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2005 LECTURE SERIESHow Could Brain Science Transform our Lives in the 21st CenturyDr. Richard Morris Thanks a lot, great. Ladies and gentlemen, what a tremendous pleasure it is for me to be here with an old friend, but also with many other old friends. I began my scientific life as something of a refugee from London up in Saint Andrew’s, which many of you all know better as the place that is the home of golf than as a university, [laughter] and was sort of making my way in a humble way of trying to make my first steps in science. I had the most fantastic opportunity to come here to Irvine in 1984; it was a visit that completely changed my scientific life. I made many new friends and they have stayed friends all through my career, for me, it’s like coming back to a second home, it’s a real pleasure to be here. What I’d like to do today is not quite captured by the title of the lecture. I think it’s a little bit of a misnomer. I want to try if I can to stand apart from the regular kind of academic stuff that we scientists talk about and try think a little bit about what is coming over the horizon and to share with you some of those things because I think what’s really great about a lecture series like this is an opportunity for a dialogue from us, the so-called experts, about what we know is happening with you because I think that it is very important for us as scientists to link out to the community-at-large and hear ideas from people about what sort of things they need quite apart from the direction that individual science is going. This is not going to be a lecture about science fiction, and I don’t think you would have come out for an evening just to hear a science fiction lecture; that would be crazy. I can point to some kind of ideas about the things in which, directions in which things are going, and to give you some kind of sense of the scientific base for those various developments, that might help you understand the directions which are happening in neuroscience today. Let me start with a movie. This is not my own research. This is a paper published in Science Magazine two weeks ago. Isn’t he great? Is that terrific? That’s a robot. Now, we are so used to seeing robots in Hollywood movies that we don’t really realize that what is happening there is actually spectacular. To get a robot to sort of work on two things is really kind of amazing. Maybe not all of you are persuaded that that is terribly spectacular. It doesn’t look as good as in a Steven Spielberg movie, does it, after all? Let me try to persuade you that that is spectacular, and I am going to do it with these two revolutionaries. They don’t look like revolutionaries, do they? Yes, one or two of you, I am sure, in the audience will know who they are. Yes? Well, they are these guys. Look at their little contraption, right? Not so different from that robot, which didn’t really look like a person; that thing flew, right? What was it, 100 feet or 100 yards? I don’t know, not very much. And yet, that is what makes it possible for me to be here tonight, right, in a Boeing 777. They went from that to what we all now take for granted: flying in and out of your local airport here, we take it all for granted, and yet, for those guys, that was a tremendous revolutionary change from something made of, well, not quite string and sealing wax by pretty primitive, and look what has happened in the last 100 years. Let’s look again at that robot but now with new eyes. It doesn’t look like much, but it looks a bit like the Wright Brothers’ plane, doesn’t it now? Something that doesn’t add up to very much, but what is on the horizon? What is coming? Well, I think what is interesting about this particular bit of research to me is that it represents a slight change of direction on the part of engineers. Engineers have made spectacular advances by just using physical principles and turning them into marketable devices, and they are going to continue to do that. What is different about that robot is that it’s a robot where the engineers have said, look, I want to be inspired by what is happening in biology because it is easy enough to make a robot that will spray a car or build a particular component of a car in a very unintelligent way; but to build a robot that can actually walk using very low power, it turns out is something that requires some knowledge of the way in which the particular limbs move and taking advantage of certain energy efficiency aspects of that in one’s design of the robot. What is necessary there, and this is going to be a theme through my talk, is that it is going to be necessary for people in one particular discipline to interact with people in other disciplines, and in this particular case, for engineers to take inspiration from some aspects of biology to think about the kind of products that they might be building. And I think that there are lessons there; there are lessons in many of the kind of software devices that we all have come to love and hate like email, right? You know, it’s all very well, email, but they flow in, don’t they, and it’s all not necessarily designed in a way that has taken account of what human attention can cope with, what human memory can cope with. I sort of watch that movie through the tinted spectacles of saying, well, what might the bits of software that we all use every day look like if it took more account of what the human mind can cope with? Would we not then have better kinds of software? And I think that that sort of thing is on the horizon. Now, predicting the future is a [unintelligible] game, right? There was this wonderful American baseball player, Yogi Berra I think he is called, and he was the sort of Dan Quayle of his age and had fantastic, the very nice Dan Quayle quote that I love, it’s if we do not succeed, we run the risk of failure. It was a great Dan Quayle quote. Yogi Berra’s went better. He said, predictions are tough, especially about the future, he said. Let’s look at the things people in Britain bought in 1947: lamp oil, prunes, prunes, my God; an iron bed stand; the gramophone record; rayon blouses, I wonder how many people here are wearing a rayon blouse tonight, my God; cod liver oil, well, that is coming back into its own actually; corned beef. Those are the kind of stuff, and I bet they were not thinking about digital camcorders or champagne or cell phones; these are all items on the retail price index in the U.K. nowadays. Prepared sandwiches: who would have thought that going out to buy a prepared sandwich in 1947, I mean, you know, God, you don’t do that. Gas barbecues; hamsters are apparently on the retail price index. And in Europe, I hasten to remind you, gas is $8.00/gallon, so reflect on that as you drive up the motorway. You have got to be very careful about predicting the future. As I say, the serious side to this is I don’t think it really would make sense for me to try to give you a sci-fi lecture about how the world would have changed in 90 years or 100 years as a constant in brain science; that would be a silly kind of thing. The first is that what is driving science is, of course, academia, and academic neuroscientists, in my view, will just continue their day job of making incremental discoveries about the basic science that they are doing. Many of these findings are very obtuse, nothing that is easy to talk about in a public way, but others may be of interest to a wider public, and I am sure the responsible science journalists in the United States pick up these stories and put them in the press for you to read about, some of them the basis of practical applications, and in particular, and it’s central to the very important efforts of people here in the Center for the Neurobiological Learning and Memory, memory and plasticity will be a key theme of these future developments. That is one sort of answer to the question, but there are two other kinds of answers that one might get, and that is that certainly in the U.K., in Europe, and I suspect indeed now in the United States as well, that we are being encouraged to think beyond the ivory tower, to think beyond the confines of our narrow little laboratories, important as that focus is, to think a little bit about needs-driven research with therapeutic potential, particularly for presently intractable brain disorders, to try to capitalize on the basic science that we do in our labs to develop new drugs or other kinds of treatments that might help people with these sorts of disorders. On top of that also, I think this work is going to, as I say from my introduction, inspire various kinds of biomimetic [phonetic] and information engineering and the creation of new software that is influenced by the brain. These emails won’t pour in quite so much because the software people will work to have much more of what people need to know rather than just simply throwing stuff at them. And I think memory and plasticity is going to be a theme here. The last, third, that all of us, I think, have a growing sense of responsibility to our community that is reflected in an arrangement like these lectures tonight to build a greater public awareness of brain research and to engage the wider community to contribute to the decision-making about the focus of research and the priorities and the ethics of what we are doing. And here again, I think there are lots of reasons for thinking that plasticity will be a major theme. Those are the kind of three arguments of my lecture tonight, and I am going to try to devote a little bit of time to each of them as things go along. One of the first things is that science is a process of discovery and not just a boring set of facts. Let me try to get that across to you. What we are doing as we look at the nervous system is we look at it at lots of different kind of levels. There will be people who come here to give lectures talking about brain imaging, there will be people who come here to talk about molecules. And one of the things that we are all trying to do is to integrate these various different levels of analysis together as best we can. Now, when we look at the early 20th century, thinking through to try to learn from the past, Henry Ford was wrong: history isn’t [unintelligible]. We do need to learn from the past and try to think what are the directions that happened in the past and how might they give us guidelines for the future? If we look at some of the major 20th century contributions to brain science, there was the work of the person, where is my little thing-a-bob, here, okay, here on the left, Raman Kahal [phonetic], great Spanish anatomist who worked out the way in which different things connected, and that the brain wasn’t a syncytium but it was individual elements that were not quite touching each other. And then, two great British scientists, Andrew Huxley and Alan Hodgkin who worked on the giant squid and identified there the opportunity to capitalize on an early discovery by Jason Young [phonetic] of a giant axon to work out the way in which messages would be sent through the connections of these brain cells. And then, the German refugee to Britain, Bernard Katz [phonetic] worked out the basis by which chemicals make transmission, make contact in this network that Kahal had talked about, sending signals from one set of neurons on to another set of neurons, and was able to record little potentials at the neuromuscular junction that reflected that. Nowadays, we are able to do other kinds of things. There is new technology coming along. Here on the right is a wonderful technique called patch-clamping [phonetic] in which you take a tiny little glass pipette and you flare it very nicely, and literally you go down and literally kiss the neurons, and in the process of doing that, touching the surface membrane, you are able to actually listen in very quietly onto what is happening without damaging the neuron. And also, wonderful imaging techniques are being developed in which you can use all kinds of dyes of one sort or another expressed using clever molecular techniques to actually see the individual things. And you can then during clever techniques using three-dimensional things get a real image of the neuromuscular junction, and this is from some work of a colleague of mine in Edinburgh, Richard Rochester [phonetic] using our confocal microscope showing neuromuscular nerve endings. This is a lovely link between Richard’s new work back to Bernard Katz. Running forward a bit, there has been tremendous developments in our understanding of the major neurons in the brain that actually do the talking from one cell to another, the so-called glutamatergic receptors, the glutamatergic systems of the nervous system, and it turns out that they are the major engines of the ability of the connections from one brain cell to another to change the machinery of brain plasticity. And these connections have a sending side called presynaptic and a receiving side, the postsynaptic, and then various kinds of receptors which sit in the membrane which can actually do the listening in of the signals, these chemical signals sent from the sending side over to the receiving side. This is important work, which people here in Irvine have made a major contribution to together with other scientists from all over the world. What has emerged out of this is the idea that various kinds of receptors can move around and jump out into the membrane, a concept which in a very abstract way was first developed here in Irvine just over 21 years ago. The particular notion is that there are two different kinds of receptors called the AMPA and the NMDA receptor, and they do different kinds of jobs. One of them, the AMPA receptor, has little pores inside it through which charged ions can move, and as those charged ions move, the transmitter binds here and electrical charged ions can flow through, particularly sodium, a positively charged ion, and as these accumulate, then that charged ion can result in a signal being sent on from that neuron onto another one. The second receptor is the so-called NMDA receptor, and it has a little pore in it, and through it, calcium can go, and that calcium can then influence the number of these receptors that are actually sitting out in the membrane. Now, I think that this is an incredibly important and deep idea, and like any sort of idea of that kind, I think it is sort of fun to try and demonstrate it to you. If you will bear with me, I am going to have to try and bring the child out in all of you because we are going to try and have a little bit of fun with this. I don’t know that this will work; it may not. But I got one enforced volunteer, which is Chris over here, and Chris is going to come up and help me build the Irvine Synapse, if that’s okay, Chris. You’ll do that? Okay. What I need is two people who would like to play baseball. Two people, okay, the hand at the back there, you? Are you a good baseball player? RICHARD MORRIS, PHD: Okay. You’re in. Great. And another one? Another person? Okay, great, there. Good, two, yes, come along, great. This is slightly silly, folks, but let’s have fun. Okay, so very good, great. Okay, so who are you? RYAN: I’m Ryan. RICHARD MORRIS, PHD: Ryan, sir, fantastic, you’re a brave guy. Okay, and? ANGIE: Angie. RICHARD MORRIS, PHD: Angie, right, okay. Angie, no, Ryan, no, Angie, you stand here. Angie, you come here, right? Great, and so, let’s, there we go, okay, so it doesn’t look like a [unintelligible] keeper’s glove to me, I tell you. So there you go, all right? Okay, fine, good, thanks. Okay, now, Chris and I are going to build the Irvine Synapse. Here we go: so this is like a TV program, isn’t it? Here we go, here we go: this is not really a real synapse, you appreciate. We are going to have a bit of fun with this, so it’s got lots of holes in it through which these ions are going to move, and then Chris, okay, now, the hole, you put that down just for a second, that’s okay. It’s all right; he is trying too hard here. Okay, so we are going to put these together, right? So we have got the hold, we have got the sending side and the receiving side, and we have got to hold those together, right? But how are we going to do that? What do we need? We need, you’re from a lab that does this stuff, come on, what do we do? We need some— CHRIS: [Inaudible] adhesion molecules. RICHARD MORRIS, PHD: We need adhesion molecules. Here we are, we have got some adhesion molecules, here they are. So they are called cadherins— CHRIS: [Inaudible]. RICHARD MORRIS, PHD: —and we are going to put some cadherins on, so they do research on this sort of stuff here in Irvine. They don’t quite use these bands and stuff, but we— CHRIS: [Inaudible]. RICHARD MORRIS, PHD: —pretty much, okay. There we go, we got some, we are going to make sure that these two things sort of line up. This isn’t quite the way cadherins work, but it’s close enough. And let’s see, so let’s go; we’ve got to do this here. This is going to take a little moment but not very long, so that’s good. And then, we put some more on, [laughter] okay? CHRIS: [Inaudible]. RICHARD MORRIS, PHD: And yes, put another one on, Chris, that’s right. He’s good at cadherins, so— CHRIS: [Inaudible]. RICHARD MORRIS, PHD: —that’s fine. Yes, that’s good. So let’s do some on the bottom here. Okay? How are you getting on there, okay? Good, yes. Actually, you should practice. Let me see if we can get them practicing for a moment [unintelligible]. RICHARD MORRIS, PHD: I’m afraid I don’t know much about baseball, so I only brought some table tennis balls, I’m afraid. [laughter] So you want to try and see if— RICHARD MORRIS, PHD: —Angie can, so let’s try and see if she can catch it. Okay. You might want to stand a little bit closer. RICHARD MORRIS, PHD: Okay, good, right. How are they doing? Not too good. Oh, well, then we’ll have a few more cadherin molecules here, or do we need more? That’s all right, isn’t it? It’s okay. Okay, now, let’s be serious about this for a moment: I told you that we needed some receptors. Now, this is slightly cheating because actually the receptors are just on one side with their ion channels, this is a little bit naughty. But I need an NMDA receptor, we are going to put an NMDA receptor in here if we can get this to work. Let’s see: is it going to go in? If we can get it lined up, there we go. We’ve got our NMDA receptor to this channel, right? And we are going to have an AMPA receptor, okay? We’ve got an AMPA receptor here, we’ve got an AMPA receptor. We start with just sort of one AMPA receptor, okay? Right, now, this is where you come in, Ryan. Okay, Chris, you need to hold one side of this, right? Good. And okay, here we go, folks. RYAN: [Inaudible]. RICHARD MORRIS, PHD: —well, okay, right, Ryan, you’re going to catch the ball here, no, here, it’s going to come through here, right? Ready? You’re going to catch the ball. Good, and then you have to send it on to her, right? Okay. Oh. Okay, well, we’ll try another one. Let’s see how they’re doing here, okay. Right, okay, now, another one of these: let’s, there you go, good. Oh, impossible, okay. Right, now, look, Ryan, it’s okay. We won’t take too long on this. Now, what happens if one of these calcium comes through, right, that’s different. The calcium is coming through the NMDA receptor, right? That doesn’t get sent on. Now— MALE VOICE: Oh, [inaudible]. RICHARD MORRIS, PHD: —doesn’t matter. Great. But what happens now is it detects that it was a calcium, it comes along because it’s read all these papers from Irvine and it shoves in another AMPA receptor, right? Let’s put in another AMPA receptor here. We have got some more AMPA receptors now; we’ll put in one more because it’s detected all this calcium coming along. We have now got lots of AMPA receptors. Now, Ryan, you’re going to have to be really on your toes now because, right, here we go, here’s another one, and here comes another one, and they’re coming really fast now, and they’re coming really good. Come on. Come on, come on. We potentiated this synapse here. Okay, [laughter] give them a big hand. Thank you very much indeed. Thanks a lot, Chris, that’s good. Okay, great, thanks a lot; that’s super. Very good, Angie. That’s very kind of you; thank you very much for being a super volunteer. That’s great. Okay, that is sort of roughly how it works. Now, the truth is, of course, that that’s a sort of idea of the thing, but what’s behind this is a lot of very elegant biology. We have learned a great deal more about these receptors and the particular protein constituents of this receptor, and we now know very much more about the way in which the particular proteins fold through the lipid bilayer that constitutes the edge of these cells, and more about the various components of this receptor. And one of my colleagues in Edinburgh, sadly now left to join the Shanga Center, has also been working on the detailed components that lie behind this individual thing. Here from Holger Hoosey [phonetic] and Seth Grant [phonetic] is a list of all the various different proteins, in fact, not all of them, just some of them that are linked into this particular postsynaptic membrane, the various proteins that link in together. What starts with a simple kind of a concept that you can push more receptors out into the membrane and then builds, and this is the way in which this research goes, builds into a much more sophisticated idea about the way in which this protein machinery works together to make these plastic synapses actually do the job of altering the ability of the neurons to connect to each other. Now, that’s fine. We can get some understanding of this molecular constituency that constitutes these individual receptors, but what are they all about? What are they really for? Well, I wanted to say that they have something really critical to do with learning and to do with memory, and that we have circuits inside our brain that contain these receptors, and as a consequence of them containing these receptors, they are actually able to store information. Let’s try to do a demonstration of that with you all, and we’d like some of you, we’ll have a sheet of paper with some little sort of crosses of wires and things on it, and I am going to have a go at trying to give you in the same sort of way some sort of an idea about how all this works together. Okay, what I want to do is to try to explain to you the basic principles of how a network that’s in your brain might actually store information. And what you’ve got is a diagram with four of these things here, and they’re all blank, if you have a pencil or a ballpoint pen or something like that, then just scribble on it as you see fit. It starts off as a completely virgin set of wires. There are four vertical wires and four horizontal wires. And you can think of them as just wires sort of like an engineer would, or you can think of them as connections that might exist in the brain, a sending thing which we call an axon, or a receiving thing which we call a dendrite, and at the points of connection will be these NMDA receptors and these AMPA receptors. And as I tried to show you with pushing extra AMPA receptors in, we can make these synapses, these connection points stronger as a consequence of particular kinds of activity. Let’s store some information, and we are going to do this using a type of arithmetic called binary arithmetic, which is dead easy. It’s just zeros and ones. Many of you will be familiar with it. And we have got a message here and another message here, okay? And let’s say that 0011 stands for wrong, okay? For wrong. This level of analysis, I have been focusing on the neuron and the connection side of things. There is another kind of top end that I think is interesting which has to do, of course, with what all of us are interested in, in the human brain. It really is just the most amazingly complicated device consisting of literally millions and millions of neurons. It’s hard to really kind of capture just how much that is, but one nice little way of thinking about it is if you counted at the rate of one per second all the connections in the human brain with its 100 billion neurons, each with as many as 10,000 connections, lit would take you three million years to get to the end. It’s packed inside our heads; it is something of just amazing connectional complexity. Now, over the last 100 years, we have learned a great deal about the various divisions of the human brain, and we’ve got a kind of bald picture of how the back vision is controlled and at the front, things to do with attention and planning, and other areas involved in sensory motor function, perception, memory, motor learning, and so on. Much of our understanding of the way in which these different brain areas perform their different functions have come from the study of patients with brain damage, and what you see are very often selective loss of individual function. That selective loss can be something which, of course, is devastating for the individual, and the clinicians have to try to find ways of helping people in those circumstances. For the scientists, it can be very informative because it can give us insights from abnormal function into normal function. One of the things that’s come out of this is the sense that emanating from the back of the brain are a couple of major pathways, sometimes called the dorsal visual pathway, the top visual pathway, which people think is involved in the control of action, of learning where things are in the world, and a more ventral visual pathway down to the temporal lobe on the sides here, which is involved in learning about what things are. I mention this because some really interesting work with an unusual patient was done by some really lovely colleagues of Mick and I in the University of Saint Andrew’s some years ago, very interesting patient called Patient DF. He is nothing that special; I mean, there are lots of unusual patients, but let’s just take one to give you some sort of an insight into how these patients can actually tell us something unusual about the brain. Patient DF had damage to this more ventral pathway out in the temporal lobes, and he was unable to see things properly so that if you showed him a drawing of an apple and asked him to copy it, this is what he would produce. Yet, curiously, his memory was intact, so if you asked him to draw a picture of an apple from memory, he could do it; curious association there. A book: that’s his drawing, that’s a book from memory. Even better, maybe the sailing boat. He has shown a drawing of a sailing boat, this is his copy of that, and there is his drawing of the sailing boat from memory. It’s an amazing association. On top of that was something else that they then asked DF to perform a number of tasks, and they asked him to hold a little kind of piece of plastic at a particular angle to, say, a line, and this line could be rotated around a full 360 degrees wherever. It’s shown in one particular orientation here, but it could be rotated around. What D could do was as you can see, was sort of literally all over the place where the controls were dead accurate; it’s all aligned to up and down irrespective of the angle of the slot here, whereas D is literally all over the place, okay? But then, the patient, they said, look, don’t just try and match; post the letter through the slot, okay? Now, from the point of view of the visual and the dorsal pathways, the dorsal and the ventral pathway, the ventral pathway just can’t do it because she’s got this brain damage there. But when it comes to posting the letter, they’ll be using this dorsal pathway, and D very accurately post the letter through a slot that she doesn’t know what angle it took. You get these amazing kind of dissociations in consciousness that occur as a consequence of this kind of selective brain damage. That kind of thing can be extremely informative in telling us about the various different bits of the brain. On top of that, we’ve had all kinds of new techniques of functional brain imaging, and I know you have had lectures here before from real experts in this field telling you bits and pieces about this, I don’t need to tell you very much about the fantastic new kind of scanning systems and the way in which we can get insights into vision that Sammy Ezeke [phonetic] was one of the pioneers of doing, and of other techniques. The trick here is as you see these pictures in the newspapers, to recognize that when one talks about activation of a particular brain area, some important kinds of subtraction are going on, but one is getting these people to do first task A and then task B, you take pictures of the brain in both situations, and you subtract the two out. And if you can cleverly devise two tasks which differ only in one respect, you can identify a particular component of cognitive function and then see the areas of the brain that are differentially activated as a consequence of that specific component. One kind of amusing example of this was the recent study by Sarah Jane Blakemore [phonetic] from the Institute for Functional Imaging Cognitive Neuroscience in London in which she asked the question of why can’t you tickle yourself, right? We can [phonetic] tickle each other, we can’t tickle ourselves. She devised this sort of tickling machine that could be used while people lay in a scanner, and this was a thing where you could either tickle yourself or somebody could tickle you. I don’t know how funny it was when you are lying in a scanner, but anyway, she did that. She tried to ask the question of what particular brain area is activated when you do this experiment where you have tickling and non-tickling, and tickling yourself or somebody else tickling you? You can imagine the experiment got a little bit more complicated in the full experimental design. What she found particularly was greater activity in the anterior part of the somatosensory cortex when the tickling was externally produced, i.e., not by herself but by somebody else tickling the subject, okay? There were different patterns of brain activity for the same physical stimulus; it was a function of whether it was done by somebody else or done by yourself. You can see that in terms of this bar graph, this is the externally produced tactile stimulus giving you this differential activity. On top of that, she also found here in what’s called the cerebellum a decrease in brain activity that was associated with a movement that generates a tactile stimulus. It’s a kind of cancellation signal that is being generated so that when you are producing a movement, you produce a sort of internal cancellation signal, and that internal cancellation signal may, she supposes, this wasn’t really proven in the study, be a signal that somehow interacts between these brain areas to decrease the level of activity that would normally happen with this kind of tickling. Whether their study is fully convincing or not, I don’t know, but it gives you an idea of the way in which you can use functional brain imaging to give insights into processes like this. Another nice example that illustrates something of the subtlety of this is trying to figure out the difference between whether something makes sense or something is true [unintelligible]. I mean, does the brain use different brain areas to do this? Or does it use common brain areas? Peter Hagelto [phonetic] who works at the Donner [phonetic] Center in The Netherlands, devised some quite clever experiments which are published recently in which he gave people sentences like, there were lots of different sentences but like Dutch trains are yellow and very crowded, which is a true statement; Dutch trains are white and very crowded, which is an untrue statement but it is grammatically correct; or Dutch trains are sour are very crowded, which is grammatically incorrect as well as being untrue. Then, what he looked at was various kinds of signals in the brain beginning with an electrophysiological signal called the N400 and was able to detect that when you had a correct signal, you got a very small N400, but when it was either an untrue statement or when it was grammatically incorrect, you got a different kind of thing. They were dealt with a common kind of way as marked by this electrophysiological marker. And also, when you looked at the actual activation patterns, particularly in the prefrontal cortex, you found that it was activated both when the sentence doesn’t make sense and when it’s true. These kinds of little experiments can be done to try to get an insight into the way in which different aspects of cognitive processes could be utilizing different kinds of brain areas. What I am suggesting really is that what is happening at the moment in terms of the directions in which academic neuroscience is going and which will in due course have an impact on all our lives, is that there are two really different bits. There’s the sort of bottom-up and a top-down approach, and the bottom-up one is focusing on the nerve cells and the proteins in it, the genes that are activated, and learning something from that, and the top-down one is taking these more complex processes and trying to work down to think about the various brain areas that are activated or to look selectively at individual patients and get insights from that. That’s good. But the problem is how are these two approaches going to meet? And there is a real chasm I think at the moment in modern academic neuroscience which is at that middle level. There are people doing cognitive neuroscience like myself and like Mick who work in a kind of top-down fashion; we think in that kind of fashion. Then there are other people like many distinguished scientists here in Irvine who are working in this bottom-up fashion. And it’s often quite difficult to achieve a dialogue between these two different bits. I think that one of the major developments that is going to happen in the next 20 years or so will be real efforts to try to link these two things together at the level of networks and neurons and maps, and so on. Let me just give you one or two examples of little trends that are happening at the moment to give you a taste of the way in which things are moving along. Well, one of the things that we’re going to have to do much more of is not just recording individual cells, which goes on in animal experiments a lot at the moment, but to record large numbers of single neurons simultaneously because the brain is like a symphony orchestra; we need to have all of the instruments and to listen to all of the instruments to hear the music properly. We need to record all these cells, and very clever recording devices here, for example, a device called a tetrode [phonetic], can actually listen into lots of different cells simultaneously and differentiate between them and get insights into the different correlates that these individual cells might have. In a spectacular example of that, I think, from the work of John Donahue [phonetic] at Brown University, he trained monkeys to move a little pole, that green thing in the middle there, which would then move a robot arm, and he used these tetrode recordings to listen into the cells as the monkey did that. Eventually, he got to a point where he could just listen into the cells and the monkey didn’t even have to move the arm at all; it was what the monkey’s intentions were that he could record and move the robot arm. The monkey eventually was just simply thinking about moving the robot arm and succeeded in doing so, an amazing experiment when you think about it. Where is all that going in terms of our ability to actually listen into cells? John and others are thinking that there may be real opportunities there for developing various kinds of neural prostheses for people with problems that might relate to this kind of stuff. Now, another example that has to do with brain plasticity is that I think that we are all used to the idea that the brain controls our behavior and that different circuits control different aspects of behavior. But what perhaps we’re less aware of is that our behavior actually orders our brain; it goes both ways, so that if you engage in particular kinds of skills like learning to play tennis or something like that, then there will actually be changes at the neural level in your brain that correspond to your development of that skill. Of course that is happening, but you are perhaps not as aware of the extent to which the choices that we make in our life about our behavior and the things that you think about actually have an impact on our brain. One very striking example, to me at any rate, that illustrates this point comes from the work of Merganka Sir [phonetic], a very interesting academic at the Massachusetts Institute of Technology, and this is a spectacular experiment that he did which was to ask the question of whether these major brain areas that are devoted to vision or hearing or somatosensory function, are they genetically wired to just deal with vision and just deal with sound? Or might they be themselves influenced by the kind of inputs that they actually get? And so, he did the following experiment. It was actually done in ferrets, which turn out to be immature when they are born and it is convenient to use those animals, in which he took this particular nucleus of the brain called the medial geniculate nucleus, which is normally projecting up to the auditory cortex; it’s sending information about sounds up to the auditory cortex. And he blocked the connection from the areas that received the initial sound information, it goes from the cochlear nucleus through to the inferior colliculus down to the medial geniculate nucleus; he blocked those connections. The medial geniculus in what he came to call rewired animals didn’t have a sound input. As these animals grew up, this is on one side of the brain only, as these animals rewired, what happened was that the fibers growing from the eye, in addition to going to this nucleus, also went into the medial geniculate nucleus. And that means the medial geniculate nucleus, instead of getting a sound input from the ears, is now getting an input from the eyes, right? It’s a kind of proof of principle experiment. But this medial geniculate is still projected up to this area of the brain, which had we all thought genetically was an auditory cortex. He then asked the question, can this animal now hear the light? Right? [laughter] So a kind of sort of crazy question that scientists like to ask, and the answer is that it could. And although I can’t explain all the details of this, it turns out that in normal visual cortex, we have what’s called pinwheels, which are areas which respond to different angles of lines and things, which are shown as little points here where it goes yellow, green, light blue, dark blue, purple, red, and there’s a sort of pinwheel there like a little child’s toy. If you looked in the rewired auditory cortex, it showed pinwheels, too, which is a clear sign that it had become a visual cortex. The inputs that you give to your brain will determine a great deal about the actual way in which that area of the brain will develop. Now, this is a developmental thing, but here in Irvine, some very important work is going on on plasticity in the adult cortex, particularly in the auditory system that Norm Weinberg [phonetic] is doing. This is the kind of direction in which people are thinking about not just the brain controlling our behavior but our behavior having an influence on our brain. I think we underestimate the brain’s capacity for plasticity and human individuality reflecting interaction of genes and the environment and so on, and behavior [unintelligible] changes in the brain structure as much as depend on it. And so, what directions will all this go? I think we are going to have greater appreciation of integrated neuroscience and all kinds of new technologies. Now, let me come on to my second answer, my last two will be much shorter than my first, which have to do with the fact that neuroscience is increasingly wanting to conduct needs-driven research with therapeutic potential, finding new drugs, and here again, memory and plasticity will be a major theme. [unintelligible] the Queen has this lovely custom in Britain of sending telegrams. In 1962, she sent 200 telegrams to people who reached the age of 100. I guess telegrams don’t happen now, but I don’t think the Queen uses email. I don’t know quite what she does. She sent 3,800 letters just a couple of years ago. To put that on a slightly more scientific footing, if you look at the demography of Scotland, a country with five, six million people, then at the beginning of the last century, this is what it looked like: lots of very young people, a lot of infant mortality, and so on, people lived to 90, they lived to three score years and ten, and so on. But relatively few did so. But if you look at Scotland in 2031, this is what it looks like. And I bet it’s the same probably here, perhaps a higher proportion; you’ve had a bit of a baby boom, so probably a higher proportion of younger people. But right across the developed world, many more older people, and so there is a lot of attention to trying to ensure that this good thing, that we’re living longer, can be sustained into healthy living in old age. Now, I like to think of myself as a young man, but I am aware that the years are going by. And like perhaps one or two of you, I suffer from moments of benign forgetfulness as well. And I should tell you a little story, slightly at my own expense, about this is that I recently had to make a trip about a year ago to London on business, and I flew down and I got into London and I got on what you call the subway, the underground. And I had to make a change at Oxford Circus onto another line to get to where I wanted to go to. When I got out of the train in Oxford Circus and onto the platform, I suddenly realized I had left my coat on the carriage. Fortunately, I was sitting in the front carriage, and so, I rushed up to a member of staff and I said, oh, I left my coat, you know, can I get it back? The train was pulling out and stuff. He said, look, run up to such and such an office and they will phone through to the next station, and I am sure somebody can go get your coat. I ran out and they phoned through and they gave me a seat to sit down at and wait, and indeed, two stops later, some member of the public had handed in my coat, and it was two stops down the line. I was told to get back on the line, go down to this place to pick up my coat. I went down, I got on the train, and as the train was pulling out, I realized I had left my bag back at the place where they had just phoned through. I went and got my coat, and the rest of the journey, I was trying to think how am I going to explain to them going back to the place. I kind of summoned up the courage and they phoned back to them, and indeed, my bags were there. I had to get back on the train and go back, and finally, I was reunited with my coat and my bags. I thought, this day is not going well. I will give up on the subway and go take a cab. I went out and got in a cab, and I don’t know whether you know London cab drivers, they like to chat. I was telling this story to the cab driver, and he was interested. And then he said, what do you do for a living? I said, well, I’m a memory researcher. So the next time you get in a cab in London and he says, have you heard the story about the memory researcher, it’s all-true. Oh, dear. Well, people have discovered that there are various genes that are important in Alzheimer's disease. One of them is called the amyloid precursor protein, and there are alterations in these genes that actually predispose people to actually have Alzheimer's disease. It’s a very small proportion of people. Once those were discovered, it created the opportunity for developing a particular set of ideas called the amyloid cascade hypothesis about the development of Alzheimer's disease, and that, in turn, then led from this human neurogenetics to building animal models, and one of the very important ones built here in California just up the road in San Francisco is something called the PDAPP mouse; no matter what that stands for, it’s an APP mutant where you build this human gene into the mouse. Lo and behold, that mouse, as it gets older, starts to develop these amyloid plaques that are one of the hallmarks of Alzheimer's disease, and deposits them over a much shorter period of time than happens in humans. I mean, it’s not a forgone conclusion that this mouse experiment would have worked, but it did. I had a chance to do some experiments in which we used a little device that I developed called a water maze, and here is a mouse swimming around in a pool of water trying to find a little platform that is hidden underneath the water there. And this is what is called a control mouse, so he is not one of these, he is actually a littermate of one of the Alzheimer's mice, and he can get to that platform relatively easily. Let’s just do that again. He’s been put in, he’s got a chance to see all the cues around the room here, he’s been trained for a while and he can get himself orientated, then swim over directly to find that platform. So that’s pretty good. Now, let’s put an Alzheimer's mouse in. Go for it. Oh. It’s terrible. But he gets there in the end. Using little tricks like that, we have developed ways in which we teach them a whole series of problems, one after the other, to try to work out what’s the kind of learning capacity of these animals, and try to get an idea of what the impact of this mutation is having upon them. When we do that, what we find is that when you test these animals repeatedly, the nontransgenic guys, they can learn about nine problems, and as they get older, they maybe drop down to about eight problems, you know, the sort of benign forgetfulness like I was showing you. But these APP animals show a precipitous drop and it’s highly significant statistically. That’s great because then we have got data that complements this pathological work and indicates that you can get progressive disorders of memory in this animal model. Now, I mentioned that it’s not just because this was work that I was involved in, but yet again, I mean, it’s an example of just the incredible position that Irvine has in the world. Some really fantastic and even more exciting work than this is going on here in the lab of Frank Lafarlo [phonetic] who has developed an even more accurate model of the human disease than this particular animal, and making great strides in his research. Now, the company that was involved in this also got involved in the idea, really radical exciting idea that you might vaccinate against Alzheimer's disease, and they developed a vaccine against this compound, A-beta 1-42, and you can see it completely clears these plaques in the brains of these mice. So both of these mice are APP mice, but the vaccinated mice don’t have these plaques, a very, very exciting result. Unfortunately, the dosing had to be suspended just about 18 months ago, two years ago, due to unexpected inflammation in a small number of patients. So that was a disappointment, but the company hasn’t given up nor have the academics given up. There has now been one paper published, I think maybe another one just recently by James Nichols [phonetic], one of the people in the European studies in Southampton, and his study indicates that while nothing much happens in the vascular system in the brain at large, then this vaccine really was working; in the one patient that he had, you could see much reduction of the amyloid plaques. There are problems, there are always problems in research; it’s difficult to kind of chug things through on this way. As Dale Shenck [phonetic] who was the inventor of this approach said, many clinical trials will be necessary before we know whether this vaccine or other treatment will be effective. It’s going to be a long haul. I think there is hope, and it’s built upon the solid foundation of basic research. What I want to say is that needs-driven research is going to actually, I think, transform our lives in all sorts of ways in the 21st century. The particular example I have given of Alzheimer's disease, understanding the neurobiology of disease, the basic science is important, and the progression on to ways in which these things are actually affecting synapses and connections in the brain. Now, there are lots of others things, I don’t really have time to talk about, but I’d like to conclude in the last few minutes just with a bit about public awareness. I think we as neuroscientists share a commons desire to build a greater public awareness of brain research, and to engage a wider community in contributing to the decision-making about priorities for research and the ethics of its application. I think from our side at any rate, we see this as a two-way process. You guys are not to be patronized at all; it is not a matter of ask the experts telling you. That day is over. It’s a desire I guess that you have to hear about what is going on, but also to empower you to help shape priorities in terms of your discussion with us, with politicians, and with other opinion formers, and understanding that scientists disagree with each other, that it’s not just a collection of facts which we all agree about. We argue like hell and have this tradition in Britain of arguing all the time and then going to the pub together afterwards, which is a good way to do science actually. It really is a good way to do it. And then, new kinds of publishing ventures are coming on the scene, which I think will start to have an impact upon people’s lives. We have Brain Awareness Week developed here in the United States where we try to tell people a little bit about the brain. In Scotland, here is my colleague Debbie Duerr [phonetic] at the Glasgow Science Center showing kids about bits of, showing bits of brains for them to play with, and I think that that is a great activity. In England, a wonderful girl called Lizzie Burns [phonetic] got a grant from the Medical Research Council where she went out to primary schools and got them to make, here is an optic nerve made out of wool, I think it’s a bit of wool laid across the thing, and there is nerve cells and stuff. I think that’s a great way to try to introduce kids to the fact that this stuff inside their head is really important. Maybe they’ll wear their helmets when they are riding their bikes a bit more often if they do that. That’s a good thing. On a slightly more serious note, I think the business of getting brain research stories into the media for people to talk about is a difficult thing. I’m a little bit worried about the amount of hype that there is, that so many stories certainly in the British press, they talk about gene discovered for this and then they end with a claim that this will lead to some new drug. I actually think patient advocacy groups are getting a bit tired of that because I think—. |
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