Dr. R. Douglas Fields

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Interview with Dr. R. Douglas Fields

June 16, 2015

Hank Grasso, Exhibit Curator at the Office of NIH History and Stetten Museum, had this conversation with Dr. R. Douglas Fields in preparation for an exhibit on Santiago Ramón y Cajal, a founder of neuroscience. Fields is chief of the Section on Nervous System Development and Plasticity in the National Institute of Child Health and Human Development (NICHD). His long-standing interest is in nervous system plasticity and in particular the cellular mechanisms by which functional activity in the nervous system affects development and learning. This includes not only synaptic development and function, but also interactions between neurons and glia (non-neuronal brain cells), and regulation of myelin by impulse activity in axons. Before joining the NIH in 1987, Dr. Fields was a postdoctoral fellow at Yale University and Stanford University. He received his B.A. from the University of California, Berkeley, in 1975, an M.A. degree from San Jose State University in 1979, and a Ph.D. degree from the University of California, San Diego in 1985 for research performed jointly in the neuroscience program and Scripps Institution of Oceanography.

GRASSO:  Tres bien.  How did you find your way to neuroscience and to the NIH campus?

FIELDS: So I started as a marine biologist at Moss Landing Marine Lab and at Scripps Institute of Oceanography. I studied sharks and a sensory ability called electroreception, which allows sharks to detect prey by sensing the electric fields around all living animals.  That led me into studying neuroscience and how the brain was involved in detecting these weak signals.  What was interesting about that study was I was presented with a sense that humans don't have, and that was extremely intriguing, to imagine the unimaginable—what does the world look like to a shark, using a sense that we don't have?

That led to studies of synaptic function, physiology, and anatomy, and, really, the studies of synapses became the focus of my career, and, in particular, how synapses are modified through learning to form memories and to rewire the brain according to experience.  That became, really, the focus of my research, throughout my career, and I came here to study the anatomy and physiology of synaptic function.

So I came to the NIH to study synaptic plasticity in the laboratory of Phillip Nelson, and I did that as a postdoc.

GRASSO:  Good, good, good.  What is different about the NIH research community?

FIELDS: What's different about the NIH, and it's so important, is that most scientists are funded through grant research, which involves a committee analyzing the grant proposals, and there's very limited funding for biomedical research. And, so, these proposals are carefully scrutinized, and the money is very carefully guarded and given to the best proposals, that will have the greatest payoff.  But people quickly realize that any time you can convince a committee of 20 people that something is new and exciting, it's probably not that new.  It's probably quite conservative.

If you really have a new idea, it's likely to be perceived as strange, and unlikely to be funded, and the NIH, and Congress, recognize this problem, a fundamental problem in science.  So the best way to resolve that problem was the intramural program at NIH, and here they just took the grant system and turned it upside down.  They selected researchers and gave them the grant funding, allowed them to pursue the research that they thought was important and innovative, and it was important that it be research that probably wouldn't have gotten funded through the regular mechanism of grant funding.  It had to be something that was new, and maybe high-risk.

And then the scientists were then equipped to do this research, and, at the end of 4 years or so, they would have a look at what had been accomplished, and if it was good research, and it was innovative, then the researcher would have another opportunity to have another 4-year cycle.

So this kind of approach is what keeps me here, the ability to do that sort of high-risk, innovative research.  It's not to say that high-risk, innovative research isn't done on the outside the NIH—it certainly is—but you have to jump through a lot of hoops to do it, and the NIH intramural program facilitates that kind of research.  And, as we know, if you've looked at the history of science, all the big breakthroughs and changes in thinking come from somebody seeing the same thing that everybody has looked at for eons, but seeing something different about it, and pursuing their unique ideas about this.

I think that, throughout my career at NIH, almost none of the projects that I carried out here would have been funded through the extramural program.  They were too—they didn't have a track record.  They were too different.  And I'm happy to say that, looking back, they've been the kind of research that I wanted to do at NIH.  It's shown to be important research and different kinds of research that really have set out new directions in my field, and new ways to think about brain function, that I'm sure it wouldn't have been funded in the extramural program.

I think it's important to maintain the kind of research that I was talking about, and, increasingly, that's becoming difficult, and there has been a trend towards adopting more of a prospective review of the research that goes on here, rather than retrospective.  And the more that that sort of system begins to model the outside system, the less we have this unique character of the NIH, and the research will change, and, ultimately, if the intramural program works just like the extramural program, there's no justification for having it.

The second problem is, you know, the Federal Government is an enormous institution with a lot of regulations, complex regulations, bureaucracy—that is to be expected—but also, increasingly, that has become a burden, and to the extent that we, in the intramural program at the NIH, get isolated from our colleagues, in industry and academia, really undermines scientific research.  That's become a concern, the regulations that impede intramural scientists from collaborating with companies, and also just traveling to attend meetings and visit with other scientists is really quite a negative impact, and I hope that we are seeing the worst of it now and that things will improve in the future, because science really depends on interaction, and if we become isolated from our peers, we will not thrive.

GRASSO:  When we talk about the collaboration that's being encouraged in the Porter Building [Building 35] by just the design of the facility, are there some case studies that you can describe that illustrate, within the work that you've been doing, cross-pollination or influences from outside your circle?

FIELDS: Yes. My research here at NIH involves collaboration with many, many institutions, and many scientists.  It's clearly one of the most important aspects of my research program.  It's amazing, at the NIH, you can find an expert here on anything.  You'll often do a PubMed search to learn about some new field, or want a reagent, or understand some new aspect of neuroscience, and find out that the scientist is in the building across the street.  That happens all the time, and I really, really rely on that.  So the collegial nature here is so valuable, and, in my research, there are just too many examples to give, and they allow me to span such a broad expanse of disciplines.  I interact with everyone from theoretical mathematicians, biophysicists, down to molecular biologists, pharmacologists, and then just people in different disciplines, electrophysiologists. 

So, to give you some specific examples, I've been interested in a new form of plasticity in the brain, which involves part of the brain that hasn't been explored.  It's the white-matter regions of the brain.  Half the brain is composed of white matter, and it's been largely ignored.  In the past, all of information processing, learning, and memory has been focused on the synapse.  So, when I became interested in the white-matter region of the brain, we were in uncharted waters, because we didn't really have a firm foundation as to how white matter might be involved in these kinds of things, but it turns out that a biophysicist here, Peter Basser, is an expert on brain imaging, developed new techniques, DTI [diffusion tensor imaging], very important to show us changes in white-matter structure in the brain of human beings.  That was very important, and I could read about that research, and did, but to be able to go over and sit down with Peter and say, "You know, how does this actually work?" and have him explain it to me was so helpful.

Again, too many examples.  Again, studying white-matter plasticity—how does the axon communicate with glial cells—this is uncharted waters here, because all communication in the brain is understood to take place at synapses, and if this communication is going on between axons and glial cells that make insulation, how does that communication take place?  And, so, I studied various mechanisms for this signaling in my lab and came up with a mechanism by which neurotransmitters are released outside of synapses, and this involved some very obscure phenomena that were in the literature, involving axons twitching when they fire action potentials, and changes in light scattering through axons.  This work came out of the pioneering studies in the 1950s, concerning the basic biophysics of how nervous tissue is excitable, and these were physicists, so they studied physical phenomena, and they found all of these mechanical changes, just buried in the literature, basically, because there was no biological function.

But I began to, one day, in my lab, stimulate neurons, and I saw the axon twitch.  That was kind of startling.  But Ichiji Tasaki is here on campus.  He is a very famous neuroscientist who discovered saltatory conduction—that's how nerve impulses work in the first place.  They don't work like you read about in textbooks, like electricity going through copper wire.  It's much more complicated.  Anyway, I walked over and talked to him, and I said, "You know, I stimulated these axons and the axons twitched," and he explained to me, "Yes, I'd seen that 30 years ago and here's how it works," and he wrote all the equations.  It's just wonderful to have that kind of interaction.

Most recently, my research, just in the last few years, has involved collaborations with electrophysiologist Dax Hoffman [at NICHD].  I've done a lot of research that involved neurons, again, involved a study that was kind of outside the box.  It's neurons firing backwards.  Instead of signals coming through the dendrites and impulses going out the axons, sometimes, especially when you're asleep, neurons work backwards, and actual potential starts in the axons, and they come back into the cell body.  And so this is, again, the kind of thing, obscure phenomenon, that we were able to study.  We found this was very important in consolidating memory and in changing synaptic strength. 

But, you know, I collaborated with a colleague who is very good at intracellular recording.  We've collaborated with the NEI, the [National] Eye Institute, in our current research.  It's not published, but we were studying how white matter changes according to electrical activity in the axons, and we began studying the retina, the optic nerve, the visual pathways to the brain, and the visual cortex, all new areas for me.  Again, if I had proposed to do this to a study section for a grant, they would have to say, "Well, you've never done this before," and probably I wouldn't get the money, and they'd be right.  But here, I walked across the street to the NEI, found out they had all the equipment to do the kind of research I needed, all the expertise, and they freely made available all their instruments and freely gave the expertise.  They could be authors on my paper—I invited them to be—but they're happy to just facilitate research.

So, I could go on and on, but, really, that is the most important thing about NIH—and this happens everywhere, in any institution that's highly successful.  It has to be integrative; it has to be collaborative, and that's what the NIH intramural program facilitates.

GRASSO:  Oh, my God, and we have great collections for Dr. Tasaki, and his wedding pictures, because we know his family, so this is going to be perfect.  We'll have a lot of good energy there.

FIELDS: So you have to read my chapter on him, in my book. I have a little vignette of him.

GRASSO:  Good.  You mentioned one “Aha” moment.  Are there any other moments that were surprising and astounding, and an, "Oh, my God" moment, and did you see it in the moment, how important it was, or did something become more significantly after?

FIELDS: Yeah. So, the research that I've really explored in the last few years here is exploring glial cells, part of the brain that's been largely overlooked, and these cells don't communicate with electrical impulses like neurons—the word means glue, glia—and they really weren't studied very widely.  Yet, there are more glia in your brain than neurons.  Eighty-five percent of the cells in your brain are glia.  So my research here allowed me to venture into this really exciting, unexplored frontier of neuroscience, and that's really captivated my interest, and I feel like there's a whole horizon of new science, neuroscience, that we're just on the verge of glimpsing now.

But often it's new techniques that bring you new insights, and that's what really broke open the world of glia, new techniques of calcium imaging.  And here, there were scientists who had developed an ability to monitor changes in ions and cells by introducing fluorescent molecules, much like a glow stick, that you break the glow stick and it will glow, by mixing two chemicals.  Scientists took these similar compounds, that, when they bound with ions, like calcium, would glow, and used these to study neurons, because when a neuron fires, calcium comes in, and they would glow.  And to the surprise of many neuroscientists, when they stimulated the neurons, the glial cells responded.

So this was definitely an “Aha” moment for me.  It was again technology, calcium imaging, but it was also new microscopy technology.  It came from the time in the 1980s where kids were demanding video games, and faster computers, and color graphic cards and things.  And we had anatomists, in the past, who were like museum curators.  You know, they would fix tissue and study it carefully, dead tissue.  But now, these anatomists took their microscopes and grafted it onto video technology—computers, video cameras, all this new technology that developed, really, for games—and this opened a new dimension of microscopy.  It allowed us to study cells while they were alive, because if you could put this dye into brain tissue or cells, and have very sensitive cameras, and hooked to computers, when you stimulated the neurons, you could see these neurons fire.

So I did that as a postdoc here at NIH, again, traveled to Stan Kater's lab, who was one of the pioneers of this technology, in Colorado.  So, Phil Nelson, my mentor at the time, encouraged me to go there and visit, because they were developing this technique.  Very difficult at the time.  The chemistry didn't work very well.  The computers didn't work very well.  Lots of bugs.  But I remember being there, late at night, looking at neurons under a microscope, flipping the switch to stimulate them, and the neurons lit up because they were glowing with this calcium, and it's the first time we'd ever seen that.  We were seeing neurons firing with our own eyes, and we all just started cheering.  An empty hallway at night, running down the hallway, cheering, because it was just so exciting.  Of course, now that's just commonplace.

But I had that same kind of “Aha” moment here because I brought the technology back to the NIH and we began to use it to study neuronal firing to begin to understand how genes are turned on in neurons by their firing.  Because everything coded in our environment is coded in terms of action potential firing, and if the brain is going to change according to our environmental experiences and learning, that means somehow action potentials have to control genes in the neuron.  So that was a big part of my research and still is—how do you control genes in neurons to change nervous system structure and function, and how does this signal get into the nucleus to do that? 

Calcium imaging was very important, but the “Aha” moment was—plenty of people were studying neurons using this technique—but I put on some glial cells, called Schwann cells, onto these axons, and they make electrical insulation, and I wanted to know if electrical activity could somehow signal to the glial cells, these Schwann cells.  Well, there's no precedence for that, no real reason for that, because there's no synapse along an axon.  Nevertheless, we did the experiment and when I again flipped a switch, the neurons glowed because they were firing as I'd seen in Colorado, but then, shortly thereafter, the Schwann cells all along this axon lit up like lights on a Christmas tree.  That meant that those Schwann cells were sensing electrical activity in the axon and that just opened up a flood of questions.  Why were they doing that?  How were they doing that?  If Schwann cells, non-neuronal cells, can sense electrical activity, how do they do that?  What does that mean? 

Well, we know that Schwann cells make the insulation on axons, the insulation makes action potentials go faster, and after a while we began to realize there was a possibility here that a big part of learning in the brain involves not just changing the strength of synapses but changing the speed at which information travels between different relay points in the brain, and the cell most suited to do that would be a cell that makes myelin.  This had been a completely unexplored aspect of information processing.  Of course in transportation systems, this is the most important thing.  How long does it take you to get to your relay point?  If you get to your connecting flight too soon, it doesn't help.  If you get there too late, you have a problem.  If you talk on a telephone with a delayed line, it completely disrupts information transmission. 

Yet this whole concept was missing from the brain.  How do we have the timing established between each of the relay points in the brain, and the brain's network is the most complicated network in the universe?  How does that get established, and if you could change the speed of transmission by changing the insulation on the axons through glial cells, this would be a new form of learning, and this has really been my major focus in the last few years, one of the areas of major focus, and we've found many molecular mechanisms that explain how glial cells, called oligodendrocytes, change the myelination according to activity in the axon, to control the speed of impulse transmission.

Now, I guess that all came from that experiment over in Building 49 with calcium imaging, watching those Schwann cells fire.

GRASSO:  Wow.  If you were looking at the long time line of neuroscience and all of the scientists who have contributed momentous contributions, are there some specific early scientists that you would consider to be progenitors, or folks who were sort of stepping stones on the way to the work that you are doing now?

FIELDS: Do you mean people that were personally helpful to me in my career, or just academic?

GRASSO:  I guess I was hoping both, one to look at the mentors and specific people who guided you, but also to look at, historically, the folks who made some of these studies possible by the work that they did, ages ago, or a while ago.  Most of the work done here at NIH is post-War [World War II], 1950s on, but there is a longer tradition in neuroscience, so I'm trying to figure out how I position each individual scientist's work on that large timeline, but, specifically, also look at within their immediate precursors and influencers and mentors, as well.

FIELDS: Well, my mentors in neuroscience were definitely my Ph.D. advisors, David Lange and Mark Ellisman. David Lange actually, he was my Ph.D. advisor at San Diego, and he went to NIH, and it ended up, by chance, that I followed him here.  He was a mentor.  Mark Ellisman is one of the leading cellular neuroscientists, especially in electron microscopy.  I can see an image and recognize that he took it, that he and his colleague, Tom Deerinck, took it.  It's really beautiful.

My postdoc career was done with Stephen Waxman and Jeff Kocsis.  Both of those were very important to me in integrating electrophysiology and electron microscopy, and studying myelination, which I ended up studying at the end of my career.  But some real giants would be Ted Bullock, Theodore Bullock, and he was at Scripps Institution of Oceanography, where I did my Ph.D., and he was really one of the great scientists of our time.  He just had an encyclopedic mind.  He was a zoologist.  It was just wonderful to go walking with him anywhere, because he could just rattle off information, natural history.  He recorded electrical activity in the brains of almost every animal that you could imagine.  He would travel around the world.  So he was a comparative anatomist, a comparative electrophysiologist, both.

It was the storehouse of information that he had, his approach, his comparative approach, his analytical ability.  He was interested in communicating science to the public, which I think is very important, and he was ahead of his time.  He was studying brain waves, way ahead of the time when we really had the technology to do it right, and I think that's going to become increasingly important in our understanding about how the brain operates.  So he was definitely a strong influence.

Here at NIH, it would be Phil Nelson.  I came to his lab to be a postdoc.  He taught me neuronal cell culture, and he did electrophysiology.  I remember when I was considering postdocs—actually, I was considering faculty positions as well as postdocs—and I had a faculty offer, but I came to the NIH.  I didn't know what it was.  It seems kind of strange.  I was used to an academic background.  But I remember walking into the lab and seeing Phil Nelson at the bench, and that's what impressed me. 

My first memory of him, actually, is you walk into the laboratory, and it was like a London fog, because in those days people smoked, and he was never without a pipe in his mouth.  So I remember seeing him through this fog of smoke and was just impressed that here was the lab chief at the electrophysiology rig doing research.  That's something that I love, and so many people don't have that opportunity as their career goes on; they end up with so many administrative responsibilities and trying to get grant funding, that they don't get to actually do the thing that they're probably the best in the world at, and that is science.

So, I learned a lot from him, and I guess I got from him a stronger interest in activity-dependent plasticity, but particularly how the environment affects development of the brain.  I'm in the Child Health Institute, and childhood is all about developing the brain.  The human brain develops after birth, for the first 20 years of life.  It takes 2 decades to build a human brain, and that's because the environment we're reared in controls how the brain is wired up, and that process is what Phil Nelson was interested in, as an electrophysiologist, and that's what really has become my main interest—that and the techniques I learned from him.  I still have some equipment in my lab from his lab, that I used as a postdoc, and I'm still using many of the methods that I used then, in his lab.

So, I could go on and on, but those are some that come to mind.

GRASSO:  That's great.  If you're thinking about folks 20 years from now, looking back on this moment in neuroscience, what would you say is the most exciting time about this moment?

FIELDS: Well, for me, I think the most exciting thing about neuroscience is that we're finally looking at what I call the other brain. We've studied synaptic plasticity for 100 years, and I love synaptic plasticity.  Let's go back to Cajal.  Cajal has provided us the foundation for our understanding of the cellular basis of nervous system function.  He gave us the idea, which is called the neuron doctrine, that neurons are separate, that they communicate by sending electrical impulses one way through a neuron, across a gulf of separation, which is called the synapse, and that fundamental neuron doctrine has guided us for 100 years.  It's been very important. 

But there's a lot more to brain function than the neuron doctrine.  That's not the end of the whole story.  And I think that even Cajal might have been a little disappointed that we haven't been a little bit more adventurous.  We had our head in the synaptic cleft, so to speak, for 100 years.  It's fascinating but it's a tiny part of the brain.  And this, I think, is very exciting.

So, looking into the future, I think because of new techniques—molecular biology, imaging techniques that are different from the past, the way we studied brain function in the past with electrodes, etc., which we still do—we now have methods that are giving us a global picture of the brain and this is going to change the way we think about brain function, approach it, and suggest new questions.  So I think that's very important, in the future.

I think always new techniques, but also looking for thinking outside the box, trying to explore the unknown.  That's really the exciting part of science, and the important part of science, and it can be very exciting, but I think that's important.  It's important for young scientists to follow their hunches and to, again, see the same thing that everyone else is seeing, but think something different, and explore that possibility.

GRASSO:  What a sound bite.  Excellent.  What have I neglected to ask here?  Is there something that you would like to share that hasn't fit into any of this?

FIELDS: Okay. The other thing I would say that is very important, and something I would like to see the NIH embrace more, and that is interacting with the public, explaining what we do, to the layman, because I think we're all scientists.  I think everyone on earth is a scientist.  We wonder about the world.  We wonder about nature.  We wonder about our bodies.  And everyone contributes in their own way.  We can't all be scientists, but everybody, through their interest and support for science, through their taxes, make it possible for people like me to do science, and that's just a tremendous feeling. I think that it's important for us to communicate, because they support everything we do, and all they ask is, "What did you do with the money?"