2024 Gruber Neuroscience Prize

Cori Bargmann, PhD, of the Rockefeller University, and Gerry Rubin, PhD, of the Howard Hughes Medical Institute’s Janelia Research Campus, have been instrumental in delineating the circuitry of behavior. Their efforts have also led to the development of a number of valuable research tools and resources that have benefited the entire neuroscience field, making it possible to probe the molecular and cellular basis of behavior. 

As Cori Bargmann embarked on her research career, she found herself drawn to the neurobiology of behavior. Bargmann decided to study behavior in C. elegans, due to the fact that the wiring diagram had recently been published, showing the 7,000 connections made by the 302 neurons found in C. elegans. “You’re trying to explore a new country, and here you have a map,” Bargmann said. “The strength of C. elegans is that you would be able to link together what molecules were doing, what cells they were acting in, and what they were doing there.”  

Bargmann performed a series of technically challenging laser ablation experiments, in which she removed individual neurons from the worm, in order to answer the question of what behaviors these neurons were responsible for. Following this cell-based approach with genetic screens, Bargmann and her colleagues were able to identify an odorant receptor in C. elegans, which sensed the molecule diacetyl, and connect this receptor with the behavior of crawling towards this molecule. “This was the first time that a specific odorant was linked to a specific receptor,” Bargmann said. The next step was to perturb the system to establish causality: Bargmann and her colleagues expressed the odorant receptor in neurons that normally reacted only to noxious odors, which had the effect of changing the worm’s behavior from attraction to repulsion. These experiments showed that sensory neurons can specify an animal’s innate behavioral preferences.

This combined approach of looking at genes, cells and behaviors would come to define Bargmann’s career, as she would follow up these early experiments with many more, all seeking to define the ways in which behavior is determined by a complex mixture of environmental and genetic factors.  

Along the way, Bargmann was an inventor and early adopter of tools for monitoring and perturbing nervous system function. “In the C. elegans field, people had a mindset of developing resources the entire community could use,” Bargmann said. “That was the mindset that people walked in the door with.” Inspired by this attitude, she helped to architect the NIH BRAIN Initiative to advance technology development in neuroscience more broadly.

After receiving his Ph.D. from the University of Cambridge, Rubin did his postdoctoral training at Stanford University, under the guidance of David Hogness. During Rubin’s efforts to clone DNA, he became interested in understanding why there were so many repetitive elements in the fly genome. This eventually led to a series of experiments, using the white locus, where Rubin demonstrated that some of the mutations found in the white locus were the result of transposon insertion, which he and his collaborator Allan Spradling realized could be useful for manipulating the fly genome. Rubin and Spradling conducted a series of experiments, which were published in back-to-back papers, demonstrating the use of P-elements for engineering transgenic flies.  

“This enabled people to conduct genetic engineering of an animal, for the first time,” Rubin said. The use of P elements for selectively modifying the fly genome opened up countless possibilities for the field. Rubin’s next major venture was to lead the efforts to sequence the fly genome, an effort that many feared would cost too much, and yield too little. “Nobody now doesn’t think it wasn’t worth it,” Rubin said, but at the time, it was a massive undertaking that many people feared would be a waste of money. 

After the fly genome was sequenced, Rubin was offered the opportunity to become the director of the Janelia Research Campus, which is the Howard Hughes Medical Institute’s research center in Ashburn, Virginia.

As part of this venture, Rubin decided to embark upon mapping the fly connectome and developing genetic tools to manipulate individual cell types, a massive undertaking that would map the various circuits of the fly brain, down to the last neuron, and offer researchers tools that could help them understand how the brain’s wiring correlated to behavior. This venture, which would take ten years and $60 million, would come to define the field of Drosophila neuroscience, by offering a powerful tool that could yield countless valuable insights into the circuitry of behavior.