How do signals between the body, the environment, and the brain come together to generate, behaviors, thoughts, and emotions? In the past few years, efforts to synthesize molecular, cellular and behavioral research into a comprehensive understanding of brain function and dysfunction have been gathering steam, but the field still lacks much-needed tools to get to the bottom of its most fundamental questions.
The Kavli Neural Systems Institute (Kavli NSI) at The Rockefeller University, launched on October 1, 2015, with an endowment from The Kavli Foundation and The Rockefeller University, will support collaborations with physicists, engineers and other scientists to develop novel techniques and concepts for tackling neuroscience’s biggest questions.
On the eve of the launch, the Kavli NSI’s inaugural co-directors, Cori Bargmann and Jeffrey Friedman, and the inaugural associate director, Leslie Vosshall, sat down with The Kavli Foundation to offer the institute’s vision for the future of this rapidly changing field.
- Cori Bargmann, PhD – Co-director of the Kavli Neural Systems Institute. Bargmann is a professor at The Rockefeller University and head of the Lulu and Anthony Wang Laboratory of Neural Circuits and Behavior. She is also a Howard Hughes Medical Institute Investigator. As co-leader of the National Institutes of Health working group on the BRAIN Initiative, Bargmann helped establish a national research roadmap for neuroscience. Her work on the neural circuitry of smell in the roundworm C. elegans has revealed fundamental insights on how genes and environmental stimuli guide complex behaviors, and in 2012 was honored with the Kavli Prize in Neuroscience.
- Jeffrey Friedman, MD, PhD – Co-director of Kavli Neural Systems Institute. Friedman is a professor at The Rockefeller University, where he directs the Laboratory of Molecular Genetics, and is a Howard Hughes Medical Institute Investigator. His research investigates molecular mechanisms that regulate food intake. Friedman was the co-recipient of the 2010 Albert Lasker Award for Basic Biomedical Research for his discovery of leptin, a key hormone in regulating appetite and body weight.
- Leslie Vosshall, PhD – Associate Director of the Kavli Neural Systems Institute: Vosshall is a professor at The Rockefeller University and head of the Laboratory of Neurogenetics and Behavior. Her research explores how chemosensory signaling and olfaction guides behavior in humans and insects, in particular the Aedes aegypti mosquitoes, which transmit a number of deadly viral diseases to humans. Vosshall is also a Howard Hughes Medical Institute Investigator.
The following is an edited transcript of the discussion. The participants have had the opportunity to amend or edit their remarks.
The Kavli Foundation (TKF): Let’s begin by discussing the mission of the Kavli Neural Systems Institute. What’s unique about the institute and how will it function in a way that’s specific to Rockefeller?
Leslie Vosshall: Because we don’t have departments at Rockefeller and we don’t hire programmatically, we grow organically by picking the best people. As a result, neuroscience here is extremely broad. In a sense, the organizing principle of the Kavli NSI is an anti-organizational principle. We want to align ourselves to investigate neural systems, but beyond that we don’t want to specialize.
Cori Bargmann: The Kavli NSI will allow us to create a center of gravity for neuroscience within the loose structure that characterizes research at Rockefeller. Through the framework of the institute, we will be able to bring neuroscientists together and set up ways to build our community without sacrificing the independence that Rockefeller promotes.
Jeffrey Friedman: At the Kavli NSI, each investigator is charged with answering the biggest and most important questions they can think of. This outlook is already embedded in the culture of Rockefeller: Laboratories are run with full independence, and there’s nothing prescriptive about the research that scientists pursue, and the new Institute will promote this.
Vosshall: We want to take the good of departments – providing community and the money to support it – without the silos they can create. But beyond the Rockefeller community, the institute will also allow us to act as a hub for researchers from other Kavli institutes and research institutions. Already, under Cori’s leadership, we have been doing this in the form of one-day meetings focused on a particular theme that bring together neuroscientists from around the region and the world, but now we will be able to formalize it.
TKF: Dr. Bargmann, you are one of the architects of the BRAIN Initiative, launched by President Obama in 2013 to create neurotechnologies for the next generation of brain research. How would you say the Kavli NSI will further that scheme’s goals?
Bargmann: In the long-term, the BRAIN Initiative has set out to address profound questions about how the brain functions, how it gives rise to our unique abilities, how it goes wrong in different disorders, and how to measure that. But in the short-term, it’s asking, “What is standing in the way of us answering those important questions?” In many cases, what’s standing in the way is that the tools and technologies available today are not sophisticated enough to delve as deeply as we need them to. Traditionally, the scientific enterprise prioritizes discovery, which is fantastic, but you can’t make discoveries without tools. The BRAIN Initiative aims to revolutionize this.
TKF: What kinds of tools are lacking?
Bargmann: We need tools coming out of a combination of different fields – not just engineering and physics and computer science, but also molecular biology and optics and microscopy. To some extent, it’s already happening; for example through optogenetic approaches that enable researchers to switch neural circuits on and off at will. But it’s not just hardware that we need. Equally important are conceptual tools – mathematical, theoretical, statistical, and computational approaches. When I started in biology, you’d take six months to do an experiment, then another six months to think about the results. Today, biology is much more effective. We have tremendous abilities to gain information. That information must be turned into insights. That’s where the intellectual tools are as important as the physical tools.
The BRAIN Initiative is making such tool development an explicit priority instead of just a little problem that you have to solve along the way to answering your big question. That sensibility definitely informs the Kavli NSI at Rockefeller. We have a great tradition of tool building going all the way back to the use of electron microscopy to look at biological samples.
TKF: The Kavli NSI will have a particularly strong focus on the intersection of biology and physics. How has the interplay of these two fields shaped research in your own labs?
Friedman: My laboratory studies the neural mechanisms that control food intake. In 1994 we identified the hormone leptin, which inhibits hunger, and since then we’ve tried to define populations of neurons that respond to leptin and that are part of an integrated circuit that controls eating. In studying this circuit we’ve developed a number of methods, but one that I wouldn’t have anticipated is a nanotechnology that allows us to control neural activity in living animals using radio waves or magnets.
The technique essentially involves hijacking a heat-sensitive molecule in neurons of the tongue that acts as a sensor of thermal pain. When it gets activated, the neuron fires. We found a way to tether this molecule to an endogenously produced iron nanoparticle called ferritin, whose job is to prevent iron from causing toxic effects by sequestering it. We found that when we insert these constructs into neurons in a living animal, exposure to radio waves or magnetic fields activates the ferritin and noninvasively activates those neurons.
TKF: How are you using this approach to study food intake?
Friedman: Many factors influence whether or not an organism will eat, but it’s not clear how the brain processes these strands of information to generate what in essence is a binary decision, eat or don’t eat. In mammals, we don’t even know where the decision is made. The ability to modulate the specific elements of the underlying circuitry will allow us to probe this question. We’ve also figured out how to make a version of the construct that inhibits rather than activates neurons, and we are using this to activate some neurons in the circuit and inhibit others and monitor the behavioral consequences.
TKF: What about your lab, Dr. Bargmann?
Bargmann: My lab’s relationships with physicists at Rockefeller have definitely pushed us toward work we might not have otherwise been doing. One example is our interaction with Stanislas Leibler, a physicist who studies biological networks here at Rockefeller and at Princeton’s Institute for Advanced Study. Engineers in my lab have been able to work with Stan to develop various tools for studying behavior in our model organism, the roundworm C. elegans. But even more importantly and profoundly, discussions with him have helped us to think about the statistics of animal behavior in a much more sophisticated way. Stan will be one of the participants in the Kavli NSI, which we’re really thrilled about. He wouldn’t consider himself a neurobiologist, but his way of thinking is extremely valuable to neuroscience.
TKF: Dr. Vosshall, you study the sense of smell, which has proven an especially tough nut for researchers to crack. How might the cross-disciplinary capabilities at Kavli NSI help solve some of its mysteries?
Vosshall: Research on the sense of smell is decades if not a century behind research on vision. We lack the principles to allow us to predict how a particular odor molecule smells, and how the brain takes in this information to produce the sensation of an odor. The only way to crack this complex code is to attack it from all sides. We need to go from single molecules in olfaction all the way to the psychophysics experiments I do, which probe human perception of smell by bringing subjects into the Rockefeller University Hospital clinic. With insects in particular, we do not understand the proteins that sense odors. Vanessa Ruta, a fantastic member of the junior faculty, is about to examine them with cryo-electron microscopy -- a boundary-pushing technique for solving the high-resolution structure of a protein, a technology that Rockefeller has recently invested in. I am confident that she will be the first person to look inside these molecules, which allow insects like mosquitoes to sniff out humans, and agricultural pests to find our food crops.
TKF: How has cross-pollination with physics and engineering played a part in the questions you work on?
Vosshall: I run a molecular neuroscience lab that investigates the genetic basis of innate behaviors. To follow what animals do, we need to build high-resolution assays. We have been using 3D printing, semiconductors, circuit design, and other techniques to build such tools. For example, one of my second-year graduate students has collaborated with an engineer at our Precision Fabrication Facility to build an innovative device that can follow mosquitoes in real time as they land to lay an egg. These do-it-yourself technologies are transforming neuroscience.
Last year, we published a study showing that the human olfactory system can distinguish between a vast number of odors, many more than 10,000 as previously believed. In this work, we collaborated with mathematical physicist Marcelo Magnasco at Rockefeller, who creates computational models of complexity in living organisms. If you are doing edgy things like redefining a sensory system’s capabilities, you need collaborators who can help you think outside of your area.
Also, a big part of the Kavli NSI’s aim is to support young researchers. Such support can jumpstart post-docs into independence by letting them do more creative projects that could become a starting point for their own careers.
Vosshall: I am thrilled about bringing our trainees into the institute. It is incredibly exciting for, say, a third-year graduate student with an idea that falls outside the mainstream to have access to what the institute can provide, such as a bit of seed money to do some truly innovative work. It really aligns with Rockefeller’s egalitarian outlook.
Bargmann: The real metrics of success at an academic institution are ideas and people. The ideas and people associated with modern biology have been concentrated at a few institutions. A tiny department at Stanford had a huge outsized influence on molecular biology in the 1970s. The same is true for Rockefeller in the 1950s, when George Palade and Christian de Duve used electron microscopy to study the internal structures of the cell. Or neurobiology at Harvard in the 1960s, when David Hubel and Torsten Wiesel explored the role of sensory experience in the development of the visual cortex. That’s the level of success that we’re striving for with the Kavli NSI: seeding a whole new set of ideas that disperse throughout the research world and take root in different places and in different fields.