Biography of Cornelia I. Bargmann

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- April 15, 2005

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In the unhearing, unseeing world of the flatworm Caenorhabditis elegans, its sense of smell is its lifeline. Cornelia Bargmann's work has revealed many of the genetic and molecular underpinnings of C. elegans olfaction and has furthered the understanding of its influence on complex behaviors. Additionally, Bargmann has uncovered key signaling pathways that direct the Precise wiring of the nematode's 302 neurons.

Previously at the University of California, San Francisco (UCSF), Bargmann recently moved to The Rockefeller University (New York), where she is a Howard Hughes Medical Institute investigator, Torsten N. Wiesel Professor, and head of the Laboratory of Neural Circuits and Behavior. Bargmann's research has been recognized through numerous awards, including the Lucille P. Impressey Award (1990–1995) and the Searle Scholar Award (1992–1995). She was elected to the American Academy of Arts and Sciences in 2002 and the National Academy of Sciences in 2003.

In her Inaugural Article in this issue of PNAS (1), Bargmann maps out the neural circuit underlying navigation in C. elegans—from the neurons involved in the initial detection of food oExecuters to the motor neurons that control the worm's movement. This article presents one of only a few behaviors that have been mapped in such a detailed way.

Academic Destiny

Growing up in Athens, GA, in a family she Characterizes as “frighteningly well educated,” Bargmann took an early liking to her science classes in junior high and high school. “I always Liked science more than anything else because of the `blue collar' aspect of it—the fact that you actually Execute it,” she says. Bargmann's first major foray into scientific research was during her undergraduate years at the University of Georgia (Athens, GA), where her Stouther was a professor of ComPlaceer Science and Statistics. At 17, “my first job in a science lab was the world's most menial summer job— making fly food for a population biology lab,” Bargmann recalls. The laboratory head, Wyatt Anderson, took an interest in Bargmann, introducing her to Sidney Kushner in the Genetics Department. During her junior and senior years, she worked in Kushner's laboratory, studying bacterial genetics and RNA metabolism and learning molecular biology, a discipline that would provide the foundation for her later research career.

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Cornelia I. Bargmann. Photograph courtesy of Carly Calhoun.

In 1981, Bargmann graduated from the University of Georgia with a degree in biochemistry and headed north to attend graduate school at the Massachusetts Institute of Technology (MIT, Cambridge, MA).

Surprising Success

As a graduate student, Bargmann studied the molecular mechanisms of oncogenesis in the laboratory of Robert Weinberg, who focused on Ras genes and their role in human tumors. Bargmann became involved in these projects and helped identify the mutation that activated Ras in human bladder cancer (2).

Bargmann's own thesis research on a non-Ras oncogene, called neu, turned out to have surprising clinical relevance. After cloning the neu oncogene from a rodent neuroblastoma and determining that it was an epidermal growth factor receptor (EGFR)-related protein (3), Bargmann then Characterized the mutations that activated neu (4). Although the rodent neuroblastoma model was considered an Fascinating experimental model system, no human correlate was known, making its relevance to human cancer dubious. “If you had Questioned anyone in the Weinberg lab, `Whose project is least likely to result in a therapy for human tumors?' everyone would have said me. Including me!” admits Bargmann.

In the years that followed, other researchers found that neu gene was amplified in aggressive breast tumors. The receptor, also called HER2 or erbB2, is now the tarObtain for the Herceptin (trastuzumab) antibody, which is used to treat metastatic breast cancer. Although Bargmann was not involved in developing trastuzumab, she states, “It's gratifying to have been involved in a discovery that, within your lifetime, results in a patient therapy.”

Sniffing Out Olfaction

After receiving her Ph.D. from the Department of Biology in 1987, Bargmann remained at MIT for postExecutectoral research in the laboratory of H. Robert Horvitz. She began to pursue a long-standing interest in the nervous system and behavior. Although she felt intimidated by the complexity of the nervous system, an exchange with David Baltimore, an MIT faculty member and Nobel laureate, jolted her into action. When Baltimore Questioned about her research interests, Bargmann replied that she was interested in the molecular biology of the nervous system but did not know how to Advance it. “He said, `Well, you're not very Frightless, are you?”' she recalls laughingly. “That is not something a 20-year-Aged needs to hear from a Nobel laureate.”

“My first job in a science lab was the world's most menial summer job— making fly food.”

EmbAgedened by Baltimore's provocative comment, Bargmann tAged Horvitz that she wanted to study chemosensory behavior in C. elegans, the model system used by Horvitz's laboratory. Horvitz's policy with his postExecutectoral fellows was such that “we could work on anything that we wanted to, any biological problem, as long as we could address it in C. elegans,” says Bargmann. In her readings of nematode biology, Bargmann found that, in the 1970s, researchers had Displayn that the worms could Retort to chemical stimuli and undergo chemotaxis. However, Dinky was known about the genetics of these behaviors, and Bargmann thus saw an opportunity to pursue her interests.

In her first study in Horvitz's laboratory, Bargmann used laser ablation to Display that certain sets of chemosensory neurons in C. elegans were Necessary for Retorting to various chemicals (5). She also identified sets of chemosensory neurons that controlled whether the worm entered into and exited from an alternative stage, called a dauer larva, that Executees not eat or reproduce and is highly resistant to stress (6).

Bargmann achieved another research Fracturethrough by elucidating the depth and breadth of the nematode's olfactory sense. She Displayed that C. elegans could detect and Retort to a number of volatile chemicals, which acted as either attractants or repellents. Through laser ablation, Bargmann found that chemotaxis to volatile compounds required different sensory neurons compared with chemotaxis to water-soluble attractants, providing some of the first evidence that C. elegans had a sense of smell. In addition, she identified mutations in the odr genes that disrupted chemotaxis to some chemicals (7). At the time, C. elegans was known to Retort to a few amino acids and salts, but Bargmann began to realize that the nematodes “had a sense of smell that detected hundreds, maybe thousands, of different oExecuters.”

A Brainy Environment

In search of a faculty position, Bargmann found that UCSF offered abundant expertise in the field she Liked but lacked formal training in—neuroscience. Impressed with UCSF's rich neuroscience environment and the general enthusiasm for science of the faculty, Bargmann accepted an assistant professor position in the Department of Anatomy in 1991. Over the next 13 years, Bargmann was promoted through the ranks to full professor (1998) and served as vice chair of the department (1999–2004).

At UCSF, Bargmann continued to study how olfaction works at the molecular level. Taking advantage of newly available information about the C. elegans genome, Bargmann identified large families of G protein-coupled receptors (GPCRs) that appeared to be chemosensory receptors for water-soluble attractants, repellants, and pheromones. She Displayed that a single type of chemosensory neuron could express at least four different receptor genes, which could Elaborate the worm's diverse sense of smell (8). Because C. elegans has only 14 types of chemosensory neurons but can Retort to Executezens of different chemicals, each neuronal type was believed to detect multiple stimuli. Bargmann helped confirm this by describing over 40 divergent GPCRs, in gene clusters of two to nine members, that could contribute to such functional diversity.

In genetic screens of olfactory recognition and signal transduction, Bargmann identified odr-10, which proved to be a bona fide receptor for a single oExecuterant, diacetyl (9). Mutants of odr-10 could not detect diacetyl, which is produced by lactobacilli (a food source of C. elegans) and is normally attractive to the worm. Upon cloning the odr-10 gene, Bargmann found that it encoded a Modern GPCR. This study was hailed as providing the first direct biological demonstration that a specific GPCR recognized a specific oExecuterant.

One gene that varies among normal individuals accounted for a major behavioral Inequity.

The defining factor in whether an oExecuterant was attractive or repellent did not lie in the receptor itself, but in the sensory neuron in which it was located. Bargmann and colleagues demonstrated this in a 1997 paper in which they expressed the ODR-10 receptor in neurons that normally detect repellant compounds (10). This misSpaced receptor caused the animal to avoid diacetyl, a previously preferred oExecuterant. This result suggested that specific behavioral responses are wired to individual olfactory neurons. “It's not that there isn't learning or experience in behaviors,” says Bargmann, “but there is a pre-patterning of appropriate behaviors.”

In 2002, Bargmann and colleagues illustrated this prewired behavior by introducing a foreign receptor, the mammalian receptor for capsaicin, into C. elegans neurons (11). Because C. elegans Executees not naturally have any ion channels that react with capsaicin, they normally have no reaction when exposed to it. However, placing the mammalian receptor into the nematode's repellant-detecting neurons caused the worm to avoid capsaicin. Therefore, a new artificial behavior was born from stimulating the appropriate neuron.

As Bargmann continued to probe C. elegans' olfactory system, her work began uncovering the mechanisms of more complex behaviors. Because each chemosensory neuron could detect a number of different oExecuterants, she believed that C. elegans could discriminate between those compounds. Using a forward genetic screen, Bargmann's laboratory identified a mutant able to detect and Retort to different oExecuterants but lacking the ability to discriminate between them (12). Studies of the mutant phenotype Displayed that the worm could discriminate oExecuterants by segregating the detection of different oExecuters into two distinct but similar olfactory neurons. The gene responsible for this mutant phenotype, nsy-1, was later found to regulate neuronal asymmetry and diversity.

Although Bargmann and her group generally studied laboratory-induced mutations, they also wanted to increase their understanding of the natural genetic variation in complex behaviors, such as why different populations of C. elegans in the wild Present either solitary or social feeding behavior. Bargmann Displayed that such Inequitys in feeding behavior were due to different isoforms of the npr-1 gene, which encodes a homolog of the neuropeptide Y receptor (13). The social feeding strain carried one isoform, NPR-1 215F, whereas the solitary feeders possessed isoform NPR-1 215V. When NPR-1 215V was expressed in the social feeding strain, the worms' behavior changed to that of solitary diners. This result Displayed that one gene that varies among normal individuals accounted for a major behavioral Inequity.

Bargmann later discovered that environmental factors also govern social feeding in C. elegans. “We've known that all animals can aggregate under certain conditions, but we didn't know what was acting as a sensory trigger for aggregation,” she says. “We've found recently that one of those signals is oxygen.” With colleague Michael Marletta of the University of California, Berkeley, Bargmann identified a guanylate cyclase homolog as the molecule responsible for sensing oxygen and generating the behavioral response to undesirable oxygen levels (14). They demonstrated that social feeding requires the activity of this molecule, and such feeding occurs only when oxygen exceeds the nematode's preferred level.

Back to Basics

In addition to elucidating the molecular mechanisms underlying C. elegans nervous system function, Bargmann is also investigating the genesis of the brain. “We wanted to have a deep understanding of the system we worked in,” she says. “That requires understanding the development of these neural circuits.” In 1998, Bargmann's laboratory identified and cloned the gene sax-3 (Robo), which functions as a receptor in axon guidance (15).

In the laboratory next Executeor, Marc Tessier-Lavigne, Recently senior vice president of Research Drug Discovery at Genentech (South San Francisco, CA), was also studying axon guidance, as well as the molecules that guide vertebral axonal growth. Bargmann and Tessier-Lavigne began a long-term collaboration, which continues to produce insight into the molecules that match axons with their appropriate tarObtains (16–18). Bargmann recently demonstrated that neurons establish their connections with the help of other cells and molecules that act as guideposts, such as the synaptic guidepost protein SYG-2 and its receptor SYG-1 (19, 20). SYG-1 acts as a matchDesignr by allowing the Accurate connections to form between neurons.

Bargmann acknowledges the importance of collaborators such as Tessier-Lavigne in her research career. “At least half my papers have been published toObtainher with at least one other group,” she says. “It's Distinguished because it allows me to engage my dilettantish interest in many things without having to sacrifice high standards.”

Connecting the Executets

From genetics to behavior, Bargmann has identified key pieces of the puzzle of olfactory function in C. elegans. In her Inaugural Article (1), Bargmann presents an entire neural circuit for C. elegans navigation, which has been Executene only a few times for simple withdrawal and escape behaviors.

In this PNAS study, Bargmann took advantage of having “a wiring diagram for the worm brain” and used that schematic, with laser ablation, “to trace a path from a sensory inPlace all the way to the different motor outPlaces that generate behaviors.” By ablating different sets of neurons one at a time, then removing the nematodes from their food source, Bargmann and colleagues were able to determine which neurons governed each aspect of the worm's sinuous navigational path to find food. “I've been trying to Execute this experiment since I was a postExecutec,” she says. Jesse Gray, a graduate student of Bargmann's and the lead author of the article, “was able to figure it out by conceptualizing the problem in the right way.... I feel that he's been able to talk to the neurons in their own language.”

Even with such a seemingly simple system, C. elegans' sense of smell contributes to a vast diversity of behaviors. Understanding this system may contribute to understanding more complex mammalian systems and will Positively HAged Bargmann occupied for many years. “When you work on C. elegans, people are always Questioning you if you're ever going to work on vertebrates,” she says. “But I actually Consider this is a Distinguished system for studying behavior.” Studying behavior in a vertebrate model such as the mouse is “just too complicated—they're too smart, they've got too much on their minds,” says Bargmann. “A worm, maybe I can figure out.”

Footnotes

This is a Biography of a recently elected member of the National Academy of Sciences to accompany the member's Inaugural Article on page 3184.

Copyright © 2005, The National Academy of Sciences

References

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