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2    Charlie Rose: The human brain is perhaps the most complex object in the known universe. It contains more neurons than there are stars in the Milky Way galaxy. The brain dictates all of our mental life from the simplest unconscious process, such as breathing, to the most complex philosophical thoughts and emotions. In short, the brain makes us who we are. We begin this evening a 12-part series exploring one of sciences final frontiers, the study of the human brain. Tonight, episode one will examine the great mysteries of the brain. For thousands of years civilization has pondered the origins of thought, consciousness, free will, and emotion. Until recently these questions were the province artists, philosophers, religious leaders, psychiatrists, and some scientists, but in the past few decades biology has emerged as a tool with which we might solve some of life's greatest puzzles. We have learned more about the brain in the past five years than during all of human history combined. This knowledge has been driven by advances in technology. The decoding of the human genome allows us to look further inside our brain cells than ever before, providing a window on how genes dictate brain function and behavior. Developments in scanning technology also offer scientists unprecedented access in to brain activity. New discoveries could someday promote mindfulness, increased cognition, and offer treatments for disease. The hope is that someday terrible illnesses such as depression, schizophrenia, and Alzheimer's will be history. Each month I will interview the most knowledgeable scientists and researchers in hopes of illuminating a new topic of study. Our subjects will enclose perception, social interaction, aging and creativity. By the time we complete the journey I hope you will share me curiosity and fascination with this wonderful and remarkable organ. We are honored and very fortunate to have as our colleague on this journey Dr. Eric Kandel. He is, as you know from watching this program, a psychiatrist and neuroscientists and professor at Columbia University. He's also affiliated with the Howard Hughes Medical Institute. He received the Nobel Prize in physiology or medicine in 2000 for his research into the biological mechanisms of learning and memory. So this is going to be for me and for him and for you a rather remarkable step as we explore this extraordinary thing that you have spent your life trying to understand. So what can we accomplish? 
303:15
4    Eric Kandel: I think we can accomplish something extraordinary. I think we can try through your approach to knowledge, a roundtable discussion, to provide a systematic view of how brain gives rise to mind, of how the various neurocircuits of the brain account for our ability to think, to act, to perceive, to feel, to explain all aspects of human cognitive functioning. And also to get some insight in to the terrible diseases that haunt mankind. As you mentioned, schizophrenia, depression, anxiety states, post traumatic stress disorders -- these are horrible disorders, enormous burdens for individuals in society. And in each program we are going to begin by trying to understand the basic underlying biology of a particular mental function and then focus in on one or more diseases that are associated with these mental functions. 
503:50
6    Charlie Rose: Let me start with some of the basic definitions, because you mentioned two of the words, "brain" and "mind." What do people like you who have spent your life dedicated to understanding brain and mind, understanding first the psychiatry then later the science of the brain? 
704:03
8    Eric Kandel: Mind is a series of functions carried out by the brain. Every single thing that you and I do, every aspect of our behavior is carried out by the brain. From the most simple reflex act -- hitting a tennis ball, running, riding a bicycle, to the most creative aspects, running Charlie Rose program, these things are all carried out by the brain. 
904:28
10    Charlie Rose: There's a velocity about how much we learn. 
1104:34
12    Eric Kandel: It's incredible. You pointed this out. I would say our progress extends over more than the last five years, but the last five years have been spectacular. But what is interesting, and you pointed this out, people have been thinking about the mind since -- 
1304:52
14    Charlie Rose: Since they thought about human kind. 
1504:55
16    Eric Kandel: The Greek philosophers were thinking about this. But in the first 19th century, people were limited to the tools of philosophy. Then psychology began to be a powerful discipline. Then brain sciences came along. And what's happened in the last few decades is these fields have come together. 
1705:24
18    Charlie Rose: You are trying to bridge them together. You and -- 
1905:34
20    Eric Kandel: Many of us. You and I are going to do this in this program. but what the field has done, it has brought psychology, brought brain sciences, brought molecular biology, brought all this together. And just like we focused on the gene as being the target of biology in the second half of the 20th century, there's every reason to believe that the mind is going to be the main focus of biological sciences in the 21st century. And this is a problem that's going to take a long time. 
2106:09
22    Charlie Rose: This is the frontier. 
2306:12
24    Eric Kandel: This is the frontier not only in biological sciences. I would say if you ask most scientists in the world what they think is the most difficult challenge, they would say understanding the human mind. Look, Charlie, we've undergone in the history of mankind a number of intellectual revolutions. The Copernican revolution, the Newtonian revolution, the Darwinian revolution, the Freudian revolution. What is the nature of creativity that gives rise to that? If we understand the human mind, we understand what allows people to think these unusual thoughts. 
2506:53
26    Charlie Rose: As I said, understand how we are wired and how we are human. 
2706:59
28    Eric Kandel: Exactly. 
2907:02
30    Charlie Rose: And these fascinating questions, like where does intelligence come from and how is it shaped? 
3107:08
32    Eric Kandel: Exactly. And how does creativity and intelligence interact. 
3307:14
34    Charlie Rose: This is incredible journey. I don't know that I have ever looked forward to going on a journalistic and scientific trip as much as I have this one. 
3507:23
36    Eric Kandel: I feel very much the same way. I would just elaborate and say one additional thing. This is going to be a wonderful opportunity to move education, if you will, in a new direction. You've provided a roundtable format for modern intellectual history. You bring together low brow, high brow culture, and the same intensity. We now want to do this to the biology of the brain. We want to see to what degree can we communicate this complex topic in straightforward, simple terms so that everyone can understand it, and with the excitement and spontaneity that can only emerge from roundtable conversation. 
3708:02
38    Charlie Rose: One thing that always comes up when I talk to a lot of wise people, and I always say to them, tell me one question that you've always wanted to know the answer to. Frequently they say what is consciousness? Why is that an interesting question? 
3908:13
40    Eric Kandel: Consciousness is an interesting question because I cannot determine what is going on in your head. Why you feel a particular wa about something is something only you can experience, only you know about. And there is no way that I have immediate access to that. Now, maybe someday we'll have way of visualizing your correlates of consciousness, but at the moment we don't have that. And this is the most mysterious problem in all of brain science. And since brain science is the frontier of all science, it's probably the most difficult question in all science. 
4108:35
42    Charlie Rose: But it's also the kind of question that people in humanities have always asked. 
4308:40
44    Eric Kandel: Absolutely. The wonderful thing about brain sciences, which you have implied, is that it's a natural bridge, like an Esperanto between the humanities and the sciences, because the sciences are concerned with the nature of human existence, and that's the function of the brain, human existence. So bringing these two areas together, which hopefully will come, whereby neuroscientists will address some of the issues that concern humanists, and humanists who begin to interact with scientists, will be really a wonderful advance. And we've seen this in psychology. Most psychology departments and most brain science departments are indistinguishable from one another. People in psychology departments are doing imaging experiments and asking various similar kinds of questions. So we can ultimately see a dialogue between disciplines. For example, how we respond to works of art is something that in principle brain sciences should be able to address. 
4509:28
46    Charlie Rose: Here is one of the things about the brain that I have always found fascinating. It's always changing. 
4709:38
48    Eric Kandel: That's right. 
4909:42
50    Charlie Rose: My little brain will be different at the end of this conversation than it was at the beginning. 
5109:47
52    Eric Kandel: And after the whole series you'll be completely different person. 
5309:51
54    Charlie Rose: But everything we do makes the brain different. 
5509:53
56    Eric Kandel: Absolutely. 
5709:55
58    Charlie Rose: Drinking this water makes it a different brain. It gives me a different experience. 
5910:00
60    Eric Kandel: This not only explains how we grow intellectually, but it also explains the enormous capability that the brain has to recover from damage. This is also another reflection of plasticity of the brain. We also will consider that in this series. 
6110:10
62    Charlie Rose: So in the end, I may come out of this with my brain changing so much I want to wear a bow tie. 
6310:14
64    Eric Kandel: That would be wonderful. I'd be glad to give you one. 
6510:19
66    Charlie Rose: And we'll have fun on this series. 
6710:21
68    Eric Kandel: We'll have a terrific time. 
6910:23
70    Charlie Rose: We begin with a reminder that the brain is at the center of our individuality and our existence. For 18 years on this program we have talked to some of the most fascinating brains in the world. Tonight we begin with four of the leading minds in their field. John Searle is one of the best known philosophers in the western hemisphere. He has taught philosophy at the University of California Berkeley for 50 years. His recent work has incorporated discoveries from biology in to the philosophy of free will, rationality, and consciousness. Gerald Fischbach is a neurologist and a scientific director of the Simons Foundation. He has spent a lifetime studying the connection between brain cells known as synapses. His current research concerns brain disease such as autism. Cornelia Bargmann -- she has performed groundbreaking studies on the brains of microscopic worms. Her research offers insight in to how genes control the function of our brain cells. She is a professor at Rockefeller University in New York. And Tony Movshon -- he studies vision and perception in both primates and humans. His lab at New York University focuses on the development and function of the primate visual system. We begin with Tony Movshon as he introduces us to the anatomy of the brain. 
7111:48
72    Anthony Movshon: What we have here to the beginning of very brief tour of the structure of the human brain. We're looking at a computer generated image of the left hemisphere of the human brain. Now, this brain is covered, as the human brain is, most prominently by the structure called the cerebral cortex, which is this gray mantle of tissue which is really almost all that is visible when you look at the human brain from the side. And the cerebral cortex is the main computing machinery of the brain, and it's also the part of the brain that's most highly evolved in humans compared to our ancestors in the animal kingdom. Now, we customarily divide the cerebral cortex into four lobes. And the four colors in the image here show you the four lobes and their positions. The four lobes have many different functions, but we characteristically think of them as having a number of sort of primary functions. The occipital lobe here shown in red at the back of the brain is the main seat of visual function. That is lobe which is particularly dear to my heart because it's the system of the brain that I work on. The temporal lobe, here shown in green, is involved in number of complex functions. It's involved in higher processing of visual information. It's involved in the laying down of memories. And it's involved in the processing of information about sounds and in the conversion of information about sounds into linguistic representations and into the programs that allow us to speak and understand language. The parietal lobe, here shown in blue, is sort of the central spatial orientation organ of the brain. The parietal lobe combines information from multiple senses, including vision, hearing, and touch. And it formats motor commands, output commands for the muscles, which allow the body to be oriented in space with respect to the stimuli in the environment. So when you navigate in the world, when you look around the world, when you decide what parts of the world to pay attention to, it's the parietal cortex which is doing the bulk of the work. Finally, in purple here, is the frontal lobe at the front of the brain. The frontal lobe is the most highly evolved part of the cortex in humans. It is the part of brain that is probably most directly responsible for making us human. It is the part of the brain that is responsible for decisions, for actions, for many functions that are often now called executive control functions -- deciding what to do, where to go, what to eat, what to say, probably more importantly what not to do and what not to say and where not to go. And so it's the ultimate sort of seat of central control in the brain. So we're now looking again at the view of the left hemisphere of the human cerebral cortex. Now, the cerebral cortex looks like a cauliflower in this kind of view, and that's the way we tend to think about it. But it is in fact a very elaborately organized sheet of cells which has been folded up so that it actually fits inside the cranium. The way to visualize that is the following. Imagine that the brain's computing machinery is actually flat like this piece of paper. But skull is not well suited to accommodating a flat piece of paper. So what do we do to accommodate it in the skull? Well, we basically crumble it and fold it and we create a series of folds. And in the next video clip, which was prepared by my colleague David Van Essen at Washington University, what we're going to see is that process in reverse. We're now looking at the right hemisphere, and this is actually a computer-generated-image, generated from magnetic resonance imaging data. And it's been colored so that the light-colored parts of the image represent parts of the brain near the surface of the skull, and the dark- colored parts of the image represents parts of the brain that are buried deep within the folds, which we call sulfide. Now, in the first section of the film, I'll just spin this around so that you can see the three dimensional structure of what we're looking at, which is, of course, similar what we have seen before. And in the next segment of the film what we'll do is treat this brain as though it were made like a child's balloon out of rubber that we can inflate it just by pumping air into it. So the brain gradually inflates. The things that were colored dark to indicate their depth in the brain are still dark so you can keep track of what was deep in the sulfide and what wasn't. But now you have a much simplified form, what we call a semi-inflated form. Finally, the last stage of this process is to flatten this semi- inflated form out in to a completely flat sheet. And now what you can see is that this cauliflower structure that we are used to seeing in the brain as this elaborately folded cerebral cortex is in fact a single flat sheet of cells. Now, this particular sheet shows by its coloring how deep in the brain the structures were. But when we talk in the course of the series, as we will, about localization of function in the brain, and talking about different parts the brain performing different operations, what we'll be talking about is different regions which are most conveniently and most accurately visualized as living on this sheet, the unfolded sheet of the cerebral cortex. 
7316:52
74    Charlie Rose: Picking up on that lesson is our conversation at my regular table with our group of scholars for episode one of the brain series. 
7517:01
76    Cornelia Bargmann: So Tony has given you the big particular of looking at the whole brain. And my perspective on the brain goes down to the exact opposite, to the individual units that create the brain, and in particular to the genetic units that allowed the human brain to be what it is. So in the field of genetics right now there's tremendous excitement because in the past 10 years or so we have decoded the human genome. And that represents the complete set of instructions for building this marvelous organ and for building into it the capability of generating unique human creative actions. So the reason that all humans can generate language is that humans have special genes that distinguish us from the animals that allow the brain to do things that animals' brains cannot do. And we have now this instruction manual. There are 25,000 genes. It's sort of like everything an encyclopedia with 25,000 entries. And we are in the position to try to understand what those entries make possible. So what the individual genes do to help to create this structure, to create the different parts of the structure that make different parts of it differ from each other. Tony just told you about the shell of the brain. There are parts deep within the brain that carry out fundamental processes like controlling our motivations and our emotions that are also under strong genetic control, and trying to understand what it is that allows these 25,000 units to create this -- ( AUDIO GAP) 
7718:40
78    Eric Kandel: -- is determined by genes versus learning? 
7918:45
80    Cornelia Bargmann: That's the essential question. And the answer is that it is that parts of behavior are determined by genetic programs and parts of behavior are determined by experience. And you can point to examples that are almost entirely one or the other. So, for example, our ability to see colors and to distinguish colors is something that is encoded by three specific genes, expressed within our eyes that compare blue and red and green to each other and split them up. And if you're missing one of those genes you're red-green color blind. And there's no amount of thinking you can do to solve that problem. That gene has determined something about the way you can perceive the world. On the opposite extreme, the fact that some of us speak English and some of us speak Chinese has nothing whatsoever to do with our genes. It's completely determined by our education and our experience. And furthermore, how well we speak English and Chinese is determined by when we have those experiences. 
8119:57
82    Eric Kandel: Because we ultimately want to understand the greatest aspirations of the human, greatest capabilities of the human mind, not only the ability to have consciousness, but to have consciousness by oneself. And I think you thought a little bit about those. 
8320:11
84    John Searle: A fair amount. But I have to say that I agree with you, Eric, that the most exciting question today for me in the sciences -- maybe we should throw in some other sciences like quantum mechanics, but in the biological sciences the most exciting question today is one we're talking about here, and that is how the hell does the brain do it? How does the brain produce consciousness? And the problem I have with a lot of neurobiology is they tend lose sight of target. They would like to know how does the brain mediate the stimulus with the behavior. That's great. But I want to know how does the brain produce this remarkable experience of qualitative unified subjectivity? All experiences we have, everything -- the smell of the rose, the depression you feel at your income tax, the sound of Beethoven, pick your favorite, the angst of post-industrial man under late capitalism, whatever is your favorite experience, it's all produced by variable rates of neuron firings in the brain. And that's why I'm here. I want you guys to ask that question for me. 
8521:09
86    Eric Kandel: We need your help. You can find the easy problem of consciousness in the hard problem. Why don't you a little bit elaborate on that? 
8721:16
88    John Searle: OK. The easy problem, and it's not all that easy, is to try to figure out what are the neural biological correlates of conscious experiences? And with imaging techniques we're now off and running with that. I mean we could do things today that would have taken the breath away of Sherrington, let's say, because we have imaging techniques that didn't exist before. That is the easy problem, is just to find some kind of correlations between the experiences that people have and the areas of brain that are active when they have those experiences. The hard problem, and it's hard to phrase this problem exactly, but it's roughly speaking, how does the brain get over the hump from neuron firings to human feelings, the human, animal feelings? Now, people sometimes say, consciousness is hard to define, but I think we're just talking about not the analytical definition that comes at the end of the investigation, but the common sense definition that identifies the target is not so hard to define. The consciousness is these states of qualitative feeling or sentience or awareness. They begin in the morning when you wake up from a dreamless sleep and they go on all day until you go to sleep again or otherwise become unconscious, and they have these remarkable features. One, there's always a special qualitative feel. Listening to music is different from brushing your teeth. There's just a different qualitative feel to it. Secondly, it's subjective. It's all going on in me. And I am pretty sure that something goes on in you that's like what goes on in me, but I have a relation to my own consciousness which is not like my relation to anybody else's. And third there's this remarkable feel -- it's unified. So I don't just now feel the shirt against my neck and hear the sound of my voice and look at all the people around the table and see these wonderful statues of the brain, but I have them all as part of a single, unified conscious field. Now that is a remarkable achievement that the brain can do that, that the brain can create all of this stuff. And I'm leaving out all these other interesting things like memory and the capacity for language and so on. If we can just figure out those -- I think that is the prerequisite to being able to get into creativity and such things as free will, because the problem of free will arises because we have different kinds of consciousness. 
8923:37
90    Eric Kandel: I think it's also important to realize that understanding the brain, the issues that we've outlined so far, are likely to give profound insight into diseases of the brain. And Gerald Fischbach is one of the people who has thought most profoundly about this. 
9123:56
92    Gerald Fischbach: I've thought about it over my career at the NIH and medical schools around the country. And I think that the time has arrived when I want to talk about it from two directions. Insights in to neuroscience now are really poised to make major contributions to our understanding of devastating neurological disorders ranging from the aging spectrum of Alzheimer's disease to diseases in the prenatal period. And it's because of the genetics and the profound sensitivity of biochemical approaches, new methods of recording from the brain, and from the much better understanding of the neuro-anatomy. I also want to make a point, and it will come out during our discussion and several subsequent sections. I want to point out how much disorders of the brain have contributed to our understanding of fundamental processes. The example, Eric, I've heard you cite I agree with is Paul Broca, the man who began us down the path of localization. He became very interested in people who could not speak, who were aphasic, and the phrase, and he was also a skilled neuropathologist. And when he finally did an autopsy on an individual who could not speak, he found a syphilitic lesion, an area of degeneration caused by syphilis just in that area, and he drew the correlation -- 
9325:27
94    Eric Kandel: Part of the brain on the left side. 
9525:29
96    Gerald Fischbach: Yes. He drew the correlation between that lesion and the inability to speak, and hypothesized that other functions would be so localized. And that opened the doors to localization. Another example I'm very familiar with because I've spent a lot of time working on and thinking about is how much our study of Parkinson's disease has contributed to our knowledge of circuits that are deep within brain that feed up to the cortex. The region called the basal ganglia, which now we know is much more involved in the control of motion, involved in motor control, it's involved in emotional life and certain aspects of cognition. And it was a mystery, I think, until people really delved in to the issues related to Parkinson's disease. 
9726:20
98    Charlie Rose: Tell me a bit about the brain and memory before we ask some general questions about how we solve these issues that we have raised. 
9926:29
100    Eric Kandel: Right. What we've learned about memory is that memory involves an alteration in how nerve cells communication with one another. And that will become even clearer once Gerald Fischbach gives us an outline how the nerve cells function. Nerve cells communicate, as he will show, through a point of contact called the synapse. And what happens with learning is the strength of these synaptic connections change. In short term memory when you learn something very briefly and you forget it in a day or so, it's a functional change. There is no change in anatomy. But if you learn something for the long term by repetition or listening to this program drawing all of your attention, there is a change in the expression of genes, not a mutation, but an amplification of how well a gene is functioning. And that leads to the growth of new synaptic connections. So if you remember this program the next day, it is because anatomical change occurred in the brain. And we hope that the people listening to these set of programs will walk out of the series with a completely different set of connections than they walked in to it. And one of the points that Gerry will make how fundamental to understanding the brain the individual unit is, because it carries with it the capability for changing. 
10127:51
102    Gerald Fischbach: I've actually done this a bit at a time on larger board. But I just want walk you through this. Basically nerve cells are the building blocks of the brain, and whatever we do to understand the genetic composition or the environmental influence must take these cells into account. Nerve cells are cells just like any other cell. There's a cell body, there's a nucleus that contains the genes. The genes encode proteins, hormones, enzymes, structural proteins that are extruded out to in the cytoplasm. There are many of these nerve cells in the brain. Some people estimate 100 billion nerve cells, more than there are stars in the Milky Way galaxy. But they're very different kind of cells and they're particularly vulnerable cells. And let me try to explain why. Soon after the nerve cell develops it's basic pattern, it begins to extend a process. One such process is called the axon, and it also extends processes called dendrites. Way back in the turn of the 19th century, turn of the 20th century, Ramani (ph) Kahal (ph) remarked that neurons are polarized. They receive information at one end and transmit it another along the axon. The dendrites are called dendrites because they're like a forest, a tree, whereas the axon grows and continues to grow and grows and grows. And for purposes of representation here I've put little breaks in them. But if this cell, which is a few hundredths of a millimeter in diameter, only observed in microscope, if this axon was drawn to scale, the cell I've drawn here would extend from this studio on 59th street to the other side of Central Park. It would extend that far. And there are hundreds of thousands times volume of cytoplasm in these processes than there are in the cell body. That's one thing that makes the neuron so vulnerable. These genes have to work hard to make protein and the energy to maintaining this cytoplasmic structure. The other thing that's extraordinary about these cells is they generate signals which will end up at the synapse. And they generate electrical pulses which are brief, about a thousandth of a second and about tenth of volt in amplitude. And many people feel that the information in the nervous system somehow is encoded in the frequency or the detailed time structure of these impulses. They are conducted at various rates, and big neurons are conducted about a hundred miles an hour. It's not as fast as an electron. And if you place an electrode near them and amplify the signal, you can actually hear them. Those little beeps are sounds of the electrical activity. Is there a second one there? This is a light being shown in the eye of an animal. And when it comes on you will hear the activity of the nerve cells. That's just one nerve cell, deep in the brain. Every time that light comes on you can hear a burst of activity. So our brains are continually active, even when asleep. And all this takes an enormous amount of energy. If blood flow is cut off to the brain for a matter of seconds, these cells will die, whereas if you cut off blood flow to intensely contracting muscle, it will survive. It will survive for minutes, many minutes, half an hour without blood flow. But these are using much more energy every second of the day and night than our muscle cells when they're contracting. So when these impulses reach the end of the axon, they contact the next cell in line at the dendrite by these structures called synapses, and that's what many of us have studied through much of our career. For every nerve cell there may be up to a thousand synapses, so a hundred billion times a thousand is a lot of synapses. But I don't believe, and I know no one here believes that's where the complexity lies. The complexity of the nervous system, if we're going to deal with this, lies in how these synapses change as a function of the genetic instructions and as function of experience. Listening, life experiences, and they do change. And as many have pointed out, these synapses grow, they form, they retract. The brain is not hardwired. It is within limits, there is an architecture to the brain. But on the micron scale is great deal of flexibility. 
10332:54
104    Anthony Movshon: One of the things that I think is very important to keep track of when you have something like this in front of you -- we often think of the analogy of the brain as computer. And in fact the brain of course is an organ whose job to process information. So it is a computing device. But the brain works the way it does because it's made of meat and not of silicon and copper. And so the fact that these axons transmit impulses at a hundred miles an hour is not the same as a computer sending a signal the speed of light. And the fact that each of these axons makes many variable contacts through chemical means with other cells is very different from connections to a transmitter or resister in an electrical component. So we may use the computer to try and help us understand what the brain is doing. But John among others has talked a lot about the fact that the reason the brain works as it does is because it isn't made of silicon. It is made of meat. 
10533:44
106    John Searle: It's a specific causal mechanism, we have to respect its specific biology. And for long time the computer metaphor was really an impediment in cognitive science because it led people to the illusion that the anatomy doesn't really matter. All that matters is the program, you get the right program. And I think for a whole lot of reasons that's a very unintelligent view, and I think we're getting out that have view. We have to, and what I like about this particular group is we all respect the anatomical, biological specificity of the brain. It's not an accidental organ. You can't do it with just anything. 
10734:17
108    Gerald Fischbach: What I want to say one more word about is these cells are organized in to circuits. And the circuits are very meaningful. And those are organized into larger ensembles. So they go from a gene alteration to a circuit that can explain a simple behavior, I think, is one -- will be one of the great triumphs of neuroscience. 
10934:39
110    Cornelia Bargmann: When we look how brain is set up, we have these genes and we have a set of problems. We have to make a lot of different brain cells, we have to make, as you said, billions of brain cells, and they're not all the same. It's not just making one thing a billion times. Actually, we don't know how many different kinds of brain cells there are. We don't really know if there are a few hundred or many thousands or more than that. And so something about which genes are being used strongly and which genes are not being used in one cell makes it different from the other cells in the brain. So first you have question of dividing out function and saying I'm going to be using some of these genes you're going to be using some of those genes. And that's going to make me really good at controlling emotion, and that's going to make you really good at sensory functions. Then you have to connect these guys together. You have billions of these guys, and they each make thousands of connections. So you have trillions of these synapses. And those synapses are not being made at random. The brains are connected to each other in patterns that are quite orderly and are reliable between different individuals. Now -- and what you find -- you can think of these as something like roads of a traffic pattern. The highways in everybody's brain are the same. The big pathways that link thousands of nerve cells together are very orderly and there are precise genetic instructions that tell the brain how to lay down those highways in different places. But then there are smaller roads that are partly genetic, and then if you have the little cow paths, the sort of small connections, the local connections, those are controlled by experience. And that is one of the miracles of the brain, it was really Eric's discovery and contribution to neuroscience that an experience in your life, that emotion that you feel, that a thought that you have is turned in to a biological, physical reality by your brain. It's the dualism in reverse. 
11136:36
112    Charlie Rose: You work with worms. 
11336:39
114    Cornelia Bargmann: I do. 
11536:41
116    Charlie Rose: And tell us about that, what your research is about and what you are learning as you have explored some of that. 
11736:50
118    Cornelia Bargmann: This is the -- when we sequence the human genome and we looked at the 25,000 genes, one of the things that came as a surprise is that very few of them are brand new, that the genes that we have are very old genes, even though we're a very new species. So in the process of making these brains that are so much more bigger and more complicated than animal brains, we didn't take a lot of new genes and suddenly build a -- have cortex genes and growth genes and Broca's area language genes. We took the genes that we already had, these old genes that we share with animals, and we tweaked them and we used them in different ways and we turned them up more and we used them for longer periods of time and we built these structures. So the genes act as a thread that connects our brains to the brains of much simpler animals. And if you're trying to think about these billions of neurons and trillions of connections and you really want to understand how they're all set up, well, good luck with that. Don't forget to write. So what we try to do is we try to work with much simpler brains, where there are smaller numbers of cells, where there are smaller numbers of connections, where we can often name a cell and we can watch a connection when it's forming and we can say exactly what that connection is going to do and what that cell is going to do in an animal's brain, and yet know that certain things about the genes in that cell and certain things the way that pathway is built are going to be used in much more complicated brains. 
11938:26
120    Gerald Fischbach: I bet you'll get that call sooner than you think. I believe there may be -- you use the phrase, which I wanted to touch on, which genes are used. Everybody in the audiences realized that every cell in the body has exactly the same genes. But the differences are in which genes are turned on and when they are turned on and how they are regulated. And that's different in different regions of the brain. 
12138:54
122    Charlie Rose: What turns them on? 
12338:56
124    Anthony Movshon: For the purposes of brain functions, the most important thing is, what turns them on is what the cell does. That is, in the brain cells are plastic because they change in response to the work that they do. And -- 
12539:11
126    Gerald Fischbach: So the point I wanted to make is, are there archetypal circuits that might be homologues to some of the things that you are identifying in a simple circuit, that maybe that the human brain isn't as complex if they're repeating -- 
12739:23
128    Eric Kandel: Well I think Cory's great contribution is to try to see the see the universal logic of the neural circuits that control behavior. And if she is successful we will have really a grammar of the neural circuitry that determines behavior. 
12939:36
130    Anthony Movshon: I'm the guy at the table to whom Cory's "good luck with that" was directed. 
13139:43
132    Eric Kandel: And "don't forget to write." 
13339:45
134    Anthony Movshon: And I'm very touched that Cory thinks that way. That means a great deal to me. But so the organism that I work on is the closest organism that we have available to us in the lab to humans, and that is nonhuman primate model in the monkey. And we do not work on monkeys because they are simple or because we think we can understand them in terms of the elementary genes and circuits. For that we do wait for people like Cory and Eric who have shown us a great deal from an animal that is -- I'm not sure which of you has the simpler system, perhaps you guys can fight that out later. But the eloquence ever modern neuroscience is that the principles of circuit construction that exists in animals like worms, like flies, like snails, are principles that seem to point to us in who work on larger organisms and larger systems the way in which things work. But what the advantage is of a larger system is that we can take an experimental animal we can ask it behavioral and cognitive questions that are the kinds ever questions that we can ask of humans. We can ask it what it perceives, how it chooses to act, how it weighs alternatives. And we can ask those things in ways that are very similar to the ways that people ask the same questions of humans. 
13541:02
136    Charlie Rose: And why do you compare primates and humans? 
13741:04
138    Anthony Movshon: Well, we are primates. I'm always forced to correct people to say you can't talk about primates and humans. But nonhuman primates have close evolutionary similarities. And as Cory points, we share with monkeys about the same number of genes that we share, very similar number of genes that we share with her worms. So if not quite true, that's still approximately true. So the systems of organization of the brain that define a monkey brain, and I was looking before I came to see if I had a model brain for the macaque monkey. I don't. But it's about the fifth of the size of the human brain and it shares the same basic architectural features. And one of the areas in which we know with some precision that it shares the same architectural features is what we think of as the early stages of visual processing, which are the stages that take information from the eye through the thalamus, which is part of the brain that carries film and some of what has been said up till represent, to the first areas if you like in the model, the green areas of the cerebral cortex perform. Those areas seem on the basis of everything we know to be very similar in humans and monkeys. Now in humans we can use the techniques of imaging and variety of other modern methods to get approximate answers to the question of how these brain areas work. What we can do in animals is we can make recordings from the brain, then we can identify at the level of circuit the kinds of things that Cory might uncover in a worm or that Eric might uncover in a snail. 
13942:33
140    Eric Kandel: But don't the experiments that you've been doing and other people have been doing show the specificity that cells, individual system, respond to only visual input, do not respond by and large to auditory. That specificity is remarkable. So I think from a philosophical point of view why the visual system responds to light seem to be easier problem than one I want to you address. How do we tackle the problem -- 
14142:57
142    John Searle: I like that problem. I don't want to lose sight of the big question that is -- 
14343:01
144    Eric Kandel: Answer the question of consciousness. 
14543:03
146    John Searle: -- how do you get that qualitative character of the consciousness experience. 
14743:08
148    Eric Kandel: That's what I'd like to you address. How do we study this? 
14943:12
150    John Searle: Well, 
15143:15
152    Ok: We want you to join us. 
15343:17
154    John Searle: OK, but here is the fun of it. First of all, the first stages you find the correlations. You find neural correlates of consciousness. And we're making a lot of progress with that because of imaging techniques. Secondly, you try to get, find out if the correlations are really causal. And you do that by the usual methods. You see if you can turn on th consciousness by turning on the neural correlative -- what they call the NCC, the neural correlative consciousness. And again you can turn off th consciousness by turning off the NCC, and we're not quite there yet. But of you got -- if you can get the correlations and then discover if they were causal correlations, and then you try to get a theory. What is it about these correlates that produce these conscious experiences, and why is it that these conscious experiences require this kind of neuronal basis? That seems to be the target. Three stages -- get the correlations, find out if they're causal, try -- and this is characteristic of history of science. If you look at the germ theory of disease, this is exactly how it developed. You find correlations, you see that they're causal, and then you get theory. We're still in the NCC stage. We're still at the stage of looking for correlations. But that's to me is the most exciting question in science today, is how to you get from the neuronal correlates of consciousness to a general causal account of how the hell the brain does it. It's marvelous fact about universe that it gives us this. And then finally try to get a theory. 
15544:39
156    Charlie Rose: I'd like to pick up what you just said, John, and sort of take it, redefine that question, go to each of you, and, as we look forward in this series, go to each of you in your own work and tell me what is the biggest question for you, and how do you think it will be answered? 
15744:56
158    John Searle: The most exciting question in science today how does the brain produce consciousness and how is it realized in the brain? And if you look at history of science you get the answer to that by going through these three steps. You find correlations, you test for causation, you try to embed it in a theory. And genetics or the germ theory disease are good examples of precisely that. Now, it's very important not to lose sight of the target. And research techniques always blind us to the larger question because we get involved in the specificity of the research and the techniques, to think what we're looking for is correlations between input stimuli and output behavior. That's not what we're looking for. 
15945:34
160    Charlie Rose: The question for you, Cory? 
16145:36
162    Cornelia Bargmann: I think the big question is how does one brain generate infinitely many behaviors? Because we sort of talk about these fixed cells and we talk about these fixed connections, but there's traffic flow through the brain. And the traffic is constantly changing. The traffic when you're asleep is completely different from the traffic when you're awake, and traffic when you're nervous is different from the traffic when you are relaxed. And so we have one brain and one set of biological structures that can generate infinitely many responses through internally generated activities, through external generated activity. I think that is great problem. 
16346:09
164    Charlie Rose: Gerry, your question? 
16546:11
166    Gerald Fischbach: Currently at this stage of my career I'm most concerned with how genes and environment interact to produce malfunction of the nervous system, in particular autism. And I think autism has a lot to say about social cognition, consciousness, empathy, emotion. And I think the problems are getting more and more urgent. But I think the issue really leads into these more profound questions, because the genetics, I hate to say it, will be easy. We will know the genetic risk factors within the next two years. And then the question is, what do you do with these? How do you do the experiment? How do you manipulate animals? What are the animal models of autism? And how do you modify that and how do you correct it? We have some therapies for neuropsychiatric disorders, but they're all symptomatic and they're all mediocre. We don't know how to cure these diseases. Cure not in the sense of reversing it and making the brain normal, but cure in the sense of stopping the pathology, and cure in the sense of somehow reversing some of the signs and symptoms. And that to me is one of the great challenges in the area I'm interested in. 
16747:28
168    Anthony Movshon: So I guess implicit in much of what we've talked about today is the challenge that I think is the one that really faces us in all of these things, that faces us in answering John's questions and in Gerry's question and in Cory's question, and that's the challenge of identifying what level of brain function we should consider when we try to answer any of these questions. The brain is unique among organs in that we have to consider its molecular structure, its cellular structure, the way the cells communicate, the way they make circuits, the way the circuits make areas, they way the areas make lobes. And each of the levels of analysis has a level of answers associated with it. The trouble with answering John's question or Gerry's question is I don't think we know what level to ask the questions at. And so although we have tools that let us approach the questions at each of those levels, we could be sniffing around in an altogether incorrect level and try to answer a question that is really answered at molecular level or at a circuit level or at a area level. 
16948:19
170    Eric Kandel: I think most people think that in order to understand the brain you have to understand the logic of neural circuitry. And I think that's a major task. And I think this is why Cory's work is so interesting and why your work is really so important. I think that one can make progress. For example, I think one of the things that are lacking in areas that interest me is the lack of progress in psychiatry. We really don't have any better drugs for treating schizophrenia than we had when I was resident in 1960. It has more side effects and is as effective as anything that has come along. There has been no new antidepressant for the last 20 years. 
17148:58
172    Charlie Rose: Amazing. 
17349:00
174    Eric Kandel: And animal models of these disorders are coming along they can be very useful. And it turns out that many mental illnesses have a memory component. Schizophrenia has a defect in the prefrontal cortex. People with schizophrenia don't organize their lives. And one can now develop animal models that have alterations in the genes that are thought to be involved in schizophrenia and see how they affect prefrontal cortical function working memory. One can do this with depression. So the combination of approaches -- knowing which parts of the brain are involved, often identify by imaging or by physiological methods, putting this together with genetics does allow us to make progress. I think one has to realize that these are immense questions. You are asking the most profound questions western thought has ever challenged. We're not going to answer it immediately. But at least we're beginning to mass the troops both intellectually and methodologically to approach those problems. 
17549:58
176    Charlie Rose: What's the most important question for you? And after answering that, as we close this out, tell me the stops that you hope and we plan to make on this journey that you and I will take together in this series? 
17750:10
178    Eric Kandel: Let me give you my own concerns right now. I am interested in how is memory perpetuated. How do you remember childhood experiences for the rest of your life? And it turns out that the new synapses that grow have to be maintained. There's active work that is involved probably for length of the time that the memory is there. We've been interested in the molecules that are capable of self perpetuation that can keep it there. So this is important question in memory, how do you maintain something for very long period of time and how do you recall it? We know very little about how I sit back and recall the first time Gerald Fischbach walked in to my lab asked me how inhibition works in the brain when he was much younger and so was I. We've outlined a family of problems today. We've talked about perception, we've talked about action, we've talked about emotion, we've talked about social interactions, we've talked about various disease states, we've talked about consciousness and creativity. Each of these topics we are now going to take up individually and explore them in great detail. The very next discussion we're going to have to about how we perceive the world and issues that John raised and Tony raised we're going to take up again and discuss in much greater detail. We're going to have specialists who deal not only with normal vision but how vision gets disturbed in various disease states. What happens with kids that are born with cataracts if the cataracts are removed later on in life? So in each case we'll end up looking -- we're going to begin by looking at the normal physiological function, action, social behavior, and then look at disturbances in social behavior. Just look at this. You can take a perfectly normal person, and this was seen with people who manage concentration camps. They had one nose two, eyes, two ears, yet they were socialized to kill. What is it that allows a human brain to be switched in one direction or another? These are profound questions, and the more we understand the functioning of the brain, we will realize what goes on. So we realize built in to the brain is the capability for both good and evil. But it's really the social context, the learning that allows them to move one way than the other. So all these problems we'll take up in much greater detail, including the diseases that result from disorders in these areas. 
17952:32
180    Charlie Rose: Thank you for this hour. Eric Kandel, thank you very much. John Searle, thank you very much. Tony, thank you. Thank you, Gerry. Thank you, Cory, very much. This is an introduction. This is where we begin. I know that you heard lot of information in this hour that was difficult. At the same time, what you hear at this table in this initial session is the excitement that they feel about the inquiries that they're making the possibilities of the journey for each of them in terms of what they learn and how it applies to this most extraordinary question, which is about our brain and the implications of understanding it for the way we live our lives and disease and so many other things. So that's what we're going to be about. And I'm greatly in appreciation to everyone at this table. And Eric and I will continue this journey and others along from this table and for many of the tables we'll join us as we try to explore the magic and the majesty of the brain. Thank you for joining us. See you next time.