The Best American Science and Nature Writing 2014 (7 page)

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 others 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.

But this was a study of just fourteen people. Cole needed more.

Over the next several years, he got them. He found similarly unbalanced gene-expression or immune-response profiles in groups including poor children, depressed people with cancer, and people caring for spouses dying of cancer. He topped his efforts off with a study in which social stress levels in young women predicted changes in their gene activity six months later. Cole and his collaborators on that study, psychologists Gregory Miller and Nicolas Rohleder of the University of British Columbia, interviewed 103 healthy Vancouver-area women aged fifteen to nineteen about their social lives, drew blood, and ran gene-expression profiles, and after half a year drew blood and ran profiles again. Some of the women reported at the time of the initial interview that they were having trouble with their love lives, their families, or their friends. Over the next six months, these socially troubled subjects took on the sort of imbalanced gene-expression profile Cole found in his other isolation studies: busy attack dogs and broken leashes. Except here, in a prospective study, he saw the attack dog breaking free of its restraints: social stress changed these young women's gene-expression patterns before his eyes.

 

In early 2009, Cole sat down to make sense of all this in a review paper that he would publish later that year in
Current Directions in Psychological Science.
Two years later we sat in his spare, rather small office at UCLA and discussed what he'd found. Cole, trimly built but close to 6 feet tall, speaks in a reedy voice that is slightly higher than his frame might lead you to expect. Sometimes, when he's grabbing for a new thought or trying to emphasize a point, it jumps a register. He is often asked to give talks about his work, and it's easy to see why: relaxed but animated, he speaks in such an organized manner that you can almost see the paragraphs form in the air between you. He spends much of his time on the road. Thus the half-unpacked office, he said, gesturing around him. His lab, down the hall, “is essentially one really good lab manager”—Jesusa M. Arevalo, whom he frequently lists on his papers—“and a bunch of robots,” the machines that run the assays.

“We typically think of stress as being a risk factor for disease,” said Cole. “And it is, somewhat. But if you actually measure stress, using our best available instruments, it can't hold a candle to social isolation. Social isolation is the best-established, most robust social or psychological risk factor for disease out there. Nothing can compete.”

This helps explain, for instance, why many people who work in high-stress but rewarding jobs don't seem to suffer ill effects, while others, particularly those isolated and in poverty, wind up accruing lists of stress-related diagnoses—obesity, type 2 diabetes, hypertension, atherosclerosis, heart failure, stroke.

Despite these well-known effects, Cole said he was amazed when he started finding that social connectivity wrought such powerful effects on gene expression.

“Or not that we found it,” he corrected, “but that we're seeing it with such consistency. Science is noisy. I would've bet my eyeteeth that we'd get a lot of noisy results that are inconsistent from one realm to another. And at the level of individual genes that's kind of true—there is some noise there.” But the kinds of genes that get dialed up or down in response to social experience, he said, and the gene networks and gene-expression cascades that they set off, “are surprisingly consistent—from monkeys to people, from five-year-old kids to adults, from Vancouver teenagers to sixty-year-olds living in Chicago.”

 

Cole's work carries all kinds of implications—some weighty and practical, some heady and philosophical. It may, for instance, help explain the health problems that so often haunt the poor. Poverty savages the body. Hundreds of studies over the past few decades have tied low income to higher rates of asthma, flu, heart attacks, cancer, and everything in between. Poverty itself starts to look like a disease. Yet an empty wallet can't make you sick. And we all know people who escape poverty's dangers. So what is it about a life of poverty that makes us ill?

Cole asked essentially this question in a 2008 study he conducted with Gregory Miller and Edith Chen, another social psychologist then at the University of British Columbia. The paper appeared in an odd forum:
Thorax
, a journal about medical problems in the chest. The researchers gathered and ran gene-expression profiles on thirty-one kids, ranging from nine to eighteen years old, who had asthma; sixteen were poor, fifteen well-off. As Cole expected, the group of well-off kids showed a healthy immune response, with elevated activity among genes that control pulmonary inflammation. The poorer kids showed busier inflammatory genes, sluggishness in the gene networks that control inflammation, and—in their health histories—more asthma attacks and other health problems. Poverty seemed to be mucking up their immune systems.

Cole, Chen, and Miller, however, suspected something else was at work—something that often came with poverty but was not the same thing. So along with drawing the kids' blood and gathering their socioeconomic information, they showed them films of ambiguous or awkward social situations, then asked them how threatening they found them.

The poorer kids perceived more threat; the well-off perceived less. This difference in what psychologists call “cognitive framing” surprised no one. Many prior studies had shown that poverty and poor neighborhoods, understandably, tend to make people more sensitive to threats in ambiguous social situations. Chen in particular had spent years studying this sort of effect.