Don’t you love those urban legends, those outrageous stories that everyone believes? There are academicians who study urban legends for a living, catalog them, track their origins in Norse mythology, get into arguments at conferences about them. But amid all that intellectualizing, it’s just plain fascinating to hear some of the stories that lots of people fall for. There’s the endlessly repeated one about the person who puts the poodle in the microwave to dry it off, or the classic about the scuba diver who gets scooped up along with a lot of water into the giant bucket of a firefighting plane, then is dropped onto a forest fire. Then there’s the one about the woman who leaves groceries in her car on a sweltering day; a tube of cookie dough explodes from the heat just as she gets in, splattering the back of her head, and she’s convinced she’s been shot and the dough is her splattered brains.
And then there’s the one about a bunch of scientists who sequenced the human genome: they can explain everything about you; all they have to do is look it up in the sequence of your genes. Sure, someone has a cousin who has a friend whose uncle swears that he can explain everything since helping to sequence the human genome. But it just ain’t so; we’re back in the domain of urban legend.
Why are people such suckers for the idea that genes are the be-all and end-all? It’s particularly bad right now. Not only has the human genome recently been (mostly) sequenced, but we’ve just come off the golden anniversary of the discovery of the structure of DNA. The celebrations have been replete with religious imagery about the genetic code as Holy Grail, the Code of Codes.
This Holy Grail business even gets trotted out by biologists, people who get paid to know better. This is surprising when it happens because, as emphasized in some of the preceding chapters, genes are not these autonomous instructors. Instead, we’re back in the realm of gene/environment interactions, a phrase that is typically the first uttered by biologists in their infancy.
The idea that genes and environment interact can mean a number of things. At the least, it means that people who get into frenzied arguments about nature versus nurture are a century out-of-date. Of more relevance, it means that while genes can (indirectly) instruct cells, organs, and organisms as to how to function in the environment, the environment can regulate which genes are active at particular times—this was one of the main points of “A Gene for Nothing.” Of greatest relevance here, it means that the thing that a particular gene most proximally produces—a particular protein—will function differently in different environments. So, in theory, you’ve got some gene that in one environment causes you to grow antlers, while in another, it causes you to fly south for the winter.
For folks still fighting the nature/nurture wars, the debate now becomes, Okay, just how powerful are those gene/environment interactions? At one extreme are those who scoff at antlers/fly-south contrasts. In that view, a gene does something or other, and environment can alter just how fast or strong or long it does that something or other. But none of those environmental influences leads to dramatically different effects. Framed in the context of genes and disease, it’s like saying, yeah, how windy it is may alter the precise speed with which the anvil drops from a ten-story building and lands on your toe, but who cares about that environmental interaction with the anvil? And at the other extreme are those who assert that interactions can be of huge consequence—say, that an environmental factor like wind could result in an anvil dropping with the force of a feather.
And so the scientists happily argue and experiment away, squandering tax dollars that could otherwise go for Halliburton contracts. Amid these debates, it’s useful to be reminded of just how powerful gene/environment interactions can be, and three recent studies provide great examples.
The first concerns the effects of one of the subtlest, least appreciated environments: the prenatal one. As was outlined in “Genetic Hyping,” strains of laboratory rodents have been bred for various traits—this strain develops a type of diabetes, that strain gets hypertension, and so on. Each strain is developed by inbreeding generation after generation of animals with some trait, until all the members of the strain are close to being genetically identical—like clones of each other. If all the members of that strain show the trait, regardless of what lab they’re raised in, you may have begun to detect a strong genetic influence (and, as the main point of essay three, even some of the genes most acclaimed at influencing behavior turn out not to have consistent effects across consistent environments).
All the inbreeding is then followed by a critical experiment known as a “cross-fostering study.” Suppose all mice of Strain A grow up to prefer Coke to Pepsi, whereas the mice of Strain B always have the opposite opinion. Take some Strain A mice at birth and let Strain B moms raise them in a Strain B colony. If they still grow up craving Coke, the typical interpretation is that you’ve found a behavior that is strongly resistant to environment; score one for nature over nurture. But are cross-fostering studies the last word?
That’s where this new study comes in, carried out by neurobiologist Darlene Francis and colleagues at Emory University, and published in the prestigious journal Nature Neuroscience. They looked at two mouse strains with differences in an array of behaviors. To simplify a bit, one strain is more anxious and skittish than the other. As compared with the “relaxed” strain, the “timid” strain is slower to enter a scary or novel environment and has more trouble learning during a stressful task than relaxed-strain mice do.
Geneticists who study mice had known about those differences for a long time. They had also confirmed that the differences were largely governed by genetics. True, some evidence showed that relaxed-strain mothers are more nurturing than timid-strain moms, licking and grooming their pups more. That evidence had raised the worrisome possibility for the gene crowd that mothering style caused the differences between the two strains. But then the acid test had been performed: relaxed-strain mice that were raised from birth by timid-strain moms grew up to be just as relaxed as any other member of their strain.
But Francis and team went a step further. With the same kind of technology used by clinics performing in vitro fertilization, the investigators cross-fostered mice as embryos. Specifically, they implanted fertilized relaxed-strain eggs into timid-strain females who carried them to term. They also did the key control of implanting “relaxed” eggs into “relaxed” females (just in case the in vitro fertilization and implantation distorted the results). After they were born, some relaxed-strain pups were raised by timid-strain moms, and others by relaxed-strain ones.
And the result? When the supposedly genetically hardwired “relaxed” mice went through both fetal development and early pup-hood with timid-strain moms, they grew up to be just as timid as any other timid-strain mice. Same genes, different environment, different outcome.
This raises two points. First, environmental influences don’t begin at birth. Some factor or factors in the environment of a timid-strain mouse mother during her pregnancy—her level of stress, perhaps, or the nutrition she gets—are affecting the anxiety levels and learning abilities of her offspring, even as adults. The mechanisms may have to do with alterations in their brain structure, hormone profiles, or metabolism. In fact, some of the same prenatal effects have already been documented in people. The second point? Relaxed-strain mice aren’t relaxed only because of their genes; their fetal and neonatal environments are crucial factors.
So that has to be a bit unnerving for folks who subscribe heavily to that urban legend about the power of genes. The next example makes the point even more strongly, mainly because, initially, it seems like one big vote for genetic determinism. This study was also published in Nature Neuroscience and was carried out by Joe Tsien and colleagues at Princeton, the folks who invented the “Doogie” mouse discussed in “Genetic Hyping.” As you’ll recall, Tsien and team generated the Doogie mouse by artificially inserting a gene that boosted the function of a particular class of neurotransmitters (the chemicals that carry messages between brain cells). And this produced a brilliant mouse that could do calculus and balance a checkbook. Now Tsien and crew generated a “knockout” mouse that lacked a key gene relevant to the neurotransmitter system, which coded for a receptor for that neurotransmitter. And thanks to some real wizardry, they were able to restrict this effect to only that one part of the brain critical to learning and memory—in terms of accuracy, this is the equivalent of a smart bomb from a hundred miles out taking out only the argyle socks in Saddam’s clothes closet. As a result, everything about that neurotransmitter and its receptor was hunky-dory elsewhere in the brains of these mice, but this receptor system was completely knocked out of business in that one part of the brain.
The authors then demonstrated that these mice had all sorts of learning problems. They were lousy at recognizing objects, at making olfactory discriminations (something that rodents, not surprisingly, specialize in), at a certain type of contextual learning. These are all subtypes of memory that normally depend on that part of the brain. And, as one of the many of their excellent controls, the authors also showed that types of memory that don’t involve that brain region worked just fine in these mice.
Wonderful, exciting. The authors have shown just how important those receptors are in that part of the brain for memory in these mice. And given that humans possess this same neurochemical system in their brains, there are immediately all sorts of implications that jump to mind. Different people have different versions of the gene for this receptor. Which might then result in the receptor working differently. Which might result, it now seems, in memory working differently. A defining feature of our individuality, traced down to the level of an individual gene. DNA City, nature trashing nurture, hands down.
Then the authors did something really interesting. There’s a classic old paradigm in psychology in which you take baby rodents and, instead of raising them in boring, sterile cages, you put them into these stimulating environments, filled with running wheels and tunnels to burrow in, and great mouse toys. Remarkably, such “environmentally enriched” rodent pups develop into smarter animals, with better brain development, all sorts of good stuff. And environmental enrichment even does similarly good things to the brains of adult rodents, good news for all of us who are no longer young pups.
So Tsien and friends took some of these genetically dim mice and placed them, as adults, in an enriched environment. And, amazingly, it corrected some of those genetically based learning deficits. To reiterate, this isn’t some subtle genetic alteration stacked up against some running wheels and squeeze toys. This was a massive genetic defect, the complete obliteration of a critical gene in a part of the brain vital to learning and memory. And the right sort of stimulating environment could correct it.
Findings like those that emerged from these two papers may give a panic attack to mouse mothers the world over: Remember the time we got all stressed out when we were pregnant? Remember that other time we got irritable with our newborn pup? One of them could be the reason the kid won’t get into the best college. However, this topic might seem a bit far afield from human concerns. And this is where the final study comes in.
This landmark paper was published in Science, by Avshalom Caspi and colleagues at King’s College, London. These researchers have been doing work that puts to shame those studies that come out of watching some fruit fly with a twenty-four-hour life span. They’ve been following a population of more than a thousand New Zealand kids, beginning in infancy and running well into adulthood, nigh onto a quarter century. Among the things they’ve examined is who, as a young adult, suffers from clinical depression. This is a useful topic to get some insight about, given that depression can be life threatening and afflicts 5 to 20 percent of us.
Caspi’s team examined patterns of depression in their subjects and discovered that it has something to do with a variant of a gene. Now, that’s nice, but not necessarily earth-shattering. Maybe the gene is involved with, say, how your ankle bones form. Hmm, its relevance to depression seems tenuous; maybe it’s just a statistical red herring. Instead, the gene they implicated is at the center of biochemical theories about depression, coding for a protein that helps regulate how much serotonin gets into neurons. Serotonin is a neurotransmitter, one of scores of different kinds in the brain, but is the one responsive to antidepressant drugs like Prozac, Paxil, and Zoloft. The serotonin-regulating gene—which for reasons not worth going into is called 5-HTT—comes in two different flavors. Both flavors code for the same kind of protein, but they differ in how much of the protein gets produced, and how readily it regulates serotonin. Humans differ as to which version of 5-HTT our genes code for. Nonhuman primates do as well, and studies had already shown that a monkey’s 5-HTT type influences how readily it deals with stress.
So Caspi and colleagues tabulated the two 5-HTT gene flavors and how they correlated with the incidence of depression in their pool of subjects. And what they discovered is worth stating carefully. Did they demonstrate that genes of a certain flavor cause depression? No. Did they even show something milder, that having one flavor of 5-HTT significantly increases the risk of depression? Not really.
What they showed was that if you have a particular flavor of 5-HTT, you have a greatly increased risk of depression, but only in a certain environment. What kind of environment? One with a history of major stressful events and traumas in childhood or early adulthood (such as the death of a loved one, the loss of a job, a serious illness). Those in their study with a “bad” 5-HTT profile who also suffered major stressful events had almost twice the risk of depression, and nearly four times the risk of suicide or suicidal thoughts, as those with the “best” profile plus an equivalent history of stress. But those who were spared a history of major stressors were no worse off for having a “bad” 5-HTT profile. (Completing this picture is work by a group at the University of Warburg, Germany, showing that stress hormones regulate the activity of the gene for 5-HTT, and do so differently depending on the 5-HTT flavor.)
So what does your 5-HTT variant have to do with your risk of depression? It’s not even a valid question to ask. The only accurate way to approach the question is to ask what your 5-HTT variant has to do with your risk of depression in a particular environment.
What lessons lurk in these three studies? Obviously, beware of simple explanations; it is rare that nature is parsimonious. And keep genes in their proper place. Sometimes genetics is about inevitability—if you have the gene for Huntington’s disease, for instance, there’s a 100 percent chance you’re going to have this awful neurological disease by middle age. But in far more realms than people usually expect, genes are about vulnerabilities and potentials, rather than about destiny.
And out of that comes a social imperative—genes do indeed seem to play a role in some of our less desirable behaviors. But what knowledge about those genes keeps teaching us is that we have that much more of a responsibility to create environments that interact benignly with those genes.
NOTES AND FURTHER READING
The study by Darlene Francis and colleagues is Francis D, Szegda K, Campbell G, Martin W, and Insel T, “Epigenetic sources of behavioral differences in mice,” Nature Neuroscience 6 (2003): 445.
Prenatal environment has been shown to have lifelong effects on metabolism and risk of metabolic disease, reproductive function, brain development, and behavior in mammals, including humans. This is reviewed in Barker D and Hales C, “The thrifty phenotype hypothesis,” British Medical Bulletin 60 (2001): 5; Gluckman P, “Nutrition, glucocorticoids, birth size, and adult disease,” Endocrinology 142 (2001): 1,689; Dodic M, Peers A, Coghlan J, and Wintour M, “Can excess glucocorticoid, in utero, predispose to cardiovascular and metabolic disease in middle age?” Trends in Endocrinology and Metabolism 10 (1999): 86; Avishai-Eliner S, Brunson K, Sandman C, and Baram T, “Stressed-out, or in (utero)?” Trends in Neuroscience 25 (2002): 518; and Vallee M, Maccari S, Dellu F, Simon H, LeMoal M, and Mayo W, “Long-term effects of prenatal stress and postnatal handling on age-related glucocorticoid secretion and cognitive performance: a longitudinal study in the rat,” European Journal of Neuroscience 11 (1999): 2,906.
The Tsien study regarding the cognitively impaired mouse rescued by environmental enrichment: Rampon C, Tang Y, Goodhouse J, Shimizu E, Kyin M, and Tsien J, “Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice,” Nature Neuroscience 3 (2000): 238. This also contains references for general reviews on environmental enrichment.
The Caspi study on the “depression gene”: Caspi A, Sugden K, Moffitt T, Taylor A, Craig I, Harrington H, McClay J, Mill J, Martin J, Braithwait A, and Poulton R, “Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene,” Science 301 (2003): 386. For a similar finding in nonhuman primates: Bennett A, Lesch K, Heils A, Long J, Lorenz J, Shoaf S, Champoux M, Suomi S, Linnoila M, and Higley J, “Early experience and serotonin transporter gene variation interact to influence primate CNS function,” Biological Psychiatry 7 (2002): 118.
Regulation of 5-HTT by stress hormones: Glatz K, Mossner R, Heils A, and Lesch K, “Glucocorticoid-regulated human serotonin transporter (5-HTT) expression is modulated by the 5-HTT gene-promoter-linked polymorphic region,” Journal of Neurochemistry, 86 (2003): 1,072.
The broad subject of the interactions between stress and depression is reviewed in chapter 14 in Sapolsky R, Why Zebras Don’t Get Ulcers: A Guide to Stress, Stress-Related Diseases, and Coping, 3rd ed. (New York: Henry Holt, 2004).
Finally, for an encyclopedic (reasonably enough) overview of urban legends, see Brunvand J, Encyclopedia of Urban Legends (New York: Norton, 2002).