Remember Dolly the Sheep, the first mammal cloned from adult cells, in 1996? She was lovely, really an inspiration. She endured endless state dinners at the White House, all grace and cordiality. Then there was her triumphant ticker-tape parade down Broadway that won over even the most hardened New Yorker. Her appearances in those ubiquitous billboard ads for Guess? jeans (jeans, genes—get it? Those advertising guys are just awesome sometimes). Rollerblading at Disneyland for charity with the cast from Friends. Throughout the media circus, she was poised, patient, even-tempered, the epitome of what we look for in a celebrity and role model.
And despite that charm, people kept saying mean things about Dolly. Heads of state, religious leaders, editorialists, fell over themselves shortly after her debut to call her an aberration of nature, an insult to the sacred biological wonder of reproduction, something that should never remotely be considered in a human.
What was everyone so upset about? Some possibilities come to mind: (a) The Dolly Sheep/Dolly Parton connection unsettled everyone in a way that they just couldn’t quite put their finger on. (b) Because the cloning technology that gave rise to Dolly could be extended to humans, we face the potential of droves of clones of someone running around, all with the exact same liver function. (c) Thanks to that technology, we might wind up with a bunch of clones who have the same brain.
Sure, the first two possibilities are creepy. But the disease prompted by Dolly was overwhelmingly, remains overwhelmingly, about the third option. The same brain, the same neurons, the same genes directing those neurons, one multibodied consciousness among the clones, a mind meld, an army of photocopies of the same soul.
In actuality, people have known that this is not really the case ever since scientists discovered identical twins. Such individuals constitute genetic clones, just like Dolly and her mother (what was her name? Why does she get shortchanged in the media?), from whom that original cell was taken. Despite all those breathless stories about identical twins separated at birth who share all sorts of traits, like flushing the toilet before using it, twins do not have mind melds, do not behave identically. As one important example, if an identical twin is schizophrenic, the sibling, with the identical “schizophrenia gene(s),” has only about a 50 percent chance of having the disease. A similar finding comes from a fascinating experiment by Dan Weinberger of the National Institute of Mental Health. Give identical twins a puzzle to solve, and they might come up with answers that are more similar than one would expect from a pair of strangers. Hook those individuals up during the puzzle-solving to a brain-imaging instrument that visualizes metabolic demands in different regions of the brain, and the pattern of activation in the pair can differ dramatically, despite the same solution. Or get yourself some brains from identical twins. I don’t mean pictures from a brain scanner. Get the real, squishy stuff, postmortem brains. Slice ’em, dice ’em, examine them with every kind of microscope, and every obsessive measure—the numbers of neurons in particular brain regions, the complexity of the branching cables coming out of those neurons, the numbers of connections among those neurons—and they all differ. Same genes, different brains.
The careful editorialists pointed this out about Dolly (and instead, some of the most disturbing issues about cloning raised by Dolly center on the possibilities of generating life simply for the purpose of banking away transplant-compatible tissues). Nonetheless, that business about identical genes supposedly producing identical brains tugs at a lot of people. And other gene/behavior stories keep getting propelled to the front pages of newspapers. One popped up shortly before Dolly with the report, headed by a Stanford team, of a single gene, called fru, that determines the sexual behavior of male fruit flies. Courtship, opening lines, foreplay, whom they come on to—the works. Mutate that gene and, get this, you can even change the sexual orientation of the fly. And that wasn’t front-page news because of our insatiable fly voyeurism. “Could our sexual behaviors be determined by a single gene as well?” every article asked. And a bit earlier, there was the hubbub about the isolation of a gene related to anxiety, and before that, one for risk-taking behavior, and a while before that, the splash about another gene, whose mutation in one family was associated with their violent antisocial behavior, and then before that…
Why do these command attention? For many, genes and the DNA that comprises genes represent the holy grail of biology, the code of codes (two phrases often used in lay-public discussions of genetics). The worship at the altar of the gene rests on two assumptions. The first concerns the autonomy of genetic regulation. This is a notion that biological information begins with genes and flows outward and upward. DNA as the alpha, the initiator, the commander, the epicenter from which biology emanates. Nobody tells a gene what to do. It’s always the other way around. The second assumption is that when genes give a command, biological systems listen. In that view, genes instruct your cells as to their structure and function. And when those cells are neurons, those functions include thought and feelings and behavior. And thus we are finally identifying the biological factors, so this thinking goes, that make us do what we do.
This view was put forward in a lead piece in the The New Yorker by a literature professor named Louis Menand. Mr. Menand ruminated on those anxiety genes, when “one little gene is firing off a signal to bite your fingernails” (the first assumption about the autonomy of genes, firing off whenever some notion pops into their head). He considers what this does to our explanatory systems. How do we reconcile societal, economic, psychological explanations of behavior with those ironclad genes? “The view that behavior is determined by an inherited genetic package”—the second assumption, genes as irresistible commanders—“is not easily reconciled with the view that behavior is determined by the kinds of movies a person watches.” And what is the solution? “It is like having the Greek gods and the Inca gods occupying the same pantheon. Somebody’s got to go.”
In other words, if you buy into genes firing off and determining our behaviors, such modern scientific findings are simply incompatible with the environment having an influence. Sumpin’s gotta go.
Now, I’m not quite sure what sort of genetics they teach in Mr. Menand’s English department, but the sumpin’s-gotta-go logger-head is what most behavioral biologists have been trying to unteach for decades. Apparently with only limited success. Which is why it’s worth another try.
Okay. You’ve got nature—neurons, brain chemicals, hormones, and, of course, at the bottom of the cereal box, genes. And then there’s nurture, all those environmental breezes gusting about. And the biggest cliché in this field is how it is meaningless to talk about nature or nurture, only about their interaction. And somehow, that truism rarely sticks. Instead, somebody’s got to go, and when a new gene is trotted out that when “firing off,” “determines” a behavior, environmental influences are inevitably seen as something irrelevant that have to go. And soon, poor sweet Dolly became a menace to our autonomy as individuals, and there are perceived to be genes that control whom you go to bed with and whether you feel anxious about it.
Let’s try to undo the notion of genes as neurobiological and behavioral destiny by examining those two assumptions. Let’s begin with the second one, the notion that genes equal inevitability, generate commands that drive the function of cells, including those in our head. What exactly do genes do? A gene, a stretch of DNA, does not produce a behavior. Or an emotion, or even a fleeting thought. It produces a protein, where a specific DNA sequence that constitutes a gene codes for a specific type of protein. Now, some of these proteins certainly have lots to do with behavior and feelings and thoughts. Proteins include some hormones and neurotransmitters (chemical messengers between neurons), the receptors that receive hormonal and neurotransmitter messages, the enzymes that synthesize and degrade those messengers, many of the intracellular messengers triggered by those hormones, and so on. All vital for a brain to do its business. But the key is that it is extremely rare that things like hormones and neurotransmitters cause a behavior. Instead, they produce tendencies to respond to the environment in certain ways.
This is critical. Let’s consider anxiety. When an organism is confronted with some sort of threat, it typically becomes vigilant, searches to gain information about the nature of the threat, struggles to find an effective coping response. And once a signal indicates safety—the lion has been evaded, the traffic cop buys the explanation and doesn’t issue a ticket—the organism can relax. But this is not what occurs in an anxious individual. Instead, there is a frantic skittering among coping responses—abruptly shifting from one to another without checking whether anything has worked, an agitated attempt to cover all the bases and attempt a variety of responses simultaneously. Or there is an inability to detect when the safety signal occurs, and the restless vigilance keeps going. By definition, anxiety makes little sense outside the context of what the environment is doing to an individual. In that framework, the brain chemicals and, ultimately, the genes relevant to anxiety don’t make you anxious. They make you more responsive to anxiety-provoking situations, make it harder to detect safety signals in the environment.
The same theme continues in other realms of our behaviors as well. The exciting (made-of-protein) receptor that seems to have something to do with novelty-seeking behavior doesn’t actually make you seek novelty. It makes you more excitable in response to a novel environment than the folks without that receptor variant. And those (genetically influenced) neurochemical abnormalities of depression don’t make you depressed. They make you more vulnerable to stressors in the environment, to deciding that you are helpless in circumstances where you are not (this particular point will be returned to in detail in essay five). Over and over it’s the same theme.
One may retort that, in the long run, we are all exposed to anxiety-provoking circumstances, all exposed to the depressing world around us. If we are all exposed to those same environmental factors, yet it is only the people who are genetically prone toward, say, depression who get depressed, that is a pretty powerful vote for genes. In that scenario, the “genes don’t cause things, they just make you more sensitive to the environment” becomes empty and semantic.
The problems there, however, are twofold. First, not everyone who has a genetic legacy of depression gets depressed (only about 50 percent—the same punch line as for individuals with a genetic legacy of schizophrenia), and not everyone who has a major depression has a genetic legacy for it. Genetic status is not all that predictive, in and of itself.
Second, only on a superficial level do we share the same environments. For example, the incidence of the genes related to depression is probably roughly equal throughout the world. However, geriatric depression is epidemic in our society and virtually nonexistent in traditional societies in the developing world. Why? Remarkably different environments in different societies, in which old age can mean being a powerful village elder or an infantilized has-been put out to a shuffleboard pasture. Or the environmental differences can be more subtle. Periods of psychological stress involving loss of control and predictability during childhood are recognized to predispose toward adult depression. Two children may have had similar childhood lessons in “there’s bad things out there that I can’t control”—both may have seen their parents divorce, lost a grandparent, tearfully buried a pet in the backyard, experienced a bully who got away with endlessly menacing them. Yet the temporal patterning of their two experiences is unlikely to be identical, and the child who experiences all those stressors over one year instead of over six years is far more likely to come with the cognitive distortion “There’re bad things out there that I can’t control, and in fact, I can’t control anything” that sets you up for depression. The biological factors coded for by genes in the nervous system don’t typically determine behavior. Instead, they influence the way you respond to the environment, and those environmental influences can be extremely subtle. Genetic vulnerabilities, tendencies, predispositions, biases…. but rarely genetic inevitabilities.
It’s also important to realize the inaccuracy of the first assumption about behavioral genetics, the notion of genes as autonomous initiators of commands, as having minds of their own. To see the fallacy of this, it’s time to look at two startling facts about the structure of genes, because they blow that assumption out of the water and bring environmentalism back into this arena big-time.
A chromosome is made of DNA, a vastly long string of it, a long sequence of letters coding for genetic information. People used to think that the first eleventy letters of the DNA message would comprise Gene 1. A special letter sequence signaled the end of that gene, and then the next eleventy and a half letters coded for Gene 2, and so on, through tens of thousands of genes. And in the pancreas, Gene 1 might specify the construction of insulin, and in your eyes, Gene 2 might specify protein pigments that give eyes their color, and Gene 3, active in neurons, might make you aggressive. Ah, caught you: might make you more sensitive to aggression-provoking stimuli in the environment. Different people would have different versions of Genes 1, 2, 3, and some versions worked better than others, were more evolutionarily adaptive. The final broad feature was that an army of biochemicals would do the scut work, transcribing the genes, reading the DNA sequences, and thus following the instructions as to how, eventually, to construct the appropriate proteins. Sure, we would torture our students with an entire year’s worth of trivial details about that transcription process, but the basic picture suffices.
Except that that’s not really how things work. The real picture, while different, does not initially seem earth-shattering. Instead of one gene coming immediately after another and all of that vast string of DNA devoted entirely to coding for different proteins, long stretches of DNA don’t get transcribed. Sometimes those stretches even split up a gene into subsections. Nontranscribed, noncoding DNA. What’s it for? Some of it doesn’t seem to do anything. “Junk DNA,” long, repetitious sequences of meaningless gibberish. But some of that noncoding DNA does something interesting indeed. It’s the instruction manual for how and when to activate those genes. These stretches have a variety of names—regulatory elements, promoters, repressors, responsive elements. And different biochemical messengers bind to those regulatory elements and thereby alter the activity of the gene immediately “downstream”—immediately following in the string of DNA.
Aha, the death of the gene as the autonomous source of information, as having a mind of its own. Instead, other factors regulate when and how genes function. And what regulates this genetic activity? Often the environment.
A first example of how that might work. Suppose something stressful happens to some primate. There’s a drought and not much to eat, forcing the animal to forage miles each day for food. As a result, it secretes stress hormones from its adrenals called glucocorticoids. Among other things, glucocorticoid molecules enter fat cells, bind to glucocorticoid receptors. These hormone/receptor complexes then find their way to the DNA and bind to a particular regulatory stretch of DNA, one of those operating instructions. As a result, a gene downstream is activated, which produces a protein that, indirectly, inhibits that fat cell from storing fat. A logical thing to do—while that primate is starving and walking the grasslands in search of a meal, this is the time to divert energy to working muscles, not to fat cells.
This constitutes a cleverly adaptive mechanism by which the environment triggers a genetic response that modifies metabolism. This is a very different scenario for thinking about where information originates in these cascades. In effect, these regulatory elements introduce the possibility of environmentally modulated if/then clauses: if the environment is tough and you’re working hard to find food, then make use of your genes to divert energy to exercising muscle. And if a human refugee wanders miles from home with insufficient food because of civil strife, then the same is probably occurring—the behavior of one human, the sort of environment that that individual generates, can change the pattern of gene activity in another person.
Let’s get a fancier example of how these regulatory elements of DNA are controlled by environmental factors. Suppose that Gene 4037 (a gene that has a real name, but I’ll spare you the jargon), when left to its own devices, is transcriptionally active, generating the protein that it codes for. However, a regulatory element comes just before 4037 in the DNA string, and typically a particular messenger binds to the regulatory element, shutting down Gene 4037. Fine. How about the following: That inhibitory messenger is sensitive to temperature. In fact, if the cell gets hot, that messenger goes to pieces, unwinds, and comes floating off the regulatory element. What happens? Freed from the inhibitory regulation, Gene 4037 suddenly becomes active. Maybe it’s a gene that works in the kidney and codes for a protein relevant to water retention. Boring—another metabolic story, this one having to do with how a warm environment triggers a metabolic adaptation that staves off dehydration. But suppose, instead, Gene 4037 codes for an array of proteins that have something to do with sexual behavior. What have you just invented? Seasonal mating. Winter is waning, each day gets a little warmer, and in relevant cells in the brain, pituitary, or gonads, genes like 4037 are gradually becoming active. Finally, some threshold is passed, and wham, everyone starts rutting and ovulating, snorting and pawing at the ground, and generally carrying on. If it is the right time of year, then use those genes to increase the likelihood of mating. (Actually, in most seasonal maters, the environmental signal for mating is the amount of daily light exposure—the days are getting longer—rather than temperature—the days are getting warmer. But the principle is the same.)
A final, elegant version of this principle. Every cell in your body has a distinctive protein signature that marks it as belonging to you, a biochemical fingerprint. These “major histocompatability” proteins are important—this is how your immune system tells the difference between you and some invading bacteria and is why an organ transplanted into you that has a very different signature gets rejected. Now, some of those signature proteins can detach from cells, can get into your sweat glands, wind up in your sweat, and help to make for a distinctive odor signature. And for a rodent, now that’s important stuff. You can design receptors in olfactory cells in a rodent’s nose that can distinguish between odor proteins that are similar to its own versus ones that are totally novel. That’s easy to construct—the greater the similarity, the tighter the protein fits into the receptor, like a key in a lock (to hark back to one of our great high-school science clichés). What have you just invented? A means to explain something that rodents do effortlessly—distinguish between the smells of relatives and strangers.
Keep tinkering with this science project. Now, couple those olfactory receptors to a cascade of messengers inside the cell that gets you to the DNA, to the point of binding to those regulatory elements. What might you want to construct? How about: if an olfactory receptor binds an odorant indicating a relative, then trigger a cascade that ultimately inhibits the activity of genes related to reproduction. You’ve just invented a mechanism to explain how animals tend not to mate with close relatives. Or you can construct a different cascade: if an olfactory receptor binds an odorant indicating a relative, then inhibit genes that are normally active that regulate the synthesis of testosterone. And what you’ve just come up with is a means by which rodents get bristly and aggressive when a strange male stinks up their burrow, but not when it’s the scent of their kid brother. Or you can design the olfactory receptors to distinguish between odor signatures of same-sex individuals versus those of the opposite sex, and before you know it, this is a mechanism to regulate reproductive physiology. If you smell someone of the opposite sex, then start that cascade that ultimately gears up those genes down in the gonads—and there’s reasonably good evidence that that mechanism works in humans as well as in rodents.
In each of these examples, you can begin to see the logic, a beautiful sort of elegance that couldn’t be improved on much by teams of engineers. And now for the two facts about this regulation of genes that dramatically change how to view genes. First, when it comes to cells in mammals, by the best estimates available, more than 95 percent of DNA is noncoding. Ninety-five percent. Sure, a lot of that is the junk packing-material DNA, but your average gene comes with a huge instruction manual about how to operate it, and the operator is often environmental. With that sort of percentage, if you think about genes and behavior, you have to think about how the environment regulates genes and behavior.
And here’s the second fact. A big deal when it comes to genes and evolution and behavior is the genetic variation between individuals. By this, I mean that the DNA sequence coding for any given gene often varies from one person to the next, and this often translates into proteins that differ in how well they do their job. This is the grist for natural selection: Which is the most adaptive version of some (genetically influenced) trait? Given that evolutionary change occurs at the level of DNA, “survival of the fittest” really means “reproduction of individuals whose DNA sequences make for the most adaptive collection of proteins.” And the startling second fact is that when you examine variability in DNA sequences among individuals, the noncoding regions of DNA are considerably more variable than are the regions that code for genes. Okay, a lot of that noncoding variability is attributable to the junk packing-material DNA that is free to drift genetically over time, because it doesn’t do much. After all, two violins must look fairly similar, whether one is a Stradivarius and the other a Guarneri, whereas packing material can be as different as old newspaper or Styrofoam peanuts or bubble wrap. But there seems to be enormous amounts of variability in regulatory regions of DNA as well.
What does this mean? Hopefully, we’ve now gotten past “genes determine behavior” to, more typically, “genes modulate how one responds to the environment.” What that business about 95 percent of DNA being noncoding implies is that it is at least as valid to think something like “genes can be convenient tools used by environmental factors to influence behavior.” And what that second fact about variability in noncoding regions means is that “evolution is mostly about natural selection for different assemblages of genes” is not as accurate as thinking that “evolution is mostly about natural selection for different genetic sensitivities and responses to environmental influences.”
By now, ideally, it should seem mighty difficult to separate genetic and environmental factors into neat, separate piles. Just as it should be. Sure, some cases of behaviors are overwhelmingly under genetic control. Just consider all those mutant flies hopping into the sack with some cartoon cricket. And some mammalian behaviors can be pretty heavily under genetic regulation as well. As a remarkable example, there are closely related species of voles that differ as to whether they are monogamous or polygamous, and it all has to do with the receptor for a particular sex-related hormone in one part of the brain—monogamous male voles have that receptor there, polygamous voles don’t. In an amazing piece of tinkering, some scientists expressed that receptor in the brains of the polygamous males—who were now monogamous (with it not being clear whether making males monogamous should count as gene “therapy”).
These cases of single genes truly having a major influence on a behavior are usually cases where the behavior is carried out in pretty much the same way by everyone. This is a necessity. If you plan to pass on copies of your genes, there can’t be much tolerance for variability in these behaviors. For example, just as all violins have to be constructed in fairly similar ways if they are going to do their job, all male primates have to go about the genetically based behavior of pelvic thrusting in fairly similar ways if they plan to reproduce successfully. (Yup, I just compared violins with pelvic thrusts. Yet more evidence for why those science majors should be forced to take an English class now and then.) But by the time you get to courtship or emotions or creativity or mental illness or you name it, it’s an intertwining of biological and environmental components that utterly defeats the notion that somebody’s got to go, and it’s not going to be genes.
Maybe the best way to finish is to give another, particularly striking example of how individuals with identical genes can, nonetheless, come up with very different behaviors. I’m a bit hesitant to reveal this, as the finding has only recently surfaced, and it hasn’t been published yet. But, what the hell, it’s such an interesting finding, I have to mention it. Remember the massive public opinion poll that was carried out in 1996, the one that canvassed the opinions of every sheep throughout the British Isles? The researchers recently broke the code and identified the questionnaires from Dolly and her mother. And get a load of this bombshell: Dolly’s mother voted Tory, listed the Queen Mum as her all-time favorite royal, worried most about mad cow disease (“Is this good or bad for sheep?”), enjoyed Gilbert and Sullivan, and endorsed the statement “Behavior? It’s all nature.” And as for Dolly? Voted Green Party, thought Prince William was the cutest, worried most about “the environment,” listened to the Spice Girls, and endorsed the statement “Behavior? Nature. Or nurture. Whatever.” You see, there’s more to behavior than just genes.
NOTES AND FURTHER READING
Dolly, sadly, died in 2003 at age seven, very young for a sheep. She seemed to suffer from some sort of syndrome of premature aging—“a sheep in lamb’s clothes” in one striking, poignant description. This precocity occurred for reasons that are still not fully understood but may have to do with her DNA being prematurely worn. The ends of the DNA that constitute chromosomes are called telomeres. With each round of cell division, telomeres get a bit shorter, and when they get below a certain threshold of length, cell division ceases. It could well be that Dolly started off life with the telomeric “clock” in each of her cells already at her mother’s age. Suffering from a variety of ailments, she was put to sleep, and her early demise stands as a cautionary note for cloning enthusiasts.
Numerous basic textbooks go over the broad features of how genes are organized and how they function. For one of the classic texts, see Darnell J, Lodish H, and Baltimore D, Molecular Cell Biology (New York: Scientific American Books, 1990).
For information about how the heritability of schizophrenia and of major depression are both about 50 percent, see Barondes S, Mood Genes: Hunting for Origins of Mania and Depression (New York: Oxford University Press, 1999).
The subject of fruit flies and genes about sexual orientation is reviewed in Baker B, Taylor B, and Hall J, “Are complex behaviors specified by dedicated regulatory genes? Reasoning from Drosophila,” Cell 105 (2001): 13. The study where polygamous voles were made monogamous is Lim M, Wang Z, Olazabel D, Ren X, Terwilliger E, and Young I, “Enhanced partner preference in a promiscuous species by manipulating the expression of a single gene,” Nature 429 (2004): 754.
For an overview of the genetics of behavior (including anxiety and risk-taking behavior), see Plomin R, Behavioral Genetics, 3rd ed. (New York: W. H. Freeman, 1997).
For two superb overviews of how the function of genes cannot be understood outside the context of environment, see Moore D, The Dependent Gene: The Fallacy of “Nature versus Nurture” (New York: Owl Books, 1999) and Ridley M, Nature via Nurture (New York: HarperCollins, 2003).