The Best American Science and Nature Writing 2014

by Deborah Blum

  Every biologist accepts this. That was the safe, reasonable part of Robinson’s notion. Where he went out on a limb was in questioning the conventional wisdom that environment usually causes fairly limited changes in gene expression. It might sharply alter the activity of some genes, as happens in cancer or digestion. But in all but a few special cases, the thinking went, environment generally brightens or dims the activity of only a few genes at a time.

  Robinson, however, suspected that environment could spin the dials on “big sectors of genes, right across the genome”—and that an individual’s social environment might exert a particularly powerful effect. Who you hung out with and how they behaved, in short, could dramatically affect which of your genes spoke up and which stayed quiet—and thus change who you were.

  Robinson was already seeing this in his bees. The winter before, he had asked a new postdoc, Cédric Alaux, to look at the gene-expression patterns of honeybees that had been repeatedly exposed to a pheromone that signals alarm. (Any honeybee that detects a threat emits this pheromone. It happens to smell like bananas. Thus “it’s not a good idea,” says Alaux, “to eat a banana next to a beehive.”)

  To a bee, the pheromone makes a social statement: Friends, you are in danger. Robinson had long known that bees react to this cry by undergoing behavioral and neural changes: their brains fire up and they literally fly into action. He also knew that repeated alarms make African bees more and more hostile. When Alaux looked at the gene-expression profiles of the bees exposed again and again to the alarm pheromone, he and Robinson saw why: with repeated alarms, hundreds of genes—genes that previous studies had associated with aggression—grew progressively busier. The rise in gene expression neatly matched the rise in the aggressiveness of the bees’ response to threats.

  Robinson had not expected that. “The pheromone just lit up the gene expression, and it kept leaving it higher.” The reason soon became apparent: some of the genes affected were transcription factors—genes that regulate other genes. This created a cascading gene-expression response, with scores of genes responding.

  This finding inspired Robinson’s kidnapping-and-cross-fostering study. Would moving baby bees to wildly different social environments reshape the curves of their gene-expression responses? Down in Ixtapan, Robinson’s collaborators suited up every five to ten days, opened the hives, found about a dozen foster bees in each one, and sucked them up with a special vacuum. The vacuum shot them into a chamber chilled with liquid nitrogen. The intense cold instantly froze the bees’ every cell, preserving the state of their gene activity at that moment. At the end of six weeks, when the researchers had collected about 250 bees representing every stage of bee life, the team packed up the frozen bees and shipped them to Illinois.

  There Robinson’s staff removed the bees’ sesame-seed-size brains, ground them up, and ran them through a DNA microarray machine. This identified which genes were busy in a bee’s brain at the moment it met the bee-vac. When Robinson sorted his data by group—European bees raised in African hives, for instance, or African bees raised normally among their African kin—he could see how each group’s genes reacted to their lives.

  Robinson organized the data for each group onto a grid of red and green color-coded squares: each square represented a different gene, and its color represented the group’s average rate of gene expression. Red squares represented genes that were especially active in most of the bees in that group; the brighter the red, the more bees in which that gene had been busy. Green squares represented genes that were silent or underactive in most of the group. The printout of each group’s results looked like a sort of cubist Christmas card.

  When he got the cards, says Robinson, “the results were stunning.” For the bees that had been kidnapped, life in a new home had indeed altered the activity of “whole sectors” of genes. When their gene-expression data was viewed on the cards alongside the data for groups of bees raised among their own kin, a mere glance showed the dramatic change. Hundreds of genes had flipped colors. The move between hives didn’t just make the bees act differently. It made their genes work differently, and on a broad scale.

  What’s more, the cards for the adopted bees of both species came to ever more resemble, as they moved through life, the cards of the bees they moved in with. With every passing day their genes acted more like those of their new hive mates (and less like those of their genetic siblings back home). Many of the genes that switched on or off are known to affect behavior; several are associated with aggression. The bees also acted differently. Their dispositions changed to match that of their hive mates. It seemed the genome, without changing its code, could transform an animal into something very like a different subspecies.

  These bees didn’t just act like different bees. They had pretty much become different bees. To Robinson this spoke of a genome far more fluid—far more socially fluid—than previously conceived.

  Robinson soon realized he was not alone in seeing this. At conferences and in the literature, he kept bumping into other researchers who saw gene networks responding fast and widely to social life. David Clayton, a neurobiologist also on the University of Illinois campus, found that if a male zebra finch heard another male zebra finch singing nearby, a particular gene in the bird’s forebrain would fire up—and it would do so differently depending on whether the other finch was strange and threatening or familiar and safe.

  Others found this same gene, dubbed zenk, ramping up in other species. In each case, the change in zenk’s activity corresponded to some change in behavior: a bird might relax in response to a song or become vigilant and tense. Duke researchers, for instance, found that when female zebra finches listened to male zebra finches’ songs, the females’ zenk gene triggered massive gene-expression changes in their forebrains—a socially sensitive brain area in birds as well as humans. The changes differed depending on whether the song was a mating call or a territorial claim. And perhaps most remarkably, all of these changes happened incredibly fast—within a half hour, sometimes within just five minutes.

  Zenk, it appeared, was a so-called immediate early gene, a type of regulatory gene that can cause whole networks of other genes to change activity. These sorts of regulatory gene-expression responses had already been identified in physiological systems such as digestion and immunity. Now they also seemed to drive quick responses to social conditions.

  One of the most startling early demonstrations of such a response occurred in 2005 in the lab of the Stanford biologist Russell Fernald. For years Fernald had studied the African cichlid Astatotilapia burtoni, a freshwater fish about 2 inches long and dull pewter in color. By 2005 he had shown that among burtoni, the top male in any small population lives like some fishy pharaoh, getting far more food, territory, and sex than even the No. 2 male. This No. 1 male cichlid also sports a bigger and brighter body. And there is always only one No. 1.

  I wonder, Fernald thought, what would happen if we just removed him?

  So one day Fernald turned out the lights over one of his cichlid tanks, scooped out big flashy No. 1, and then, twelve hours later, flipped the lights back on. When the No. 2 cichlid saw that he was now No. 1, he responded quickly. He underwent massive surges in gene expression that immediately blinged up his pewter coloring with lurid red and blue streaks and, in a matter of hours, caused him to grow some 20 percent. It was as if Jason Schwartzman, coming to work one day and learning that the big office stud had quit, morphed into Arnold Schwarzenegger by close of business.

  These studies, says Greg Wray, an evolutionary biologist at Duke who has focused on gene expression for over a decade, caused quite a stir. “You suddenly realize birds are hearing a song and having massive, widespread changes in gene expression in just fifteen minutes? Something big is going on.”

  This big something, this startlingly quick gene-expression response to the social world, is a phenomenon we are just beginning to understand. The recent explosion of interest in “epigenetics”—a term literally me
aning “around the gene” and referring to anything that changes a gene’s effect without changing the actual DNA sequence—has tended to focus on the long game of gene-environment interactions: how famine among expectant mothers in the Netherlands during World War II, for instance, affected gene expression and behavior in their children; or how mother rats, by licking and grooming their pups more or less assiduously, can alter the wrappings around their offspring’s DNA in ways that influence how anxious the pups will be for the rest of their lives. The idea that experience can echo in our genes across generations is certainly a powerful one. But to focus only on these narrow, long-reaching effects is to miss much of the action concerning epigenetic influence and gene activity. This fresh work by Robinson, Fernald, Clayton, and others—encompassing studies of multiple organisms, from bees and birds to monkeys and humans—suggests something more exciting: that our social lives can change our gene expression with a rapidity, breadth, and depth previously overlooked.

  Why would we have evolved this way? The most probable answer is that an organism that responds quickly to fast-changing social environments will more likely survive them. That organism won’t have to wait around, as it were, for better genes to evolve on the species level. Immunologists discovered something similar twenty-five years ago: adapting to new pathogens the old-fashioned way—waiting for natural selection to favor genes that create resistance to specific pathogens—would happen too slowly to counter the rapidly changing pathogen environment. Instead, the immune system uses networks of genes that can respond quickly and flexibly to new threats.

  We appear to respond in the same way to our social environment. Faced with an unpredictable, complex, ever-changing population to whom we must respond successfully, our genes behave accordingly—as if a fast, fluid response is a matter of life or death.

  About the time Robinson was seeing fast gene-expression changes in bees, in the early 2000s, he and many of his colleagues were taking notice of an up-and-coming UCLA researcher named Steve Cole.

  Cole, a Californian then in his early forties, had trained in psychology at UC Santa Barbara and Stanford, then in social psychology, epidemiology, virology, cancer, and genetics at UCLA. Even as an undergrad, Cole had “this astute, fine-grained approach,” says Susan Andersen, a professor of psychology now at NYU who was one of his teachers at UC Santa Barbara in the late 1980s. “He thinks about things in very precise detail.”

  In his postdoctoral work at UCLA, Cole focused on the genetics of immunology and cancer because those fields had pioneered hard-nosed gene-expression research. After that he became one of the earliest researchers to bring the study of whole-genome gene expression to social psychology. The gene’s ongoing, real-time response to incoming information, he realized, is where life works many of its changes on us. The idea is both reductive and expansive. We are but cells. At each cell’s center, a tight tangle of DNA writes and hands out the cell’s marching orders. Between that center and the world stands only a series of membranes.

  “Porous membranes,” notes Cole.

  “We think of our bodies as stable biological structures that live in the world but are fundamentally separate from it. That we are unitary organisms in the world but passing through it. But what we’re learning from the molecular processes that actually keep our bodies running is that we’re far more fluid than we realize, and the world passes through us.”

  Cole told me this over dinner. We had met on the UCLA campus and walked south a few blocks, through bright April sun, to an almost empty sushi restaurant. Now, waving his chopsticks over a platter of urchin, squid, and amberjack, he said, “Every day, as our cells die off, we have to replace 1 to 2 percent of our molecular being. We’re constantly building and reengineering new cells. And that regeneration is driven by the contingent nature of gene expression.

  “This is what a cell is about. A cell,” he said, clasping some amberjack, “is a machine for turning experience into biology.”

  When Cole started his social psychology research in the early 1990s, the microarray technology that spots changes in gene expression was still in its expensive infancy and saw use primarily in immunology and cancer. So he began by using the tools of epidemiology—essentially the study of how people live their lives. Some of his early papers looked at how social experience affected men with HIV. In a 1996 study of eighty gay men, all of whom had been HIV-positive but healthy nine years earlier, Cole and his colleagues found that closeted men succumbed to the virus much more readily.

  He then found that HIV-positive men who were lonely also got sicker sooner, regardless of whether they were closeted. Then he showed that closeted men without HIV got cancer and various infectious diseases at higher rates than openly gay men did. At about the same time, psychologists at Carnegie Mellon finished a well-controlled study showing that people with richer social ties got fewer common colds.

  Something about feeling stressed or alone was gumming up the immune system—sometimes fatally.

  “You’re besieged by a virus that’s going to kill you,” says Cole, “but the fact that you’re socially stressed and isolated seems to shut down your viral defenses. What’s going on there?”

  He was determined to find out. But the research methods on hand at the time could take him only so far: “Epidemiology won’t exactly lie to you. But it’s hard to get it to tell you the whole story.” For a while he tried to figure things out at the bench, with pipettes and slides and assays. “I’d take norepinephrine [a key stress hormone] and squirt it on some infected T-cells and watch the virus grow faster. The norepinephrine was knocking down the antiviral response. That’s great. Virologists love that. But it’s not satisfying as a complete answer, because it doesn’t fully explain what’s happening in the real world.

  “You can make almost anything happen in a test tube. I needed something else. I had set up all this theory. I needed a place to test it.”

  His next step was to turn to rhesus monkeys, a lab species that allows controlled study. In 2007 he joined John Capitanio, a primatologist at the University of California, Davis, in looking at how social stress affected rhesus monkeys with SIV, or simian immunodeficiency virus, the monkey version of HIV. Capitanio had found that monkeys with SIV fell ill and died faster if they were stressed out by constantly being moved into new groups among strangers—a simian parallel to Cole’s 1996 study on lonely gay men.

  Capitanio had run a rough immune analysis, which showed that the stressed monkeys mounted weak antiviral responses. Cole offered to look deeper. First he tore apart the lymph nodes—“ground central for infection”—and found that in the socially stressed monkeys, the virus bloomed around the sympathetic nerve trunks, which carry stress signals into the lymph node.

  “This was a hint,” says Cole: The virus was running amok precisely where the immune response should have been strongest. The stress signals in the nerve trunks, it seemed, were being either muted en route or ignored on arrival. As Cole looked closer, he found it was the latter: the monkeys’ bodies were generating the appropriate stress signals, but the immune system didn’t seem to be responding to them properly. Why not? He couldn’t find out with the tools he had. He was still looking at cells. He needed to look inside them.

  Finally Cole got his chance. At UCLA, where he had been made a professor in 2001, he had been working hard to master gene-expression analysis across an entire genome. Microarray machines—the kind Gene Robinson was using on his bees—were getting cheaper. Cole got access to one and put it to work.

  Thus commenced what we might call the lonely-people studies.

  First, in collaboration with the University of Chicago social psychologist John Cacioppo, Cole mined a questionnaire about social connections that Cacioppo had given to 153 healthy Chicagoans in their fifties and sixties. Cacioppo and Cole identified the eight most socially secure people and the six loneliest and drew blood samples from them. (The socially insecure half-dozen were lonely indeed; they reported having felt distant from othe
rs for the previous four years.) Then Cole extracted genetic material from the blood’s leukocytes (a key immune-system player) and looked at what their DNA was up to.

  He found a broad, weird, strongly patterned gene-expression response that would become mighty familiar over the next few years. Of roughly 22,000 genes in the human genome, the lonely and not-lonely groups showed sharply different gene-expression responses in 209. That meant that about 1 percent of the genome—a considerable portion—was responding differently depending on whether a person felt alone or connected. Printouts of the subjects’ gene-expression patterns looked much like Robinson’s red-and-green readouts of the changes in his cross-fostered bees: whole sectors of genes looked markedly different in the lonely and the socially secure. And many of these genes played roles in inflammatory immune responses.

  Now Cole was getting somewhere.

  Normally, a healthy immune system works by deploying what amounts to a leashed attack dog. It detects a pathogen, then sends inflammatory and other responses to destroy the invader while also activating an anti-inflammatory response—the leash—to keep the inflammation in check. The lonely Chicagoans’ immune systems, however, suggested an attack dog off leash—even though they weren’t sick. Some 78 genes that normally work together to drive inflammation were busier than usual, as if these healthy people were fighting infection. Meanwhile, 131 genes that usually cooperate to control inflammation were underactive. The underactive genes also included key antiviral genes.

  This opened a whole new avenue of insight. If social stress reliably created this gene-expression profile, it might explain a lot about why, for instance, the lonely HIV carriers in Cole’s earlier studies fell so much faster to the disease.