Omr conversations Marcus Raichle, M. D. [music] [00: 00: 10]



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OMR Conversations

Marcus Raichle, M.D.
[music]
[00:00:10]

We are in Boston at the Sheraton, which is the headquarters for an amazing meeting called One Mind for Research. It’s been described as a moonshot into the mind. One of the panels this morning was a symposium called “Connectome, Mapping the Brain” and one of the speakers in that panel who talked about the human brain at work was Marcus Raichle who is a neurologist, professor of radiology, neurology, neurobiology and biomedical engineering at Wash U, St. Louis. So, welcome.


Thank you.
The theme, the thrust of your story this morning, as I listened to it, was the brain’s basically in the prediction business.
Correct.
And you also gave some amazing stories about self-control and impulsivity in juvenile offenders. Those are the two things I wanted to get to, remind us to talk about, but Patrick had set the scene first of all, since you’re one of the founders of the field of brain mapping, PETs and FMRI and so on, give some sense of where you think the field really is at, at this point, and how effective it is.
[00:01:17]

Oh, I can give you a sense of where I think it might be going. We entered this field as almost a parallel to neurobiology in the past in terms of mapping functions in the brain, whether you put an electrode in or you look at it with some optical or whatever your technique was, the basic paradigm was to have a task or have a stimulus or something and you looked at what the brain did when you delivered the stimulus. You turned something on and if you were privy to the behavior you tried to correlate all of this. So, this was a, very much an idea that certainly can be traced back to people like Sir Charles Sherrington who, later in his life, I think, migrated somewhat from that, but he was well known for this view - that we’re thinking about it as a reflexive system. That it’s waiting for something to happen and then it engineers a response. And interestingly enough, actually in the symposium on perception this morning, that was kind of the paradigm that introduced that section. And it’s been hugely productive, I mean, in the brain, again, people talk about Hubel and Wiesel and how much we learned from that paradigm, but as the imaging story evolved and we followed that and developed many of the tools that were – paralleled that by putting people in scanners and asking them to do things. So, things came up along the way. One of them was the realization that as good as we were at seeing these changes in the brain, they were incredibly small. They just didn’t represent a very big change. Surely, they must be important, but they weren’t very big. And that was one of the things I wanted to illustrate this morning.
[00:03:06]

And so, then the question was, you have this organ sitting there and it’s one of the most expensive organs in the body. It chews up 20% of the cost of running the body. And the question is, well, if the changes that we can elicit are a few percentage locally, then what in the world is going on with the rest of this? And so, several things that evolved – the idea that a lot of what the brain is doing is not a new idea by any stretch of the imagination. People actually, a fellow named Brown who was a pupil of Sherrington’s raised this issue many, many years ago and you can even go back into early philosophers who kind of talked about what the brain was doing. Kant and other talked about this, although they didn’t have any neurobiology, the notion that the brain could be developing, you know, a background and a context for the way you perform, is a thought that’s been around for a long time. So, the first thing that tripped us to this was, you know, these darn things aren’t costing very much, but we knew this a number of years ago and in fact, we weren’t the first to notice this. It goes back clear to the late 1940’s and Kety and Schmidt and others noticed that changes cost very little. Then, another thing came along the way and that was that, by golly, if you ask somebody to do something, and we call these, like, goal directed tasks, that not only did the expected areas go up, that is, if you moved your hand, your hand area went up. If you showed a visual stimulus, you got something in the visual cortex, etc., etc. And, but by golly, if you just started out with, as your control state, doing nothing, things went down. Certain things went down in addition to what went up. And, when this first came up was, we noticed this just kind of by accident, and in fact, we had been criticized that you never study a brain that you don’t control. So the tasks that you do should be accompanied by a control state that has everything in it but the little thing you want to know about. So that you don’t dare let this (laughs) organ run on its own. But, we did, for reasons that I’m – probably are lost in the dustbin of history or in my head somewhere – we did on regular occasions just have people lay in the scanner as one of the control states and it was from that state that we noticed that things would go down and then we became aware of the fact that the ones that were going down were highly systematic. They weren’t just randomly occurring. And this ultimately led to a serious look at this. We described it first just as a phenomenon in 1997 and then came back and defended this idea more physiologically in 2001 and called it a default mode of brain function. And the poster child system of that was what’s become known as the brain’s default mode network.
[00:06:26]

So this suggested that not only was the brain very expensive, that induced changes were small, but that its intrinsic activity was organized on a grand scale of some sort. That would have been difficult to go forward in and of itself. But, it laid the groundwork for how we thought about it. And then, one of the other things that I mentioned was that as we and others did, you know, imaging with FMRI, you had this thing called the bold signal which moves along in there and people treated its kind of intrinsic ongoing activity as noise. Like we do for any signal, you know? It was noise. So what do you do with it? You just average it out. We got rid of it. And this fellow Bharat Biswal, who’s a physicist up at the Medical College of Wisconsin, in 1995, he said, hey wait a minute. There’s this noisy signal here and is there any possibility that it’s correlated with anything? And he just happened to look at it over the motor cortex and lo and behold, there was the other motor cortex. And people weren’t moving a muscle! He actually knew about some, again, every time you think you’ve discovered something, you know, you find out it’s been – the observation has been around. And when I entered this field some 45 years ago, some of the first meetings I attended, people actually had been noticing these waves, oxygen waves in the brain, using electrodes and whatever. And there was no interest in their role in organizing the brain. It was to do with the fact that maybe capillaries in the brain opened and closed like they did in the lungs. This was since, it was subsequently disproven and one of the pieces of evidence for disproving it was to show that the oxygen was to show that the oxygen waves were correlated symmetrically in the brains of rodents. And then this just kind of went into the drawer of history. (laughs) And Biswal knew about this and I did, but he thought of it and I didn’t. And he looked at this and by god, there it was. Well, then there ensued a huge hue and cry about, well, wait a minute here, these are just blood vessel changes. This could be due to respiration or variations in heart rate and all this kind of stuff.
[00:08:49]

So, Biswal and Mark Lowe and his other colleagues kind of went on the defensive for a number of years. Although, many of us knew about this, it just didn’t seem to be going anywhere. And the seminal event for me was that I went to a meeting in Japan and by this point, our default mode network, I could see it in my sleep. We’d published on it. We’d talked about it and so forth. And I was at this meeting and I looked across the room. I walked into the poster room late one evening. Nobody was around. And here was two posters clear across the room that had the default mode. And I thought, okay, another poster. I’ll just walk over and look at them. And the way they had seen it was to look at one element of it, back in the midline here, and they just said, what is this signal correlated with? And out pops this network. Now, I knew this network and so (laughs) I raced back to St. Louis and told one of my graduate students, Mike Fox, who is now a neurology resident here at Harvard and a colleague of mine, Avi Steiner, I said, “We got to get serious about this. This is, this is for real.”
Now what year is this?
[00:10:03]

You know, I can’t pin it down exactly. We published our first paper having to do with these ante correlated networks was 2005 in PNES and I’m judging it was two and a half to three years before that because, it turns out to do this right, while you can kind of do it just quick and dirty like he did it, to really do it precisely, there’s a lot of tricks to it. So, we had to learn all those tricks and play these games. (laughs) And so that’s how I got there and all of a sudden, we were staring at this very high level organization of the human brain and it had nothing to do with the observable outgoing behavior. And, of course, there was then and has been a lot of discussion, well wait minute, you’re daydreaming and all this. Well, for the default mode network, it’s a kind of maybe. But what about the motor system? You know, you’re not moving anything. You’re just laying there. And it turns out that this ongoing activity is also present under general anesthesia. There are differences in the way it’s affected by that, it’s still there. And it’s present, as best anybody can tell, during sleep. So, during states where you’re not having any daydreaming or cognitive activity, it’s present. And so, you know, it obviously has been of great interest to us and also, to understand what exactly is this signal that first off, gave us FMRI and then is giving us this kind of information in terms of a neurobiological phenomena. Because people often way, well, you know, you’re just (laughs) to put it crudely, you’re looking at the plumbing of the brain and that’s a long ways from what neurons are doing. I really don’t believe that. But, it was very, very important then to get to the neurobiology of this thing. And this led us to studies using electrocorticography in epilepsy patients where we could do both FMRI and a decent electrophysiology in the same brain. And sent us down this path of thinking very much more specifically about what the imaging signal is as a representative of one very narrow part of the electrical spectrum. But it turns out to be a very important part, these very slow frequencies which encompass the up and down states, but they’re a bit broader as best we can tell it. Signal changes in cortical excitability, which then leads one down the path of organized changes in cortical excitability setting the system up in various ways to respond and then one adds to that, the fluidity of this thing, or non-stationarity and then you have a system that’s non-stationary, highly organized and capable then of putting itself in a predictive mode. (laughs) That’s a lot –
The recency of all of this, though, is –
[00:13:11]

This is evolving very quickly and –
Quite amazing, though.
Yeah, it is really, I must say the story is evolving, at least in my own mind, very interestingly and it’s evolved very rapidly over the last year or two. How we’ve come from a very simple straightforward paradigm that, for me now, is excitingly complex.
There’s a ten year plan here.
Yes.
For neuroscience. From molecules to brain health.

Yes.
You’re involved with this obviously. I mean where –
[00:13:43]

Well, I’m involved and in the sense that I was invited, which I was delighted. This has been a real delight to participate.
So, what are the prospects over the next ten years? I mean, there was a decade of the brain, of course.
Yes.
But most people out there are saying, what was that all about?
[00:14:00]

What was that all about? I think they are rather significant. I think what’s really interesting to me is that as we have moved forward here, that neuroscience, that human neuroscience is become a real player in the story. That it isn’t that the only place we can look in a sophisticated way is in a Petri dish or in some other species. All of which are important, but we can relate that to things in the human that are becoming increasingly sophisticated in both giving a context for what it is we want to know and also providing some insight into even what the processes are that are involved. So, I don’t doubt for a minute that Karl Deisseroth’s ability to play with neurons, I mean, that’s clever as heck. Or Jeff Lichtman, who I’ve known for years, figuring out the synaptic stuff. But as I see it, the human part of this provides an enormous context without which we’re not going to move forward, but we’re getting our hands on it. So, I’m rather optimistic actually in seeing our ability to make some progress because the human has become a meaningful part of the story in a way that we can actually talk to a Jeff Lichtman or talk to a geneticist and make sense out of things.
Well, that was interesting and Jeff showed some wonderful slides down to the synaptic level. Then showed how it was organized there and said what does this tell us? And he said, “Nothing.”
That’s right.
Because as he then drew back to the view from 30,000 feet, you could see the immensity of the landscape of these, mindscape.
[00:15:50]

Yeah, and you could, you know, on one hand you could throw up your arms and say, it’s impossible! I’ll never understand this. It’s so mysterious. But on the other hand, you know, you’re never going to understand depression at the level of a few thousand synapses. You’re going to have to understand it in the context of the larger issues here and so, I was thinking, you know, if you want to understand, you know, the beauty of a violin, knowing the atomic structure of a violin string is not necessary.
Right.
[00:16:29]

You know, maybe it would be interesting. And I happen to be an oboe player, so knowing the, the biology of cane, which I have to use for my oboe reeds, probably might make my reeds better. (laughs) But there is much more to it. So you need all of these things, as I see it.
Yeah. Does a number – obviously a number of elements being put together here, as you said, the first symposium’s on perception, the second one on mapping the brain, the connectome, as it’s now called.
Yes.
One going out the moment on the genetic evolution.
Um hmm.
Let’s talk about the genetic stuff at this point because, again, there’s a parallel here. You know, one hears stories in, you know, newspapers about a gene for something. And one knows that, in fact, the genetic story, the connections and the number of genes involved in specific diseases that actually, in most cases, is very elaborate.
Yes.
As we, you know, Ralph Greenspan’s story of, you know, people talking about the fruit fly fight club, the aggression. The aggression gene in Drosophila, in fruit flies. Well, there isn’t just one. There’s eighty.
Yeah.
So, the parallel between finding genetic solutions for neurobiological diseases and using the kind of tools that you use, could you –
[00:17:59]

Could we find a way forward here?
Yeah.

[00:18:01]

Well, I would say, how about, well two things would come to mind. One would be Alzheimer’s because what’s happened here, which it’s kind of astonishing in a way to me, but as we looked at Alzheimer’s disease, as you know now, you can map with PET, you can map the distribution of amyloid plaques which has been used as one of the signatures of Alzheimer’s disease. And, well, I think there’s been some knowledge of where they were, what was really stunning about it was, when you actually looked at a PET image of the distribution of plaques, it was a picture of the default mode network. It really is. As Randy Buckner may say tomorrow, I’ve heard him say it before, that you could give a talk and you could use these images interchangeably because they look at the same system. So, obviously, it attacks a system that must have something about it that has a unique property to it. Well, one of the unique properties which I talked about, and again, I did this really on the fly, was that the metabolism in the default mode network just simply distinct. And by that I mean, that it takes this molecule of glucose and most of it, of course, like the rest of the brain is burned up to CO2 and water and produces a ton of ATP. But it has an unusually large fraction of it that never goes there. That somewhere it goes to doing other things. Now, glucose, as the cancer biologists have been saying for years, does all this other stuff. It’s critical, you know, in biosynthesis of lipid membranes and proteins and DNA and RNA. It’s critical in adjudicating apoptosis. It actually, if it goes into the pentose shunt, there is a very specific well known pathway that actually serves as a break on apoptosis. It manages the –
That word meaning cell death.
[00:20:05]

Yes. Cell death, yes. And it handles these dangerous things called radical oxygen species in the brain. It’s critical for managing all this. Plus then, it provides a small amount of energy, but it targets the pumps in the brain, like sodium, potassium, ATP, it gets its energy from glycolysis. So, one could say, well, wait a minute, what risks does choosing this sort of metabolic thing, rather than it’s neighbor right next door, primary visual cortex, equally active, but doesn’t do this like that. Or, the hippocampus, which is actually quite non-glycolytic, surprising, as is the cerebellum. What’s different about this? And the other thing that’s interesting about glycolysis is that if you come into the world prematurely, your brain is almost entirely glycolytic. This was stuff published by the PET people, some people in our lab many, many years ago. And I used to think, well, you know, why risk it? You’re in utero. What if there’s not enough oxygen around? Just don’t risk it. Just go the expensive route and do it with glucose. If you come in on time, you come in at term, your brain is still 30% glycolytic and then when I started to think about this, guess what? You’re building a brain at that time. And what we know only partially at this point is by the time you’re age two, it’s using as much glucose as you would as an adult. And by the time you’re age nine, it’s twice the adult. But what we don’t know is where this is going. So, this whole issue then of both a developmental trajectory that has got significant metabolic components and we know the enzymes that are regulating this. Well what about the genes that regulate the enzymes that do this? Are there developmental trajectories? Are these things getting in trouble in Alzheimer’s disease? By noticing this kind of stuff, it seems to me then you could say, okay now, whatever is controlling this, I want to know about it. And the beauty of the glucose story as kind of an exemplar here, is that the oncologists are way ahead of this. I mean, there are just all kinds of ways that other cells do this sort of thing. And it seems to me, if I were going to – rather than get a whole screen of the brain’s genes, I’d like to say, okay, in this area, what’s different between that and another area and does it change with development? Does it change with disease? I mean, what the heck is going on here? And so I would think more targeting things where you can focus on a problem like this would be useful. But, it’s just an example, but I can imagine others.
Um hmm. So, in fact, the theme here obviously is integration across a great many distances?
[00:23:01]

And I think that’s de – you know, as I talked about the electrophysiology, I mean, people doing, you know, basic membrane biophysics in terms of up and down states and so forth, I, you know, I’d like to go around like, to at least get others who have those kind of tools interested in some of the questions that we have that only they can answer. ‘Cause I’m not a geneticist. I’m not a membrane biophysicist. I am now talking more to people that do stuff in mice because (laughs)__So_I_signed_up_for_what_would_be,_now_they_call_biology._And_I_went_into_this_class_and_it_was_taught_by_Dixy_Lee_Ray._Do_you_know_who_Dixy_Lee_Ray_is'>(laughs), people like Dave Holtzman, who is at this meeting and we’re now doing some work actually on genetically engineered mice that are at risk for Alzheimer’s and looking at synaptic metabolism, actually. So, it’s those kind of bridges that I think are really important here.
Francis Collins and his talk was – put a lot of great emphasis on this new center that they have for neuroscience and regenerative medicine, he talked about. And he also talked about the National Center of Advancing Translational Science. So, obviously, much more emphasis now on translate – is that something that you’d go along with?
[00:24:13]

Well I, yeah, I really enjoyed listening to his talk. He brought up a number of things there, these things where, yeah, and various resources that might be available to think about problems like this. The other group that I find interesting to keep tabs on is the Allen Atlas out in Seattle where, you know, they did the gene expression of the mouse brain, which in incredible detail, but they’ve now done work on the human and now they’re doing work on development. And I’m thinking, ooh! This is really the sort of thing one needs. And I was thinking, you know, now what I need (laughing) is a post doc or graduate student who knows that side of it who can come listen to my part of the story here. But, those are the links that, to me, will make progress in some of these complicated things.
So, how do you see the future of your particular area developing? I mean, the imaging area?
[00:25:14]

Wow. (laughs) It’s hard to predict because I, you know, (laughs)
I mean, there’s a – all right, there’s –
Well, the big areas that I think, yeah, I think, you know, I think the –
Over interpreting stuff.
Yeah, I think, well, there are a couple of areas I find deeply interesting. One of them is the ability to get serious about human development and there’s a lot of imaging work going on and it’s – obviously, you’re not looking at task – that’s why this ability to look at intrinsic activity in the nervous system is so useful and productive, because you can put a swaddled baby in a scanner who’s, you know, satisfied and asleep and we can look at this stuff. And that’s being done. I’m not doing it personally, but others are doing it. So, I really see that as important in just getting a sense of how we build a brain. You know, we spend so much of our time as, you know, as a neurologist, we look at how we tear the brain apart and we try to figure out how it works. Well, my feeling is, let’s watch how we’re building the darn thing and, of course, there’s a whole world of developmental neuroscience, but what we need to add to that is human developmental neuroscience and take it beyond the rich behavioral data we have on this and begin to touch into the developmental. And I think, you know, that one little example I talked about, about the impulsive teenagers is, I think, a useful way to think about it. And what it involves is not your usual kind of neurological way of thinking about a problem of a lesion behavior model. But rather, a complex disintegration or misintegration of, within and among systems of the brain that, when you get into these complex behavioral things are not going to – there’s no spot in the brain for autism. And there’s no spot in the brain for impulsivity. It is the relationship between systems and so, and thinking of it that way for me allows one to begin to think more rationally about what we’re talking about in terms of treating these things or preventing them.
Just revisit that story, if you don’t mind.
[00:27:30]

Well, the impulsive – this came about, I was part of a 3 year project with the MacArthur Foundation on Neuroscience and Law. They were trying to figure out how to bridge that gap. It’s quite a challenging gap to bridge. But in the course of this, a number of experiments were launched and one of them was fueled by the fact that one of the persons involved in the project was Kent Keel. He’s a well known investigator. Has worked on psychopathy for many years and he had persuaded the government of New Mexico to purchase an MR scanner, put it in a truck and it could be driven to the prisons. So, he had access to, he had data, on a very large number of adult psychopaths, which we actually had a look at. But he also had these juveniles. And what I argued, there were various people had a look at these kinds of data, people looked at the anatomy. People looked at tasks and various things. And I said, look, we’ve (laughs) if I’m involved in this, we’ve got to look at this resting state business. So, at my urging, they did collect this on a group of adults who turned out not to be all that interesting because so many things were wrong with these adults brains. I mean, after all, they’d been in prison and out of prison. They’d had drug abuse. They’d had trauma and so forth. But there were these hundred and seven juvenile offenders who obviously had committed a serious enough crime to be in the prison system. And they had been evaluated in terms of what’s called the Harris Psychopathy Scale. It’s a – there’s a juvenile version of this and the thing that proved most interesting about this was the measure of impulsivity that they had. This turned out to be the key to unraveling this. So, what we did was we took this 107 young folks, and we have a means by which now this a reasoned algorithm that will come out as part of this paper in PNAS shortly, but was basically to go into the brain and without any preconceived notion of where the problem was, have it search for coherent relationships among systems. And so it just picks a spot and starts and says, does this correlate with impulsivity? And if it does, it then takes that apart and so forth. So you end up with this enormous survey and what came out of this was – the observation I showed was that these two areas, I mean, they’re just basically symmetrical, they’re right behind the frontal eye fields, and they have to do, based on a lot of cognitive neuroscience, to do with motor planning and motor output. They’re very specific what they do. So, two things happened. One is, is this really? Because after all, we had used this massive search algorithm. There’s all sorts of ways you could get false positives and so forth. And so the acid test of this was to, you have a 106, 107, you set one aside and you take the 106 and you recompute the model. And say, can I predict that 107th person? And you do this 107 times. Now, fortunately, we had just gotten our first supercomputer. Because this would have taken a year to do this on a PC of any sorts. And we did it in a week. And by god, you – it was amazingly specific. So, with confidence that there was something very special about these two areas, was then to ask, well okay, who do they talk to? What do they – what sort of systems do they represent? And it turns out that in a normal, healthy adult, and in non-impulsive teenagers, these areas are coherent with what is called the dorsal attention system in the brain. And this is a system that increases its activity when you engage in a goal directed task. It’s well described by people like Corbetta and others.
[00:31:39]

In addition to that, it is coherent with what are called these frontal control systems. There’s one in the midline and one down on the left side here that are very important when you’re engaged in the task of holding you onto the task. So, you might imagine that your motor output systems would be, you know, congenially coherent with things that hold your attention and also guide you in terms of what’s appropriate. All right, so that’s the normal set up. In the impulsive – oh, and I should also add that they were anti-correlated with this default mode network. So, normal people like you, if you engage in a task, you have an attention system, a control system, a motor output system that goes up a bit and a default mode network which is highly self-referential and probably be attenuated. It’s absolutely the opposite in the impulsive teenagers.
Hmm.
[00:32:34]

And so, you might imagine that what’s happening here, just thinking about it, is that now motor output is being largely coordinated with an internal self-referential drive and at a time when you’re actually attenuating attention to the environment and controlling your behavior. So, you can see the dissociation here. So, if you think about it this way, you’d say, well now, is this an abnormality? Or is this just a delay in development? And so, what’s also in this paper is a rather large cohort of normally developing children from the age, about 5 and 6 all the way up to adulthood. And, as I think all of us who have been around children and, I have ten grandchildren, you realize that, you know, when they’re 5 or 6 or younger, they’re impulsive. (laughs) And then as you grow up, you begin to socialize and you begin to understand the rules of society and how you get along. So, the question was, in this group of subjects that were culled from a group working out at the University of Oregon, friends of ours, they showed that you start out as an impulsive, young, normal child, looking just like impulsive teenagers incarcerated in a prison. But, you develop over time and you reverse those relationships. So, it again sets the stage for how are we going to think about these very complex diseases and conditions and personality disorders that affect humans? I see it as emerging out of this very interesting, complex organization of these systems that, you know, could be looked at at a number of levels. But, certainly, looking at it with imaging and electro – there’s a lot of tools we can bring to bear on it. And then we could bore in, in terms of, you know, in some instances, our metabolic issues or genes or whatever important, but what governs this kind of normal development and shift of balance between systems in the brain. There’s no lesion here. It’s a matter of how systems balance once against the other and how an environment helps sculpt that. And what is that environment? Or what is the genetics of this?
And you can see why that would be of interest to the Neuroscience and Law Project, because it relates to all sorts of philosophical problems –
Oh, absolutely.
Legal questions.
You know, why is –
Who’s responsible for development?
[00:35:05]

Sure, and you know, when do you give people a driver’s license? And when do you consider somebody even culpable? That is, you know, I now forget the actual age, it’s something like 6, of a 5-year-old somehow or other picks up a gun and somebody is killed, you know, they’re not considered responsible for that, period. And there’s some age in there. And eighteen is also another critical age. Well, how did we arrive at that? Well, probably from just empirical observation. But I think we could do better than that and we could probably do better if one’s predictive capacity based on these models is good working at a single individual, which is what some of this data suggests, we could make assessments of individual persons in this, possibly.
Just interested, how did you initially get into – I know that you’re an oboe player as well, because on your website,
Yeah.
- you have a picture of your boat and you have a picture of an oboe, a horn or something –
Yeah, I’ve been sailing for six – I’m, I play the oboe family. Oboe is – there’s a family of instruments. It’s the oboe. When you go to the symphony, the guy sitting up there generally they’re playing the oboe. The next most common one, which is a big solo instrument, is the English horn which is the tenor oboe. And I’m the sole English horn player for the orchestra I’m in. So, that picture is me with my English horn. But, I play both instruments. And there’s two other members of the family, the d’amore, which is largely used in Baroque music. Bach wrote a lot for it. It’s a beautiful little instrument. It’s kind of a miniature English horn.
So how did you end up in science? I mean, because it sounds as though you could almost have done music as another –
[00:09:34]

Well, no, no, it wouldn’t have been. That was always been just a hobby for me. My father was a lawyer and I was going to go to law school. And I went to the University of Washington as a history and political science major. I did take some math classes and I, you know, I don’t even remember why, maybe just because I liked it. And I was going along and in order to graduate, I had to take some science. And so I asked my dad and he said, well, you know, take zoology. So that’s what I did. (laughs) So I signed up for what would be, now they call biology. And I went into this class and it was taught by Dixy Lee Ray. Do you know who Dixy Lee Ray is?
No.
Okay, well Dixy Lee Ray at that point in time was a marine biologist. She was a captivating lecturer. And I got into this class and I thought, wait a minute. This was my junior year (laughs) at the University of Washington and I took this class and I thought, wait a minute, maybe I should re-think this a little bit. To give you a background for this lady, she did a number of things. She was very much involved and interested in the environment. She was appointed by Richard Nixon as the head of the U.S. Atomic Energy Commission later. And then she went back to the State of Washington and became governor of the State of Washington. A very colorful individual who I’m told – I, by that time, left Washington – she lived in her trailer with her dogs while she was the governor. And she was not re-elected and she died a number of years later at her home on Orcas Island and I’ve always regretted, although the class was like three hundred people, that I never had a chance to either meet her or thank her. Because I, and I can only half imagine how many careers this lady influenced. It was really quite remarkable. So anyway, then I went to – I had to take an extra year of college to get, you know, chemistry and physics and all this stuff and it was, nothing was as good as her class. (laughs) And then I got into medical school and my first year, you know, I was surrounded by all these people who said, oh, this is boring. We’ve had this in college. And I was thinking, holy smoke! I haven’t. and then Fred Plum walked into my, our class. And he was at the University of Washington, at that point, the youngest chairman of neurology in the United States, and every Friday, he would come in, lock the door, Fred being Fred, and he would talk to us about clinical pathologic correlations in neuroscience. And for some reason, I hit it off with Fred Plum. And when I was a junior student, Harold Wolff had died at Cornell and Fred went back to become chairman of neurology. So I went to ask him, well, look, how about my coming to Cornell with you? And so I spent my senior year on the neurology service at Cornell and also I had the privilege, because I had to take some surgery, of going on the neurosurgery service there that was, it was Bronson Ray who was Harvey Cushing’s last resident. He was one of the most elegant human beings I’ve ever met and I had a chance to hold suckers for Bronson Ray. (laughs) And so I was hooked. And Fred and Gerry Posner introduced me to studies in blood flow and metabolism, because they were interested in metabolic brain disease.
Fred was also, he also had that persistent vegetative state, the locked in syndrome. He –
[00:40:16]

Yeah he was big on that and Nick Shiff is his, is the fellow that’s – well Fred and Gerry wrote this really famous monograph which, when I was a resident, we were learning from the galley proofs of Stupor and Coma, this little bla – now, it’s a big fat book, but it was this beautiful little thing and it was the key to understanding. And I guess the thing that I enjoyed being around these people, although Fred could be stressful, but was a notion that there were these interesting metabolic problems that in the brain were highly reversible. This was, he was very interested in coma and this kind of thing. And every coma patient that ever went into the New York Hospital, we had them on our service and we took care of them because that’s what he wanted and, then I was very interested in these tools of blood flow and metabolism. So I spent a good chunk of one year working in the lab with him and Gerry, learning this. And, then this was at the peak of the Vietnam war and I’d been in what’s called the Berry Plan so I could survive all this training. And then I was whipped into the Air Force as, and trained as a flight surgeon and then they sent me to the school of aerospace medicine, which had 1500 Rhesus monkeys and some of the most incredible laboratories you could imagine. They could simulate any environment you could imagine. Because they were going to – this was at the time, they were going to put a spy satellite up, the Air Force was.
[00:41:41]

And plus, the astronauts all came through here. I was part of their clinical service there as well. So, I not only flew around in exotic planes, but I knew how to – learned how to do research on monkeys and the like. And then, I was on a, I was invited to, while I was in the Air Force, to give a talk on some stuff I had done with Plum in London and I met Mike Ter-Pogossian, who is the physicist who pioneered positron isotopes in biology and medicine. He said, “How’d you like to come to St. Louis and try playing with these things?” And my wife couldn’t believe it. (laughs) Because we wanted to go back to Seattle. That was forty-one years ago.
(laughs)


And I’d been there in St. Louis about 18 months and Godfrey Hounsfield had announced the CT scanner and I was in a group, with Ter-Pogossian’s group, that were all physicists and chemists. I was the only neurobiologist there. And they first wanted to build a better CT scanner, but that kind of fell through and they had all these algorithms and then Gerry Cox and Mike Phelps said, “Hey wait a minute. Maybe we could use this and build something called PETT.” It was P-E-T-T in those days. So, I had these probes and things that I was using. They said, “Can we tear that down and build our first scanner?” And so they did. And my job then was to, was to figure out how to use the darn thing.

So, positron emission tomography?
Yeah.
At the very beginning?
Oh, I was – they were building – they built the first scanner right on the side of my office. And the first table top models were built out of the electronics and probes that were mine. (laughs)
But what a strange, interesting trajectory. One of the questions I ask people, I mean, you’ve had lots of students as well. There’s a lovely little book by Sir Peter Medawar called Advice to a Young Scientist.
I believe I have that on my shelf somewhere. It’s been a long time since I’ve looked at it.

What would be your advice to a young scientist? Any of the folks downstairs, the ones that are just starting out, for example?


[00:43:41]

One of them would be courage. (laughs) And, you know, I think as you move forward – I’ve wondered about this. What distinguishes the students that really do well from the students that don’t do so well? And I mean, there are certain things that are utterly intangible, as best I can tell it. I mean, there’s kind of a intuitive sense of how to think about a scientific question and particularly the data that you get from it. And I don’t know that I can teach that. It’s almost like, you know, being a Michael Jordan, basketball player, there’s just something about some people. They kind of have this. Or being a great musician or somebody who writes and so forth. There’s a certain creative element of it that you’d like to nurture, but I don’t know that it’s possible to teach it. But the other thing is that science, you know, where the fun begins for me has been where you come to the end of the road and you run into something completely new. And for some people, they get very uneasy about this. I’ve seen this happen. Super bright, but they want to be sure they can confirm everybody else (laughing) and, this is where this issue of courage, I think, comes up in science. And I learned this, in part, when we published a paper – we actually published a lot in 1986 (laughing) and ’88, that has turned out to have some impact. But, we were out to confirm the notion that when the brain’s blood flow goes up, it goes up to deliver more oxygen to the brain. I mean, that just seemed like it absolutely had to be that way. And it turned out it wasn’t. and we published a thing in PNAS and said that. And then in 1988, we came around and said, “Wait a minute, we better check on glucose and see what it’s doing.” And by god, it went up with the blood flow and, still, the oxygen consumption didn’t go up. We took an enormous amount, there was an enormous push back on that, those two papers. I was accused of doing bad science. Some people said, “We’re worried about your career.” And yet, we had spent years working on these techniques that we used to get this. And I couldn’t believe we were wrong. But, for a young investigator, that’s tough going, when that happens. And it was Seiji Ogawa at the Bell Labs. I’d never met Seiji or David Tank and I get this invitation to go give a talk at the Bell Labs (laughs). And when I was there, they ushered me into Seiji’s lab with his 9 tesla magnet and little rodents hanging upside down in it. And they showed me what turned out to be the BOLD signal. And I said, “Holy smokes!” And there she was. So, now thousands of times a day I feel good. (laughs) Because, you know, but there’s occasional persons that still quibble with these observations, but you know, I’m used to it now. But, it’s being able to kind of live through a thing like that. And understand the disappointments that you have. And somehow or other maintain a vision or something.
[00:46:53]

And the other thing that some people, you know, seem to want to – maybe you need it more today – is some sort of grand plan. There’s this wonderful piece on – I love the News Hour on PBS and so there’s this one ad on there. There’s these young people that come on, you know, and they say I want to know everything about everything. And science is all this and one young fellow comes up always and they keep using these, says, I’m going to be the first to cure cancer. And my sense of the science has been that, yeah, you have a general sense of it, but you follow your nose. And there’s just wonderful things that kind of happen in front of you and you take advantage of what’s laid on your lap there and, you know, you could say well, curing cancer is like discovering consciousness in the brain. Do I think that we play around with things that are related to that? The answer is sure. But, it isn’t my objective.
All right, so given the scope of this meeting and given the fact that the Kennedys are involved and so on, this is very much intersection of science and social policy which is -
Yes.
- what we do at The Science Network. One of the questions I ask people a lot and Eric Lander, of course, is involved as well. When he came into office, President Obama said that one task of the administration was to restore science to its rightful place.
Um hmm.
But he didn’t say where that was. So I ask people, what do you think is the rightful place of science?
[00:48:26]

That’s a interesting question. I think it’s rightful place is as an important part of the public dialogue in terms that – I think it’s deeply important that people understand it and us better, in terms of what we do and how we ought to think about issues. I often reflect as I, you know, even listen to the public dialogues that sometimes are really troublesome in terms of how people are describing events, characterizing things and so forth, and just to be able to think as a scientists or think quantitatively about problems that we face, which are enormously complex, but when you come at it as a scientist, you have certain ways of thinking about problems. So there is that aspect of it. But I think when it comes to the brain, developing a better understanding of what the brain really is all about here, I find it interesting that, but there’s not much of this. While I come from a rather liberal leaning, not surprising I suppose, one of the persons that I find very interesting who struggles with this or works on this a lot is David Brooks who writes for The New York Times. And I just recently read his latest book which took some criticism. I frankly enjoyed it, but I think, you know, as we get into this thing and people talk about, you know, well, you know, the American public says or a rational person would think and so forth, and I’m thinking to myself, well, wait a minute. I, as a neuroscientist who are thinking about how the brain works and what it’s doing, I think we need a better understanding of what we’re talking about here. And I think as we see things that are deeply troubling about how people behave, we are going to be in a position to understand that better. Even if we can’t change it, we can at least understand it better. You know, this, I think it’s kind of stunning when you think of the fact that, you know, we think, you know, we’re in kind of control of everything and, you know, we’re the master of ourselves, but, when you think about it, the window of conscious awareness is a few hundred bits per second at the most. And there is this wonderful observation that my great friend Mike Gazzaniga made a number of years ago on the splint brain patients, the so-called interpretative brain.
Um hmm.
[00:51:00]

You’re familiar with that? You split the brain in half, you ask the right brain to do something and then the only brain you can talk to is the left brain and you ask it to explain it. It has no idea why you did it. And it comes up with an explanation. And I’ve wondered so often how, when we are asked for a rational explanation for something, how often we provide a post talk explanation when we are asked well, why did we like this or why didn’t we like that or why did we vote for this or we don’t that. And an understanding of that, if we can help people understand how these sorts of things are likely to be working would be, I think, deeply important. I’m not optimistic we’re going to do that any time soon. But I’d like to see that as part of the dialogue. That for us to be civilized people, we need to understand better what we are. (laughs)
You mentioned a number of historical figures there, including Sherrington and so on. Another question I like to ask people is, if I gave you a time travel token and you could bring to your dinner table anybody with whom to have a conversation. I mean, who would you like to ask some questions of? Who would you like to sit down and talk to?
[00:52:11]

Well, I suppose you could pick up somebody like – I, you know the person that is so quotable, I mean, any time you’re hung up for something to say about something, you think of William James. And I have several copies of his Principles and some other things he did and I, you know, I just see that as an incredibly remarkable, insightful, amazing human being. And I think it would be utterly wonderful to sit down at a table and talk to somebody like that. There are others that probably are far less well known, but occasionally you run across somebody and you think to yourself, what a wonderfully interesting person. And one of them was a fellow named George Bishop. Now, I don’t know whether that rings, probably doesn’t. George Bishop is the – to give the George Bishop lecture at Washington University in neuroscience, that is the lecture of the year. And he was essentially the young investigator working with Erlanger and Gasser and they, of course received the Nobel Prize for the work they did and he was the kind of engineering genius behind that work. And he went on to a very distinguished career at Washington University, as you might imagine. And, you know, he was a man in the background. When I showed up, he was quite elderly. My only memory of him was walking by his office and he was asleep in the chair in his office. So, I never knew the man. But, recently I was going through the work of Charlie Schroeder which I mentioned today and I admire his work a lot and he mentioned a paper of George Bishop in 1933. And so I pulled up this paper and I read it and it was one of the most marvelous scientific papers I have ever read. And what he was talking about, he was stimulating the rabbit optic nerve and looking at the responses in the rabbit visual cortex. And what he said was and what he observed was that, by god, no matter how careful he was in stimulating the optic nerve, there was variability in the response in the cortex. And he, of course, these papers in those days are more of a narrative. And he talked about, before he even got to how he thought about it, he talked about the heuristic value of a hypothesis. And he said it probably has even greater value because it’s based mainly on moonshine. He just (laughs), this is just a charming read. And then he goes on to talk about the state of the system governs its response. And that he even used terms like the mental state of the brain. I mean, talk about prescient ideas that were at the heart of what I was saying today.
Yeah.
[00:55:05]

And I thought, that was a man I came very close to meeting and never did. And it would be fun to sit down with someone because it was just the wit and charm that comes, came out of that paper and the incredible insight that he had in 1933 that nobody had had before that.
Last quick question. When you used that phrase that you were not optimistic about achieving certain things very soon. What are you optimistic about?
[00:55:37]

I think, you know, I think we will see actually some real insights in some of the more complicated diseases that we’re faced with. And I would put those in the category of psychiatric diseases. I think they’re the most – they’re probably the most interesting and the most challenging ones that we’re faced with currently. And I do think that we will, we will see some progress in beginning to get a sense of what’s disorganized in those brains and be able to understand it at a level we haven’t before. And I think that would be very, very useful. And I think, as I mentioned earlier, this whole idea of understanding development better and the factors that government watching us build a brain and figuring out what, in fact, is involved, socioeconomic status, genes, you name it, what’s the difference here? Why does some kid, you know, who’s impulsive end up in prison and another one is just a cute little grandchild of mine? (laughs) So, I think those things will happen. Beyond that, I don’t know. I just keep sniffing along! (laughs) Seeing what’s happening.
Well it’s been great to talk to you. Marc Raichle, thanks very much.
You’re entirely welcome.
[END OF RECORDING]
/gmc

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