she suffered a shoulder injury at the age of 24. That meant Jacobs-Wagner, a graduate student in biochemistry at the time, had to permanently trade her racquet for a pipette, but she didn't leave her spirit of competition behind. "At our lab parties we would have pipette-throwing contests and do serial dilutions for speed," says Hue Lam, her first graduate student, who's now a postdoc at the Brigham and Women's Hospital. "Christine usually won. If she didn't, she'd be upset with herself. She's just the most driven person I know." "Even the simplest game you want to play with her, it's just a nightmare," laughs former postdoc Jean-Yves Matroule of the University of Namur, Belgium, "because she always wants to win." She brings that drive to her science. "I would worry about having to compete with her," says Jeff Errington of the University of Newcastle. "She's extremely dedicated, intellectually rigorous, and if you look at her publications, she's been spectacularly successful." Over the past 10 years that success has played out in a handful of papers in Cell, Science, and other high-impact journals, where Jacobs-Wagner, now at Yale University, has showcased her award-winning work on bacterial physiology and development. Her pioneering studies on the molecular mechanisms underlying cell shape and cell polarity in Caulobacter crescentus, says Errington, "have helped change the way people think about bacteria. Now there's a whole new field of people who are working on bacterial cell biology using the same sorts of approaches used to study eukaryotes. And Christine is one of its leading lights." "From the time she was a graduate student, consistently all the way up to this point in her career, she's been on a tear," says Rich Losick of Harvard University. "I regard her as one of the emerging stars in microbiology." Beta-lactamase all over the world Jacobs-Wagner's career started off with a bang when, as a graduate student at the University of Liège in the early 1990s, she discovered that some bacteria can induce the enzyme beta-lactamase when exposed to antibiotics such cephalosporin, rendering them resistant to these drugs. "It's the physiology that interested me, the physiology I really wanted to understand," she says. "How do bacteria know they are under attack, and how are they able to respond by making protein that inactivates the antibiotics?" To answer that question, Jacobs-Wagner spent time in five different labs in four different countries. "It was an unusual PhD, and I wouldn't want any of my graduate students to do what I did," she says, "but it was a great experience and it worked for me. What I did was go to different labs to learn their techniques. Instead of collaborating, I would move to those labs to do the experiments there. Since they already had things set up, I could move much faster." Working with experts in protein chemistry, genetics, beta-lactamase biochemistry, cell wall synthesis, and medical microbiology — in Belgium, France, the United States, and Sweden — Jacobs-Wagner discovered a regulatory protein that can sense the peptidoglycans that accumulate when antibiotics disrupt cell wall synthesis, and then activate transcription of beta-lactamase, the enzyme that disarms the drugs. "It was a remarkable piece of work," says Losick, and it earned Jacobs-Wagner the 1997 young scientist award from Science and Pharmacia. "People knew there was a connection between enzyme induction and cell wall breakdown," he says. "But finding a regulatory protein that directly interacts with one of the breakdown products — that was unprecedented and really quite exciting." Stalks, swarmers, and kinases After she completed her thesis work, Jacobs-Wagner had one main goal: "I wanted to stay in the same place for more than two years." So in December 1996, she joined the lab of Lucy Shapiro at Stanford University, where she spent four productive years exploring how Caulobacter coordinates its developmental program with cell-cycle progression. When Caulobacter divides, it does so asymmetrically, producing daughter cells that have different fates. One daughter, the swarmer cell, grows a polar flagellum and swims off. The other daughter, the stalk cell, attaches itself to a rock. That stalk cell will grow and at some point divide to produce another swarmer. Each swarmer cell will eventually differentiate into a stalk cell and begin the cycle again. In Shapiro's lab, Jacobs-Wagner studied a histidine kinase involved in initiating some of the differentiation events in swarmer cells. To determine where in the cell the kinase would go, Jacobs-Wagner tagged the protein with green fluorescent protein and then took her samples to Losick's Harvard lab, which was set up to do fluorescence microscopy. "At the time they had only one microscope," she recalls. "Since I was the outsider, I got to use it from two o'clock in the morning until 6:00, which was the only time it was free. So I was working all night and e-mailing Lucy my results." Jacobs-Wagner found that the kinase changes its location during the cell cycle. "At certain times it was going to one pole, at other times to both poles, and at one point it actually delocalizes," she says. That movement was key for the cell's growth and survival. "It was a very beautiful piece of work," says Shapiro. "It was the first that we knew that a regulatory protein was dynamically localized. This is a bacterial cell. It's two microns long. Everybody thought any protein could get anywhere by diffusion and that no protein needed to be anywhere in particular." "Still to this day it amazes me," says Jacobs-Wagner. "Bacterial cells are so tiny. So what's the point of a protein being 'here' when it only takes milliseconds for it to go anywhere?" A crescentin takes shape Jacobs-Wagner continues to explore this question. "We've made some progress in understanding that certain bacterial proteins are localized," she says. "But we still don't know why they do it, or how." While they were pursuing this question, Jacobs-Wagner and her postdoc, Nora Ausmees, discovered crescentin, the protein that gives Caulobacter its characteristic crescent shape. Ausmees was searching for mutants in which a few proteins of interest were no longer localized. Instead she stumbled across a cell that was no longer curved. "We thought it was intriguing," says Jacobs-Wagner. So they studied these straight cells and found that they lacked crescentin, a protein that forms a filament along the inner curvature of the bacterium. Even more stunning, crescentin polymerizes into a structure called an intermediate filament, a cytoskeletal element that had been seen before only in animal cells. "It was a big surprise," says Yale's Thomas Pollard, an expert on the cytoskeleton. "It's always fun when someone outside the field — Christine was definitely not working on intermediate filaments before this — shocks everybody in the field by finding something they thought didn't exist." "She goes beyond picking the low-hanging fruit," notes William Margolin of the University of Texas Medical School. "She picks that fruit and then keeps climbing the tree to the top." In the case of crescentin, he says, "someone else might have said, 'oh, we found this cool gene' and published, but she went several steps beyond that," showing that crescentin looks like an intermediate filament and determining its migration within the cell. Her drive to tell a more complete story means Jacobs-Wagner "doesn't pump out a ton of papers," says Margolin, "but the ones she puts out are really excellent, and they appear in journals like Cell." She's authored 15 papers on original research, plus a handful of reviews, since her graduate school days. Those high-profile publications ultimately benefit her students and postdocs, though they say the process can be a bit painful. "When she's working on a paper, she'll look at the data, and if she thinks you can make the story even slightly stronger by doing another experiment, she'll ask you to do that experiment," says Lam. "She's amazingly smart and she can quickly find the cracks in any result." She's equally critical of the writing. "She'll work on a sentence for half a day, until she considers it perfect," says former postdoc Jean-Yves Matroule of the University of Namur in Belgium. "But in the end it's worth it because her papers are always strong." The fact that English is not her first language, says Lam, "makes her writing all the more impressive." More than making ends meet Since the publication of the crescentin discovery in 2003, Jacobs-Wagner and her colleagues have gone on to identify and characterize other interesting Caulobacter proteins, including one that serves as a landmark that allows cells to figure out which end is which. In this case, Jacobs-Wagner and Lam used a bioinformatics approach. They reasoned that any protein that acted as a cell-pole marker probably works by recruiting other proteins. "So we decided to search the genome for proteins rich in protein-interaction domains." Of the nine proteins they identified, three localized to specific sites, and one was the marker protein they named TipN. "It was a pretty weak rationale," she says, "but it worked." At about the same time, another team identified TipN in a genetic screen. "We were looking for genes that regulate flagellar function or positioning," says Patrick Viollier of Case Western Reserve University, who overlapped with Jacobs-Wagner as a postdoc in Shapiro's lab. "We looked for mutants that didn't swim properly and isolated a bunch of genes," one of which turned out to be TipN. Caulobacter that lack TipN assemble their flagella in the wrong place. When Viollier discovered that Jacobs-Wagner was working on the same protein, he says, "I was terrified. This was the first story I was working on as an independent lab leader, and early on you can't afford to get scooped." The complementary approaches, however, made for a stronger story, and the groups published their findings in back-to-back Cell papers in 2006. "That discovery was as significant, perhaps even more so, than the work on [crescentin] curving," says Margolin. "Most cells, including eukaryotic cells, are polar: They have a top and bottom, but it's not well understood how that happens." Approaching the problem in simpler organisms, such as Caulobacter, he says, "could bring us closer to understanding how any cell can make each of its ends different." Jacobs-Wagner will no doubt continue to do her part to understand the roots of polarity and other fundamental questions in cell biology. "All through her career she's been at the forefront," says Viollier. "The rest of us are trying to keep up with her," which is good for science. "It moves the field forward, although at times it can be challenging," and even nerve-wracking. "Every time you open up a new issue of Cell or Genes & Development, you just pray that you don't find an article she's published on something you're studying." Other than that, says Viollier, "you just try to stay out of her way."

A Fierce Competitor

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Karen Hopkin

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April 2008

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