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I Smell a ... Worm

For Howard Hughes Medical Institute investigator Cori Bargmann, the worm's the thing.

By | August 1, 2005

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For Howard Hughes Medical Institute investigator Cori Bargmann, the worm's the thing. And not just because studying worms can tell us more about ourselves. Bargmann, who recently moved her lab from the University of California, San Francisco, to Rockefeller University, has taken to looking at problems from the worm's point of view. In addressing questions relating to nematode neurobiology and behavior, for example, "it helps to think about what the nervous system has evolved to do," she says. "What are the challenges the animal faces? What is the world it actually lives in?"

The approach has led to an appreciation of what it means to be a worm, and it has helped to explain some otherwise perplexing observations. Consider Caenorhabditis elegans' surprisingly sophisticated sense of smell. "Our own olfactory system has about 350 receptor genes," says Bargmann. Flies have maybe 150, mice around 1,000. "Worms have between 1,300 and 1,700 receptors whose main job seems to be detecting molecules in their environment," she says. Odorant receptor genes account for almost 10% of the worm genome. "That makes no sense whatsoever until you know how complex their environment really is."

Cori Bargmann Hist Cite Analyses

http://garfield.library.upenn.edu/histcomp/bargmann-ci_auth/

http://garfield.library.upenn.edu/histcomp/bargmann-ci_auth-citing/

A gram of garden soil, says Bargmann, contains some 107 bacteria, representing 1,000 different species of which fewer than 10% have ever been cultured in the lab. And many of those are toxic to C. elegans. "The soil is a community where everyone is basically trying to poison everyone else," says Bargmann. "So the worm is traveling through this minefield of monsters." The surfeit of chemosensory receptors, among other things, presumably helps the animals sort food from foe.

And it provides biologists like Bargmann with plenty of fodder for investigation. By identifying the molecules, cells, and neural circuits that underlie olfaction, Bargmann has provided insight into how worms sense and interact with their world. And because many of these systems are conserved through evolution, her findings could lead to a better understanding of our own brains and behavior, and thus the defects that lead to neurological disease.

SNIFFING OUT CHEMOSENSORY MOLECULES

Bargmann made her way into the field of worm chemosensation as a postdoc in Bob Horvitz's lab at Massachusetts Institute of Technology. "I was interested in behavior and realized that back in the 1970s people had shown that worms had chemotaxis behaviors," she says. "They had shown worms can react to some salts and some amino acids and small molecules like cyclic AMP. And they found a few mutants that were defective in these processes. But then the projects fizzled." For one thing, no one had yet figured out how to clone the responsible genes. "So if you did get mutants, you didn't know what to do with them."

By the time Bargmann joined the Horvitz lab, that situation had changed: Molecular biologists had successfully cloned the first worm genes. But before using these powerful genetic tools to identify the molecules involved in worm olfaction, Bargmann wanted to confirm that the critters could actually smell, and indeed they could. "It turned out the worms responded to half the things I ordered at random from chemical catalogs," she says. The worms moved toward or away from hundreds of different compounds. In addition to vastly expanding the borders of their sensory world, the discovery "made the problem seem much more interesting," says Bargmann.

She then spent most of her time at MIT mapping out the worm chemosensory system. Using a technique called laser ablation, developed by John White and Leon Avery, Bargmann obliterated C. elegans' 30-odd sensory neurons one by one. She ended up with a diagram of what the neurons do. "This neuron senses pheromone, this neuron senses attractive aldehydes and ketones. You could walk through the whole thing like that."

Bargmann also determined that individual olfactory neurons could detect multiple compounds; this realization gave her a handle on how to design genetic screens that would yield useful results. "If you just look for worms that can't smell diacetyl, you get hundreds of mutants," she says. "You get worms that can't move well or worms that are just sick or distracted, and a huge number of worms in which the entire sensory nervous system is just a mess. Those things will just overwhelm you."

Knowing what each neuron can do allowed her to screen for mutants with more specific defects. For example, says Bargmann, "A neuron called AWA detects diacetyl, which smells like butter, pyrazine, which smells like potatoes, and thiazoles, which smell like dirty gym socks." Worms apparently adore all three odors. And searching for mutants that can no longer detect diacetyl, but that continue to rush headlong toward the eau d' sweaty gym socks, should yield worms that have lost a molecule involved in processing butter smell.

"It was a great time to be in her lab," says Piali Sengupta of Brandeis University, one of Bargmann's first postdocs. "Every gene we cloned was something really cool." Together Bargmann and her associates isolated receptors, ion channels, and many of the components that form the signal transduction pathways that drive olfaction in worms.

WHEN WORMS GET TOGETHER

From there, Bargmann and her cohort went on to pursue the molecular basis of more complex behaviors, such as aggregation in the presence of food. Many natural strains of C. elegans are social eaters; they huddle together when they encounter Escherichia coli or other tasty microbes. Although laboratory strains of C. elegans don't ordinarily aggregate, one of Bargmann's students stumbled across a mutant that did. Postdoc Mario de Bono, who's now at the MRC Laboratory of Molecular Biology in Cambridge, UK, then cloned the gene responsible for this social behavior. He showed that the wild variants that aggregate, "amazingly, have mutations in the exact same gene," says Bargmann.

More recently, Bargmann and her collaborator, Michael Marletta of UC, Berkeley, have identified the nerve cells and the molecule that worms use to sense oxygen. The researchers had set out to study how worms might use nitric oxide (NO) as a chemical messenger, and they targeted a protein whose sequence suggested it would bind to NO. David Karow and Jesse Gray, the grad students involved in the project, "were in Cori's lab gassing worms with NO trying to look for a response," says Marletta. Eventually the team realized that NO had nothing to do with it. The protein was binding to oxygen. "It opened up a whole new area of oxygen sensing in animals that we didn't know existed," Marletta says.

"Cori is fearless when it comes to trying new things, setting up new experimental approaches that differ from what she's been doing," says Marletta. "She also has a broad range of interests and a broad perspective," he adds, which makes her "terrifically good at throwing out new ideas."

"She's incredibly smart and creative, curious and insightful, and she has the guts to go after difficult problems," says UCSF's Ulrike Heberlein, who used to join Bargmann "in the jacuzzi to discuss science for hours and hours – the California way of doing things."

THE WORM HOTEL AND JACUZZI

Now at Rockefeller, Bargmann doesn't have much opportunity to engage in "jacuzzi-chat," or to work hands-on in the lab. But she does still dabble, at least at the bench. "I walked in about a week ago and there was a big pile of paper towels taped to the PCR machine that said, 'Experiment in progress. Cori'," says Gray. "We had no idea what was going on. It was quite amusing." Bargmann, as it happens, was running a thermal gradient, attempting to determine whether worms prefer to congregate at a particular temperature. All other things being equal – in other words, for example, plenty of E. coli to munch – they seem to prefer a relatively chilly 15°C.

The worms also have a preference when it comes to oxygen: Less is better. Worms find the oxygen concentration used in the lab, an atmospheric 21%, "particularly dislikeable," Bargmann says. Given a choice, C. elegans will flock to an area that features a more comfortable 7% oxygen concentration, which she says makes biological sense. "Soil is low in oxygen compared to the atmosphere, so a worm's natural environment is really quite low in oxygen." Too much oxygen can actually be stressful.

But Bargmann doesn't worry unduly about stressing her worms. "Living in dirt, a worm probably has to deal with a lot of environments that aren't its favorite," she notes. "It spends a lot of its time starved, praying that food will become available. So we're providing one stressor in a life that's probably full of stress. I think we're giving them a pretty good ride." Gray agrees. In exploring C. elegans' environmental preferences, he says, Bargmann and her ilk are coming seriously close to "being able to design a luxury hotel for worms."

Although the hotel is not on the drawing board, Bargmann is excited about designing chambers she can use to expose worms to odorants while keeping them still enough to monitor the activity of individual neurons, yet letting them wriggle enough so she can assess whether they're trying to advance or retreat. "When a worm is a millimeter long and you have big clumsy fingers, it's a lot harder than it sounds," she says. The tiny chambers allow Bargmann and her team to look at the activation of specific neurons while an animal behaves. "A big step forward for us," she says.

"This represents two PhD-level man years of work," says Bargmann as she runs the movie showing a worm with its nose stuck in a stream of 21% oxygen, its little oxygen-sensing neuron glowing an angry red. "It's really pretty cool."

And as the worms adjust to fluctuating oxygen concentrations in their environment, Bargmann continues to adjust to her new East Coast digs. "Rockefeller's a great place for concentrating on science," she says. "There are no medical students to teach, no hospitals to run, and no campuses to be built." And, therefore, no building committees to join. "It was at the point that [UCSF] put me on the furniture committee that I thought I would crack up. Every piece of furniture I own, here or elsewhere, was either given to me or stolen," she says. "Why would anyone assume that because I have two X chromosomes I know something about furniture?"

For her part, Bargmann would rather stick with manipulating C. elegans' environment. At least she knows how to figure out what worms like.

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