Cori Bargmann's studies of olfaction and her work on the connections between neural circuits, genes, and behavior caught our attention. Curious to know more, BioTechniques contacted her to find out about the ambition, character, and motivation that led to her success.The Big In-Between
What is your current research focus?
The central problem we are studying right now is what the neuroscientist Vernon Mountcastle calls “the big in-between.” We understand a lot about sensation and sensory processing and a fair amount about action through motor systems. But between sensing and acting, there are decisions, emotions, memories, and thoughts. What we would really like to understand now are the processing events that represent decision making.
This seems very complex. How do you go about studying those events?
Using the nematode worm, C. elegans, we are trying to understand the genetic underpinnings of behavioral diversity between species and for individuals within a species. More importantly, we are exploring behavioral diversity in single animals—why one animal acts differently at different times. C. elegans is ideally suited to these studies because there are exceptional tools available for genetic manipulation and this species has a simple, well described neural circuit that we can understand in its entirety.
Different worms pop up in compost heaps around the world with slightly different behavioral traits. Using classical genetic approaches, we try to map what genes allow these animals to respond differently to pheromones or exhibit different behavioral strategies for exploring their environment. At the neural level, we are trying to understand how you can get different behavioral outcomes from a common stimulus. Are the signals independent? How can animals adapt different forms of behavior? We are developing methods for quantitative analysis of neural activity and behavior as well as tools to look at defined stimuli and their precise behavioral responses.
What would you say is the biggest challenge to approaching these questions?
Over the years, we have often been held back by the desire to do experiments that weren't physically possible. As scientists, we try to remove variability from our experiments to make them completely reproducible. But behavior is not simply programmed and reflected; real behavior is variable. So to study variation in behavior, we had to get rid of as much of our own experimental variability as possible.
Ten percent of all C. elegans genes are G-protein coupled receptors (GPCR) used for detecting odors and other chemicals in the environment. This is by far the richest way worms interact with their environment and therefore represents the best system for us to study behavioral diversity. But odors stick to everything; they're in the air, in the water, and you never know how much is there. In fact, everything smells including Eppendorf tubes, pippetes, and other lab equipment, making experiments hard to interpret because the worms patiently report to us that the Eppendorf tube smells. Getting all this under control is a constant battle in the lab.
We now perform many behavioral studies in microfluidic devices where the animals are moving around in a perfectly defined environment. In these microfabricated chambers, we can expose them to known concentrations of chemicals in various temporal patterns and monitor the response to the stimuli in thousands of worms. We can also monitor neural activity under the same circumstances. Creativity, intuition, and insight are very important to science, but technology development is really what enhances it; bringing microfluidics and microfabrication into our lab finally allowed us to effectively study olfaction.
Over the course of your career so far, what has been your biggest surprise?
When the human genome was sequenced, I looked at it and realized that there really wasn't a lot of innovation at the gene level between the worm and the human. Mammals and humans are immeasurably more complex than simple animals like worms and flies, but this complexity didn't come about by inventing a lot of new genes. Instead, old genes have been repurposed in new ways. The changes are all subtle twists and turns and bells and whistles. This is particularly true of the nervous system. Most of the genes we think are interesting and important in the human nervous system are also present in flies and worms, including almost all of the genes implicated in higher order human cognitive processes or neurological and psychiatric diseases.
The insight that the biology underlying normal nervous system function was so similar across animals came as a surprise, even to those of us who had been working on invertebrates and relying on the idea that we would be able to understand nervous system fundamentals by studying simple systems. This retrospectively lends a lot of support to using model organisms to understand human biology and behavior.