Cori Bargmann, Ph.D., the Torsten N. Wiesel Professor at Rockefeller University, recently received the Kavli Prize in Neuroscience. A Howard Hughes Medical Institute Investigator, she heads the Lulu and Anthony Wang Laboratory of Neural Circuits and Behavior.


Sandra Aamodt: When most of us think of genetic traits, I suspect what comes to mind are the examples we learned in school, like the genes for brown and blue eyes. What complexities are we missing when we think that way?

Cori Bargmann: The human genome project has demonstrated the incredible diversity between people. If there are three billion bases in the genome, there are three million differences between you and me. Most differences between people are probably built up from multiple layers of genetic diversity, not from a single gene for this or a single gene for that, as the newspapers often imply.

In classical genetics, strong mutations in individual genes are characterized to understand something about the biological underpinnings of a process. That’s not so far from the brown eyes and blue eyes approach. But there’s a second kind of genetics, which represents the differences between individuals in a population. Personality traits, like being introverted and extroverted, tend to be correlated between identical twins, even those who are raised apart. We know essentially nothing about the molecular mechanisms that account for those kinds of differences between normal individuals. We know something about the more severe psychiatric diseases like schizophrenia and autism, and we know a lot about the rare disorders caused by mutations in a single gene. The more common something is, the more we interact with it in day-to-day life, the less we understand about it. Anxiety and depression are extremely common disorders. We don’t understand the genetic basis of either, but it’s clear that they have genetic components.

Sandra Aamodt: Don’t anxiety and depression share the same genetics to a large extent?

Cori Bargmann: Yes, there’s a big overlap between genetics of anxiety and depression. Ken Kendler has done the epidemiology of anxiety and depression and showed the correlation between them. He’s also showed not only that there are environmental risks for depression, but exactly what those are. For example, childhood sexual abuse interacts with genetic risk to greatly increase the odds of developing major depression as an adult. These are tough problems to understand. Genetic factors almost certainly interact with other genetic factors as well as environmental factors.

Sandra Aamodt: It gets hard very fast.

Cori Bargmann: Yes, it does. As for environmental factors, we’ve done a fantastic job of addressing this in my lifetime, but it was well known in the middle of the 20th century that if pregnant women got rubella, their children could be severely impaired. They could be blind and deaf or autistic or have a high risk of developing schizophrenia later in life. Most of brain development happens before birth, and maternal infection or fetal malnutrition is a serious risk for later psychiatric disease. We know what some of the environmental risk factors are, though we may have forgotten.

Sandra Aamodt: It’s curious that the better the environment gets, the more important genes become in determining individual differences.

Cori Bargmann: Yes, several studies show that’s true for intelligence. Tom Bouchard also makes that point about the Minnesota Twins Study, that the more freedom and independence you have in your own life, the more you will probably end up taking some sort of genetically disposed path. My people were farmers, but I have freedom that they didn’t have. I might have been a really bad farmer.

Sandra Aamodt: Is the complexity of these interactions why you use worms for your own work?

Cori Bargmann: The first reason for working on worms is that we think genetic variation is important, but that there will be complex interactions between genes. The simpler the organism, the faster its generation time, and the more control you have over its genetics, the better your chances of dissecting those elements.

The second reason is the idea that behavior comes from evolutionary precedents. If an animal behavior has existed for a long time, there may have been some problems that the nervous system started to solve very early. For example, Andy Knoll at Harvard is a geologist, who works on trace fossils, like tracks in the mud, that give us clues about early invertebrates. He found that as soon as the organisms started moving around, they started preying on each other. Everyone started doing things like hiding underground and making exoskeletons to keep themselves from getting eaten.

Sandra Aamodt: Makes you wonder about vegetarians.

Cori Bargmann: Vegetarian is clearly a derived state. [laughs] I say that as a vegetarian.

Generally, once evolution has arrived at a good solution to a problem, then that solution gets elaborated, improved, and duplicated, but rarely replaced completely. It’s reasonable to hypothesize that idea of conservation would apply to basic behavioral problems as well. Therefore if you looked at animals that were very divergent and tried to understand the essential elements of their behavior, you might gain insight into the initial building blocks of behaviors that appear in people as well.

It’s striking how many components of behavior you can recognize across different animals. The rules for aggressive behavior are so similar. If you look at lobsters, rhinoceroses, or deer fighting, the interactions, the escalations, the point at which it gets broken off when a defeat is recognized, the stable recognition of defeat, they’re remarkably similar. Looking at this complex behavior suggests that there are basic rules that a lot of different animals share. That’s the hope for working on worms, that there may be basic rules about building fundamental behaviors, in a system where we can ask questions about how groups of genes interact with each other to produce the behaviors.

Sandra Aamodt: How do you study decision-making in worms?

Cori Bargmann: We study a fun behavior with the fabulous name of the exploration-exploitation decision, which I did not make up. It’s from the animal behavior literature and also used in human psychology. It describes the decision between remaining in one environment and harvesting the resources there versus exploring to see if things might be better in another environment.

In the roundworm C. elegans, we looked at how the animal decides whether to abandon a decent but not optimal food source. Different individuals vary based on genetic differences by a factor of twenty in whether they’ll stay or look for a new environment. Some will wander off every five minutes looking for something better, others every two hours. This decision incorporates all the features you’d want to consider in a higher-order behavior. Worms take into account how good the food is, how much food there is, whether there are other guys around competing for the same food, and whether there are potential mating partners nearby, as well as their own experience. An animal that’s been exposed to good food will leave a mediocre food supply. An animal that’s only ever seen mediocre food will stay. Everyone can relate to that decision between staying where you are and trying something new.

Sandra Aamodt: Do you try to fix that difficult relationship or move on?

Cori Bargmann: Exactly.

Sandra Aamodt: What have you learned about this behavior?

Cori Bargmann: We were able to identify two molecules that were involved, both G-protein-coupled receptors for internal neuromodulators. They sense signaling molecules that represent an internal state. That gives you a clue that the decision is being made by integrating an internal mood or motivation with the external conditions.

One of molecules was a receptor for adrenalin-related compounds (tyramine and octopamine in the worm). Invertebrates and vertebrates use adrenalin-related compounds that are highly conserved in evolution, and their receptors are very similar too. When humans switch between different cognitive tasks, adrenalin is associated with that switch in decision strategy. It’s a little early to say what that means, whether some kind of relationship between adrenalin signaling and decision-making goes all the way back in animals, but similar molecules are engaged in similar kinds of decisions in these different animals.

Next we asked where the worm puts together information about the environment and internal motivation. The answer is that the receptor for internal cues sits on the sensory neuron that is sensing environmental quality and determines how well sensory neurons connect to behavioral outputs. The same neurons respond to the internal motivation, which is the genetic variation, and the external cues. We think that the decision between two alternative behaviors is always going to represent the interaction between external conditions and internal motivation. Even at the simplest level, whether you eat something or not is going to be determined by both whether it looks palatable and how hungry you are. In David Anderson’s recent paper, he showed that the effect of hunger is to effectively couple or uncouple the sweet taste system to the brain. You’re much more sensitive to sweet if you’re hungry than if you’re not. The nervous system combines internal motivation with external conditions as early as the first neuron that senses the stimulus.

Sandra Aamodt: Then you might not even realize that an environmental event had occurred if you were in a motivational state that made you insensitive to it?

Cori Bargmann: Yes, it’s as if you’re not detecting the sensory input at all. A striking example is the complete suppression of the pain pathways in some emergencies. I’ve been in a car accident, and I remember noticing that my head was bleeding and not knowing whether I was badly injured or not. Because you feel no pain whatsoever for some brief period of time. The adaptive value of that is clear. If you’ve been bitten by a tiger, you should run away.

Sandra Aamodt: I was struck by your finding that evolution in worms was driven by social interaction with other animals. I’ve seen that idea proposed in humans as well.

Cori Bargmann: Social behavior, I think, is one of the really primitive forms of behavior. Every animal spends part of its life in association with other members of the same species. The more we know about these interactions, the more widespread they become. One of the big recent discoveries in microbiology is that unicellular bacteria communicate with each other by making and detecting particular chemicals. They use this information to coordinate their physiology and gene expression and collaborate to overwhelm the immune system of the host through quorum sensing. There are probably biological components that are deep underlying regulators of social behavior.

Now sometimes your interests are aligned with other individuals of your species and sometimes not. The best strategy varies based on a lot of different conditions. It can be to share information, to compete with each other, or to diversify behaviors because other individuals are nearby. There’s also good evidence for density-dependent selection, where the best behaviors are different at a low versus high density of individuals.

We analyzed a set of inadvertent experiments that scientists had done when they brought C. elegans into the laboratory. Whenever humans start to breed plants or animals, whether it’s for agriculture or circuses or the lab, they start to cram a lot of them into a small amount of space. In his book "Guns, Germs, and Steel", Jared Diamond makes the point that the animals that can’t be domesticated are the ones that can’t be kept at high density. Zebras will just kick each other to death, so they’ve never been domesticated.

Patrick McGrath in my lab realized that by growing animals in high-density conditions, people had been inadvertently selecting for different neural processes and behaviors. Laboratory organisms tend to be solitary and dispersed under conditions in which wild C. elegans would always be in large groups. One reason was scientists picking up the animal that was far away from the other guys when moving an individual to a new plate, just because they’re easier to grab. In addition, the aggregation behavior of C. elegans is a response to a stressful environment. As laboratory strains became adapted to that environment, they displayed less aggregation. After a thousand generations in the lab, they decided they could live with it. Those two pressures selected for worms spending less of their time in aggregates.

A different selection was done in other labs by keeping animals at very high density. C. elegans has a boom-and-bust lifestyle. If you have a single worm and it finds some delicious food like a rotting apple, it can have 300 progeny in three days, 90,000 worms in a week. If the food stays around, in two weeks, there will be over a billion worms. When the density reaches a certain level, you’re going to run out of food no matter how much you have. So the natural life cycle is find some food, grow like crazy for a couple of weeks, then run out of food and possibly not find any food again for a long time.

Worms have essentially figured out this relationship in their genomes. They detect pheromones to find out if there are a lot of other worms around, which predicts a loss of food. They then change to a form that’s good at surviving starvation and migrating to where there might be a new food supply. A couple of labs for many years allowed the worms to grow to high density without a change in food supply, breaking that relationship. Those worms stopped responding to density by regulating their development. In both labs, the worms solved this problem by knocking out the receptor genes for the density pheromones. Their genomes changed to stop detecting a cue that was no longer informative to them.

One of the mysteries of the olfactory system is that there’s an incredible number of receptors, and they’re not conserved at all. In humans, compared to other primates, we’ve lost a hundred and gained a hundred odor receptors. Furthermore the human genome shows strong evidence for positive selection pressure on olfactory and taste receptors, which is relatively rare, suggesting that there were selective advantages to changing perception over time. Our results show that changing smell and taste receptors in worms changes their response to other animals.

Humans are also living at higher densities than our wild ancestors, and we’re eating different food. Between cooking and food storage, our diets have changed enormously compared to other primates. We changed our own environment, and then we probably changed our genomes to match it. Lactose tolerance is the great example. We domesticated the cow, and then the human genome followed along by making us better at drinking cow’s milk.

Sandra Aamodt: How has what you’ve learned about science changed the way you live your life?

Cori Bargmann: The element of being a scientist that probably most changes my view of the world is understanding how probability works. Not everything that happens has a cause and effect. Some things happen by chance. At a lot of universities, you have to take calculus if you’re a premed, but you don’t have to take statistics. I don’t think most doctors ever use calculus, but if you’re a doctor, you’re making statistical decisions every single day.

I also think that ethical actions change when you extend your understanding of the world. If you understand science, then you understand that climate change will disproportionately harm the poorest people and the poorest countries, and that creates certain ways of acting. I think if you asked people, “Should you be doing something that would cause the poorest people in the poorest countries to starve?” they’d say, “Well, no.” But science changes your understanding of what would cause that condition. You can look further ahead and farther abroad for the implications of your actions.