THE GENOME CHANGES EVERYTHING

(MATT RIDLEY:) For the first time in four billion years a species on this planet has read its own recipe, or is in the process of reading its own recipe. That seems to me to be an epochal moment, because we're going to get depths of insight into the nature of human nature that we never could have imagined, and that will dwarf anything that philosophers and indeed scientists have managed to produce in the last two millennia. That's not to denigrate what's gone before, but the genome changes everything. We know that just because the first one or two glimpses inside this box, the first lifting of the lid of the human genome, reveals to us enormous insights into what's going on, and just from the first few genes we're looking at.

What I've set out to do, both in Genome and in Nature via Nurture is to try to put these in historical context, because I think it is important not only to understand how the old debates are going to be refracted through the new genomics, but also to simply tell some of the stories that are coming out of the genomics labs and other psychology and evolution labs that are using genetic information. The sheer leverage that genomic science now has, compared with sciences that went before, is very striking. What I mean by that is that with a small amount of effort you can get really big results. You can get stuff that doesn't need statistics to prove that it's significant in molecular biology in a way that you can't, necessarily, in brain imaging or particle physics studies or something like that, which requires a lot more effort to get a small amount of data.

The substance of what I'm interested in is that it's the genes that are related to behavior, and how they work. The big insight is that genes are the agents of nurture as well as nature. Experience is a huge part of a developing human brain, the human mind, and a human organism. We need to develop in a social world and get things in from the outside. It's enormously important to the development of human nature. You can't describe human nature without it. But that process is itself genetic, in the sense that there are genes in there designed to get the experience out of the world and into the organism. In the human case you're going to have genes that set up systems for learning that are not going to be present in other animals, language being the classic example. Language is something that in every sense is a genetic instinct. There's no question that human beings, unless they're unlucky and have a genetic mutation, inherit a capacity for learning language. That capacity is simply not inherited in anything like the same degree by a chimpanzee or a dolphin or any other creature. But you don't inherit the language; you inherit the capacity for learning the language from the environment.

That's a good example, because for the first time we've now got a gene, the FOXP2 gene on chromosome 7, which looks like it may be an important cog in that machinery. It would be surprising, given it's the first gene that we've been able to look at, if it was the most important cog, but it's certainly one of them. What happens is that if that gene is broken you get, essentially, a human being with a great difficulty in generalizing grammatical rules and in developing fluent speech. You get a general language disorder. But what's interesting about that gene is that although you might say, "Well, here's the language gene, and humans have got it and nobody else has it," this is not so—it's present in mice; and chimpanzees, orangutans and every other mammal has this gene. Indeed, it's a very highly conserved gene with very little change over the past few million years. 

So you might say, "How can it be important in language?" If you take Svante Pääbo's work on it and you look at what's been going on in it, it appears that it's had very little evolutionary change in it until you get to the human lineage. And then, since the common ancestor of the chimpanzee there have been two amino acid changes in the gene, which is as much in the whole of the rest of the mammalian pedigree. Those two sense-changing alterations in the gene have happened in the past 200,000 years. It was probably about 200,000 years ago they happened, and they've elbowed aside all other versions of the gene. There's been a selective sweep of these mutations through the species. So what we're looking at here is a gene that was under very strong selective pressure around 200,000 years ago, which is around the time that we think human beings first started using language in something like the form that it is today. How that genetic change changes the wiring of the brain in order to enable language learning I don't know, and nobody knows the answer. But the point is the word enable there. Genes are enablers and not constrainers. People tend to think about genes as being constraints on what human beings can do. In fact, that's a very misleading way of looking at it. What's happened is that genetic changes are necessary to enable kinds of learning, to enable kinds of nurture, and to enable kinds of experience to get into the organism. In that sense genes are just as important a part of the story of nurture as they are the story of nature. When you start to see it that way, you can resolve the old nature-versus-nurture debate, and you can instead start to talk about nature via nurture instead.

So one important point is that genes are designed to produce human behavior through nurture. But there's another phenomenon going on too, which is equally important and which again people in these kinds of debates over human nature have missed. They couldn't have failed to miss it until recent molecular biology made a difference. That is, behavior affects genes. It doesn't change the code of the gene, and it doesn't change the encoded genome. Sure, you can change your encoded genome by having a mutational accident, by flying in an airplane and having cosmic rays damage your DNA. But what I'm talking about is changing the expression of genes through things you do in your life. The encoded genome is a set of DNA. The expressed genome is the RNA that's translated from it and then made into proteins. That process of expressing the encoded genome is controlled by transcription factors and all these other things that interact with the promoters, which turn the genes on and off and turn the volume of the genes up and down like thermostat switches, or whatever analogy you want to use. That process is itself at the mercy of the way we behave because you can do things in your life that literally lead you to alter the expression of genes. 

Two quick examples of that to get the point across: One is stress. When you're under stress, the physiological result is that cortisol increases in your body and has a lot of effects. Cortisol is a transcription factor; it actually alters the expression of certain genes. It does so largely in the immune system, which results in the suppression of immune activity. It lowers your immunity, which is why when you're under stress you're more likely to catch a cold. So here's an example in which something outside you—whatever it is that causes stress, an argument or an exam—affects the expression of your genes in your immune system. But a much more everyday example is simply the process of learning and memory. Associative memory, conditioning the association of one stimulus with another, is an immensely important part of learning. That process involves the changing of the strength of synapses between neurons in real time. As you form a long-term memory, you change the shape and the size of the synapse, so that when two neurons that are connected keep firing together—meaning that you're associating a particular smell with a particular sight or something like that—then the connection gets strengthened. In the future only one of them need fire and it will provoke a memory of the other.

That process of changing the strength of synapses between nerve cells is mediated by genes. It actually requires the switching on and off of genes in order to change the synapses. These genes we now know, because of work on fruit flies, are called the CREB genes. There are about 17 of them in that particular system, and they're also in mammals and humans as well. They prove that memory and learning is a genetic process. That doesn't mean that it's a hereditary process—of course not. What we're talking about here is changing the expression of the genes in real life in response to what is literally the formation of a new memory—a new experience, in other words.

So the simple linear model of going from genes to behavior, which both the nature people and the nurture people have subscribed to—the nurture people saying, that model doesn't work, the nature people saying, that model does work—is wrong. It's nothing as linear, as deterministic, or as frightening as nurture people would have you believe, nor is it anything nearly as linear as the nature people would have you believe. It's much more interesting than that. With these feedback loops, from behavior back into the expression of genes, it means that the process of the creation of human nature and the alteration of human nature throughout your life intimately involves genes and experience at the same time. The more genes you have, the more genetic programs you have, the more experience you can get into the organism.

This doesn't fit into the wars between people on the nature side and the nurture side very easily, and one of the things I've tried to do is to get away from the idea of the nature-nurture debate being a simple pendulum from one side to the other. The important point about this argument is that it's empirically driven. It starts with molecular biology. It starts with Seymour Benzer and other people discovering the genes involved in learning and memory; it starts with the discovery of real genes, and what they're actually doing—the work of someone like Cathy Rankin, a brilliant young scientist in Vancouver who has essentially observed in real time the changes in the nematode as it learns a new experience. She's done so by getting the genes to light up, literally. The cells that are expressing this process light up. She's also finding that those who have had a social upbringing behave differently than those with a solitary upbringing—in other words if they've been to school or been brought up at home, if you like. These are worms, remember, nematode worms with 302 neurons. Total. Maximum. No brains. And yet you can see an effect of developmental upbringing, social upbringing, etc., and it's these same synapses that are involved in the process of learning and memory. Discoveries like that are driving this new way of seeing the world, not theories. And to some extent the theories have got to be a bit humble before the new data. That's my epistemological position.

There's a possibility that you can adjust your theoretical thinking to this knowledge and say it was what you were saying all along, and to some extent there's a degree of fairness in that. But there's an awful lot of people who've been trying to put an end to the nature versus nurture debate, saying, "Come on. It's gene-environment interaction, etc." But the one thing I'm absolutely sure of is that if you go and look at the history of the nature-nurture debate—from Galton, through the 20th century, through Lysenko, Skinner, Watson on one side of the fence, and Chomsky, and people on the other side—you find that it's always very useful to pay attention to what people are saying about their own theories. It's very misleading to pay attention to what people are saying about each other's theories. On the whole, people have been pushing each other into extreme positions that they don't occupy, saying, "Look, I'm in the middle of the road. He's the guy who's on the verge. He's the extremist."

What I find happens all the time in this debate is that you say that there are genes involved in, let's say, sex differences, and people say, "Oh no, no, no. Sex differences are social. They've done an experiment that shows that sex differences are socially caused." And I say, yes, sure, sex differences are socially caused. I never said they weren't. I just said there are genes involved too. Indeed, there are genes involved in the social causation. That's the whole point. I don't actually know how sex differences and behavior come about, and I don't think anyone does yet. But it's pretty likely that what happens is a form of prepared learning, whereby there is an instinct for boys to end up one way and girls to end up another. But the way that instinct works is for boys to have an instinct to pick up from the world what boys do, not to arrive in the world with a program in their head saying, "Pick up a stick and go Pow! Pow! Pow! with it." It's "Ah, I like it when people go Pow! Pow! Pow! with sticks. That fits with my perceived way I'm heading in the world." Or I don't, according to which gender I am.

The classic and best experiment in this is Susan Mineka's work with a group of monkeys in Madison in the '80s, where she set out to examine the ontogeny of an instinct—in this care fear of snakes. Wild-born monkeys are afraid of snakes. They're so scared of snakes that they will cower in the back of the cage screaming rather than reach across a plastic model snake to get at a peanut when they're very hungry. Captive-born monkeys are not afraid of snakes; they happily reach across the model snake to get at a peanut. So what's going on here? That means that fear of snakes must be learned. But how on earth do you learn fear of snakes? The conventional classical conditioning wouldn't work very well, would it, because either you have a bad experience with a snake to learn from, in which case you're dead, or you don't have a bad experience, in which case you don't learn that snakes are frightening. So how are you going to end up acquiring a fear of snakes? It seems an absurd thing to acquire. She argues that what's happening is that there is a program for fear of snakes, an instinct if you like, but that that instinct needs to be socially triggered—in some sense triggered by a vicarious experience, by observing another monkey having a fear of snakes. So she set up an experiment in which she videotaped the wild-born monkey reacting with fear to a snake, and she then showed this video to a captive-born monkey, which immediately acquired a fear of snakes and was not then prepared to reach across even a model snake to get a peanut. She now doctors the video, so that it has the same monkey reacting in the same way in the background, but the bottom half of the screen now instead of having a snake has a flower. Again, the captive-born monkey has never seen a flower, so after it sees a monkey reacting with extreme fear to this new thing called a flower it should just as easily learn a fear of flowers. But it doesn't. It just learns that some monkeys are crazy. So what's going on here is that there is clearly an instinct for fear of snakes, and that's not surprising. Human beings have snake phobia. It's the commonest of all the phobias, even though most of us hardly even ever see a snake in our lives, but it requires an input from the environment. It requires a nurture input to be triggered. We know this is happening in the amygdala, and we're getting a bit of a handle on which cells are involved. We're not yet down to the gene level, but I'd bet my bottom dollar there's going to be a little pathway of genes in here that's mediating this process.

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Judith Harris has made an immensely important contribution in that she has blown the whistle on a huge mistake that's been made, which is to assume from the correlation between parents and children that children are learning things from parents. It turns out that once you control for heredity, through the use of behavior genetics, twin studies and adoption studies, you find that in the development of personality in particular—and that's quite a narrow point—children do very little learning from their parents, but they do quite a lot of learning from their peers. That seems to me a very important breakthrough. Judith Harris is building upon the behavioral genetics studies, where people like Thomas Bouchard and others with their studies of twins have made an immensely valuable contribution. But just because they're proving that genes are important in things like personality doesn't mean they're proving that environment is not important.

What it means is that they're proving that variations in family environment within a particular society don't change personality. It's a bit like vitamin C. If you don't get enough vitamin C it can cause a huge variation in your health, in this case scurvy. But as long as you're getting enough vitamin C, having extra vitamin C doesn't make you any healthier. And that's probably the way families are. You've got to have a sufficient level of love, affection, interest and stimulation from a family, but once you've got that, having extra doesn't change your development, whereas genes do vary all across the spectrum, and can change your development even in a constant environment. It's a bit like saying a kid with one toy in its entire life is obviously massively worse off than a kid with ten toys, but a kid with ten toys is not noticeably worse off than a kid with a hundred toys—or in my son's case, five million toys, as far as I can make out.

There's a lot of people who want the twin studies to go away. They want them to turn out to be methodologically flawed. They want to find that these twins knew each other all along, or that somebody's faking the data—as indeed happened in the case of Cyril Burt, as far as we can make out, although there are some people who don't accept that. People who wish for that are going down the wrong alley. The methodological criticisms have run out of room to be any use. For example, people will say that you can't learn anything from comparing identical twins because identical twins have shared a womb. The point is that a lot of the argument's answered by the fact that you're also comparing non-identical twins reared apart, as well as identical twins reared apart. And once you've got a decent database of these things, you come up with these very strong results saying that variations of personality within American society are caused by variations in genes. Variations in intelligence within American society are caused mostly by genes, partly by family environment. These results are fantastically robust now. They're not just from Bouchard's study in Minnesota; there are also in the Virginia studies, the Australian ones, the Dutch ones, and the Danish ones. There are big studies about twins reared apart all over the world, and they're all coming to the same conclusions, so it's no good wishing them away. But the people who don't like these studies, and who wish them away, are actually allowing them to be more powerful than they are, because they're essentially thinking that they're proving that genes are important at the expense of environmental factors, and they're not. Often, the stronger the environmental factor, the more genetic variation you're going to pick up.

A good example is short sight. In a society where only half the people are literate, the correlation between genes for short sight and short-sightedness is quite poor. In a society where everybody's reading books as a child, the correlation gets much better. So when the environmental factor, which is early reading, becomes stronger, the genetic variability becomes stronger. So actually what these studies are picking up is that the environment is good enough in American society to bring out the genetic variation between people. On the whole you're holding it constant. You're sending them to similar schools, giving them similar curriculums, and giving them similar toys to play with and similar television stations to watch. So you're bound to pick up the genetic differences. However, the twin studies have done a fantastic job of proving heritability of things like personality in particular societies. Going from that to finding out which genes are involved has proved immensely disappointing. There's no question that this is a huge failure. A lot of people ten years ago would have said it's now going to be comparatively easy to start walking down the genome, hunting the actual genes involved in extroversion or neuroticism, and it just doesn't work. Endless results show a small positive effect and then vanish, because it turns out either that the effect is associated only with one population, or it just doesn't replicate. Why is that? Is it because there are so many genes involved in these things that you can't pick out the ones with very small effects? Most of them do have very small effects. I don't think so; it's subtler than that. What's happening is that you're getting gene-environment interactions that are under the radar of the normal gene-hunting techniques.

A very nice example of this, which is still quite a controversial study, is Terrie Moffitt's work on antisocial behavior and the mono-amine oxidase-A gene on the x-chromosome, which is going to set the standard for how to understand the genes involved in personality and behavior. I write about it in Nature via Nurture. She's done a study of a cohort of New Zealanders in Dunedin who've been followed ever since birth. All the kids in this town were followed every year of their life to see what happened to them. It's about a thousand kids. If you take the 400 boys in the sample who have all-white genetic ancestry up to the grandparent level—boys because we're talking about a gene on the x-chromosome—and you look at their mono-amine oxidase-A gene, and you look at whether it's the high-active or low-active version—there are essentially two versions of this gene according to how active they are, according to whether the promoter on the front of the gene has got a certain number of repetitions or a lesser number—does the less active version of the gene correlate with ending up a young adult who is antisocial and who's in trouble with the law? No, it doesn't, in significant correlation. If you then break the data down, though, into those who were abused in their childhood and those who weren't, you find a very strong correlation with this gene. It turns out that if you have the low-active version of this gene, and you had an abusive childhood, then you're going to end up with an antisocial adult—not deterministically, but with a high probability. That seems to me to be a terribly important study, because it shows that when you parcel out the gene-environment interaction, you can find genes in here that you wouldn't have found with the conventional gene-hunting techniques—genes that correlate with behavior, but that react to the environment. 

What are the social implications of finding this? Well, essentially there are none, because we were against child abuse before we knew which genes were involved, and we're against child abuse afterwards. It's possible that you can start to say to a kid who has been abused and it's too late to intervene, "You are going to be all right, because you don't have the particularly responsive version of the gene," or "You're not going to be all right, and therefore we should start putting you on Ritalin or Prozac to try and adjust your brain chemistry during your life." We're a long way from that yet, but that's the kind of social implication you could pull out of it.

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If you go back to before the first two months of 1953, and ask yourself what people thought life was, you find nobody with anything like the right guess. Absolutely nobody is talking in terms of a linear digital code, until the morning of the 28th of February, 1953, when Jim Watson puts the base pairs together, and suddenly the idea of spelling out an infinitely long, infinitely variable, but completely faithfully reproducible code falls into place. You can say that Schrödinger used the term code script at one point, but he talked much more about quantum mechanical ideas and things like that. There were ideas that the secret of life was going to be some kind of piece of chemistry, a piece of energy, or a piece of quantum mechanics. There were all sorts of ideas out there, but nobody thought it would have anything to do with linear digital information, like we use in books, strings of alphabetical letters. That is why that is such an important moment, not because the thing was shaped like two spirals—that's just aesthetically pleasing—but because the world changed on that day. It took a long time for the world to realize it had changed, and Watson and Crick got invited to give zero seminars in Cambridge during the next three years, which is worth remembering, and there was nothing in the newspapers about it. 1953 was better known for many, many years as the year when Everest was climbed, the Queen was crowned, the first issue of Playboywas printed, and all these other tremendous anniversaries. But in retrospect we can see that it doesn't really click with the population at large until O. J. Simpson and Monica Lewinsky put DNA on the map in the '90s. It's forensic DNA, Alec Jeffries' discovery of DNA fingerprinting, that really brings it home to people what we're talking about here, which is a bar code, a message.

It's uncanny the way Turing and Shannon and all these people come together with ideas of computability, digital information theory, and cybernetics at around the same time as DNA falls into place. Suppose the base pairing mechanism of the double helix had been discovered in the 1920s, which is not totally impossible. The x-ray diffraction stuff wouldn't have been possible, but it's conceivable that a chemist could have worked out what was going on in DNA without x-ray diffraction. In the '20s, before computing, would we have even understood what we were looking at? Possibly not. Would we have been able to imagine one day reading it, and having the storage capacity to decode it? Or the other way of looking at it then is to suppose that DNA happens on schedule and we invent machines for sequencing DNA, but we haven't actually got computers by the '90s. How do we store the data? Do we have a lot of clerks writing it down instead of computers? It is wonderful the way the two branches of information technology, one called life and the other called electronics, fall into place at the same time. I don't understand how that kind of serendipity works in history, but it's an intriguing one.

In retrospect it became inevitable once we knew the genetic code and how it was spelled out that one day we'd read the entire script of the human recipe. It's quite surprising to think back to the mid-'80s and realize how controversial it was that people suggested it. It was a tremendous distraction for biology from most important tasks. It's far too expensive, and most of it is junk anyway. We shouldn't read the whole thing, but should just do the interesting bits. The idea of the human genome was a very controversial one. But a lot of people had faith that if you start reading genes, the technology will catch up and get cheap enough so that you can finish the job. And so it proved. Let's face it, the human genome project started in about 1986 or '87, and between 1986 and 1998 it read maybe 10% of the genome. And then it read 90% in the last year. I personally think that the trajectory would have been much the same without Craig Venter's intervention. What would not have happened is the publishing of a draft rough sequence in 2000. The key date would have been the finishing of the golden, perfect sequence in 2003, which is just happening as we're speaking. The trajectory to getting to that actually wasn't changed by Venter's intervention, but in order for the human genome project to announce a dead heat with Craig Venter's shotgun sequencing technique, we all think of 2000 as being the year when it was finished. In fact, what was finished then was a pretty messy draft that wasn't much use. 

What's next? Lots of other genomes. It's going to be very important to get the chimpanzee genome. The dog is going to be interesting, because then we can start to look at the behavioral differences between breeds of dogs, and that'll pull out genes to do with behavior. The mouse is obviously a key one for medical research. We've already got the mouse genome. The rat comes soon. All the others like the rice genome, which has just been finished. There's going to be scores and scores of genomes sequenced. Then we can start talking about individual genomes, and Craig Venter foresees the day when you or I can have our genome done for a thousand dollars. I suspect there won't be much point in doing whole genome sequencing for individuals, but there's going to be a huge significance in doing the interesting bits once we start to work out what they are.

There's no question that the discovery moves in silicon now. In other words, a huge amount of the significant stuff that we do next has to be both understood inside a computer and modeled inside computers. The modeling of gene interactions is something that is beyond the power of a man with a pencil. It's going to require people who are good at systems dynamics. People who come out of business schools are quite good at this kind of thing. It's going to come from some funny directions. The economists are quite good at this kind of thing. The genome is going to turn out to be quite like an economy. When you adjust interest rates you have some effects here and other effects there, and then they have effects and they affect what affects interest rates and so it all feeds back on itself. A lot of genomic phenomena are going to turn out to be like that. So I do think that bioinformatics is the way a lot of this is going. You only have to look inside a molecular biology lab these days and see that they spend half their time comparing sequences on the Web with other sequences, pulling out sequences that are similar, saying, "Oh my goodness, this gene is like that one in fruit flies." But there's still going to be room for a lot of very important wet biology in this, particularly when you get inside the brain, because what's going to turn out is that the gross structure of the brain conceals immense amounts of detail about which nerve cells are talking to which nerve cells, and the genes are going to be the key to finding out what's going on there. These alternatively spliced genes that seem to enable each nerve cell to have almost a unique bar code on it that tells it who it needs to link up with when it gets to its target. There's still room for some heroic biology in there.