Fire Together, Wire Together: Carla Shatz on Scientific Breakthroughs

SWANSON: Neuroscientists are explorers, adventurers, boldly posing big questions and working to discover incredible insights about the least understood organ of the human body: the brain. For 50 years the Society for Neuroscience has celebrated these scientists and physicians and provided venues for them to explore together.

We'll discuss the most significant trailblazing moments in the history of SfN, with some of our current, past, and future leaders. I'm your host, Dr. Larry Swanson, past president of the Society for Neuroscience and professor of biological sciences and psychology at the University of Southern California.

In this episode, we speak with Dr. Carla Shatz, SAPP Family Provostial Professor of Biology and Neurology at Stanford University, as well as past president of the Society for Neuroscience. In addition to being past president, Dr. Shatz is a member of the Gruber Foundation Neuroscience Prize Selection Committee and has served as a member of the Government and Public Affairs Committee, the Ralph W. Gerard Prize Selection Committee, and the Publications Committee.

Taylor Johnson, SfN's multimedia manager, talks with Dr. Shatz about the history and evolution of the annual meeting, including the 25th anniversary meeting of the Society, Dr. Shatz's discovery of the “fire together, wire together” phenomenon, and her hopes for the future of neuroscience research.

Be sure to visit neuronline.sfn.org/listen to subscribe to our podcasts, and to tune into more of our audio content. That's N-E-U-R-O-N-L-I-N-E.org/listen. Without further ado, Taylor, take it away.

JOHNSON: Thank you, Dr. Swanson. Hi, this is Taylor Johnson. With me today is Dr. Carla J. Shatz. She's a professor at the department of neurobiology and biology at Stanford University. Dr. Shatz, welcome.

SHATZ: Thank you.

JOHNSON: Thank you so much for being here. First of all, before we get into the discussion of this episode, which will actually focus on scientific breakthrough and achievement throughout the last 50 years of the Society, I'd also mentioned that we will probably bring up the fact that you were the president of the Society during its 25th anniversary, and sort of pick your brain on that, if that works.

SHATZ: Absolutely. I'll be really happy to talk about that. It was a very, very fun event. It's pretty exciting that we're coming up to the 50th.

JOHNSON: Absolutely. So, before we get into all of that, I was wondering, we'll sort of jump into the scientific breakthrough and achievements and everything, just in general with SfN. However, if you wouldn't mind, could you give us a bit of a primer of your academic training background and your core focus of research, please?

SHATZ: Yeah, sure. Well, first of all, when I became a neuroscientist, in fact neuroscience wasn't really a field. So, my undergraduate degree was in chemistry. When I was thinking about what to do, making career decisions, I think there were only two neurobiology departments in existence, one at UC San Diego, and the other at Harvard Medical School. I was thinking that this was a very exciting area, and a very new area, in fact, that had grown out of the field of physiology.

So, I went to Harvard Medical School. I got my PhD in neurobiology from the department of neurobiology at Harvard Medical School, and actually, I was the first woman to go through the program and get a PhD in that program. Then, after a postdoc with Pasko Rakic, who was at Yale, had moved to Yale University, I became an assistant professor of neurobiology at Stanford Medical School and rose through the ranks and then was recruited, first to UC Berkeley, and then back to Harvard, where I became the first chairwoman of the department of neurobiology at Harvard Medical School.

Then, after about eight years of enjoying that position, I was recruited back to Stanford. Now, I'm not only professor of neurobiology and biology, but I direct something. It's a wonderful Stanford program called Bio-X. I'm happy to talk about that in more detail, but the bottom line is it's a way of catalyzing research on the life sciences and the clinical world, not only from biology and medicine and so on, but also from engineering and computer science and other fields that traditionally were not really participating in these areas of science. It's been a huge blast to be back here at Stanford, doing that.

JOHNSON: Actually, if you don't mind going more into that, how Bio-X came about, that'd very interesting to hear about.

SHATZ: Well, Bio-X is about, was actually formed in about 1998, 1999. It came about at Stanford because two wonderful scientists, one of whom is a biologist and working on actin, and the actin inside a skeleton, and the other a physicist, were collaborating together and were bemoaning the fact that it was too bad there was no more formal program or mechanism to encourage these sorts of cross-disciplinary collaborations.

And so, when I came back to Stanford to run the Bio-X program, I realized that this was a huge opportunity to create resources and new knowledge at the intersection of many of these disciplines. And of course, now you know, Stanford has been doing this for a long time, and I think it's become an extremely exciting area for many universities, to do this kind of interdisciplinary collaborative work.

It really feeds right into the entire BRAIN Initiative, President Obama's BRAIN Initiative, in the concept that the first few years of the BRAIN Initiative also really focused on technology building and efforts to encourage our engineering colleagues and our applied physics colleagues and chemists to come into the field of neuroscience.

Bio-X is much bigger than just neuroscience. It includes all areas of biological and clinical research beyond neuroscience, but in fact I think it really, this Bio-X program really influenced this kind of interdisciplinary approach, writ largely, not just about neuroscience, but we've all benefited from it.

JOHNSON: That's amazing. So, it sounds like that Bio-X was really servicing a need that may not necessarily have been serviced prior to this. I mean, was this a breakthrough in its own right, or were there any antecedents to it, or…?

SHATZ: Well, I think, I mean, if you ask any neuroscientist, she will tell you that neuroscience is fundamentally an interdisciplinary field. In fact, it really grew up out of electronics and engineering during the Second World War, and physiology. So it's really, studying the brain has always required a bigger skillset than just the biology skillset. Then of course, with the advent of molecular biology and genetics and the human genome, that's exploded even further.

The idea of these interdisciplinary approaches to science is not necessarily a new idea. I think the problem and the issue has always been, How do you support and really facilitate these sorts of collaborations? I think we've all sat around with our colleagues, discussing how, "Wouldn't it be great if you could, you know, build such-and-such a device and then use it to record from neurons in the brain?" The issue has really always been that there's been no funding for it.

I mean, it sort of sounds obvious perhaps, but one of the major ideas about Bio-X was to create resources at Stanford that would actually be competitive, so competitive grant resources, that would fund faculty and students to work and train on the intersection of disciplines. And so, the whole idea for Bio-X is, and has always been, to fund really early-stage, high-risk, interdisciplinary experimental research. It could be in any area.

So, really, part of the breakthrough, if you want to call it that, was figuring out a way to actually let this happen, by funding projects and by funding them at enough level that they could succeed. So, not giving them $10,000 projects, but maybe more like $100,000 or $200,000 for a few years, so that you could really make progress. And that, I think, really has influenced the way many grants now are given at the NIH, the idea that these interdisciplinary grants are now being funded.

These have been extremely successful for Stanford students and Stanford faculty, and I like to think that it has really influenced other fields and other approaches. Certainly, there have been many Stanford faculty who've contributed in major ways to the Obama BRAIN Initiative, including Bill Newsome, a colleague here at Stanford who co-chaired the initiative with Cori Bargmann and people like Karl Deisseroth and Mark Schnitzer, who were on the planning committee as well. I think they were quite influenced by how Bio-X has worked, and certainly it's affected my own research projects.

JOHNSON: I was going to ask you about how it has affected your own research projects.

SHATZ: Well, I mean, there are several ways. First of all, my lab is interested in trying to understand, at the cell/molecular level, how circuits change with learning during developmental critical periods. Just to make a little joke about that, I mean, I would like to really understand why it is that kids can learn a language, or two, three, four languages, so effortlessly, while it's so hard for me to learn French as an adult, without an accent.

So, this is a great example of a developmental critical period, that is, a time during which an experience, in this case a sensory experience of learning another language like French, and then the production, the motor part of it, producing the language, can be done effortlessly, whereas it's harder to in adulthood. So, it's not that you can't learn in adulthood, but it's not as easy to actually produce a perfect accent.

And so, I've always had this little dream that it would be nice to have a pill that I could take, as an adult, so that I could then learn French without an accent. But it turns out that, in fact, even though it's kind of silly, it turns out that my lab and other labs have learned enough about these mechanisms of these developmental critical periods to be able to make genetic, or even pill-like, manipulations. In other words, by infusing recombinant proteins into the brain of mice, we actually can reopen the critical period in the adult mouse brain.

That gave us, my lab, the idea that maybe we might be able to use that approach of generating juvenile-like plasticity in the adult brain to do things like maybe treat a stroke or Alzheimer's disease. One of the marvelous things about Bio-X and this collaborative environment at Stanford is that we embarked on two, and now even three, different collaborations that were funded at a very early stage. That has allowed us to really explore the fundamental knowledge we learned from studying the developing brain, in the context of Alzheimer's disease, for example.

And, for example, we were able to collaborate with a combination of immunologists and people who are expert in Alzheimer's disease, and my own lab, to work on a mouse model of Alzheimer's that — it turned out we could protect from getting memory loss by manipulating the very genes that we were studying — that are important in juvenile brain plasticity. And we couldn't have done this, and we certainly couldn't have gotten any more follow-on funding, without this very early-stage, high-risk funding that we got from the Bio-X program, for example.

So, in that sense, it's really been wonderful, just for my own research experience, and also for my graduate students and postdoc training experience, because we've gotten more sophisticated. I wouldn't say we still really know a lot about immunology, but we're learning much more about immunology, because that turns out to be relevant to some of the themes that we're exploring now in the lab.

So, this kind of interdisciplinary approach has not only let us maybe move things a little bit toward translational neuroscience, but also to make additional fundamental discoveries.

JOHNSON: Wow. Well, it sounds like we could almost use a Bio-X pill, to—

SHATZ: That pill, I'll tell you, that pill is really pretty easy. That pill, you don't even have to do any genetic engineering, but it involves getting money.

JOHNSON: Right, right, the true pill. Right?

SHATZ: The true pill. Or, we could call it the bitter pill.

JOHNSON: The bitter pill. Well, if we step back a little bit, and just take a look at scientific breakthroughs, in a neuroscience sense, the Society has been around — I mean, it seems like you've already talked about how interdisciplinary actions have taken root over the recent years. How has it changed over the past 50 years, in other ways? Or, what kind of different progressions or developments or waves have you seen during that time?

SHATZ: Well, the fundamental fact of the field of neuroscience is just so amazing because, if you think about it, 50 years ago there wasn't really a field. That's what's really amazing. I mean, you could not major in neuroscience as an undergraduate at a university. There was no such thing. I think very few fields right now have the privilege of being able to say that the field has grown from nothing to its existence today, over the last 50 years.

I think this is something huge to celebrate, and I hope we go crazy and celebrate it at the 50th meeting, because the concept, I think, is a very important concept. The field was really born 50 years ago, and germinated, and then has exploded. And I think, in a way, if you look into the future, it will be the field of the future, if it isn't already, because I think long after... I'm really being hopeful now, but long after we'll have cured horrible diseases like cancer or AIDS, I think we're still going to be working on the brain, and trying to understand the brain in both health and disease.

But to go back 50 years, really the field was physiology. I mean, you only have to... I don't even know if you can go back 50 years in PubMed. You might have to do a special search for that, but the papers were being published in the Journal of Physiology, the Journal of Neurophysiology, Philosophical Transactions of the Royal Society. I mean, and people were using, really, one major approach, which took advantage of the electrical properties of neurons, and the fact that communication is through action potential activity and synaptic transmission.

If you compare that work and those papers with what we have now, it's just, you can see the explosion in terms of the addition of so many other fields to the field of physiology itself. So, things have been augmented by the fact of the sequencing of the human genome, for example, a major, major accomplishment that really resulted in our being able to have molecular approaches to studying neurons.

If you think about today's understanding of the nervous system, and the extraordinary diversity of neurons and glial cells and microglial cells in the nervous system, and how we still have to know a lot more, but... I mean, nobody, I think, would ever have imagined that there would be a way of not only using that diversity to identify and categorize neurons and other cell types, but also to manipulate them.

With Mario Capecchi's discovery of homologous recombination, and then the implementation of that to make the first knockouts of genes in the nervous system, in order to study neuronal function, so that was about 50 — 40, 50 years ago, and something we not only take for granted nowadays, but nowadays everybody's excited about this next new thing, which is CRISPR engineering technology.

So, it's just like night and day. The arrival of neuroengineering into the field of neuroscience extends the great power of molecular biology even further, permitting the development of ways of recording from hundreds of neurons at the same time, computer science allowing us to monitor the huge data sets that are being generated, imaging technologies and the combination, sort of the wedding of genetic techniques with imaging to permit genetically encoded sensors of neural activity to be placed in neurons, and then practically imaging the whole brain of things like zebra fish. It’s sort of mind-boggling.

JOHNSON: Literally.

SHATZ: And this is something, right. I mean, I feel very lucky. This has happened since, really, I started as a graduate student in 1971. So, you can just imagine how this enormous change has happened in my lifetime, and certainly over the course of the 50 years of the Society for Neuroscience.

JOHNSON: That's the thing. I mean, the Society was there at the beginning, and has kind of grown up with the field of neuroscience, just in general, which is amazing to think about it. I mean, everything that you've said, it's... I do think we take it for granted, but it is amazing to look back and think about all that's happened, and that the Society has been there from the beginning.

And so, I guess, moving more into the Society, at this point. When exactly did you start at the Society? Were you a grad student? At what point in your career did you join the Society?

SHATZ: I think that I attended the second... My first Society for Neuroscience meeting was the second SfN meeting, I believe, in history. I think it was in Saint Louis. You can check the facts on that, but I know it was in Saint Louis, and it was the first time the Society had been to Saint Louis, and I was a graduate student at that time.

That was a really memorable meeting. And again, I think maybe there were 300, maybe 400 people at that meeting, and now there's, what, 30,000? I don't know what it is.

JOHNSON: Even more, yeah.

SHATZ: I don't know what's even being anticipated for this meeting coming up. So, it was a much more intimate meeting. And I'll never forget it because, because it was so intimate, pretty much everyone went to every session. There was a session on neural development and, at the time, there was a big argument in the field. You know, it's interesting because it's still the same questions, but many of them have been...

We understand them better now, but this was a question of, it was sort of the nature versus nurture argument. How much of the connections between the eye and the brain are hardwired, and how much of them can be remodeled? There were two famous neuroscientists who were both giving talks. I won't say who they were, but one guy came up and he gave his talk. Then the next guy stood up and basically couldn't repeat any of the experiments that the first neuroscientist had done.

So, the first guy gets up and he said, "Well, that's just because you're totally incompetent, and you can't do experiments properly." And I'm sitting there, as just a new fresh graduate student thinking, "Oh, my god. This is my field, and this is what I'm going to have to face when I give my first talk." So, it wasn't that bad when I gave my first talk.

But it was a wonderful time, in a way because the field was small, and you could know everything because it was all new, and it was easy to kind of keep pace. Nowadays, even just to do reading and stay apace of things, it's pretty much impossible. You're always missing things, and it doesn't matter what kind of email device you have that tells you about the newest papers or whatever, or your students who always tell you about the new papers. There are just hundreds and hundreds of things to know.

So, I can't imagine what it would be like to have a fresh brain of a graduate student, today, coming into the field with the unbelievable diversity, not only of knowledge, but of choices.

JOHNSON: Right. So, moving from the beginning, sort of your intro into the Society, in 1985 you actually received SfN's Young Investigator Award. Is that correct?

SHATZ: Yeah. I shared that award with Tony Movshon, in fact. Yep, that was a real honor. That was, I guess, the first of... That was a really meaningful national honor, in the first, I think, of a number of really important awards that I received from the Society. It was totally unexpected, and it was just absolutely wonderful.

Tony and I, we both work on the visual system. He was working, and still is, on how computations are done in the visual system, resulting in perception. And I was working on development of the visual system. So, we're both still working on the same thing, and I hope we’ve both made a lot of progress since then.

JOHNSON: Did that award, how did it impact your career going forward, at that point? I guess I'll say this: Within a decade, you were president of the Society for Neuroscience.

SHATZ: Right, right. So that was, right, '94, '95 that I was president. I think it gives you confidence that you're on the right track. I think that's the most important thing that these recognitions can give you, is some confidence that what you're doing is meaningful, and that other people also recognize that meaning. That's really important, especially if you're doing things that aren't particularly conventional or typical, and you're trying to go off the beaten track a little bit.

So, it certainly... That's why I think all of these awards are extremely important. I think, if you don't get them, I think that's so much, that's really, you just have to live without them. I mean, I always feel like, whenever I receive something wonderful, it's like, "Oh, that's so great. I never expected that." You know, you just can't think ahead, but you can look back and be incredibly grateful.

And I think the other thing that it did for me was, it really, it was a recognition, I think, not just to my own work, but that of my students. That's always been true, that you never are anywhere without the great students and postdocs that you have in your lab, and that was certainly true at the time. I had some of the most fantastic students in my lab, to start off my career, and I'm sure that that Young Investigator Award was a recognition of the progress that we all made together, as a team.

JOHNSON: Was the team, around this time, was that the team that worked with you for the “fire together, wire together”?

SHATZ: That was the beginning. Yeah, that was the beginning.

JOHNSON: That was the beginning. Okay.

SHATZ: Yeah, that was the beginning of that team. Exactly.

JOHNSON: Do you mind explaining that period, if you don't mind?

SHATZ: Bottom line is that the “fire together, wire together” little saying came about because, when we started to look at how the retina connects to the thalamus, to the lateral geniculate nucleus of the thalamus, I think people had made the assumption — again, this is the genes versus environment theme. I think people had made the assumption that these connections had to be hardwired all the way, all the way through to the final patterning that gives rise to the eye-specific layers in the lateral geniculate nucleus.

So, the inputs from the right eye and the left eye don't just sort of randomly connect with the LGN neurons, but they're segregated into very beautiful layer patterns. And because they're so reproducible from one animal to another, it was thought they had to be hardwired. What that meant at the time was that there had to be sets of genes not only to get the eye to the visual part of the brain, but also to get the right eye to right eye layers, and the left eye connections to left eye layers.

What's turned out to be the case is that, in fact, this wiring pattern is a combination of strict molecular cues that get the growing connections from the retina to the LGN, followed by a period where neural activity is required to refine and pattern connections. And, that's the “fire-wire” part.

And so, the first sets of experiments we did were simply to look at whether these eye-specific layers were present initially, in development. And, to our surprise, and to many other people's surprise, we found that they were not. In fact, the inputs from the two eyes are mixed, to start out with, and then, only later, sort out into these layering, this right-eye, left-eye layer pattern.

And so we thought, maybe neural activity is needed for that remodeling process. We blocked neural activity during development, and this was really early in development, so it was a hard experiment to do. That's what my first few students and postdocs did. We worked on these experiments together, and we discovered that when we blocked the neural activity, then this layering pattern did not emerge during development.

So, at the time, there were a lot of computational models for how you might make order out of disorder, and how neural activity might create patterns of connectivity, such as the eye-specific layers. One idea was that neighboring cells might fire together. This was based on the Hebbian idea that the repeated firing of pre- and post-synaptic cells would strengthen connections. So, that's what led to my little saying, "Cells that fire together, wire together."

And so we thought, maybe that's what's happening in the connections, as they grow from the retina to LGN. It's not just sufficient that there is neural activity there, but it might be that the activity had to be patterned such that cells in the same eye, that are near each other, would be firing together, and retinal cells between the two eyes might be out of sync. That would give rise to this idea, "Out of sync, lose your link."

We tested that by looking in the retinas for patterns of natural activity that might be present even before vision, because these connections between the eye and the brain all develop before vision, and even before the rods and the cones are present. So, this is when the next wonderful team of students and postdocs came to my lab, including people like Rachel Wong and Marla Feller. When we discovered that there were actually endogenous patterns of activity that were generated spontaneously in the retina well before vision, that, in fact, were like waves of neural activity in which neighboring ganglion cells, the retinal cells, were firing together.

So, that really led to the idea that it's this very highly patterned neighboring correlations of activity that are needed to form these eye-specific layers. So, this is beautiful, because it's sort of a combination of both nature and nurture, in the sense that there is a genetic program that is producing these patterns of neural activity. And then the neural activity itself is needed to drive mechanisms of synaptic plasticity, which strengthen cells that fire together. It strengthens those connections, and break cell set are out of sync, break those connections. So, this would be mechanisms that are like long-term synaptic potentiation, LTP, or like long-term synaptic depression, LTD.

Then, we went on to actually explore those synaptic learning rules in the retinogeniculate connections, and show that they were adequate to explain this Wire/Fire, Out of Sync, Lose Your Link kind of mechanism.

JOHNSON: All of this took place around 1992. Is that correct?

SHATZ: Yeah. Well it was actually, and later, too [inaudible 00:36:26]. I mean, in fact, in many ways a lot of these kinds of experiments, in many ways they're still going on, even now. Because, now in the lab, we're trying to understand how the neural activity that's present in development, how it drives the actual structural remodeling of the connections. Right? Because the activity is strengthening or weakening connections, but then that leads, downstream, to long-term changes in the stability of those connections.

So, some are retained and grow, and others are weakened and removed. Those sorts of activity-dependent mechanisms have led us to search for genes regulated by neural activity, and to discover genes that are important in the removal of synapses, sort of the “out of sync, lose your link” side of the story.

JOHNSON: Right. Essentially, obviously ongoing research, but I guess the term was coined around '92 and—

SHATZ: Oh, yeah. You're right, because, I mean, the term was coined well before '92. It was published. I published a little Scientific American article on early brain development and discussed a lot of these mechanisms in that article, and published the phrase in that article. But actually, I was giving talks well before that in which I was talking about "Cells that fire together, wire together," because we had already...

I'm just trying to think. We had already thought about this issue of how neural activity would be translated into a lasting structural change. And I think actually, just trying to think. I guess we really discovered the retinal waves in a wonderful collaboration with Denis Baylor and Markus Meister in 1991. That really led us... This was Rachel Wong and Markus, who's now a professor at Caltech. Rachel is now a professor and chair of the Cell, I think, and Anatomy Department at the University of Washington, Washington University in Seattle, and Denis Baylor. That was wonderful. We made that discovery in 1991, but we were already talking about the discovery well before that.

JOHNSON: Great. But I mean, I guess all of this is leading up to '95 — '94, '95. So all of this is happening at the same time, and that's when you're president of the Society for Neuroscience, at their 25th anniversary.

SHATZ: Yes.

JOHNSON: I thought maybe we could just quickly touch on your experience at the 25th anniversary, especially considering that now we're basically at the 50th anniversary, and your thoughts about that.

SHATZ: I know. Well, I mean, it's just sort of inconceivable that it could now be 25 more years because, I mean, I don't know, I've had so much fun, it's just been such a wonderful period between that '95 event, '94, '95 service to the Society, and the current day. I mean, it's just been unbelievably exciting, not just in my lab, but to see our field and its evolution in the last 25 years.

I think in the first 25 years, what's sort of amazing to me is that, at that 25th anniversary, first of all, it was kind of like I couldn't conceive that we'd even gotten that far. I mean, 25 years to me, at the time, that was pretty much like my whole career as a neuroscientist. I kind of thought, "Wow, this is amazing, just the last 25 years." But I was also, I just have to say that was wonderful.

It was a meeting, it was in San Diego. And it was a huge celebration. I remember we had speeches, we had remembrances, we had fireworks and champagne looking over the San Diego Harbor. It was really beautiful. And then, one thing I'll never forget was a very funny thing, and that is — I tried, I thought it would be really nice to have the history, the previous 25 years and the founding history of the Society for Neuroscience kind of written up.

I have to say that, when I tried to get a coherent story from some of the first presidents of the Society for Neuroscience, and I'm just trying to think who they were: Ed Evarts and maybe, I think Dr. Perl, and maybe even... I'm just trying to think. You can look them up. But it was pretty funny, because nobody agreed. Nobody quite agreed on who had the idea, and who was the first person, and how it was founded, and everything. There were actually several versions. So, I'm wondering if we'll have a new history available at the 50th.

The other thing I remember is that I was completely terrorized that this wouldn't go off as a good party. It was a tremendous pressure, you know, and I can really sympathize with everyone planning for the upcoming meeting, because, I mean, I don't remember how many. There were probably, maybe 20,000 members at the time, and now there are 40,000, or whatever, attendees, whatever it is. You know? The pressure's on even more. But all I can say is, I'm sure it'll be a great party, just as it was on the 25th.

JOHNSON: Well, I certainly hope so.

SHATZ: Yeah.

JOHNSON: Well, here we are. We are coming to the 50th, and I think we're about to wrap it at this point. But now that we're at the 50th, final thoughts that you might have in terms of what you hope to expect at the party for the 100th anniversary, and your hopes for science research, neuroscience research in general, for the future.

SHATZ: I'd love to make it to the 100th. That would be a breakthrough, anyhow. You know, I think first of all, I think the complexity... The problem of complexity in the nervous system, and circuit complexity, is still a major problem to look forward to solving. I think it's going to keep a lot of people very busy.

My hope is that we will progress beyond solving the problem in the mouse, which is a very popular — and I'm guilty of it as well — animal model. And we'll really develop the tools and the understanding of much more complex brains, including the human brain, and we'll be able to get beyond noninvasive imaging of the human brain at the level of centimeters and millimeters, really down to where we need to be.

My dream would be that by maybe even just, even the next 25 years, we'll be able to image at the level of, functionally image at the level of synapses, which is where we really have to be if we're not only going to be able to diagnose, but also understand human brain function and dysfunction. So, I think this is a big technological challenge. And it's not really enough, in my opinion, to stay with the current level of resolution of these imaging techniques. We have to learn much more about how the brain works at the level of circuits and synapses, and I mean the human brain.

One thing that surprises me, even about my own students, is how amazed they are when they have an opportunity to, with the medical students, dissect a human brain, or even a sheep brain, anything bigger than a mouse. It really provides a context, and it really reminds people of the challenges, going forward.

And the other thing I would say is that, I think we have to... I mean, I would hope that in the next 25 years, some of the devastating disorders of the nervous system, including developmental disorders, and particularly including aging disorders like Alzheimer's and Parkinson's, that we will not only have a treatment, but we will have an understanding of what the causes are, what the root underlying causes are.

My last point is, that in order to do this, I feel that our field and our funding organizations, particularly the NIH, have to re-embrace the concept of funding completely high-risk, potentially high-reward, fundamental science that has no clear translational application at the time it's being done. This is the way major breakthroughs have come in the past.

Part of our understanding of brain circuits, complex brain circuits, came from David Hubel and Torsten Wiesel's exploration of the fundamental workings of the visual system, with no concept of application. And yet, the visual system has become one of the favorite areas in which to explore even disease models, for example, in mice. I'm very worried about the survival of this kind of innovative fundamental research.

And so, I would hope that when we look back in the next 25 years, and certainly in the next 50 years, we will see a major reinvestment in fundamental discovery-based research without a clear application, and we will also see its major payoffs in the application and translational realm.

JOHNSON: Well, yeah. I hope so, too. I really do. Dr. Shatz, thank you so much for all of your wisdom, all of your time, and just all of your stories. This has been really great, and we really appreciate you talking to us.

SHATZ: Well, I just would like to say that it's been a huge privilege and honor to be part of the Society for Neuroscience, as a member, and also to be able to serve our community. It's something I never thought that I would do when I started my career as a college student. It's just been a tremendous privilege, a great privilege for me to be able to participate in what has been an amazing 50-year voyage.

JOHNSON: It really has. Again, thank you so much for talking to us about this, because it really is a time of celebration and appreciation. So thank you.

SHATZ: You're welcome.

SWANSON: Thank you for listening to this episode of The History of the Society for Neuroscience: 50th Anniversary, brought to you by the Society for Neuroscience, the world's largest organization of scientists and physicians devoted to understanding the brain and nervous system.

You can hear the rest of this series on iTunes or SoundCloud or by visiting neuronline.sfn.org/listen. That's N-E-U-R-O-N-L-I-N-E.org/listen. We'd like to know what you want to hear in future podcasts. Please take a moment and check out the episode description for a survey link. Help us make the content you want to hear. Find out how you can join SfN’s nearly 36,000 members from more than 90 countries by visiting www.SfN.org/join.

For more information about the benefits available to SfN members, visit www.SfN.org/membership. This episode of The History of the Society for Neuroscience: 50th Anniversary was written and produced by Jack Lee and Taylor Johnson. Senior producers include Amanda Kimball and Melissa Thompson Ayoub. Music and editing were provided by Human Factor Media. Thank you for tuning in and we'll see you next time.