David Van Essen

David Van Essen

Alumni Endowed Professor of Neuroscience, Washington University School of Medicine

By David Zierler, Director of the Caltech Heritage Project

February 25, 2026

DAVID ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. Its Wednesday, February 25, 2026. It is my great pleasure to be here with Professor David Van Essen. David, wonderful to be with you. Thank you for joining me today.

DAVID VAN ESSEN: Thanks for the opportunity.

ZIERLER: To start, please tell me your current title and institutional affiliation.

VAN ESSEN: I'm the Alumni Endowed Professor of Neuroscience in the Department of Neuroscience at Washington University School of Medicine in St. Louis.

ZIERLER: Let's now go to some overall research questions. I'm taken by just how vast neuroscience has grown, certainly over the course of your career. What surprises you about the growth of neuroscience, and what might you have seen coming earlier in your career?

VAN ESSEN: Well, I was very fortunate to enter the field of neuroscience in the late 1960s at a time when the field was transitioning from what is now regarded as the classical period into the modern neuroscience era. It's truly amazing how neuroscience has exploded in the ensuing decades. I certainly did not see it coming, even though I was an optimist, and mindful of the many domains in which the field had the potential to grow. That it has indeed expanded so dramatically and in such diverse ways is one of the impressive aspects of modern science. When I was a postdoctoral fellow in the lab with Hubel and Wiesel, I remember thinking that they were making great discoveries that seemed at the time like it was taking all the icing off the cake! It wasn't clear how much in the way of crumbs would be left for those of us who'd follow. But I gradually evolved to a very different perspective - namely, the more we learn about the brain, the more we realize how much there is left to learn. And for all the tremendous amount of knowledge gained, we really do have a long, long ways to go before we can say we understand how the brain works.

ZIERLER: That boundary point that you mentioned, where the field transitions from its classical origins to its more modern version today, what is that boundary point? What are the experimental and even theoretical markers that allow us to understand what transitioned?

VAN ESSEN: A major factor is that the technology evolved in such a way that more powerful experiments could be done and interpreted, leading to an explosion of new discoveries accompanied by vast amounts of experimental data. For example, back in the 1960s and beforehand, neurophysiologists used the limited tools available to study the function of the brain using electrical recordings of one sort or another, but they didn't much care about the anatomy of what they were studying. In parallel, anatomists studied the structure and connections of the brain, but they didn't think hard or care much about the function that these structures and connections gave rise to. Going back to your question, perhaps it was the emergence of an integrated approach to neuroscience that was the most important defining aspect of that transition. One early indicator of that integration was when Harvard initiated a new department of neurobiology, rather than just hiring more anatomists in their anatomy department and physiologists in their physiology department. They recruited Steve Kuffler to be the chair of neurobiology, and Kuffler recruited Hubel and Wiesel, who were spectacularly successful in neurophysiology, but also brought anatomy into their approach to studying the brain and the visual cortex in particular. Kuffler brought Ed Kravitz in the field of neurochemistry, Ed Furshpan and David Potter in cellular neurophysiology. Together they initiated a graduate training program that I was fortunate enough to join as the first entering class. And we learned the basics of neurophysiology, neuroanatomy, and neurochemistry from world leaders at the time and were trained in that integrative approach that is, I think, extremely important.

ZIERLER: Is that still dominant in the field, the primacy of looking at the physiology and the anatomy in an integrated and holistic sense?

VAN ESSEN: I'd say it's widely accepted, and now it's expanded to the realm that not just looking at anatomy and physiology, but also looking at gene expression. And you have the ability to record from a single neuron in the brain and view its structure in intricate detail, view its physiology in richly explored ways, and then to extract its RNA and determine the gene expression profile and the cell class that it belongs to. This illustrates the expansion of that integrated approach across a whole new domain that wasn't even remotely on the radar screen back in the 60s and the 70s. Gene expression was just not on the horizon. The tools of molecular biology were still in their infancy at that time.

ZIERLER: That's to say that gene expression is answering questions that the earlier generation of anatomists and physiologists wouldn't have even known to ask?

VAN ESSEN: That's right. That is a major point.

ZIERLER: What kinds of things do we know about the brain because of gene expression?

VAN ESSEN: Well, to step back, the classical anatomist Ramon y Cajal, who was the premiere neuroanatomist from his work in the late 19th and early 20th century, had identified many anatomical classes based on the structure of the cells - their dendritic arbors, what they were shaped like, and where their axons projected to. That led to the realization that the brain isn't just a hodgepodge of randomly configured cells but instead consists of highly specific cell types that are distinct for each brain region. But it wasn't clear how many cell types there were. The guesses were there could be maybe just a few basic cell types, or there might be dozen, or some wildly speculated there might be 100 or so cell types in one or another brain. And what we now know from gene expression studies, pioneered by the Allen Institute but many, many other labs around the world, is that in the mouse, for example, there appear to be on the order of many hundreds and possibly more than a thousand cell types. And in our own brains, likely even more, but that's still a work in progress. But to understand what those cell classes are doing, how they perform in an integrated, intricately orchestrated way, that's where there's still a lot of mysteries left to be solved.

ZIERLER: I'll ask a philosophical question. If you've ever heard of the philanthropist Fred Kavli and his support of research institutions around the world, his founding idea was that he wanted to support work at the smallest levels, the nano, the largest levels, the cosmological, and what he called the most complex level, neuroscience and consciousness. Does that sound right to you? How do we quantify complexity as it relates to neurobiology?

VAN ESSEN: Well, first of all, I am indeed an admirer of Kavli and appreciate his wisdom and foresight in identifying cutting-edge fields and including neuroscience in that orbit, and for providing extremely important support to the field that buttresses what the NIH and other federal agencies have been able to provide and what many private foundations have also contributed. But could you restate the question?

ZIERLER: Kavli's assertion is that neuroscience is the most complex study that humans can undertake. Do you agree with that? And how would we even quantify complexity?

VAN ESSEN: I certainly agree that neuroscience is among the very most complex domains. But when you ask how we quantify it, I'd say the enormous richness of many types of information at many scales, from the nanometer and atomic scale up through the whole brain scale, they all need to be analyzed, interpreted, and integrated in a coherent, cohesive way that the field is still struggling to achieve. I think we have hints and ideas of how to go about it. However, I take issue with those who say we can synthesize and computationally emulate a whole brain in the way that, for instance, the European Human Brain Project has aspired to do. I think such efforts have led to significant progress but are far from reaching a satisfying endpoint. The reality is, the complexity of the brain still far exceeds what we can integrate with our tools and data at hand.

ZIERLER: What would be the expansion or the improvement of those tools that would better wrangle such complexity? What would that look like?

VAN ESSEN: The honest answer is, I don't really know, but I can speculate and have fun doing so. I'd say the emergence of artificial intelligence is an example of something that already is having a very large impact on neuroscience. Stepping back to the early days, when I was at Harvard, I was mindful that there were folks over at MIT who were championing an early approach to artificial intelligence by trying to make brainlike algorithms and models that captured what the brain does, and to apply that to the world of artificial intelligence. In its early decades it was in my opinion only modestly succssful. In the early 1980's, I became more enamored of this approach through reading the work of David Marr, who wrote eloquently on some of these issues. I became convinced that a robust computational approach would become extremely important for neuroscience.

What I didn't see coming (nor did many others) was the truly transformational impact of AI in the past few years. It has broken through and successfully tackled problems that are beyond what individual humans can do just with their own brains. In the field of neuroscience, an increasing amount of what's called deep learning is impacting the field. Some might dispute whether this qualifies as artificial intelligence, but in my view, it's intimately related and fits under the broad rubric of what machines can do to analyze extremely rich datasets and infer complex relationships, such as the identification of diverse cell types that I mentioned from gene expression studies. That illustrates one of many ways in which computational approaches and artificial intelligence-type approaches are helping synthesize more powerful approaches to studying the brain.

ZIERLER: Let me continue with another speculative question because it's so interesting. Where do you put consciousness, the study and understanding of it, within the overall framework of what AI and deep learning can do? In other words, does consciousness become scientifically more tractable with these new tools?

VAN ESSEN: Yes, at least to some degree. I've had many interactions over the years with Christof Koch, who's one of the champions of studying consciousness. As an aside, and to go back in history, I remember helping recruit Christof to Caltech back in the 80s and enjoyed interacting with him over the years and watching him emerge as a leader in this effort to study consciousness. But I don't pretend to be an expert myself or to follow the consciousness field all that closely. I see it as posing profoundly important questions, but in my view, the field is not far enough along to have dramatic success in modeling, let alone explaining or understanding consciousness. I'm not against that kind of effort, but my own instincts are that it may take decades more of building the infrastructure before we can attain a deeper understanding of consciousness. But that's just sheer speculation. It's really hard to predict when major discoveries are going to occur.

ZIERLER: Let me ask some overall questions about your research career. Let's start with subjects. Your study of humans and non-human primates, do you look at that as two different research agendas, or is it all integrated? Is it all one unified study of brains?

VAN ESSEN: I see them as highly integrated. I see myself first and foremost as doing cortical cartography. I make maps of the brain, with a particular focus on the highly convoluted cerebral cortex. And we make these cortical maps for humans, nonhuman primates, and even for mice and other species. And we use that as a framework for understanding the organization, function, connectivity, development, and evolution of each of these species, and I try to tackle these issues in as integrated a way as possible.

ZIERLER: How far back does the notion of cartography as it applies to neuroscience go? What's the history of that?

VAN ESSEN: I'd say the deep history, in my view, goes back to the classical anatomist Korbinian Brodmann and other great neuroanatomists early in the 20th century. They studied the structure of the brain and made maps of those structures, but those early maps were rather crude. The classic Brodmann map was just a drawing of what cortical areas you could see on the outside of the highly convoluted cerebral cortex, leaving fully two-thirds of the cortex buried in deep folds and hidden from view. His map thus illustrated the utility of having a map, but also the profound limitations of having maps that failed to respect the fundamental organization of the cortex, namely, that it's a two-dimensional sheet of tissue that's very thin, has a large surface area, and necessarily must be crumpled up to fit inside the skull. But unless and until one can represent cortex as a two-dimensional sheet and folded or unfolded as one chooses, then the tools are inadequate. When I began working on monkey visual cortex, working with Semir Zeki in England in 1974, that glaring challenge became an obsession of mine. I could see the need to make two-dimensional maps of the cortex, but the tools were simply not there. I invented a pencil and tracing paper method of mapping the cortical sheet. That key to our progress in those early days and set the direction of my Caltech research program for the next two decades.

ZIERLER: What is the advantage of a cartographic approach? What kinds of questions can you best pursue?

VAN ESSEN: I see it as fundamental to understanding the organization of the cerebral cortex. It may help to turn the tables using the following analogy. Suppose that humans who want to study the Earth, navigate the Earth's surface, and identify the political and geographic subdivisions of our planet, were suddenly not allowed to make or use physical or digital maps of the Earth's surface. Our ability to navigate in the modern world is utterly dependent on exquisitely detailed and accurate computerized maps of the Earth's surface at many levels of spatial resolution. My broad assertion is that our ability to navigate, understand, and interpret how the cerebral cortex is organized and how it works is likewise highly dependent on having accurate maps of the cortical sheet. However, the challenge is compounded by the fact that your cortex is crumpled and folded in a very different way than mine. Every individual has a unique pattern of cortical folds, so we can't simply say that one configuration fits all. We have to work extremely hard and carefully to align or register one human cortical sheet to another in order to make accurate comparisons of what's similar and what's different across individuals.

ZIERLER: What about development, studying the brain at various stages of life? What are the advantages of not only using a particular snapshot in time?

VAN ESSEN: Studying brain development broadly and cerebral cortical development in particular is indeed extremely important! Profound changes occur both prenatally and postnatally as the cortex starts from a very small and smooth sheet that expands and differentiates into a mosaic of many areas having extremely complex connections that depend heavily on experience. The cortex is also extremely vulnerable to trauma or aberrant formation of circuits, either from genetic disorders or from experiences in early childhood that impact brain development and lead to myriad disorders that impact a substantial percentage of children and adults. Understanding how the cortex develops, what sensitivities it has to the experiences or traumatic influences in life - these are extremely important issues, not just for scientific curiosity, but for human society to deal with.

ZIERLER: You look at the evolution of a cortex within an individual specimen. What about evolution across millennia, across millions of years? Do you look at evolution in that context as well?

VAN ESSEN: Absolutely. Comparisons between humans and nonhuman primates entails looking at different species that have had separate evolutionary pathways for about many millions of years. What is striking about the human cortex is that it has expanded dramatically relative to even our closest living relatives, the chimpanzees and orangutans. Our cortex is three times larger in surface area than a great ape, and it's 10 times larger than the macaque monkey, which is the most intensively studied nonhuman primate. But that expansion is not uniform. Our primary visual cortex is only twice as large as a chimpanzee's or monkey's because the eyes provide very similar inputs, and we need comparable amounts of cortex devoted to analyzing vision. In contrast, cortical regions involved in language and in higher cognitive functions greatly expanded in humans relative to all nonhuman primates. Understanding precisely where those regions of expansion have occurred across millennia of evolution and what it signifies for the function of those cognitive and specialized areas is a domain of intense interest for me and for many others.

ZIERLER: What do these physiological, anatomical differences tell us more broadly about how, or when, or why Homo sapiens diverged from other primates?

VAN ESSEN: Again, it's a domain of intense interest where we don't currently have clear-cut answers to many key questions. Returning again to the molecular and gene expression side, there are aspects of gene expression that are unique to humans and may contribute to the selective expansion of these higher cognitive regions, and much more will be learned on that front in the coming years. But we also need to understand from functional imaging, FMRI and other neuroimaging tools which cortial areas are unique to humans, and what is their evolutionary linearge? What are the neural circuits in these higher cognitive regions that evolved from what was present in our common ancestors but is more powerful and flexible in our brains compared to apes and monkey. In my view, we are still in relaatively early days of attaining deep insights, but many issues are tractable using the techniques that are currently at hand.

ZIERLER: Is there any aspect of your work that is explicitly translational? In other words, is a starting point for a research project for you and your colleagues sometimes a disability or a disease, and then you reverse-engineer the research to address that? Or is it always basic science, and then by happenstance, you might find something that could be relevant for therapies?

VAN ESSEN: In my own situation, it's been more of the latter. For example, in the early 2000s, for example, we initiated a collaboration to study folding patterns in children with Williams syndrome, which is a developmental disorder characterized not just by behavioral deficits, but by a mixture of some deficits and some unusually strong attributes such as unusually expressive language spoken by children with Williams syndrome children. And we found differences in how the cortex is folded. That is relevant to understanding a disease, but it did not lead to, for example, altered treatment for those kids. A different and more recent example involves my leadership of the Human Connectome Project from 2000 to 2016. My extremely talented MD/PhD student, Matt Glasser, and I spearheaded the effort to make better maps of the cerebral cortex, essentially in the same spirit as Brodmann from more than a century ago, but using neuroimaging techniques that yielded a map of 180 cortical areas in each hemisphere. That study was based on healthy young adults, but a subsequent set of projects used what we call the ‘HCP-style' approach to studying neural function and circuitry in a variety of brain disorders.

If we fast forward to the current state of affairs, Matt has been intimately involved in a collaboration with neurosurgeons who have planted recording electrodes into small regions of the brain in patients with ALS. These patients unable to move and unable to speak, so they have effectively been locked inside their brain with very limited communication abilities. By putting these electrodes into precisely defined regions based on the cortical maps that Matt and I identified and our ability to identify those areas in each individual, we were able to help guide the positioning of those electrodes in such a way that they're spectacularly successful in allowing these ALS patients to think what they want to say and let the signals from their brain be fed into customized interpretive software to generate speech in real time. It's transformative for those individuals and benefits from the basic science tools that Matt, and I, and the whole Human Connectome Project team had put together.

ZIERLER: This has been a wonderful overview of your research and the history of the field. Let's go back now and establish some personal narrative. Let's start with your parents. Tell me about them and where they're from.

VAN ESSEN: My parents, Dorothy and Roman Van Essen, were born in the US but from Dutch and Scottish immigrant lineage a couple generations before. They met and married in Southern California. I was born in Glendale and spent my early years, in Tujunga, California. Then, my father got a job as a radio technician repairing radio communications for the Highway Patrol and Forestry Department. That brought us to Fresno in the central valley of California where I spent my grade school years. We then moved a bit south to Visalia, where my father got a promotion to a higher position. While in junior high and high school in Visalia, I became utterly fascinated by science.

ZIERLER: What captivated you then?

VAN ESSEN: Rockets. Back in the early 50s, even before Sputnik, rockets intrigued me. At that time, I actually designed a rocket that was intended to transport me and my family, including my grandparents, to the moon and back, so I had that ‘vision thing'. But I glaringly lacked the appreciation of fundamentals of rocket propulsion and fuel, logistics. It was very much a fun experience, but not connected with the reality of rocket design But it was imprinted on my early memories of what I wanted to aspire for.

ZIERLER: Was rocketry something that put Caltech on your radar as an undergraduate?

VAN ESSEN: I think I soon expanded my horizons and was fascinated by science altogether, but especially by physics. I remember when I started thinking about college–let me step back. The other thing I was fascinated by was mathematics. I remember taking a summer school course in mathematics at Berkeley, and it was a great experience. I learned a lot. But something I also learned was that my brain is wired to enjoy and appreciate mathematics, but not to have the deep command of really high-level mathematics that would make it sensible to aim for a career as a mathematician. That moved me in the direction of physics, which drove my enthusiasm for applying to, and fortunately, getting in to Caltech. But in my freshman year, when I took the physics course, I did well in it in terms of getting A's in the course, but I again realized that my brain was not powered to take me to the frontiers of theoretical physics. I shifted gears and said, "Maybe chemistry is a better fit for me." And I quite possibly would have remained a chemist, but the spring of my freshman year, I had arranged for a summer project working in the lab of Carl Niemann, a chemist who, unfortunately, died of a heart attack that spring. That left me briefly in the lurch until a biochemist, Jerry Vinograd, at Caltech offered to let me work in his lab for the summer. And that shifted my focus more towards biology. However, the solid background in the fundamentals of physics, chemistry, and mathematics provided in the first two years of the Caltech curriculum proved vital to many aspects of my future intellectual development as a neuroscientist.

ZIERLER: What was Vinograd working on at that point?

VAN ESSEN: DNA in bacteria, trying to understand the biophysics and biochemistry of DNA replication. I enjoyed that, but again, I wasn't really grabbed by it. The second summer after my sophomore year, I was again working in Vinograd's lab. One day I wandered into the Caltech book store and picked up a book called Machinery of the Brain by Dean Wooldridge, who was one of the trustees of Caltech. I devoured that book and was utterly fascinated and essentially, from that point onward, was committed to becoming a neuroscientist.

ZIERLER: What was the message of the book? What was so interesting to you?

VAN ESSEN: That one could explore and make sense, to an interesting degree, how the brain works. He, for example, had an extended section there on the pioneering work of Hubel and Wiesel, who I mentioned earlier in our conversation were leaders in introducing the modern era of systems neuroscience using physiology and anatomy to make sense of how a visual cortex works, at least in an early approach to that.

ZIERLER: Was there anybody at Caltech in the mid-1960s who would've called themselves a neuroscientist? Was that a term of art back then?

VAN ESSEN: I think neurobiology was the more commonly used term. When the Society for Neuroscience was founded in 1969, I don't know whether there was debate about it, but that choice of term, I believe locked in neuroscience as the dominant term for pointing to studies of the brain.

ZIERLER: Perhaps it was also an assertion that, "This is real science that we're doing."

VAN ESSEN: Yeah. But Caltech, for sure, had made major investments in neuroscience well before that time. The Biology Department had recruited Roger Sperry many years before, and he was obviously a pioneering neuroscientist, and several other neuroscientists as well. And I remember, while I was an undergraduate, they recruited Seymour Benzer as a geneticist studying the brain of the fruit fly, Drosophila, expanding on a rich tradition of Drosophila genetics. Soon after I graduated, Caltech made a further commitment to neuroscience and got support from Arnold Beckman to establish the Beckman Labs for Behavioral Biology that turned out to be crucial for my subsequent recruitment to the Caltech faculty.

ZIERLER: Did you interact with Benzer or Sperry? Did you try to work with them?

VAN ESSEN: I took a great course in neurobiology taught by Felix Strumwasser, and I subsequently did a small research project in his lab. I remember meeting Seynour Benzer to ask about opportunities for graduate school in neuroscience because there weren't many neuroscience graduate programs. And basically, his bottom-line recommendation was that I should check out the new Department of Neurobiology at Harvard that had just been established, as I told you earlier in our conversation, where Steve Kuffler was chair. That was very influential. I took a psychobiology course from Sperry, and it was fascinating, but I have to admit, he was not the greatest or most inspiring lecturer. I learned something, but not as much as I might have under better didactic conditions.

ZIERLER: In the chemistry department, who were the mentors? Who were the most important professors for you?

VAN ESSEN: Norman Davidson was my advisor, and gave me sound advice, and encouraged me in my work in Jerry Vinograd's lab. And later, after I was on the Caltech faculty, I had many interactions with Norman that were very influential in a positive way as well.

ZIERLER: What was Davidson like?

VAN ESSEN: He was an avid tennis player, anecdotally. He was very intense, very thoughtful. He gave good, honest advice and was somewhat intimidating to me.

ZIERLER: Had he become interested in biology himself at that point?

VAN ESSEN: Yes, he had. He and Jerry Vinograd were among the chemists who were enthusiastic about building bridges with biology, definitely.

ZIERLER: When you graduated, was the draft for the Vietnam War something that you had to contend with?

VAN ESSEN: Yes, indeed. [Laugh] To make an extended version of that, my parents were very conservative, and I was basically of a Goldwater Republican mindset when I was at Caltech. When I went to Harvard, I, by good fortune, got into a situation living in an apartment with four other graduate students. As one would expect back in the late 60s, political discussions were pretty intense. And my mindset shifted strongly towards a much more liberal perspective. I remember campaigning for Gene McCarthy up in New Hampshire for the 1968 presidential campaign. Then, through fortunate developments, I met Isabel in August of 1968, and we were married less than a year later. In the fall of 1969, we were living in an apartment in Boston, and I got a call late one evening from a high school friend saying, "Hi, David, how are you doing?" I said, "OK." And he said, "Hey, isn't your birthday September 14?" I said, "Yes, what about it?" He said, "I just saw that that was number one on the draft lottery." I was, indeed, number one, and my student deferment was canceled. I was called to the draft board, and I actually passed my physical! I was on the cusp of either going into the Army just for two-year regular service, which could quite possibly have taken me directly to Vietnam or not far from there. The alternative of volunteering and getting a three-year hitch, but lower risk of being in the infantry on the firing line, as it were, was another option.

Another option was going to Canada or somehow just reducing that risk by overt action. I was torn among those alternatives, and I don't know which one I might have chosen. Then fate intervened when one weekend, Isabeland I drove to her brother's in Rhode Island and played touch football with her beefy brothers. We went swimming in a swimming hole after that, and I remember feeling my groin as I was in the swimming hole and feeling an outpocketing that immediately reminded me that many years earlier, I had a hernia operation, and that touch football experience had essentially given me a fresh hernia. And I went from, "Oh, no, here's another injury that has befallen me in these challenging times," to a lightbulb moment of, "Hey, I've got a hernia, and I can't be forced to have it operated on." I basically got a medical deferment and kept my hernia until I was past draft age and was extremely fortunate for that situation, especially since the hernia was not debilitating. I could still play tennis and go hiking, I just couldn't carry groceries up to our fourth-floor apartment.

ZIERLER: That's a lucky hernia indeed right there.

VAN ESSEN: The way good fortune can sometimes strike in the most unexpected of ways.

ZIERLER: The new program at Harvard, as you explained earlier in our conversation, the integrated pathway that it took, did you feel that in real time? Did you feel like you were a part of something that was building from the ground up?

VAN ESSEN: I was indeed aware of that. I was very close with my two graduate student colleagues, Eric Frank and Jim Hudspeth, who also were part of the entering class. We were aware that this was something special. I don't think we were by any means as fully appreciative as I am now in retrospect. But it was definitely a feeling that we were on the cusp of what could be a big thing, and indeed, turned out to be.

ZIERLER: Did the integrated approach extend both from classroom studies and laboratory work?

VAN ESSEN: Yes, in the classroom and also in the seminar room. Harvard became sort of a mecca for neuroscientists around the world to visit and give lectures and seminars. What was, I think, special to the point of unique about those seminars were the intense engagement of the audience in probing not only what was done, but why it was done. Steve Kuffler was a very charming and, I'd say, not an aggressive questioner but a studious and persistent questioner, asking sometimes what seemed silly and naive questions but turned out to expose limitations and weaknesses in what the seminar presenter was trying to say. Between those penetrating questions from the faculty and the fact that Eric, Jim, and I were strongly encouraged to join the questioning, I learned the importance of thinking critically about how science is done rather than just saying, "That was a cool story," and taking a seminar's story at face value. Often, the seminar hour would extend to an hour and a half, and the speaker would still not be halfway through their presentation because of these many questions that were the hallmark of that period, at least as I remember it in retrospect.

ZIERLER: Tell me about developing your thesis project. What did you want to work on?

VAN ESSEN: I arrived at Harvard, thinking that I might want to work in neurochemistry because of my chemistry background. But from work that I'd done in a project at Caltech working in Felix Strumwasser's lab, recording from sensory neurons in crayfish, seeing action potentials on an oscilloscope and hearing neuronal ‘spikes' on an audio monitor, just the thrill of hearing the brain in action was extremely influential in getting my mindset oriented toward single-neuron neurophysiology studies. When I got to Harvard, Eric, Jim, and I started a fun side project of recording from lobster neurons. That and other parts of my experience got me particularly interested in working on the so-called simple systems, invertebrate systems. Fortunately for me, John Nicholls arrived from Yale to join the faculty during my first year. John had been a collaborator with Steve Kuffler earlier.

When I met with John, we hit it off, and I joined his lab. I did my thesis work on single neurons in a leech with the focus on neurophysiology. By good fortune, Ed Kravitz, the neurochemist in the department I had mentioned, had worked with one of his postdocs, Tony Stretton, to develop a fluorescent dye called Procion yellow that could be filled into a micropipette and injected into individual neurons, enabling one to see not only the structure of the neuron but link that structure to the physiology recorded from the same electrode as used to inject the fluorescent dye. This ‘stick and stain' method was part of my thesis research, which was basically to look at sensory neurons and show that activity reduces their sensitivity to touch. Intense activity can also change the way nerve impulses flow into the neuron, by blocking action potentials from spreading to all of the branches of a neuron. This ‘branch point failure' of impulses became a hypothesis of my thesis research that was awarded in 1971.

While I found my thesis research to be fun and interesting, it was not what I considered a groundbreaking discovery. It did motivate me to seek for my postdoctoral research a project that studied structure and function concurrently. That, in turn, pulled me awat from my initial bias towards simple nervous systems such as the leech. Right down the hall from the Nicholls lab was the Hubel and Wiesel lab, where they were doing their spectacularly successful studies of single-neuron physiology in cat visual cortex. That raised the enticing prospect of using the dye injection (stick and stain) method that I had successfully applied in the leech, to test for possible correlations between neuronal structure and function in the visual cortex. Hubel and Wiesel offered me the opportunity to be a postdoc in their lab in collaboration with an anatomist, Jim Kelly, who had come from Washington University in St. Louis (where two decades later I found myself on the faculty). Jim Kelly and I were able to carry out these stick and stain approaches to cat visual cortex and make some interesting discoveries that helped propel our careers forward.

ZIERLER: Let me ask a technical question. You emphasized just before that you wanted to pursue structure and function concurrently. How did the postdoctoral work address that? How could you do that at the same time?

VAN ESSEN: Because we used the same methodology of taking microelectrodes filled with a fluorescent dye, using those microelectrodes to record and characterize the responses to visual stimuli, then injecting the dye into neurons and characterize their morphology - their shape. Basically, the punchline of our story was that Hubel and Wiesel had physiologically identified two functional types in the visual cortex that they called simple cells and complex cells for reasons that are a story unto itself. But for the moment, just accept that there were two physiological cell types. What Jim Kelly and I were able to show was that the cells of one type, the simple cells, had a different morphology than the complex cells to a statistically significant degree. It wasn't a perfect correlation, but it was robust and demonstrated the ability to explore structure and function at the single-cell level in mammalian visual cortex.

ZIERLER: Let me broaden out the question. Thinking about your mentorship, your work with Hubel and Wiesel, what were they trying to build more generally? What was the overall goal of this effort?

VAN ESSEN: They wanted to understand how the visual cortex works and how it was influenced by disruptions of normal visual experience. Most notably, closing one eye (by suturing the eyelids) briefly during an early ‘critical period' of development profoundly changed the wiring of the visual cortex in ways that could explain the lack of vision through that temporarily blinded eye later on in adulthood. In adults, blocking vision through one eye for a year leaves vision perfectly intact. But even a brief period of sensory deprivation at an early stage in the critical period can have a profound sensory deficit. The ability to understand what's called plasticity of brain circuits and brain function, and to probe that in experimental models, was very exciting at the time. Basically, going back to your question, I think their general aspiration was to understand how the visual cortex works and how it is impacted by sensory perturbation and deprivation. For that, they received a Nobel Prize in 1981 - along with Caltech's Roger Sperry.

ZIERLER: Let's now move on to your European sojourn. This has been a decidedly American story up to this point. Was part of your interest seeing what was happening elsewhere in the world in the field?

VAN ESSEN: Yes. In the 1960's and ‘70's it was common for talented young American neuroscientists to spend a couple of postdoctoral years in a top European neuroscience lab before returning to the U.S. I got to know Dale Purves and Mike Dennis, two postdocs in our Harvard department who had taken that route, and they recommended it highly. I became intrigued by the possibility of doing a postdoc in Europe myself. Midway through my two-year postdoctoral training with Hubel and Wiesel, I applied for a and received a Helen Hay Whitney Fellowship, which was basically a three-year fellowship with no strings attached. I decided to spend the first two years working with a Norwegian colleague, Jan Jansen, who had come on sabbatical to the John Nicholls lab wen I was a graduate student there. I got to know Jan personally as well as at a scientific level. And the idea of spending a couple of years in Europe, in Norway in particular, in Jan's lab, was very appealing and indeed, turned out to be highly successful from both a scientific perspective and from the personal experience of living abroad in a country where we could speak English to our scientific colleagues but learn enough Norwegian to get along in that community.

ZIERLER: Scientifically, how did this work broaden your horizons?

VAN ESSEN: It again showed my willingness to adapt opportunistically to scientific situations. Prior to coming to the Nicholls lab, Jan had mainly worked on crayfish as an experimental preparation. He came to the Nicholls lab, learned to work with the leech, and when we talked about what I might do as a postdoctoral fellow if I did go to Norway, to Oslo, we had decided that provisionally, I would work on the crayfish preparation that he had had years of experience with. When I actually arrived there, we had intense discussions for some period and decided to shift our gears and use the leech model for some experiments on sensory re-enervation after crushing of peripheral nerves, and that turned into a moderately interesting story. But the highlight of my Norwegian experience scientifically arose serendipitously when a British colleague, Michael Brown, arranged for a sabbatical in Jan's lab, and he arrived shortly after I did. Michael and Jan decided they focusing on a phenomenon called transient polyneuronal innervation of skeletal muscles previously reported by a lab in Australia.

This project arose essentially ‘out of the blue' as a different kind of question on a different topic than what I was familiar with. Jan and Michael encouraged me to partake in daily discussions about their project. It turned out to quickly become sufficiently exciting that they invited me to join in their experiments so as to maximize progress during the limited time Michael was on sabbatical and I was there as a postdoc. We published one lengthy paper that was highly influential, showing that skeletal muscles at birth have many synapses per muscle fiber, but this is reduced to a single synapse per fiber in the adult.

ZIERLER: Which tells you what? Why is that so significant?

VAN ESSEN: We still do not know why this so-called multiple innervation occurs at the neuromuscular junction. But it's now clear that excess connectivity is widespread in the central nervous system and is a major aspect of what is called ‘neural plasticity'. However the phenomenon remains most accessible in the simpler neuromuscular situation. So, it's essentially a way to use the most powerful tools available to study synapse elimination as a phenomenon in a part of the nervous system where we can actually dig down and better characterize what's occurring and how it occurs, and use that by inference to help better understand plasticity throughout the nervous system. I decide to continue line of research when I set up my lab in Caltech. It turned out to be professionally very important in keeping me engaged in thinking about neural development as well as brain function in the visual cortex that was my main focus during the Caltech years.

ZIERLER: Tell me about joining the faculty at Caltech. Had you remained in touch with anyone there throughout graduate school or your postdoctoral work?

VAN ESSEN: I was not in close touch with anyone at Caltech once I left for graduate school. However, word got around about the success of my stick and stain visual cortex project with Jim Kelly. When we started on the job market, Jim and I arranged joint interviews at multiple institutions. I had known that Caltech was continuing its expansion in the neuroscience arena, and I honestly don't remember whether I wrote to the chairman and inquired or whether they had heard by word of mouth that Jim and I were among the crop of neuroscience postdocs looking for jobs. But in any event, I arranged to visit Caltech, where I hadn't been for many years, gave a job talk, and was fortunate enough to receive a job offer. I had to choose between the Caltech offer, an offer at Stanford, where John Nicholls had since moved, and an offer at Harvard, where Hubel and Wiesel were still doing their amazing work. There were obvious attractions to returning to the physical and intellectual ‘orbit' of my postdoc advisors, Hubel and Wiesel, or my graduate advisor, John Nicholls. However, I opted for independence and felt I would, on balance, be better off pursuing my career fully independently. That was one of several factors that made Caltech my preferred choice, and one that I have never regretted.

ZIERLER: Tell me about setting up your lab as a new faculty member. What was most important?

VAN ESSEN: I knew that I wanted to focus my research program primarily on visual cortex in monkeys. However, my fascination with neuromuscular synapse elimination motivated me to ask if I came to Caltech, could I set up a lab with two very different research projects. Bob Sinsheimer, the chair who recruited me, was very agreeable. That was an indicator of his flexibility and willingness to invest in this upstart young neuroscientist who wanted to do two seemingly totally different research thrusts in one lab.

ZIERLER: How did you present the winning case? What do you think was most captivating to Sinsheimer about this proposal?

VAN ESSEN: I don't remember the details. I remember my mindset was that maintaining a broad perspective can be beneficial under some circumstances. I felt that it was a way for me to avoid getting trapped in a narrow intellectual ‘corridor' but instead to keep my horizons as broad as possible. Sinsheimer in essence said, "If that's what you want to do, we'll invest in that and support you." That was great.

ZIERLER: How did that play out, the duality of your lab?

VAN ESSEN: Basically, it was successful because I was able to get NIH funding for my visual system work and NSF funding for my neuromuscular development. The bottom line then, as now, was, if you want to have a sustained research program, you have to get grant support. The ease or difficulty of getting grant support has fluctuated over the years, but I was successful not only in obtaining support, but in making important scientific contributions on those two fronts.

ZIERLER: In both fronts, I wonder if you could walk me through the apparatus of the lab. What were the instruments, what were the research subjects?

VAN ESSEN: In the visual system studies, we set up a neurophysiology recording setup. When I was in the Hubel and Wiesel lab and in Zeki's lab, the way in which visual stimuli were generated in order to study visual function was essentially an entirely manual procedure, having a slide projector mounted on a tripod with a flexible positioning so one could project bars of light at a particular location or sweep it in one direction or another to identify what is called the receptive field, the region out on a visual screen that the monkey's eyes are looking at, find out where on that screen was effective in activating or driving neurons, and what characteristics of the stimulus, what orientation, what color, what stereoscopic depth, and other basic features.

Doing that entirely manually worked well for Hubel and Wiesel, but it was unsatisfactory in that it was fundamentally very non-quantitative. One of our major objectives was to computerize the process so that data could be acquired and analyzed quantitatively. With support from Caltech, I was able to get a computer (a PDP 11/34) that I shared with Jim Hudspeth. It turned out Jim had also gone from Harvard to join the Caltech faculty a year before my arrival. Our labs were adjacent, and sharing a computer turned out to be efficient in terms of common systems management. Our graduate students, John Maunsell in particular from my lab, did the computer programming that brought us into a new world of computerized visual stimulation. That ability was important in getting our lab to be among a new generation of labs that quantified neuronal responses in visual cortex carefully and systematically rather than relying on the qualitative approaches that Hubel and Wiesel had emphasized.

ZIERLER: To clarify, the emphasis on quantitative precision, is that made possible because of computation, because of technological improvements?

VAN ESSEN: It was made possible for me by having computers that could quantify precisely the presentation of visual stimuli, and then to quantify the neuronal responses and link those to the timing as well as the nature of the visual stimuli. That was a critical transition for the field of systems neurophysiology in general, and my lab was by no means the only one. But I'd say we were among the early labs in the mid-1970s to bring this quantitative approach to characterizing neuronal responses in visual cortex.

ZIERLER: Why the emphasis on quantitative analysis? What are the big questions that you can pursue now that you're counting precisely?

VAN ESSEN: That goes back, in a way, to a famous or infamous quote I recall from David Hubel. He said something to the effect of, "If you have to do statistics on neuronal responses to decide what's going on, you're getting trapped in the weeds." He was convinced by listening to neurons and correlating that with his manually controlled visual stimulation that he was quickly and efficiently extracting the essence of what a neuron ‘does'. I was amused when I first heard him articulate that position, which he did repeatedly when I was at Harvard, but I found it unsatisfying and took a different perspective in that I became increasingly convinced that neurons in the visual cortex are actually embedded in a very complex network and are not simply doing one thing or another. To express that in a little bit more colloquial way, the mindset of the Hubel/Wiesel and many other investigators in sensory physiology was that neurons are ‘bar detectors' that detect whether a bar is present and whether it is vertical or horizontal or a particular orientation, and that is its ‘job'. Other neurons are color detectors, and other neurons are motion detectors, but that in general, the working hypothesis was that each neuron does its thing and is responsible for representing or firing, if there's evidence for a particular feature in the visual world. It was in essence a ‘feature detector' hypothesis and mindset. I progressed toward a more complex, multidimensional perspective in which yes, some neurons are very selective for orientation, and that's just about all, but many neurons, arguably most, are essentially multitasking, and they're signaling evidence for motion to the left, but also, what color is it, and what orientation is it, thereby representing many types of information concurrently. I would say the jury is still out, to some extent, but I think my view that the field currently leans towards accepting this multidimensional, multiplexing perspective than the countervailing feature detector perspective. But it's still an ongoing debate in the field, and these are hard problems to really nail down, even with all the powerful techniques that we have at hand.

ZIERLER: Why do you remain convinced that the multidimensional approach is correct?

VAN ESSEN: Mostly, by virtue of seeing, over the years, evidence from our lab and other labs that neurons are indeed encoding many types of information. Indeed, recent studies show that in the primary visual cortex in the mouse, neural activity is influenced by other things than visual stimuli, like whether the mouse is moving, walking or running, or is being influenced by signals that are coming from different modalities than just the visual domain itself. For these and other reasons, my current perspective, and I think a lot of investigators in the field would agree, going back to what I said much earlier, the brain is extraordinarily complex, and even understanding the primary visual cortex completely remains an elusive target. While we know a lot, including many fundamentals, there are mysteries lurking to this day in even the earliest areas of the cerebral cortex.

ZIERLER: Let's branch out a little bit beyond your lab at Caltech. How was neuroscience evolving more generally at Caltech and even around the world during these years?

VAN ESSEN: I'd say the biggest factor in my mind was the emergence of a computational approach. I had touched on aspects of this earlier in talking about Christof Koch and about David Marr. In my own intellectual evolution, I had read Marr's book, which on its own shifted my priorities to a feeling that it was critically important to bring a computational perspective to bear on my own research agenda. I did not know how to do it, I just had a strong intuition that that's what I wanted to include in my evolving approach to studying brain cortical function. Around that time, Murph Goldberger became president of Caltech, and one of his aspirations was to recruit and promote the recruitment of John Hopfield, who Murph had known while they were both at Princeton. Murph thought John Hopfield would be a great attraction to Caltech, so he encouraged the Biology Division to recruit John Hopfield.

Truth be told, the reception among the biology division faculty was lukewarm, and it wasn't successful in its initial efforts. Murph didn't give up, so he basically persuaded the chemistry division to recruit Hopfield, and so Hopfield came to Caltech. Soon after his arrival, I remember arranging to meet with him. I can't remember who initiated it, but we both agreed it would be a great idea for us to talk. And we did have several early conversations, but despite a desire to connect, we were not successful in that early going in saying, "Here's a way we could collaborate or jointly tackle problems with common interests." The spirit was willing, but the intellectual flesh didn't offer immediate opportunities. But it planted a seed that got fertilized in various ways. My own thinking continued to ponder this opportunity. In the meantime, John Hopfield arranged to give a course at Caltech co-taught with Carver Mead from the engineering division, who was building VLSI circuits that were neuromorphic, as the term emerged, were neuronally inspired in their architecture and meant to emulate neural circuitry and neural function. Geoffrey Fox in the physics division also had common interests in thinking about computation with neurobiological and computer hardware perspectives.

They taught a course that sparked campus-wide interest in an interdisciplinary exploration of questions of that broad sort. Shortly thereafter, Christof Koch emerged as someone who had excellent graduate training with Tommy Poggio at MIT and was on the job market. Cristof visited Caltech at a time where there was this campus-wide interest in setting up something interdisciplinary in the realm of neural computation. John Hopfield, Carver Mead, and Geoffrey Fox, with me supporting enthusiastically from the sidelines at the time, helped Caltech to establish what became the Computation and Neural Systems Program with Christof as the first faculty recruit in that arena. In the meantime, in the biology division, we had successfully recruited Jim Bower, who was studying the olfactory system and, it turned out, was also highly enthusiastic about bringing a computational approach to the questions that he was interested in. Thus, in the mid-1980s, the Computation and Neural Systems Program was launched. I became administratively as well as intellectually involved by serving as the option representative for the graduate program. Christof and Jim Bower jointly taught a course, I taught a course on computational vision, and there was widespread interest and enthusiasm in the program. It was one of the more successful interdisciplinary endeavors of those years.

In addition to these efforts in graduate student education, I greatly enjoyed teaching Caltech undergraduates. When I joined the Caltech faculty in 1976, Jim Hudspeth and I agreed to co-teach Biology 150 ("Bi 150"), an introductory neurobiology course and a successor to Felix Strumwasser's Bi 150 course that I had taken in 1966! Jim and I put much effort into preparing lectures and in generating thought-provoking weekly problem sets and exams that challenged the bright and inquisitive Caltech undergrads. For the problem sets and exams, we were greatly aided by talented graduate student teaching assistants, many of whom subsequently became prominent neuroscientists, The regular preparatory sessions with the TA's effectively served as lessons in ‘teaching how to teach' that benefitted students, TA's, and faculty alike.

ZIERLER: As you're narrating it, this is obviously quite an exciting time at Caltech for you personally, for your colleagues. It begs the question, what was so interesting or attractive about moving to Washington University in the early 1990s?

VAN ESSEN: A couple things. One was, on the administrative front, when I first got to Caltech, I envisioned myself having a small lab and keeping my focus solely and intensively on scientific research. As it turned out, I got kind of sucked into putting a moderate amount of my effort into administrative matters. Initially, I was the executive officer for neurobiology in the biology division, and then as I just mentioned, as option representative for the CNS program. I found that, to my surprise, I was sufficiently competent that opportunities continued to arise, and I found they were more positive than I had anticipated, so that's part of the story. There are two other scientific drivers to the transition to WashU. One goes back to the brain mapping effort. Where we left off a fair ways back in our conversation, I had developed, at University College London, a manual pencil-and-tracing-paper method of making cortical flat maps. We continued that as our bread and butter way of linking anatomy to physiology in the monkey visual cortex. While it was fundamental to our research endeavor, it was also frustrating because I knew from the outset that using pencil and tracing paper was crude and inelegant compared to what ought to be possible using computerized efforts at cortical topography.

My commitment to switching from manually presented visual stimuli to computer-controlled stimulus presentation and data acquisition had taken only a couple of years to bring to fruition on the neurophysiology side. On the neuroanatomy side, the effort to computerize the cortical topography effort took much longer than I had anticipated. We worked on that from the late 1970s throughout the 1980s with, I would say, limited success. Enough to whet our appetite, but not enough to actually make the major breakthroughs that we felt were essential. That remained part of my still incomplete or immature scientific agenda at that time. Then, put that on pause for a moment and turn to another thrust. Mark Konishi, one of our very important colleagues at Caltech, had organized a small conference. I guess it was back in the early 1980s. One of the speakers was Marc Raichle from Washington University, who was using positron emission tomography (PET scanning) to demonstrate visual responses in human visual cortex. That was intriguing, but it was still early days on that front. It prompted John Allman and me to jointly propose a collaboration with Marc and his colleague, Peter Fox, to use PET scans to study human visual cortex. (John was my colleague on the second floor immediately below my lab, who studied visual cortex in owl monkeys while I was studying visual cortex in the larger-brain macaque monkeys.) We were successful in launching that collaboration, which established an initial link to WashU, where I visited several times and got to know their approach. However, PET scanning is rather limited in its capabilities for technical reasons and was not an easy tool to apply to exploration of human visual cortex. However, in the early 1990s, magnetic resonance imaging (MRI) emerged as powerful new tool that seemed at the time, and indeed did turn out to be, a complete game changer by enabling computerized mapping of brain structure and function.

With that as a multi-faceted background story, in the fall of 1991 I was contacted by a colleague at WashU in 1991 who asked whether I was potentially interested in exploring an opportunity to become a department chair at WashU. I decided that it was worth a visit, even though I thought it was unlikely that I would want to leave Caltech. When I visited WashU in January of 1992, I became excited by the scientific opportunities, particularly to connect with the excellent human neuroimaging community at WashU, which at the time was not a viable option at Caltech because of various practical limitations. Moreover, I found myself willing to seriously countenance taking on a much heavier administrative burden. I quickly decided that it felt like a great fit. In March of 1992, I made the commitment to close the chapter on the Caltech front, which had been extremely valuable for those 16 years, and to jump into a new phase at WashU. Renovations of my new lab proceeded rapidly, and we moved to St. Louis later that summer.

ZIERLER: You narrated what seems like a duality with opposing sides, that at once you considered your scientific career immature, or at least certainly unfinished, but you had agreed to take on increasing administrative duties. How did you think you were going to square that circle in St. Louis?

VAN ESSEN: Part of it was the assurance from the Dean that department heads at Wash U are expected to continue a vigorous research program, which was supported by conversations with many colleagues. By putting in long hours, as is my longstanding habit, I was able to succeed on both fronts. But it wasn't without challenges, to be sure.

ZIERLER: What were the scientific objectives when you got to Wash U? What did you want to do first?

VAN ESSEN: I wanted to get computerized cortical cartography underway.

ZIERLER: Which requires what? What are the resources involved?

VAN ESSEN: It required getting the computers and programming staff to accelerate that effort and make it happen, and we were able to do that.

ZIERLER: And this is a matter of funding, of technology development? What's required exactly?

VAN ESSEN: It's both. The funding, which initially, Wash U offered a strong startup support so I could get underway, and then as is generally the case, I was able to transition that into NIH funding for the programming effort. But it's also fair to say that I was by no means working in isolation, so efforts in the field in general were developing and sharing the tools needed for a broad multi-institutional approach to computerizing cortical cartography. Colleagues at UCSD, for example, were pioneers as well as colleagues at Harvard and Mass General Hospital. The field as a whole was moving in that direction, and we were able to be a part of that broader international effort.

ZIERLER: What were some of the early signs that you were on a path to success, that this effort was working out?

VAN ESSEN: It took several years, but by 1995 we were able to actually make computerized cortical surfaces and flat maps. We could then say, "Proof of concept. We've done it rather than relying on these manually generated maps." We could actually transition to the computerized maps and publish our results using these new methods. Having said that, there is, has been and continues to be, strong inertia in the field - a reluctance to move from what has worked and been used in the past to take advantage of these newer developments. My first exposure to that mindset was shortly after I arrived at Caltech, I wrote a grant that proposed to analyze visual cortex using my original pencil-and-tracing-paper method for making cortical flat maps. I submitted one version of that to National Science Foundation and a very similar version to the National Eye Institute. From the NSF proposal, I received, six or seven written reviews that had a consistent message. To paraphrase, they effectively said: "This is a promising young investigator who has bright ideas and some good approaches. However, he proposes to use cortical flat maps that are just confusing and represent a step backwards rather than a step forward." The NSF perspective was that I should abandon cortical flat mapping techniques because the reviewers at that time simply didn't get the idea. In contrast, the National Eye Institute provided very positive reviews, and that institute supported my research for many years. The broader message is that the mindset in the field spans quite a range, from those who are willing to support innovation and pushing the envelope to those who are conservative and aim to preserve the status quo. Even to the present day, as computerized flat mapping and surface modeling has become increasingly prevalent and powerful, the majority of current neuroimaging investigators stubbornly resist transitioning to demonstrably superior methods. This is a frustrating reality that I've grappled with for decades. I've done my best to help accelerate this transition, and am cautiously optimistic that the pendulum of progress will move more quickly in the next few years.

ZIERLER: After achieving the proof of concept, what was the science that you could do that might convince people otherwise that this was the right approach?

VAN ESSEN: The best example of that is what we call the HCP-style brain neuroimaging, where HCP stands for the Human Connectome Project. The NIH initiated a competition for the Human Connectome Project back in 2009 in order to promote advances in human neuroimaging of healthy, young adults in as broad and impactful a way as they could. A consortium involving many investigators at WashU, along with Kamil Ugurbil and colleagues at University of Minnesota, Steve Smith and colleagues Oxford University, were successful in getting this $30-million grant. Over the ensuing six years the HCP studied more than 1,200 healthy young adults, developing and using major improvements in the methods for acquiring, analyzing, visualizing, and sharing the data. That's what we mean by the HCP-style neuroimaging paradigm, which we have promoted and which has been highly successful in getting, I would say, broad engagement and buy-in from the field. But to reiterate my earlier point, it's still not the majority approach of the field. There are still all too many investigators who are aware of this opportunity, but for their own various real-world assessments choose to stick with what we consider to be lower-quality data, less easily interpretable, but in the comfort zone of what I think of as the rearguard domain of neuroimaging community.

ZIERLER: The name Human Connectome Project is certainly reminiscent of the Human Genome Project. Is that by coincidence, or is there an obvious connection there?

VAN ESSEN: It's not by coincidence. It reflected the intention of the NIH leadership, not our consortium, who chose that name. Knowing many of the leaders who were making this commitment, I'm pretty sure they wanted to make that analogy or comparison visible. It's a good term in some respects insofar as a key objective has been to learn as much as possible about the human "connectome", which is the precise and extraordinarily complex pattern of connections that make our brains function as they do. However, the term is, I would say, misleading in two major ways. First, the scale of the Human Genome Project was in the billions of dollars, even from the outset, and many billions spent in follow-up endeavors over ensuing decades. And rightfully so. That investment in the Human Genome Project has been exceedingly beneficial. The original Human Connectome Project was two orders of magnitude smaller, $30 million rather than billions. It was followed by many ‘HCP-style' connectome projects, but these in aggregate still pale in comparison to the scale of genome-related funding. Second, the HCP did not aim, and indeed, has not succeeded in revealing the connectivity of the human connectome at the exquisite granularity that has been vital to the success of the genome project.

To expand and clarify that, the Human Genome Project is extremely successful because it can identify every base pair with extraordinary precision for nearly all of the three billion base pairs in the human genome. For example, when I talked about the gene expression profile of individual neurons that I touched upon earlier, that's reliant on the extremely accurate mapping of base pair sequences, whether it's RNA or DNA, in individual neurons. For the connectome project, we would dearly love to have comparable accuracy and fidelity in identifying the connections of every single neuron of the 80 billion or so in each of our brains, and how those are shaped and wired to all the other possible target neurons. We are not remotely close to that because the resolution and sensitivity of human neuroimaging methods, most of them magnetic resonance imaging-based, are far coarser. They're at the level of millimeters rather than microns, and that dramatically impacts the fidelity with which one can estimate connections. Those are sobering reality checks on what we can and can't achieve using current HCP data. But I think part of your starting question was, what do we offer with the HCP-style imaging? It's the ability to map very accurate the identity of individual cortical areas of the hundreds within each individual brain and to get some estimates, but more limited in fidelity, of the connections, that is, the strength of interactions between each of these many different cortical areas.

ZIERLER: Earlier in our discussion, you emphasized that you made a strategic decision in your career as you explained that you wanted to look at structure and function together. The fact that the Human Connectome Project has that duality, that it uses structural and functional methods for imaging, is that directly related to this decision that you made earlier in your career?

VAN ESSEN: I'd say they're definitely related and yes, I have an abiding commitment to learning as much as possible about brain structure and function in conjunction and in a way that's motivated by that awareness from the earliest stages that bringing structure and function together is extremely important for understanding and modeling how the brain works.

ZIERLER: The headwinds that you've just described to me for the HCP, what aspects of that are technical or computational limitations, and where are they limitations of resources, the number of scientists available to work on these questions?

VAN ESSEN: If one looks at the wording of the NIH request for proposals for the HCP, it is strongly aspirational, but understandably somewhat vague in terms of what was actually being requested. I think one can look back and state with confidence that the HCP was indeed highly successful in meeting its core objectives. Nonetheless, it does fall short of what some might have hoped and expected because it didn't acknowledge the serious practical limitations of neuroimaging technology at that time.

ZIERLER: We'll move our story closer to the present. When you stepped down from your position as chair of the Anatomy and Neurobiology Department, was that simply because you wanted to spend more of your time in the lab, to be more engaged purely in science?

VAN ESSEN: That was part of it, for sure, but it is also part of Wash U governance policy, that the department chairs are expected to retire on or before their 70th year. While there have been some exceptions to that, I did not want to be one of those exceptions, and I was more than happy to hand off the department leadership baton to my successor, Azad Bonni.

ZIERLER: With that time, the additional time in the lab, what did you choose to focus on?

VAN ESSEN: Mostly on the neuroimaging and HCP project and successor projects to study aging and development. But also on a pet project of my own, which is understanding cortical development, and in particular, how the cerebral cortex gets its convolutions, what forces drive the folding process, and what the mechanistic basis for that is. This all stems from a project that began serendipitously in the late 1990s. One evening I was sitting in my living room and thinking about how the cortex gets its folds because I had a project done by a postdoc, Tom Coogan, who had used a clever technique to look at the formation of connections between early visual areas, what's called the primary visual area, V1, and its neighboring area, V2, in the macaque monkey. Tom had some prenatal brain samples, and we discovered that the connections between these two areas, V1 and V2, are established right around the time that the cortex gets its folds. The pattern of folding is very strikingly correlated with these cortical areas.

What we call a gyral fold is an outward fold that occurs right along the borders between V1 and V2. I realized that this fold could be explained if, as those connections form between V1 and V2, if there's mechanical tension within axons, tugging away and trying to bring strongly connected regions closer together to reduce their wiring length. If that were to occur, it could account for many aspects of why the cortex folds in the particular ways that it does in each individual. That became the heart of my paper published in Nature in 1997. That story has continued to evolve, but also it has been challenged. In 2010, colleagues at WashU reported that axons are indeed under tension within some regions of white matter but not in the regions proposed to drive cortical folding. I have challenged their interpretation and contend that on careful scrutiny, mechanical tension is highly likely to be important not only in explaining how the cortex gets its convolutions, but also why it's a thin sheet instead of a big blob like many other parts of the brain. Addressing issues of that type has been an increasingly important part of my agenda in recent years.

ZIERLER: In your quest to share data as widely as possible from brain mapping, do you consider neuroinformatics simply a means to facilitate that sharing? Or has neuroinformatics developed into its own scientific field?

VAN ESSEN: Neuroinformatics, as the term is commonly used in the U.S, is the field of managing the acquisition, storage, and sharing of neuroscience-related data. In recent years, neuroinformatics has expanded rapidly for human neuroimaging, but it is by no means restricted to that domain. I've supported and worked hard to move neuroinformatics forward, starting from the Human Brain Project in the US in the 1990s and continuing to the present. It has been, I'd say, another of the uphill battles that I alluded to earlier. For the first two decades (i.e., until ~2010), most neuroscientists had a low opinion of neuroinformatics, finding that its utility was overall quite low. The success of the many HCP-style projects and the need for neuroinformatics tools to access, analyze, and share HCP data has been instrumental for making neuroinformatics ‘come alive' for a growing number of investigators. Despite various challenges that I mentioned, it has been enormously successful in providing the highest-quality, richest publicly accessible neuroimaging-related database that has led to thousands of publications and petabytes worth of data-sharing.

ZIERLER: We'll bring the story right up to the present. What are you currently working on?

VAN ESSEN: Right now, I'm working on more of the above, from modeling cortical development to working with Matt Glasser, my long-time colleague, with whom I share a laboratory, and working to get better maps of the cerebral cortex and other domains, like the cerebellar cortex, and to get better acquisition, analysis, and sharing of these rich and highly informative, but at times vexing, datasets.

ZIERLER: You're still at it, strong as ever.

VAN ESSEN: Still at it, as long as my brain and body will keep me going here.

ZIERLER: For the last part of the talk, I'd like to end with some retrospective questions, and then we'll end looking to the future. First, if the goal is a complete mapping of the human brain, how do you define that? What would an end goal look like, and how might you define, over the course of your career, what the end means based on all of the advances that you and your colleagues have made?

VAN ESSEN: A complete brain connectome would aspire to identify all the neurons in a brain of a particular species, all of their connections, and all of their cell types based on gene expression and other characteristics. It would also include all of the supporting glial cells–they're rich, functionally important entities unto themselves. It should include the small and intensively studied mouse brain, marmoset and macaque monkey brains, and eventually, much of the human brain. Also important are various species within the amazingly diverse range of invertebrates. As an illustration, we already have a complete Drosophila connectome that is extremely accurate and is an extraordinarily rich resource that is allowing exploration of how the fly brain works down to the level of specialized algorithms for navigation and other specific behaviors in highly insightful ways that benefit from the availability of this complete connectome. That's proof of principle that it is possible in some very small-brained species to generate a complete connectome and to make excellent use of it, leading to new, richer discoveries about brain structure and function. As I mentioned a few moments ago, the BRAIN Initiative has a large component directed towards high resolution and quantitative and extensive connectomes of mammalian brains, and there's been significant success in the mouse of a millimeter cubed of brain tissue and revealing insights from that approach that are, in my view, highly encouraging. New technologies are emerging that offer prospects of getting something close to a complete connectome for nonhuman primates, particularly the marmoset monkey, but possibly also the macaque monkey. There are also efforts to apply such approaches to substantial chunks of the human brain, cerebral cortex and subcortical structures. The paths towards dramatic improvements in these connectome domains are, to me, very enticing and appealing. And if support for science continues, it offers a real prospect for ongoing major improvements in the amount, and quality, and scale of anatomical and related data that will advance our understanding dramatically in the decades to come.

ZIERLER: As you just alluded to, it's a political question, of course. There are significant concerns about threats to funding. How concerned are you that the breakthroughs that you're hoping for might be delayed or might even be derailed?

VAN ESSEN: The events of the past year have been traumatic and dramatic but have not been as devastating as many of us, myself included, were fearing a year ago. Basically, congressional support for science appears to have a resilience and robustness that offers prospects of getting past the current danger zones that have transpired from the current administration. And I am, I would say, cautiously but strongly hopeful - optimistic would be overstated - that we will weather this current storm and emerge with a future stronger commitment to investing in science for the benefit of humanity and the public welfare.

ZIERLER: Amen to that. One more question, if I may, looking to the future. For however long you want to or are able to remain active, what do you hope to accomplish personally, and then beyond your timeline, thinking about your students, your postdocs, your younger colleagues, what are you most excited that they will accomplish?

VAN ESSEN: For myself, I aspire to continue pushing the envelope on the neuroscientific frontiers that I described before, from cortical development, folding, and wiring to functional organization and cortical evolution. There's much to be achieved, and I enjoy the process so much that I'll continue putting as much energy into it as I can manage. The occasion of my 80th birthday symposium last fall, that is iconified in the t-shirt I'm currently wearing, caused me to reflect on these kinds of issues at some length. An important part of the story that I didn't insert into earlier parts of our conversation involves a longstanding collaboration with my colleague Charlie Anderson, who is a physicist turned television engineer turned computational neuroscientist, who joined forces with me at Caltech for some years and then moved to WashU with me. Over the years, we developed a perspective on how the brain computes and how the brain is exceptionally well-engineered in ways that are not fully appreciated in mainstream neuroscience as much as I think they deserve. Thinking of the brain as a well-engineered system in ways that are easiest to appreciate in structures like the eyes and ear but are likely to be embedded in the actual wiring of the brain and central nervous system itself, I think, is extremely important. I hope to continue articulating that vision and point of view. I hope that my scientific progeny help carry that perspective forward as much as possible in the years to come.

ZIERLER: David, on that note, this has been a wonderful and quite insightful conversation, and I want to thank you so much for spending this time with me.

VAN ESSEN: Well, thank you for devoting your efforts to this project, which is a noble endeavor on behalf of Caltech.

[End]