RESCUING MEMORY

Steven Rose [6.13.99]
Topic:

What has always obsessed British biologist Steven Rose is the relationship between mind and brain. His approach to understanding this relationship has been to look for ways in which we can locate changes in behavior, thought, or action, which can be mapped in some way onto changes in physiology and biochemistry, and changes in structure in the brain, that is in processes that you can study biologically. For most of his life the search has been focused on how we should understand learning and memory.

Rose points out that the reason for this is obvious. He is an experimental scientist. "I work with animals," he says, "and when an experimental animal learns, it changes its behavior. And it's always easier to measure change than stasis in science. You can then ask what changes happen in the brain when an animal learns a particular task, and you can study those changes in ways that we can manipulate in the laboratory. When I started doing this, back in the late 60s, early 70s, this was a deeply unfashionable field. People thought these were questions beyond the edge of science, you couldn't actually touch them. Now it's the hottest area in neuroscience."

Steve and I got together in New York after he attended the memory meeting at Cold Spring Harbor, which is the home of molecular biology and molecular genetics. "Jim Watson decided a few years ago that the focus of neuroscience should be learning and memory," he said, "and he started setting up molecular techniques and genetic techniques there, with some very bright guys working on it. They have a conference every two years, and we have a matching conference in Britain and across the rest of Europe. And these are the questions which now we're beginning to approach for molecular answers."

At Cold Spring Harbor, Rose was talking about his discovery of a new molecule "which seems to be able to rescue the memory loss that you get with the disorder of the Alzheimer proteins. What started as a sheer intellectual excitement also looks like it's going to have rather significant human payoff, and that's good news."

JB: How did you get started?

STEVEN ROSE: I started as a school kid doing chemistry in the back yard, and went to university to study chemistry where I discovered that there was this incredibly exciting area called biochemistry, and graduated as a biochemist in Cambridge in the late 50s.This was a time that Watson and Crick had done their stuff, and Fred Sanger had got the first of his two Nobel Prizes, and the department was awash with champagne. I was pretty arrogant, and so I decided that all the interesting biochemical and genetic questions have been answered, and the next frontier is the brain. So I went off and did graduate study at the Institute of Psychiatry in London and then a postdoc in neuroscience at Oxford, and eventually set up my own laboratory at the Open University, where I've been these past 30 years.

The crucial thing in any sort of science is to find a reliable model that you can study. One of my old advisers, Hans Krebs, the great biochemist, said for any problem in science God has created the right organism to study it. For me it turned out that the right organism for studying brain and memory was the chick because day-old chicks have this tremendous capacity to learn very fast about their environment. Back in the 70s I did a series of experiments on imprinting in chicks along with Patrick Bateson and Gabriel Horn, which set a sort of standard in the field for how you can study these things.

More recently I moved on to a simpler model. When you give a chick a small bright object, like a little bead, to peck, they will peck at it spontaneously; they're discovering their environment, what's good food, what's bad food, and so on. If you make the bead taste bitter, they'll peck it once, they'll really dislike it, shaking their heads and wiping their beaks, and they won't peck at a bead like that afterwards. With one trial, ten seconds, this animal has learned something which lasts a good chunk of its lifetime.

So what's going on in the brain under those circumstances? To study that, you need to pull together all the available techniques to study electrical properties, cellular properties, molecular properties, do the connections in the brain change, can we actually study those by actually looking at them in a microscope? Can we identify the molecules involved in the change, and so on.

Now we're at the point where we know pretty well the molecular cascade of processes that go on when the chick learns this task; what it comes down to in the end is that the chick makes a set of new proteins which stick together the connections between the cells, the synapses, in some new configuration. We've identified this class of proteins, we're analyzing their structures in a variety of ways. It has been an intellectual pursuit of mine for 30 years and its greatly fascinating.

I always argued that this was a pursuit which was about pure science, and there wasn't going to be a payoff, as it were, Except that we would learn more about ourselves and how we work. But what's happened in the last 3 or 4 years is something really interesting, because it turns out that among the molecules which were involved in this key process of putting memories together are the substances which get disordered in Alzheimer's Disease.

So for the last 2 or 3 years a good chunk of the work in our lab has been to look at these molecules to try to understand what they're doing in the brain in terms of how they help stick cells together when memories are being made, how they go wrong when the bits of the external sections of the molecules get broken off, and, very excitingly, what you can do to reverse that, or prevent that from happening. One of the things that I was doing at Cold Spring was talking about a new molecule that we've discovered — a little peptide , five amino acids long, which seems to be able to rescue the memory loss that you get with the disorder of the Alzheimer proteins. What started as a sheer intellectual excitement also looks like it's going to have rather significant human payoff, and that's good news.

JB: How did you make this discovery?

ROSE: It came about in a rather classical scientific way. What we did first was to show that in order to make long-term memory, that is memory that persists for more than half an hour or so, you need to make a new class of proteins. Then, using standard biochemical techniques, we were able to identify what the class of proteins were. They turn out to be a group called cell adhesion molecules. That is, they're molecules whose job is to stick together the two sides of the synaptic junction, the business end of the relationship between one cell and another. And that was interesting in itself; you can discover how they work, you can show how you have to unstick them and restick them in new configurations.

I was looking at this, and then I suddenly realized that one of the key proteins which is a major risk factor for Alzheimer's Disease, is itself a cell adhesion molecule. The question was could that be involved in memory as well? And it turns out that the normal functioning of this molecule is necessary for long-term memory to be made; if we stop the molecule from functioning — you put an antibody into the brain which binds to the molecule, or a specific bit of RNA which stops it being synthesized — then the memories can't be made.

Then if you look at the structure of this molecule, the amyloid precursor protein, it turns out that there is a very small section of it which is just a few amino acids long which seems to have some very special properties. It's those properties which you can mimic by making an artificial peptide, and it's that it turns out will rescue the memory which is lost otherwise. Clearly that's a long way from having a drug which will cure or protect from Alzheimer's Disease. But nonetheless, being able to rescue memory in this sense seems to me to be a step which is potentially in the right direction.

JB: What steps are necessary to make this available for human use?

ROSE: There's a lot more work to be done in animals first of all, the standard sort of drug development stuff would have to be done, and then you would have to show that you can take it orally without it breaking down — at the moment we have to get it in by injection. Or else you have to find a way of protecting it so it can get into the brain. Then there are various other bits and pieces of peptide controls that we need to do, and so on. You're talking a few years downstream, but you're moving in that direction.

JB: What has been the reaction among scientists?

ROSE: People are pretty excited about it. The formal scientific paper is just in press.

JB: When will it come out?

ROSE: Within some months from now I suspect. What we haven't done is patent it.

JB: For ideological reasons?

ROSE: I suppose so, yes.

JB: Then somebody will come and patent it.

ROSE: No, they can't once it's published. You can only patent it if it's new. Patent law is a bit different in Europe. I have to say that a fair number of my molecular neuroscience colleagues, mainly on this side of the water, have got companies in which they're trying to develop molecules which will do this sort of thing. That's fine, but I would prefer to publish in the scientific press and develop things that way.

JB: Did you see the Arnold Schwarzenegger movie Total Recall ? How long will it be before you begin to implant memories?

ROSE: That's a different story. People are unclear about what we mean by a memory-enhancing drug. If you go to the smart bars in San Francisco and buy a smart drug, a memory drug (none of which work, I have to say, but they're good marketing for the health food stores and bars) what you don't get is something which will give you someone else's memory, or even bring back memories you lost when you were just a few years old. What they do is they help in the transition from short- to long-term memory.

If you take someone with Alzheimer's Disease, then the first problems that people notice are things like you don't know where you've left your car keys, whether you've done your shopping this morning, whether you know the person who's ringing your front doorbell. The early stages of the disease are stages in which you will remember things for a few minutes but then you will forget them. What we need to do is find a way of helping people in the early stages of Alzheimer's Disease to remain in the community rather than have to be in care. To do that they need to be able to hold their short-term memory. Most of the so-called smart drugs are looking at doing that.

Further downstream there's the question of why do people get Alzheimer's Disease in the first place? Is there something we can do by way of neuro-protection? Is there something you can take like you take Vitamin E or half an aspirin, something like that which will build up some protection. Interestingly, the best evidence for neuro-protection comes not out of the lab but out of epidemiology. It turns out that post-menopausal women who are on HRT are much less likely to get Alzheimer's Disease than if they're not on HRT, and that has to do with estrogen, although it's probably not estrogen itself in the brain.

What happens is that the sex hormones, the steroids, are converted in the brain into things called neuro-steroids, brain steroids. My guess is that if we're going towards neuro-protection there will be an interaction between these peptides I'm looking at, the neuro-steroids, and some other growth factors in the brain. So it will be possible to get a cocktail of processes which will be able to provide neuro protection in this sort of way. That will be the long-term aim.

There are a lot of risk factors for Alzheimer's Disease. Some of them are genetic, or in other cases there are genes you've got that are risk factors, and they will interact with things in the environment. The proteins that we're looking at are the risk factors for Alzheimer's Disease. They are proteins called presenilin, the amyloid precursor protein and so on. Somehow there's an interaction between whether you've got these proteins, whether you have some problems — for example if you've had concussion as a kid, you've been involved in a football game and banged your head or had a car accident, or you've had general anaesthesia, you are more likely to get Alzheimer's when you're old than if you've had none of those things. So there's a whole lot of environmental risk factors. How they play together no-one knows.

JB: How does this line of research play into Darwinian ideas?

 

ROSE: It depends what you mean by Darwinian ideas, which is one of the problems. Darwin's basic idea is very straightforward. What is not controversial is that evolution occurs. What is at issue is the mechanism of evolutionary change. And the Darwinian evolutionary process says something which is also incontrovertible, that like breeds like with variations, that all organisms produce more offspring than can survive into adulthood and reproduce themselves. Those variations which are best able to survive are more likely to survive into adulthood and breed in their turn, so you get evolutionary change like that. No question. That's one of the fundamental mechanisms of evolutionary change.

But if you read Darwin himself, he was very clear that there are others as well. Sexual selection is one, random changes are another. And chance — the issues that Steve Gould calls contingency — becomes very important here as well. Darwinian mechanisms are very good for species getting better at what species do, but they're not good at making new species. Darwin himself was very well able to recognize this which is why the Galapagos became very important. Here were islands very close together populated by species which seemed similar but had particular differences from island to island.

Much later when he was looking at the specimens that he'd got from the different islands, particularly at finches of which there are generally agreed to be 13 different species in the different islands, Darwin came to the conclusion that what must have happened is that the original parents of all these finches had come from the mainland, from Ecuador, which is about 400 miles to the east. Once they were on the islands, they bred and they radiated out. In the different islands there were different potential foods available and the finches became more specialized accordingly — some of them are cactus eaters, some of them are insect eaters, some of them are ground finches, there's a woodpecker finch, there's An insect eating warbler finch, and so on. All which probably came from the same original stock. This is one way in which new species were produced, by arriving in a virgin territory and then radiating out from there. So all these mechanisms become very important as far as evolution is concerned.

Now we come to the question that you were asking, which is about the evolution of humans, and the relationship between our brains and our brain processes and evolutionary mechanisms. We are evolutionary products. The particular evolutionary line which has led to humans has been one which has achieved species success by the individuals developing bigger and bigger brains. Now brains aren't necessarily the only way to evolutionary success — bacteria (Lynn Margulis would say proctista) outnumber us, and will probably outsurvive us in the world. But once you start on the evolutionary line which leads to brains, once you're an omnivore, you have to hunt your prey, or you have to learn to escape from prey, then there's an evolutionary pressure to get smarter — that's the route that led to humans.

What our evolution has given us is brains which are enormously powerful and adaptive, capable of enabling us to live in the very complicated social circumstances in which we do, and capable of creating our own history and our own technology. There's a lot of debate which you get from the ultra-Darwinians about free will.

Richard Dawkins ends one of his books by talking about the power of humans, that only we can escape the tyranny of our selfish genes. Somehow free will rescues from the sort of determinism which is given by our genes. I don't look at it like that.

I don't take free will very seriously. I would say something different, and that is that we have to get rid of this whole attempt to create dichotomies between nature and nurture. The real thing about our brain development, our development as organisms, is not a dichotomy between nature and nurture, but a dichotomy between specificity and plasticity or perhaps between process and outcome. What is required is a developmental system which is partly not modified by the environment and partly capable of responding to the environment.

 

Why must it not be modified by the environment? To take a very simple example, a new-born baby's eyes are connected via other brain regions to the visual cortex, at the back of the brain. As the child develops, the eye grows, the different brain regions grow, and the visual cortex grow — but they grow at different rates. What you've got to do is keep an orderly relationship between the inputs from the eyes finally to the inputs to the visual cortex. Otherwise you'd cease to be able to see or make sense of what you saw. And you don't really want that to be too much screwed around by the environment. So you've got to have specific developmental mechanisms which hold that wiring and make sure that the connections are made and broken in an orderly way. That's specificity.

On the other hand, you've also got to have plasticity, the ability to modify your response to the environment by depending on experience. Take the visual system again as an example — how the visual system is finally fine-tuned depends very much on the shapes and patterns that you experience as a young and developing child. Equally we have to learn, and learning means that we have to make and break and remold connections in our brains the whole time.

This intense dynamism which is fundamental to understanding developmental processes, is lost in the argument that the ultra-Darwinians have that there is, if you like, almost a direct line between a gene and a phenotype, unmodifiable by environmental change. The crucial thing we have to understand, or that I want to understand as a scientist, theoretically and experimentally, is the way that this interplay occurs during development. And that's in a sense what memory is a special case of. Pat Bateson discusses this at some length in his new book Design For a Life.

JB: Let's talk about your trip to the Galapagos with Pat.

ROSE: The idea actually came originally from my partner Hilary. She's a sociologist of science. She said to me one day, we've seen where Marx and freud lived, and developed their ideas; isn't it time we looked at some of the origins of that other extraordinary founder of modern ideas, and that's Darwin. Of course you can go to Darwin's house just outside London and that's interesting enough in itself, but the obvious place to go is the Galapagos. We invited a group of ten social scientists and biologists, chartered a boat called The Beagle III — Beagle I being Darwin's Beagle, Beagle II being the boat that was owned by the Charles Darwin Research Center in the Galapagos which sank it a few years ago — Beagle III is the new one. And we flew to Ecuador where the group — an Anglo-American Italian party of biologists, and social scientists, including Hilary and myself, Pat Bateson and his daughter Melissa, who works with starlings, and Ruth Hubbard, who's the biochemist and critic of genetic determinism and gene technology from Harvard. Pat Bateson is the colleague who I worked with for many years on imprinting of a chick , and he and I have worked together and shared ideas on many things over most of our lives, as it happens. But he knows a tremendous amount, much more than I do, as an ethologist, a student of animal behavior, about life in the wild.

Pat knows a tremendous amount about bird life. And we managed to recruit for ourselves a brilliant young naturalist guide from the Charles Darwin Research Center who traveled with us. The Research Center is on one of the biggest islands in the Galapagos, Santa Cruz. There are only three inhabited islands within the Galapagos. The whole ecology is of course very fragile. When Darwin visited there the animals were incredibly tame. He describes how the birds would come and sit on his hat — a hawk came and sat on the end of his musket. Of course at that stage he wasn't ecologically sensitive in the sense that you would recognize now. He and his colleagues were only too pleased to kill and eat the animals; they did very well out of killing and eating the land tortoises, for example.

 

The indigenous population is now threatened on some of the islands, particularly by goats, by farming, by dogs, by feral cats, feral pigs and so on. Last year's El Niño produced a particular disaster on one of the bigger islands, Isabella, which has two fertile areas, separated by a very large lava field. The goats were confined to one of the fertile areas, and the belief was that they couldn't cross the lava field, and on the other side of the fertile area is a volcano which is a feeding ground for the land tortoises. During El Niño, when the drought came, the goats did in fact cross the lava field, and there are now at least 10,000 of them destroying the vegetation on which the land tortoises are dependent. So there's now an attempt to eradicate them. It's a very interesting argument, why should we privilege tortoises over goats? But somehow we do, because the tortoises live only there, and there are lots of goats — but for the individual goat, or the individual tortoise, I feel the argument is a bit more complicated than that.

In order to preserve the ecology you're not allowed to sleep on the islands. What you can do is go on designated tracks on them with a guide. You can go within a meter of the animals, but of course the animals come much closer to you because they're still pretty unafraid of humans. It's really a paradise for watching — the sea and land iGuanas, the sea lions, the little lava lizards — birds. Frigate birds, the males have these huge red pouches that they blow up in order to attract the females, so it's like flying with sort of a great red balloon strapped to your chest. The tropic birds, the waved albatrosses, the blue-footed boobies, the vermillion fly-catchers, and then of course the Darwin finches themselves — which are small, rather unassuming birds, but nonetheless of course intensely interesting.

Our trip was both fascinating from the point of view of ecology — and I haven't said anything about the flora, only the animals — but also because of the group that was there. There was a continuous seminar and debate about the nature of evolutionary processes — arguments about how what Darwin was writing relates to what the ultra-Darwinists are arguing now. The nature of selection, the nature of adaptation, and so on. It was a fascinating experience apart from being very beautiful.

We tended to travel by night, and probably if one went east to west or north to south it would take about 20 hours in a boat to get from the furthermost extremities of the islands at one end to the other. Some of them are very small, only a few hectares across, others are much larger. They're mainly volcanic. Some of them are almost completely naked lava, and have virtually no vegetation, or other life on them at all. The volcanoes are still active on some of them. In geological terms its very recent; you're talking over 3 million years, something like that, since the islands were formed. And they're at the intersection of a number of sea currents, the Humboldt current, the Cromwell current and others, so the sea ecology is also very interesting.

JB: You had some of the world's leading biologists on the boat — how did this group see things differently from than Darwin?

ROSE: The issue which obsesses Pat and myself — the relationship between genes and development — has been a problem for biology since Darwin's day. The tragedy for biology is that whereas in the beginning of this century developmental biology and genetics were, if you like, part of one science, as Darwinism and Mendelism became merged, so genetics and developmental biology separated. What I mean by that is this: development became the study of similarities. How is it that we all grow up with two arms, five fingers on each hand, more or less between one and a half and two meters high and so on. Those extraordinary universalisms. So what is the nature of the developmental process which generates this?

 

Whereas in contrast genetics became a science of differences. That is, what is it that makes me different from you? One person has brown eyes, one person has blue eyes, or whatever. And yet the two questions are two sides of the same coin. But they've become very polarized in the history of the way the sciences have grown up. I suppose that Pat's concern as a developmental biologist is really the nature of the rules of development. If you look at his new book, he has this cooking metaphor which runs through it, as to how you start, if you like, with the raw materials and you transform them in the cooking process and the cooking is development.

But you can't then separate out the ultimate cooked product into X percent of this or Y percent of the other. Ruth Hubbard and I start as biochemists, and I suppose from our point of view the question is to try to understand what genes actually do in the molecular dance with the cells during development. but what we biochemists mean by genes is very different from the way that theoretical biologists, or evolutionary biologists, like Richard Dawkins, or John Maynard Smith would talk about them. For them genes are — I think both of them would agree with this, John certainly would — the genes are almost theoretical postulates, that you look at the ways in which animals behave; you have a mathematical model of their interactions, what would produce evolutionary success. Then you postulate a gene that does X, or a gene that does Y. It doesn't matter for you in that sense if there is really a gene, a bit of DNA which does X or does Y. I mean it's a bit that you fit into an equation. And if you look at John's evolutionary stable strategies, or the other models, which are tremendously important, that he's made very much of his own — these are mathematical constructs.

Take an example from a different field — there's an interesting discussion between Roger Penrose and Stephen Hawking in which they debate the reality of the physical models that they're working with. Penrose believes in the reality of the constructions he's handling. Hawking says no, so far as he is concerned, what matters is simply whether the equations work. And if you could make a different set of equations and they could work as well then fine — the important thing is the equations. And it doesn't matter if they map onto "reality" — tables, chairs, molecules, or whatever.

And in a sense, part of the problem with the whole fight in evolutionary biology at the moment goes right the way back to this philosophical distinction — but if you're a biochemist, if you're a neuro-scientist like myself, and you get your fingers sticky with real bits of DNA, with real cellular interactions — I work with DNA in the lab — then you see it in a very different way — it matters to you that these are real processes and not just theoretical mathematical models that are going on. There is an element — I mean okay, in all this dispute, which is partly ideological, partly philosophical and so on, but there is an element of a difference between whether you are a sticky-fingered biologist who actually does research, or whether you sit and make models of things.

JB: What did you learn on the Islands? What would you tell Darwin?

ROSE: That's an interesting question. What we would talk about with Darwin are some of the things he began to think about towards the end of his life especially development. He was very interested, for example, in observing the development of his own children. He's got marvelous descriptions of when his children do particular hand actions, mimic faces, and so on and so forth — that whole process of development and learning is something that I think that it would be interesting to have a very rich discussion with Darwin about.

Darwin was much more open-minded about these processes than the present fundamentalist, religious Darwinians like Wilson and some of those who now call themselves evolutionary psychologists. If you note the sort of metaphors they use, they are quasi-religious. Dorothy Nelkin has examined some of these closely for a new book that Hilary Rose and I are editing. There's a deep Judeo-Christian almost original sin sort of element floating through their genetic determinism which is quite fascinating.

 

One of the things that Pat, Melissa and I were interested in, and which we kept coming back to all the time in the discussions, is if you see an animal behaving in a particular sort of way, or its behavior being modified depending on the environment in which it is in, how do we understand this, whether we understand it as learning, or the expression of innate developmental rules, and also how much is adaptive.

You see a tremendous variety of colors in tropical fish, for example. Do we have to assume that each of those has actually been selected, or not? Let me give you the classical example — Pat uses it in his book and also in his chapter for the book Hilary and I are editing: on some of the islands there are flamingos which are a beautiful pink color. Back even before the present fights, back in the beginning of this century, Thayer, an American naturalist and illustrator suggested that the pink color of the flamingo was an adaptation so they would be less visible to predators against the setting sun.

But in fact the pink color depends on their diet. If they eat a lot of shrimp they go brighter pink, if they don't eat a shrimp diet they go a paler pink. It would be very hard to argue that the pink color was a Darwinian adaptation to protect against predators rather than an epiphenomenon, a consequence of the diet. That's one of the things that is actually an extremely important issue within biology: what's adaptive, what's not adaptive, what's accidental in some sort of ways. And the flamingos make a very good example.

Then Pat and I were talking about another one — I keep cats, he breeds cats, and apart from birds he knows a great deal about cat genetics and cat breeding. We all know that a cat sits on your lap and purrs. Is that purring adaptation? Why do cats purr?

The answer is, we haven't the slightest idea though one can think of it as some type of social signalling mechanism. But how could one study that experimentally? You might exploit natural variation in the amount of purring and look for correlations in the response of social companions or to try rather brutal surgical interventions to de-purr a cat, and you'd have to deafen its litter-mates and its mother as it was being reared; you'd have to look at what effect that had on its behavior and its social organization. No one wants to do an experiment like that.

But if you ask why cats purr, and you asked ultra-Darwinians, they would probably say there has to be an evolutionarily adaptive explanation for it — an alternative could be what Steve Gould calls an exaptation, something which arose during evolution for other reasons or by accident and then got coopted for current purposes, the point is that we need to be much more eclectic and much more open to there being multiple explanations of why anything happens in nature. That there are explanations is clear, but they cannot simply be reduced to the working out of the imperative of the selfish genes.