From extending lifespan to bolstering the immune system, the drug’s effects are only just beginning to be understood.
Eve Marder’s quest to understand neurotransmitter signaling is more than 40 years old and still going strong.
October 1, 2015|
PHOTOGRAPH BY MIKE LOVETT/BRANDEIS UNIVERSITYEve Marder has her junior-year college roommate to thank for her initial fascination with neuroscience. “She came back from the first day of an abnormal psychology course and said, ‘Eve, you have to take this course! The professor has an English accent, wears a three-piece suit, and has a dueling scar,’” recalls Marder, a professor of biology at Brandeis University in Waltham, Massachusetts. “Of course, I agreed. What could be more romantic than that?” The course focused on schizophrenia, which at the time, in 1967, was thought to stem from a genetic predisposition coupled with competing sensory inputs or stressors that the brain couldn’t turn off. “The professor, in passing, said that some people think there may be a [cellular] basis for schizophrenia, including deficient inhibition of electrochemical signals in the brain. I thought, ‘What does that mean, inhibition in the brain?’” says Marder. To find out, she read everything she could about the role of inhibitory neurotransmitters—and, in the process, decided she would become a neuroscientist.
Marder began her graduate studies in biology at the University of California, San Diego (UCSD) in 1969. “I was a molecular biologist at heart because I was intrigued by molecules and cells rather than the large systems many were studying,” she says. That same year, a new assistant professor, Allen Selverston, joined the department. “He was the only real neurobiologist in the biology department, so I decided to work with him.” In the summer of 1970, Selverston introduced Marder to the lobster stomatogastric ganglion (STG), a then-new and relatively simple model for studying neuronal connectivity that she has studied ever since.
“Every time we were really stuck—not trivially, but stuck on a deep intellectual level—that has driven us to rethink, go sideways, or turn the problem inside out and come up with something new.”
Here, Marder explains why her choice to become a scientist during the 1960s counterculture was more conservative than what her friends and peers were up to, how her penchant for beautifully written neuropharmacology papers led her to a postdoc in Paris, and why we are not training too many PhDs.
A political slant. Growing up in the 1960s in Westchester County, New York, at the height of the civil rights movement, Marder was involved in a local youth civil rights group. In 1965, when she entered Brandeis University as a freshman, Marder thought she wanted to be a civil rights lawyer. But during her sophomore year, a post–World War II European history course that required memorization of every country’s political parties, “all alphabet soup and boring, with an odious black textbook with double columns of text,” changed her mind. After taking the final, Marder walked out of the lecture hall and pressed her mental delete button. “I forgot all of it on purpose and changed my major to biology,” she says.
Perfect sense. “I remember in high school when we learned about respiration and photosynthesis and the other molecular machinery hiding inside things that on the surface looked solid. I realized all of these molecular dynamics were inside cells, and that is what really fascinated me—these mechanisms of biological systems. Biology just made complete sense to me.”
The road less travelled. Before graduating and heading off to grad school, Marder presented an honors thesis on muscle biochemistry. At the time, most students who did an honors science thesis were men headed to medical school. “I remember having a funny conversation with one of them my senior year. He asked if I was also applying to medical school, and after I said no, said, ‘But why not? You’d get in.’ I said, ‘But why would I want to go to medical school if I don’t want to be a doctor?’ And he just kept saying, ‘But you would get in,’ and ‘Why wouldn’t you want to be a doctor?’”
A new model. When Marder joined Selverston’s lab as his first graduate student, he had just learned how to make in vitro preparations of the STG. “It was brand new and a simple example of a pattern-generating circuit,” says Marder. The STG, just 30 neurons, controls the rhythmic movement of the lobster’s stomach muscles during digestion, similar to the circuitry that controls breathing or walking. The STG cellular circuitry continues to generate motor patterns in vitro that resemble in vivo action potentials, but without the need for external stimuli. “This was something not possible then with vertebrate neuronal preparations.”
Thinking outside the circuit. For her graduate thesis, Marder set out to identify the neurotransmitters of the STG. “It was already clear that there were a bunch of different molecules used as transmitters, but no one had any idea why there were so many. There were researchers studying GABA, dopamine, serotonin, and other neurotransmitters separately, but no one was asking why there were so many transmitters in the brain and what their functional organization was. I wanted to understand the whole circuitry,” she says. Marder was the first to describe neurotransmitters in the STG. She discovered that acetylcholine functions as both an excitatory and inhibitory transmitter in some of the STG’s neurons. “This turned into a lifelong chase into transmitters and modulators in functional circuits.”
A singular vision. Marder learned a lot in graduate school, but her desire to understand the molecular underpinnings of neuronal communication remained strong. “At the time, the field was interested in working out wiring diagrams, because the scientists, who mostly came from electrical engineering, thought the neuron circuits worked like electrical circuits. My advisor echoed what many said at the time. ‘What you are doing is just pharmacology, it doesn’t really matter.’ In their minds, it only mattered whether the signal was inhibitory or excitatory; the actual signaling molecule wasn’t going to matter.”
A conservative choice. “Of the people I graduated college with, half were going to change the world, some were going to live on a commune, some guys ran away to Canada to avoid the draft, and others were going to a farm in Vermont to grow their own food. Long-term career plans were sort of weird for us—we were all counterculture. Graduate school at the time was a very conservative thing to be doing amongst my friends. When I finished my PhD, I just thought about the next step but didn’t have long-term career goals.” Marder spent a year as a postdoc in David Barker’s laboratory at the University of Oregon and then, in December 1975, with a fellowship from the Helen Hay Whitney Foundation, set off for Paris to work in JacSue Kehoe’s laboratory. “She had written, just head and shoulders, the most beautiful neuropharmacology papers. I had read every paper in the field and these were just so much better than what anyone else was doing.” There, Marder collaborated with Danielle Paupardin-Tritsch, publishing three papers, including a study of the responses of the crab STG to three different neurotransmitters.
More than on/off switches. When she came back to the U.S. in 1978, Marder joined the faculty at Brandeis as an assistant professor in the biology department and has remained there ever since. Along with her first graduate student, Judith Eisen, whom Marder credits with early successes in her lab, Marder provided the initial evidence for the existence of neuromodulators that can prompt longer-term changes influencing how neurons respond to fast-acting neurotransmitters. Eisen initially characterized the pharmacology of the synapses, figuring out which neurons had receptors for which signaling molecules.
Predicting behavior. In 1989, Marder met Larry Abbott, then a theoretical physicist at Brandeis. “It was clear that for a true mechanistic understanding of how the dynamics of the circuit arise from its components, we needed to be able to do modeling,” she recalls. With Abbott, Marder’s lab developed the “dynamic clamp,” a method that uses a computer to introduce a conductance—the ease with which an electric current can pass through a circuit—into neurons to model their behavior. They also worked out the negative-feedback system within neurons that allows for changes in parameters while maintaining their normal function. “We were building models and they were fragile. We would change a parameter, and the model would crash. I kept saying that the cells don’t crash all the time, so how do cells balance their number of ion channels? What we came up with is a very simple way of thinking about this.”
The bigger picture. “The big themes that have come from the STG model, and partly from our lab, are that neuronal circuits are multiply modulated, that modulators reconfigure circuits, and that there have to be pretty simple global regulatory mechanisms that help neurons maintain stable electrical activity despite the fact that their ion channels—the proteins in the cell membranes that carry out electrical signaling—are being constantly replaced.”
Heterogeneity. For the last 10 years, Marder’s lab has been working to understand the extent of variability within individual nervous systems that still allows the systems to remain stable. “For quite a long time, people thought that all nervous systems had to be very tightly tuned,” she says. “And what we are seeing is that, actually, they can be quite variable and change over time and still work well enough because there is a lot of degeneracy in the way circuits are constructed.”
The new normal. Before 1968, many life-science PhD programs had informal quotas, restricting the number of women accepted, says Marder. But that year, the draft law changed, and graduate school enrollment was no longer a valid way to defer the draft. Life-science graduate programs suddenly switched to gender parity. Marder’s class at UCSD was the first to have a large proportion of women—13 women out of a class of 30; in prior years there were only two or three women per class of 30. “There was a lot of hubbub about it. ‘What are we going to do with all these women? Civilization as we know it will end!’ was how the professors talked about it. But by May that year they had completely forgotten about it,” Marder laughs.
The big picture. “I have always been good at figuring out how to use the same nervous system to ask a bunch of different questions. And I’ve always been pretty good at finding the general principles amongst the idiosyncrasies of a neuronal system. I think that is key if you work on model organisms.”
The benefits of being stuck. “Everything important we did in the lab arose because something wasn’t working as expected. In Judith’s original work, we finally realized after getting different answers from every experiment that there were nine different possible outcomes connecting only three neurons, all consistent with our recordings. So we had to design a completely different experiment. The activity-dependent regulation work arose only because of my total frustration with having to tune conductance-based models. So every time we were really stuck—not trivially, but stuck on a deep intellectual level—that has driven us to rethink, go sideways, or turn the problem inside out and come up with something new.”
A worrisome trend. “I am very concerned with science right now because I think the push to have high-impact papers is having a deleterious effect on the way people design experiments, and it definitely has a deleterious effect on the way researchers write their papers. The most common critique you see from reviewers is that authors are overselling their work, and it’s because the researchers believe high-impact papers are necessary for their careers. So the science we are doing is being warped.”
A scientist in the rough. Marder recently wrote a commentary against the push to decrease the number of students accepted into science PhD programs.“We’re very bad at spotting who is going to be a good scientist and who isn’t [based on graduate-school applications],” she says. “While students are in college, they are fundamentally consumers of knowledge, and becoming a scientist means you have to learn to be a creator of new knowledge. But the tools that allow you to be a great consumer of knowledge don’t set you up for the kind of frustrations and sidewise thinking and problems that you have to confront to be a knowledge creator. You can take the best undergrad students, and they may not be the best graduate students. And the ones who complete the best PhDs may not be the ones that stay in the field. I think it comes down to drive, persistence, willingness to confront failure, creativity, passion—all of these other attributes that we can’t measure easily on an application. So to take just the top undergraduates, you’re going to be missing many of the best ones. The real problem here is that the US government is not funding enough science.”
Potential to fly. “It’s crazy right now because biology in general, and neuroscience specifically, is at this extraordinary moment in time when there is so much really wonderful science that can now be done that was inconceivable even 10 years ago. We are at this incredibly exciting moment for discovery and at the same time the field is being destroyed by extraordinary anxiety about [funding] resources. If we didn’t have this extent of resource anxiety we could be flying, but the funding situation is crippling, and we are crippling ourselves with this incredible collective anxiety.”