The DNA Files:
Unraveling the Mysteries of Genetics
As heard on National Public Radio
Minding the Brain
Hosted by John Hockenberry
2991 Shattuck Avenue, Suite 304
Berkeley, California 94705-1872
For further information about genetics and these programs, as well as the producers who brought
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and the Alfred P. Sloan Foundation.
JOHN HOCKENBERRY: Welcome to The DNA Files. I'm John Hockenberry. Our show today is called, "Minding the Brain," and it's about uh um--it's about, oh, you know, stuff like:
MAN: Hi, honey, it's me. I'm just leaving the office now.
WOMAN: Oh, okay, fine. Oh, and don't forget to stop at the grocery store.
MAN: Oh, that's right. Uh what was it that you wanted me to pick up again?
JOHN HOCKENBERRY: Memory, that's it. Memory. Memory, and learning, and the brain.
DAVID GLANZMAN: Memory is a dual edged sword. In other words, we've all had memories that are highly unpleasant, and you don't want just any experience stimulating memory.
PATRICIA CHURCHLAND: I remember when I held a whole human brain in my hands for the very first time, and here was this astonishing machine.
JOHN HOCKENBERRY: Don't drop that brain. We'll be right back after the news.
JOHN HOCKENBERRY: This is The DNA Files. I'm John Hockenberry. And today we're going to see what genetics can tell us about memory and learning and the brain, or I could just as well say, memory, learning, and the mind. The mind and the brain are the same thing, right? Or are they?
PAUL CHURCHLAND: I remember wondering as a teenager what thought was, and I remember thinking, "Well, I guess it has to be electricity."
PATRICIA CHURCHLAND: I remember when I held a whole human brain in my hands for the very first time, and here was this astonishing machine
JOHN HOCKENBERRY: Paul and Patricia Churchland are philosophers at the University of California at San Diego. They're kind of unusual for philosophers, because they spend a lot of time studying neuroscience. Sometimes they call themselves "neurophilosophers." Anyway, the question known as "the mind/brain problem" or "the mind/body problem" is an old one. It goes back at least to the 18th century, to the French philosopher, Descartes.
PAUL CHURCHLAND: People didn't really appreciate that the brain was responsible for seeing and hearing and feeling and thinking and so forth until fairly late in human history. Even the Greeks were confused about it. Uh was it uh uh --
PATRICIA CHURCHLAND: Well, Hippocrates --
PAUL CHURCHLAND: Yeah, Hippocrates.
PATRICIA CHURCHLAND: Knew the brain did all those things, but nobody had the slightest idea how this mass of stuff could produce such a thing as perception or thought or regulate sleep. So the mind/body problem as we know it emerged with Descartes. He came to the view that the brain was just a kind of conduit for sensory signals in and motor signals out, and that the soul had to be a nonphysical thing that did the thinking and the deciding. There were really two reasons for thinking that. One, Descartes understood about mechanical devices, and he thought, "The mind is creative, and how could a mechanical device be creative?" The other reason was that he felt there was genuine choice that was uncaused, so that when we made a decision to give alms to the poor, that such a decision would not be caused by any antecedent physical event. And consequently it's really with Descartes that we get this idea that there is the mind, which is nonphysical thing on the one hand, and the body, which is a physical thing on the other hand. Then the problem is: How do they interact?
PAUL CHURCHLAND: [laughs]
PATRICIA CHURCHLAND: And nobody was able to solve the difficulty. And now, of course, we don't think there is a mind/body problem, because we don't think there are two kinds of stuff.
JOHN HOCKENBERRY: The Churchlands say Descartes got it wrong. The mind is entirely caused by the brain. It's the same thing. There's no difference. This does seem like a practical, no nonsense way to solve the problem. All the same, questions come up. For example, if you cut your finger and I say, "I feel your pain," believe me, that's just a courtesy. I don't actually feel a thing. I may empathize with you, because I know what it feels like when I cut my finger, but I have no access to your sensations. In theory, I could check out everything that's going on in your brain when you cut your finger. I could watch the activity of your nerve cells. Your mind though--only you can experience that.
PAUL CHURCHLAND: That's certainly true, but I don't think it's terribly surprising. The parts of my brain that make judgments like "I'm in pain" or "I'm happy" or "I'm afraid" is connected to the rest of my brain in intricate ways that is not connected to yours and similarly for you. So it's no surprise that I should have direct knowledge of my own internal states, and you have a knowledge of your own internal states, and we have to tell one another about them.
JOHN HOCKENBERRY: All right. Let me take another shot. If we are entirely physical creatures, then everything we do or think or feel must have a purely physical cause. Doesn't that mean we're somehow just machines?
PATRICIA CHURCHLAND: No, it doesn't mean that you're just a machine. Simple machines are the model for what we have in mind when we say we're just a machine, like a television set or a desktop computer. We're vastly more complicated than that. A sea slug is a relatively simple machine, but even it's not simple, and we are vastly more intricate than that.
JOHN HOCKENBERRY: The sea slug, that relatively simple machine, is interesting to neuroscientists precisely because it's so simple, but it can learn and remember, and it can tell us something about how we learn and remember.
Near Miami, Florida, out in Biscayne Bay on a little spit of an island, there's a two-story building shaped like a shoe box, more or less the color of the sand all around. If you notice it at all, you might take it for a warehouse or a lumberyard. Yet the sign reads, "National Resource for Aplysia Facility," and if you go in the door, you'll see hundreds and hundreds of fish tanks, like the tanks you might keep tropical fish in at home--tanks just sitting there, bubbling away in the air-conditioned gloom. And in these tanks are odd creatures.
TOM CAPO: To the touch, they're soft, like a piece of liver. There's no real structure to them. So if you pick them up, they tend to flop off each side of your hand. So they're sort of like a pliable ball in your hand.
JOHN HOCKENBERRY: These are Aplysia. Aplysia californica. Sea slugs, yeah. The National Resource for Aplysia Facility funded by the National Institute of Health is a slug farm. Aplysia can get pretty big--two or three pounds if they've been eating plenty of seaweed, but basically you can think of them as ordinary garden slugs with some extra hardware for underwater living.
TOM CAPO: There's two flaps of skin called parapodia, and underneath or between these flaps of parapodia are the gills and the remnants of the shell. They do have a shell. So if you rub it, you can sort of feel something a little stiff. That's the remnant of the shell for Aplysia, and that's the basic animal, except that if you annoy it enough, it will release purple ink and make a mess. But we have plenty of water that we can wash the ink away.
JOHN HOCKENBERRY: Tom Capo, the manager here, says he's shipping out 30,000 Aplysia this year to researchers all over the country. What with growing tons of seaweed to feed them and pumping and cleaning the water from Biscayne Bay, this is a big operation.
TOM CAPO: We're running water 24 hours a day, cooling it 24 hours a day, and we have one person that just takes care of the seaweed. We have another person that takes care of growing the larvae. So when you think of all the pumping and all the people 24/7 that goes into keeping this facility afloat, it's a pretty expensive proposition.
JOHN HOCKENBERRY: Expensive, when you consider the limited interests of the sea slugs.
TOM CAPO: In the laboratory, all they do is eat, sleep, and copulate.
JOHN HOCKENBERRY: What matters to scientist are the nerve cells, the neurons. Aplysia have humongous neurons.
DAVID GLANZMAN: Most neurobiologists , 99% of the time, they'll go for the big neuron. That just makes life easier.
JOHN HOCKENBERRY: David Glanzman studies the neurobiology of learning and memory at the University of California at Los Angeles. The great thing about Aplysia neurons, he says, besides being big, is how they work. They work the same as human neurons.
DAVID GLANZMAN: I wouldn't be working on Aplysia if I didn't believe that on a fundamental level, the cellular and molecular mechanisms of learning and memory in sea snails weren't the same as they are in our brains, and actually I believe that.
JOHN HOCKENBERRY: When we think of evolution, we usually think of the big changes that have happened over a long period of time. Evolution is radical in this way, but it's also conservative. The basic building blocks of biology are used over and over again.
DAVID GLANZMAN: Minds evolved. They evolved, because brains evolved. And our brains evolved out of simpler brains, but the mechanisms on a fundamental cell and molecular level remain the same. When an animal learns something you and I learn something, there are changes in the strength of the connections between neurons and our brain.
JOHN HOCKENBERRY: Okay, let me draw you a picture here. I'm getting a big sheet of paper and some charcoal and yeah, true, neurons are complicated, and I don't draw all that well, but I can make you a stick figure version. It's a cinch. It's like a child's drawing of a tree. You make a long line for the trunk, and then at the top, you sketch in some little lines for the branches, and at the bottom, more lines coming out for the roots. Simple, huh? A child's image of a neuron. The branches up top are called dendrites. Information comes into the neuron through the dendrites. It moves down the trunk, which is called the axon, and exits at the bottom through the roots called axon terminals. So branches, trunk, roots. In through the dendrites, down the axon, out the axon terminals, that's the information flow. Got it?
Now I'm going to draw a second neuron under the first one. Here we go. Dendrites, axon, oh I love that, that’s nice, that’s nice, axon terminals, another stick tree, you see? I've drawn it so the branches, the dendrites of this lower tree are almost, but not quite touching the roots, the axon terminal of the top tree. There's a tiny, little gap between them. The synapse. So if the first neuron, the tree on the top, wants to talk to the second neuron, it will have to send a messenger across this gap. This synapse. The messenger is a specialized chemical called a neurotransmitter. It bubbles out from a root, an axon terminal makes his way across the gap, and it's picked up by dendrites, the branches in the lower tree.
DAVID GLANZMAN: So the way information travels in the brain is that an electrical impulse travels down the axon until it reaches the end of the axon, which we call the axon terminal, and when it does that, it releases a neurotransmitter. The neurotransmitter binds to receptors in the dendrites of the next cell, and then the electrical impulse will travel down the axon to the next neuron, etc., etc., etc.
JOHN HOCKENBERRY: Coming up, we'll find out what goes on when a sea slug learns. We'll be right back.
JOHN HOCKENBERRY: Welcome back. You're listening to The DNA Files, and our show today is called "Minding the Brain." We're talking about memory and learning. To acquire a new behavior like riding a bike or playing the kazoo, you need to learn how to do it, and then remember. Now, scientists believe that when we learn and remember something, there are changes in the flow of information between our neurons. The question is: What changes? What exactly are these changes? I warn you, if you ever put this question to a practicing neuroscientist like David Glanzman --
DAVID GLANZMAN: Cyclic AMP when it synthesizes …
JOHN HOCKENBERRY: Make sure you're sitting down.
DAVID GLANZMAN: …causes the activity of a kinease, known as protein kinease A, and protein kinease A can travel from the cytoplasm to the nucleus and phosphorylate CREB, and when CREB is phosphorylated that in term stimulates the process of gene transcription…
JOHN HOCKENBERRY: Talk about complicated. This is really complicated stuff.
DAVID GLANZMAN: Those are very complicated questions. I think of those as the lifetime employment act for neuorscientists, because [laughs] they're so complicated, it's going to take me the rest of my life to figure them out.
JOHN HOCKENBERRY: Fortunately, we can simplify. We can make a child's version of memory, the same way we made stick figures for neurons. In fact, we can do an experiment with Aplysia, a cartoon version of a real experiment. No actual sea slugs will be harmed in this reenactment.
Picture this. Here's our buddy, Aplysia the sea slug meandering around its fish tank in the laboratory. It's having a good day. The seaweed lunch was especially delicious today, and it's happy. Its gill right under the flaps of skin on its back is busy filtering oxygen out of the water. All is well.
But now since we are pretending to be scientists, we are going to give Aplysia a tiny electric shock. Nothing dangerous, you understand, just a wee shock. Hmm, doesn't like that. We know it doesn't like it, because Aplysia pulls in its gill and shuts it down. This is an instinctive reaction to the shock, perfectly natural. When something ugly happens, you batten down the hatches. Of course, after a while, if there's no further unpleasantness, you forget about it. So the gill comes out again, and Aplysia is happy once more. It has learned absolutely nothing.
Next, we're going to do something clever. We're going to give Aplysia a gentle tap--let's say, on the butt. This won't get much of a response, maybe the sea slug equivalent of "Huh?" The tap isn't threatening. The slug doesn't care, unless right after the tap, we give it a shock. If we keep doing things--tap, zap, tap, zap, tap, zap, tap, zap--[clears throat] over and over, our little slug will begin to learn. It will start to associate the tap with the shock that follows. After a while, we can drop the shock. The tap alone will cause the Aplysia to batten the hatches. This is new behavior. Ladies and gentlemen, this is learning. This is memory.
And our question was, you recall, "What's happening in the neurons--in the nerve cells when memory is formed? Since Aplysia has wonderfully large neurons, scientists are able to follow the action while the slug is being tapped and zapped. What do they see?
All right. Let's go back to my stick figure drawing. I drew two neurons, remember? Like trees with branches and roots, one right on top of the other, almost touching. Let's pretend now these are neurons inside Aplysia while our learning experiment is going on. The top tree, the top neuron is coming in from the rear of the slug. The lower tree is going out to the gill. It's telling the gill to retract. So, incoming butt neuron on top, outgoing gill neuron on below. Normally, there wouldn't be much going on between these guys. The tap doesn't mean a lot until Aplysia starts to associate it with the electric shock. Once it does though, the butt neuron figures it better send a message to the gill neuron. Now we have tap on the butt, information running down the butt neuron through the end of the axon, and bingo--a messenger, a neurotransmitter is sent out. The neurotransmitter hotfoots it over to the gill neuron, hooks up with the dendrites there and information continues down that neuron all the way to the gill itself to say, "Yo, gill, danger. Pull in."
The more we repeat our experiment--tap and zap, tap and zap, tap and zap--the more neurotransmitters flow from one neuron to the next. What was once a trickle becomes a flood. The connection between the neurons is getting stronger. The slightest tap to Aplysia will cause it to retract its gill immediately. This is memory at work, and this connection can get even stronger. There may be structural changes. Word may go to the nucleus of the cell in the crown of the tree right under the dendrites to the DNA. "Wake up, it's construction time. We're going to need carpenters, bricklayers, electricians, plumbers," and the DNA swings into action. As scientists say, it expresses itself. And the heavy building begins. You might see new roots, new axon terminals built on to one neuron, new branches, new dendrites built on to another. These are serious physical changes. You end up with more connections and stronger connections between the neurons. This is now good, solid, long-term memory. Aplysia is going to remember that tap on the butt for a long time.
There you have it. Now you know at least in cartoon form what happens in the neurons when we form a memory. You know there's increased flow of neurotransmitters between the nerve cells, and then as we move to long-term memory, genes are expressed to help make structural changes between neurons. Memory is all about strengthening the connection between nerves.
And now that neuroscientists are beginning to understand what goes on in the nerve cells when we form memories, so what? What good does this do, you may wonder. What difference does it make? Well, look at this.
DR. TIM TULLY: We're going in here. So this--this is the outer room that's like the control center. Let me step over there, and I'll just give you a view.
JOHN HOCKENBERRY: This is Dr. Tim Tully at Cold Spring Harbor Laboratory on Long Island. It's kind of Star Trek in here--computers and buzzing wires and solenoid thingies. But what it's all about is fruit flies. You know, those tiny flies that seem to emerge spontaneously from the cantaloupe or the peaches you left on your kitchen table. There are lots and lots of little flies here in little plastic jars. The jars have openings or channels through which scientists can inject odors.
DR. TIM TULLY: One smell is a chemical called octynol that smells kind of like licorice. And the other one is methylcyclohexonol, which smells a little bit like my tennis shoes in July. So flies are first exposed to the smell of licorice, and they're shocked on their feet. A mild shock. It's just--it just makes them feel uncomfortable, and then we pass fresh air through the chamber, and then expose them to my tennis shoes in July without shock, and we do that for 10 pairings. And subsequently, when we give them a choice between licorice and my tennis shoes in July, the flies will run away from licorice.
JOHN HOCKENBERRY: So the flies associate a smell with danger. Like our sea slugs, the flies learn and remember. What's unusual here in Tully's laboratory is that some of these flies are much better than others. They're [laughs] superflies. They learn faster. They remember longer. How is that possible?
DR. TIM TULLY: When we make new structural connections in the brain, it's basically a growth process. When the biochemistry is properly activated, that connection between two neurons grows stronger. So that structural process is a building process, and we found the general contractor, and so as I was saying --
JOHN HOCKENBERRY: The builder.
DR. TIM TULLY: Yeah.
JOHN HOCKENBERRY: The neuronal builder.
DR. TIM TULLY: The master builder, and it's actually called CREB. C-R-E-B. So CREB is the general contractor, and the analogy is good. If you want to build an addition on to your house, you call the general contractor and you say, "Here's the structure I’d like. Go ahead." He says, "Okay, I know how to do this," and he will call the electricians and the foundation guys and the bricklayers and the carpenters, and organize the whole process of building that structure, and then when it's all done, all the subcontractors and the general contractor goes away.
JOHN HOCKENBERRY: So something in the urgency of the experience--smell, shock, smell, shock, smell, shock--triggers something in the genome to say, 'Call CREB."
DR. TIM TULLY: So CREB in technical terms is a protein called the transcription factor, and transcription factors are proteins that regulate the expression of other genes. So as a transcription factor, CREB is controlling the raw materials needed to grow a structure. And back to the contractor analogy, the phone call that you make to the general contractor is the signal from an active neuron on to CREB. So when a neuron is electrically active from an experience, it starts a biochemical signal to CREB, and when CREB gets it, he goes, "Okay, I got it. I know what you want now. I'll call the subcontractor."
JOHN HOCKENBERRY: So the neuron is basically saying, "Whoa, this is pretty heavy duty. I think we need to nail this one down for life."
DR. TIM TULLY: Right.
JOHN HOCKENBERRY: And that's called long term memory.
DR. TIM TULLY: That's right. So we believe that a long term memory resides in that structural change at the connections among neurons, and CREB is a general contractor for that construction process.
JOHN HOCKENBERRY: So what do you do, if you want to improve that? Would you hire more laborers for CREB? You get more CREBs? What do you do?
DR. TIM TULLY: You could do those things. What we happen to find was a drug that had the effect of making the call, the phone call to CREB stronger. Again, if you imagine working out your structure, your addition to your house with a contractor, you're not going to make one phone call. You're going to make several phone calls. You got to convey a lot of information to the general contractor. So it's going to be a few phone calls. And so basically we found small molecules that increased the signal content to CREB.
JOHN HOCKENBERRY: So you created, biochemically, a situation where I want to put a deck in my house. I call up the contractor. They answer on the first ring, and they're on their way over there with the trucks that afternoon.
DR. TIM TULLY: They understood what you wanted. They know down to detail how to do it. Fine, they got it. So we just turn the gain up on CREB, and that means that we got that building process going with less practice.
JOHN HOCKENBERRY: Now, Tully says the CREB amplifying chemical he's found might be available to you and me one of these days. If that happens, who would want it? You can think of unimpeachable reasons to pop a memory pill, for example, to stem the forgetfulness that comes with old age. You can also think of some not so unimpeachable reasons like "I got to memorize this Shakespeare sonnet for English class tomorrow."
DR. TIM TULLY: The objective of spending the millions of dollars that it takes to find drugs of medical usefulness is not to memorize Shakespeare. It's to cure problems that we get with our brain, either because of age or injury or heredity. We can do these things in principle. That's what medicine is all about. One such example is rehabilitation after stroke. So a stroke is a very focal event in the brain that damages the circuitry. And when you rehab after stroke, what you're doing is reactivating the learning and memory and plasticity machinery to rewire the circuitry around the damaged area to regain lost function. And slowly but surely, your brain uses that memory biochemistry to rewire the damaged area, and you get some recovery of function.
JOHN HOCKENBERRY: There are several companies trying to develop a so-called memory pill, and you can imagine there'd be no shortage of buyers. There are a lot of hurtles to making such a drug, but if the FDA ever approved such a pill, that still doesn't mean you couldn't get in a world of trouble with it. Do you remember David Glanzman who studies sea slugs at the University of California at Los Angeles?
DAVID GLANZMAN: Most people's ideas are, "Well, look, I want to remember. So CREB is a good thing. So the more CREB I have, the better off I am." I once had a colleague who came to me and said, "You know, I'm going to go on a trip to Italy, and I wish I could take a drug that would just stimulate CREB in my brain so I could learn Italian in two weeks." And I said, "Well, maybe you'd be able to learn Italian in two weeks, but if anything bad happened to you, you'd never forget it." That's the opposite side of memory, the thing that people don't understand at first, because they're so obsessed with improving their memory, they don't realize that in fact, memory is a dual edged sword. In other words, we've all had memories that are highly unpleasant, and you don't want just any experience stimulating memory.
JOHN HOCKENBERRY: So far, we've been talking about memory at the level of genes inside a neuron, but brains are networks of neurons. Human brains house something like 100 billion neurons. Each one of them can have thousands of connections to other neurons. Pick up a model of the brain. Hold it in your hands. It looks like a mysterious toy with interlocking parts. What do the parts do? How on earth could you figure it out? Well, you may possibly recall from childhood experiments on watches or clocks that one of the most tempting ways to figure out what a part is doing in a machine is to break it. Afterwards, when you see what's stopped working, you may be able to deduce what the part was meant for. In a similar way, over the years, neurobiologists have learned a lot by looking at broken brains. The scientific literature in fact is chock full of stories of folks who've been whacked on the head with a hammer, blown out bits of their brain with a dynamite stick, accidentally plugged themselves with a cross-bow, and so on.
HOWARD EICHENBAUM: I would come in early in the morning. We would sit down. I would introduce myself. I would describe the test we were going to do. We'd spend the next two hours going through these agonizingly slow and tedious tests. Of course, they didn't seem all that tedious to him, since he wasn't able to really track how long and slow all this was taking. But then typically after an hour or two of this, I would take a quick break, come back not two minutes later, and he simply didn't know me, didn't know what we were doing or anything about it, and we had to just start over again from scratch.
JOHN HOCKENBERRY: Howard Eichenbaum, director of the Center for Memory and Brain at Boston University. He's talking about his work with a famous amnesiac, known only by the initials, H.M. H.M.'s amnesia is not the Hollywood cliche where the hero can't remember who he is or beans about his past. H.M. has a grip on all that, and his short term memory is good enough to carry on a conversation with you or finish a crossword puzzle. What he can't do is convert a short term memory into a long term one. He lives in an eternal present.
HOWARD EICHENBAUM: Each day he gets up. He's again unconcerned about his condition. He doesn't act like today's a catastrophe when he looks old in the mirror. He simply proceeds on with the day in the present moment. He can solve a crossword puzzle. He can follow the storyline on a television show. As long as it doesn't tap something he's seen recently, like what he did this morning, he does fine, and he'll proceed through the day like that, and then just go to sleep that night and wake up and start over again. He could be given the same crossword puzzle and solve it as if he'd never seen it before.
JOHN HOCKENBERRY: Every day for H.M. is a new day.
HOWARD EICHENBAUM: That's right. Very much a new day in which he lives in the present.
JOHN HOCKENBERRY: What does he think happened?
HOWARD EICHENBAUM: That's an excellent question. I don't think he thinks about that.
JOHN HOCKENBERRY: So what does go through H.M.'s mind?
SUZANNE CORKIN: Do you know what you did yesterday?
H.M.: No, I don't.
SUZANNE CORKIN: How about this morning?
H.M.: I don't even remember that.
SUZANNE CORKIN: Could you tell me what you had for lunch today?
H.M.: I don't know, to tell you the truth.
JOHN HOCKENBERRY: How did H.M. wind up with such a damaged memory? We'll tell you after the break. You're listening to The DNA Files.
JOHN HOCKENBERRY: Welcome back. This is The DNA Files. I'm John Hockenberry. We've just been introduced to H.M., whose amnesia has taught scientists a lot about learning and memory. What happened to him was this: as a child, H.M. suffered from epilepsy. The older he got, the worse it got. Finally, when his seizures became utterly incapacitating, a desperate remedy was conjured up. A surgeon cut out part of H.M.'s brain, including most of a small horseshoe-shaped structure called the hippocampus. The operation was a home run as far as the epilepsy went, but ever since, no new long term memory. Here's H.M. talking with one of the many scientists who worked with him.
SUZANNE CORKIN: What do you do during a typical day?
H.M.: Oh. See, that's tough. What I don't--I don't remember things.
SUZANNE CORKIN: Uh huh. Do you know what you did yesterday?
H.M.: No, I don't.
SUZANNE CORKIN: How about this morning?
H.M.: I don't even remember that.
SUZANNE CORKIN: Could you tell me what you had for lunch today?
H.M.: I don't know, to tell you the truth. I'm not --
SUZANNE CORKIN: What do you think you'll do tomorrow?
H.M.: Whatever is beneficial.
SUZANNE CORKIN: Good answer. Can you tell me what you look like?
H.M.: Well, let's see. I have brown hair.
SUZANNE CORKIN: Uh huh.
H.M.: Dark brown hair.
SUZANNE CORKIN: Any grey hair?
H.M.: I don't know. See, I don't--I don't remember that at all.
JOHN HOCKENBERRY: It turns out H.M.'s defect is only for a special kind of memory, for what's now called declarative memory, as in "I declare I saw you at the movies last week" or "I'm sure I had ham and eggs for breakfast." H.M. is no good at this. But if you ask him to do something with his hands, let's say, trace a pattern with a pencil, he may not do so great the first day, but he does a little better the second, better still the third, and by the fourth day, he's got it down. He's learning. He's remembering, even though as far as his declarative memory is concerned, he's never seen the pattern before. This is a gigantic clue. Howard Eichenbaum says it shows memory is not one simple thing located at one place in the brain.
HOWARD EICHENBAUM: H.M. was the beginning of our understanding that there are multiple forms of memory, that these different forms are supported by different brain systems, and each have different operating characteristics. Each have different brain pathways. That was news to the world at the time. Most scientists thought that memory was just kind of an inherent property of the processing system, of other functions.
JOHN HOCKENBERRY: It existed everywhere in the brain equally was the idea.
HOWARD EICHENBAUM: That's right. It existed everywhere equally.
JOHN HOCKENBERRY: You remove somebody's hippocampus; memory vanishes, and suddenly the thought is, "Maybe memory is more of an appliance."
HOWARD EICHENBAUM: Right, that it was a gadget itself, and even more like a tape recorder in the brain or something like that. You could find the place where memories are stored. That turned out not to be entirely accurate either.
JOHN HOCKENBERRY: The more scientists look, the more different kinds of memory they find, each with its own network of neurons. We mentioned declarative or conscious memory. There's also procedural memory, which you use unconsciously for everyday tasks, like tying your shoes or riding a bicycle, and there's lots of others. The human brain, after all, is the most complex object in the known universe, or so they say. Science is a little flashlight in a great darkness.
Some philosophers believe that the scientists poking around with their little flashlights are never going to be able to see everything. Do you remember Paul and Patricia Churchland, the neurophilosophers we met at the beginning of this program? They were tackling one of the oldest and hardest problems in philosophy--the mind/body problem or mind/brain problem. The Churchlands told us this problem goes away the minute you shine a light on it. They've concluded our thoughts, our minds are entirely caused by our physical brains. They're the same thing. End of story.
But not everybody buys this neat solution. Colin McGinn teaches philosophy at the University of Miami. He agrees with the Churchlands that the mind is caused by the brain, yet he doesn't think that mind and brain are exactly the same. For example, he says, "Think of the Eiffel Tower." Okay. There. Now think of, let's say, a goat. Obviously, the Eiffel Tower is way bigger than a goat, but was your thought of the Eiffel Tower bigger than your thought of the goat? Think it over. Thoughts don't seem to have any size at all. It's as if the mind, unlike the brain, has no spatial dimensions. So does this end the mind/brain debate? Colin McGinn thinks not.
COLIN MCGINN: I think every position that's been staked out historically has quite serious problems, very serious problems, indeed devastating problems. [laughs] So then the question arises: Are we assuming that we can arrive at a solution to this problem where in fact we might not be able to arrive at a solution to it? The brain is responsible for the mind, and yet, it isn't completely reducible to the brain. So what should we say about that?
JOHN HOCKENBERRY: Well, he thinks a good start would be admit the problem looks insoluble.
COLIN MCGINN: It looks like what we got is a kind of miraculous convergence where it just so happens that when one of these subjective things happens in our minds, one of those objective things happens in our brains.
JOHN HOCKENBERRY: So if the problem is insoluble, he says, if it's a mystery, what's wrong with that? We can handle it. Evolution has shaped our brains for survival in the physical world, not for philosophy.
COLIN MCGINN: The brain is an evolved organ. Its functions are not different essentially from the brains of other organisms. In the case of the human species, as an offshoot of our intelligence, we have the ability to do science and mathematics and philosophy. But it can't be true that the brain was designed to solve the problems of the universe. The brain evolved for straightforward, adaptive reasons. Those had nothing to do with plumbing the secrets of the universe. It's not surprising that we don't know something. What's surprising is that we know as much of the universe as we actually do know, given that there's no reason why we should. In physics, even the most basic concepts, we just don't know what matter really is. We don't know what charge really is. We don't know what a field really is. Does anybody know what an electron is in itself? No. If we don't know what matter is in itself anyway, is it so surprising we don't understand how matter can generate minds? But in the end, if it turns out there are mysteries which we can't understand, is that a tragedy? That's just life. [laughs] That's the way it is.
JOHN HOCKENBERRY: Of course, most scientists aren't trying to understand everything. They're happy if they can get a handle on even a little piece of the big picture. Some scientists are finding they can skip the mind/brain question all together, and just look for ways to change the brain by using the mind. Here's an example. Did you ever wonder what--what's going on? Did you ever won--hey, wait a minute. Okay, all right, that's it. Cut it out. All right, then. Are we back? I think we're back. Did you ever wonder what it would be like to live with attention deficit hyperactivity disorder? ADHD, as they call it. Could it be sort of like having somebody changing channels on you all the time?
Susan Smalley at the University of California at Los Angeles says ADHD is actually just a different way of handling memory and attention and stress.
SUSAN SMALLEY: So we're starting to recognize that having a disorder is basically being at an extreme on a normal continuum. For example, I always use height. If you're 7'6 and you're a teenager in high school, that can be rather impairing, but being very tall is just a difference in the population. We recognize that the impairment part arises, because the individual with their particular brain organization and way of responding to the world runs up against a culture or a school system that isn't that accepting of that way of seeing and processing the world. For example, kids and adults with ADHD underestimate time. So they have very different ways of perceiving time. We have a stopwatch, and we time a 15 second time interval, and then say, "How much time elapsed?" An individual with ADHD will perceive that time as shorter than on average an individual without ADHD. There's nothing right or wrong about the way you perceive time, but it does have implications in you being on time.
JOHN HOCKENBERRY: Smalley says people with ADHD may be more sensitive to emotional stress, which gets in the way of their short term memory. They forget where they put their car keys and what a friend just told them. ADHD may be just a different way of processing the world. All the same, Smalley is among the scientists who think the cause is mainly genetic.
SUSAN SMALLEY: Gene studies have led us to identify maybe five to ten percent of the cause of ADHD, but we think genes play maybe 75 percent. So there are many, many genes we have not yet identified.
JOHN HOCKENBERRY: Smalley and her colleagues are busy looking for those missing genes. They expect to find a lot of them before too long, maybe in a couple of years. However, simply having a gene doesn't mean anything by itself. The issue, she says, is whether the gene is turned on or off, whether it's expressed.
SUSAN SMALLEY: There are many environmental factors that can contribute to the expression of genes in the population, and some of the work that we're doing has to do with looking at our own ability to self-regulate our brains, our bodies, and subsequently our gene expression. We're really at the very, very beginning of this field of research, but if you look at a lot of the work that's coming out of mind/body medicine, you'll see that individuals have a much greater capacity to regulate their brain and body biology than we perhaps previously thought.
JOHN HOCKENBERRY: Hmm. Did you catch that? Mind/body medicine. Do you see where we're headed?
MAN: Let us begin. Settle yourself into your chair. Put both feet flat upon the floor and notice all the points of contact. Now let's focus on the breath, drawing the breath in easily through your nose or through your mouth, follow it down through your throat, into your chest, letting your tummy rise slightly, following the breath all the way in.
JOHN HOCKENBERRY: That's right. Meditation. Smalley and others have begun treating ADHD patients with meditation techniques. Some of these patients were taking medicine for ADHD, some weren't. They all said they liked meditating. It made them feel better. The idea, which Smalley hopes to prove in a clinical trial is that meditation will actually change their brains and alter their gene expression.
SUSAN SMALLEY: It's really important to remember that we're not talking about actually changing the structure of our DNA, but rather we're talking about every cell contains the same DNA information, but we know that certain cells express certain genes, and other cells express other genes. There are many factors that contribute to gene expression.
JOHN HOCKENBERRY: Do you remember our experiment with Aplysia where the slug's genes turned on, expressed while it was learning? You could think of that as a gene expression in response to the environment. Stress, cigarette smoking, many things in your environment can alter your brain biochemistry. Indeed, wouldn't any experience that changes your mind change your brain as well?
SUSAN SMALLEY: The future will probably yield much greater insight into how we as an individual will be able to regulate our own gene expression. We just have a little bit of knowledge right now about it, but the future will really help us uncover how much can we regulate our own biology, including our gene expression.
JOHN HOCKENBERRY: How much we can regulate, we might control. This is the Holy Grail in brain science. So much that happens in the brain goes on without our conscious control or intervention, and that's something to be grateful for, really. Imagine having to remind yourself to breathe or to pump your heart every few seconds, but this research seems to open a new door to direct intervention into the brain through influencing gene expression. It makes sense, really. You're trying to regulate your biology every time you decide to exercise or go on a diet, but what if there was a pill for things like memory? Why not a pill for playing the violin? A pill for learning Greek? The point is, the more neuroscientists learn, the more the rest of us can wonder what's next. Sure, there's hype--no, not everything will pan out as a simple pill, a silver bullet, but hey, we can sure wonder, right?
Remember our primitive pals, Aplysia, the sea slugs? No, no, you--you're blanking? How about my name? Do you remember that? No? [laughs] This is The DNA Files. Does that ring a bell? Okay. Who's the president? What's your mother's maiden name? Come on. The color of water, last year's winner on American Idol. Think harder. Let's get those neurons firing.
MAN: I'll get it.
MAN: Oh, hi, June.
JUNE: I hope I'm not interrupting dinner. I just stopped by to pick up the tickets.
MAN: Uh, tickets?
JUNE: Yeah. Audrey said you had the two spare tickets to the game tonight?
MAN: Oh, no. I had them with me at work, and I left them sitting on my desk. Listen, if I leave now, I can go and pick them up and drive them over to you.
JOHN HOCKENBERRY: There. Is it coming back to you? We now know that forming long term memory involves real physical changes, structural changes in the nerve cells in your brain. So the point is uh --
MRS. WILLIAMS: Yes?
WOMAN: Mrs. Williams, there's a gentleman here to see you from textile products.
MRS. WILLIAMS: Textile products?
WOMAN: Yes, Mr. Graywall.
MRS. WILLIAMS: Graywall? Oh, of course, show him right in, will you? I'd forgotten all about that appointment. I meant to write that down as soon as I got back to the office. Oh, boy.
JOHN HOCKENBERRY: Let's leave Williams and Graywall to their little drama, and I'll leave you with this. If you remember anything about this program a week from now, it will be because I have changed your brain. [laughs] That's right. I changed the chemistry of your brain, but no humans were harmed in the production of this program, as far as we know.
This is The DNA Files. Thanks for listening.
To find out more about memory, learning, and genetics, visit our website at dnafiles.org where you can download a podcast of this program. This series, The DNA Files, was produced by SoundVision Productions with funding by the National Science Foundation, U.S. Department of Energy, National Institutes of Health, and the Alfred P. Sloan Foundation. This program, "Minding the Brain" was produced by Larry Massett. The DNA Files is managing editor, Loretta Williams, editor, Deborah George, science content editor, Sally Lehrman. Research director is Adi Gevins. Production support by Noah Miller, Julie Caine, and Jenn Jongsma. Office support provided by Steve Nuñez and Beverly Fitzgerald. Our web director is Ginna Allison. Technical engineer and music director is Robin Wise. Our host is John Hockenberry. Our theme music was composed and performed by Steve White. Additional music by Larry Massett, Conrad Praetzel and Robert Powell. Marketing of The DNA Files is by Schardt Media. Legal services by Cooper, White and Cooper, and Spencer Weisbroth. Special thanks to Murray Street Productions. Thanks also to Universal Training for the memory training audio and to Suzanne Corkin for the audio of amnesiac, H.M. Send your responses and letters to email@example.com. For CDs and transcripts, call 888-303-0022. That's 888-303-0022. The executive producer is Bari Scott. This has been a SoundVision production, distributed by NPR, National Public Radio.