Science Watch

Jeanne Brooks-Gunn, PhD, is giddy with excitement. Steve Suomi, PhD, says he hasn’t had this much fun in years. And John Cacioppo, PhD, says he’s seeing the most remarkable findings of his career.

These venerable researchers are energized by a new branch of research that has the potential to revolutionize how scientists study the way genes and environment interact to influence behavior and health. The research is called social genomics and it uses molecular biology tools to measure which genes are at work in specific cells. The idea is that, while our genes can directly influence health and behavior — the way a single gene causes Huntington’s disease — the environment can also affect genes, forcing some to turn on and others to turn off.

University of California, Los Angeles, genomics researcher Steve Cole, PhDMany of the 22,000 genes in human cells only turn on in response to external input. Our experiences — and how we see the world — “color the molecular biology of our body and create a different us,” says University of California, Los Angeles, genomics researcher Steve Cole, PhD, who is at the hub of this burgeoning field. Trained as a psychologist and a molecular biologist, Cole has developed some of the key analytic technology to understand those patterns of gene activation.

Although he does some of his own research, more often he collaborates with other scientists who want to apply his techniques to their own research, including the University of Chicago’s Cacioppo, who is studying how loneliness influences health, and the University of British Columbia’s Greg Miller, PhD, who is exploring how early childhood experiences influence adult health. Their findings suggest that social adversity primes the immune system to use its inflammatory response more often, which increases a person’s risk for disease.

As these findings suggest, Cole’s social genomics approach is enabling the field to “make some very significant and very rapid advancements in our knowledge,” says Miller. “We’re able to peer into cells and see what’s going on at the molecular level in a way that we’ve never been able to do before.”

Defensive programming

Many of the researchers who are using social genomics are interested in how chronic adversity affects immune function at the genetic level. Several lines of research on seemingly disparate populations suggest that adversity, including stress, poverty and loneliness, may reprogram the immune system to be ready for trouble. In the short term, it’s probably a good strategy. But in the long term, it can lead to health problems, including an increased risk of heart disease and some types of cancer.

Cacioppo sees this in his studies of chronically lonely people. His work builds on epidemiological research showing that people who feel socially isolated get sick more, and die sooner, than people who feel socially connected. Over the years, he’s found that lonely people have vascular changes that increase their risk for high blood pressure, and they have elevated levels of the stress hormones cortisol and epinephrine.

Social genomics has allowed him to look more closely at lonely people’s immune systems. In his first study with Cole, published in 2007 in Genome Biology (Vol. 8, No. R189), he examined gene activity in the white blood cells of 14 people enrolled in a longitudinal study of loneliness. Half scored in the top 15 percent on the UCLA loneliness scale and half scored in the bottom 15 percent. They found that genes that promote inflammation were more active in lonely people and genes that inhibit inflammation were less active. That finding, in combination with past research showing that chronic inflammation can promote cardiovascular disease, neurodegeneration and some types of cancer, may explain why loneliness can be bad for your health.

In a follow-up study with an expanded group of 93 participants, published in February in the Proceedings of the National Academy of Sciences (PNAS) (Vol. 108, No. 7), Cole and Cacioppo pinpointed the types of immune cell that exhibited changes in gene activity. The genes that were overexpressed in chronically lonely people originated in a “myeloid” line of immune cells that are very old in evolutionary terms. These cells patrol the body scanning for damaged tissue and mount inflammatory responses as the body’s first line of defense against infections. In addition, genes in B-lymphocytes — cells that typically fight off viruses and that are evolutionarily quite young — were less active.

The pattern of changes in gene expression suggest that lonely people’s immune systems are primed to fight off bacterial infections and less prepared to fight off viruses, says Cole. That can be a problem, he explains, because our immune system is not good at switching from one type of immune battle to another. So, once the system is primed to fight off a bacterial infection, it’s harder for it to switch gears to fight off a virus and vice versa. That’s why people often die from pneumonia after successfully fighting off the flu. Having primed myeloid cells means the inflammatory response is on a hair trigger, and too much inflammation is bad in the long-term.

Other work shows that it’s not just lonely people who appear to have overactive, pro-inflammatory genes. Research examining the effect of early childhood adversity on adult health finds similar patterns. As with loneliness, epidemiologic studies consistently show that people who grew up in stressful or impoverished environments are at higher risk of heart disease and some types of cancer.

Miller confirmed those findings when he teamed with Cole to compare activity in the immune system genes of adults who grew up in low socioeconomic-status households and those who grew up in higher-income homes. The researchers found that the pro-inflammatory genes of people who grew up in poverty, regardless of their current SES, were more active than those same genes in the comparison group.

“Early life adversity tunes the immune system to be vigilant for stress and a little tone deaf to cortisol, the hormone that helps manage inflammation, so the pro-inflammatory reaction can proceed unrestrained,” says Miller.

Suomi, chief of the Laboratory of Comparative Ethology at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, wanted to know how early these changes in gene expression show up in primate immune systems. To find out, he worked with Cole and University of Chicago economist James Heckman, using a paradigm he’s developed in his studies of rhesus monkeys. In it, he compares monkeys raised by their mothers in naturalistic groups with monkeys raised in isolation with a warm, fleece-covered mother “surrogate” for the first 37 days and then housed with same-age peers. Peer-rearing, he finds, is mildly stressful for the monkeys.

For the social genomics study, currently under review, Suomi obtained blood samples from the monkeys when they were four months old and sent them to Cole, who examined gene expression in the white blood cells. Already, the cells of the peer-reared infants expressed different genes than the cells of their mother-reared counterparts. In fact, they looked a lot like Cacioppo’s and Miller’s samples, with an amplification of genes involved in inflammation and suppression of genes involved in viral defense.

Programmed for survival

The findings coming out of social genomics need to make sense in evolutionary terms, says Cole. Why would our body be sensitive enough to environmental cues to change how the immune system works? In their March PNAS article on loneliness, Cole and Cacioppo take a first stab at explaining it.

In their view, our early ancestors either lived in social groups or in isolation, ostracized from the group. People who live in close contact with others are more apt to pick up viruses because viruses transmit primarily within members of the same species. In contrast, people who are trying to survive on their own are more at risk of injury and, as a result, bacterial infections from wounding. People, they surmise, will survive longer if their immune system is good at anticipating what the body is likely to encounter — bacteria or viruses, says Cacioppo.

“So [the immune system] puts all its chips in one or the other basket,” says Cacioppo. “It’s kind of banking in advance to increase its odds of survival.”

The same likely applies to childhood adversity in which the risk of bacterial infection increases when people live in poverty or when children are left to fend for themselves.

“It’s this kind of developmental plasticity that allows us to live successfully in a wide range of social and physical environments,” says Northwestern University biological anthropologist Thomas McDade, PhD.

‘Mind-boggling’ potential

For Suomi, Cacioppo and other psychologists who have spent their careers trying to convince researchers outside the field that the environment plays a powerful role in biology, these findings are not only exciting, they’re gratifying.

“We started off with showing that the environment creates behavioral differences,” says Suomi. “Now we’re looking at biological factors and finding that this early experience is affecting virtually every aspect of behavior and biology, including gene expression.”

The social genomics revolution will allow researchers to ask how much exposure to an environmental trigger causes changes in gene expression and whether, once the changes occur, interventions can reverse them. Suomi has already started down this path. In his study with Cole, one group of peer-reared monkeys kept their mother-surrogate even after they were placed with their peers. For them, the changes to gene activation were muted.

Researchers also hope to look beyond the blood to other tissues. In one study, with the University of Iowa’s Susan Lutgendorf, PhD, Cole showed that social circumstances influence gene expression in cancer cells. They found that more than 220 genes were turned on in the cancer cells of women with low levels of social support and high levels of depression — genes that were not active in women who experienced less social stress. Some of those genes are associated with higher rates of cancer spreading from one organ to another, says Cole.

The potential of these studies is myriad, says Columbia University’s Brooks-Gunn, who is working on a grant proposal to team up with Suomi. She wants to look at gene expression in the “fragile family” cohort, which includes data from 4,500 nationally representative children born in 1999 and 2000 and their families. Adding social genomics to what is already an enormously rich data set that includes family histories and measures of health, behavior and cognition will allow the researchers to study how, at a molecular level, early life conditions relate to health and behavior.

“It’s kind of mind-boggling,” says Brooks-Gunn. “The science and the knowledge will be unbelievable and will have policy implications. It takes what we do now and gives it a dimension and understanding of mechanisms that we’ve never had.”

Cole likes to think that he’s studying the “psychology of cells.” The take-home message, he says, is that genes and environment are not separate things.

“The environment makes its way into genes and controls what your genome becomes,” he says. “Our genetic capacity creates a sandbox of possibilities and what kind of castle you build in that sand depends on your experiences.”

Beth Azar is a writer in Portland, Ore.