September 16, 2013
BehindTheMedspeak: Your DNA is not a blueprint — "A cell is a machine for turning experience into biology"
A world-view shaking revolution has been taking place in biology over the past several decades, for the most part under the popular radar.
Long story short from David Dobbs' excellent article on the new social science of genetics: "Your DNA is not a blueprint. Day by day, week by week, your genes are in a conversation with your surroundings. Your neighbors, your family, your feelings of loneliness: They don't just get under your skin, they get into the control rooms of your cells."
If there is a better science writer than Dobbs I don't who that might be: he is a master synthesizer.
Scientists have known for decades that genes can vary their level of activity, as if controlled by dimmer switches. Most cells in your body contain every one of your 22,000 or so genes. But in any given cell at any given time, only a tiny percentage of those genes is active, sending out chemical messages that affect the activity of the cell. This variable gene activity, called gene expression, is how your body does most of its work.
Sometimes these turns of the dimmer switch correspond to basic biological events, as when you develop tissues in the womb, enter puberty, or stop growing. At other times gene activity cranks up or spins down in response to changes in your environment. Thus, certain genes switch on to fight infection or heal your wounds — or, running amok, give you cancer or burn your brain with fever. Changes in gene expression can make you thin, fat, or strikingly different from your supposedly identical twin. When it comes down to it, really, genes don't make you who you are. Gene expression does. And gene expression varies depending on the life you live.
Every biologist accepts this. 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.
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 response 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 Stanford biologist Russell Fernald. For years, Fernald had studied the African cichlid Astatotilapia burtoni, a freshwater fish about two 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, 12 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 to learn 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 15 minutes? Something big is going on."
Steve Cole, a Californian then in his early 40s, had trained in psychology at the University of California-Santa Barbara and Stanford; then in social psychology, epidemiology, virology, cancer, and genetics at UCLA.
In his post-doctoral 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 stand 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."
He said, "Every day, as our cells die off, we have to replace one to two percent of our molecular being. We're constantly building and re-engineering new cells. And that regeneration is driven by the contingent nature of gene expression. This is what a cell is about. A cell... is a machine for turning experience into biology."
In collaboration with University of Chicago social psychologist John Cacioppo, Cole mined a questionnaire about social connections that Cacioppo had given to 153 healthy Chicagoans in their 50s and 60s. Cacioppo and Cole identified the eight most socially secure people and the six loneliest and drew blood samples from them. 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 one percent of the genome—a considerable portion — was responding differently depending on whether a person felt alone or connected.
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.
But this was a study of just 14 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 15 to 19 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.
"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 60-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 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 31 kids, ranging from nine to 18 years old, who had asthma; 16 were poor, 15 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.
But in this study, Chen, Cole, and Miller wanted to see if they could tease apart the effect of cognitive framing from the effects of income disparity. It turned out they could, because some of the kids in each income group broke type. A few of the poor kids saw very little menace in the ambiguous situations, and a few well-off kids saw a lot.
When the researchers separated those perceptions from the socioeconomic scores and laid them over the gene-expression scores, they found that it was really the kids' framing, not their income levels, that accounted for most of the difference in gene expression. To put it another way: When the researchers controlled for variations in threat perception, poverty's influence almost vanished. The main thing driving screwy immune responses appeared to be not poverty, but whether the child saw the social world as scary.
But where did that come from? Did the kids see the world as frightening because they had been taught to, or because they felt alone in facing it? The study design couldn't answer that. But Cole believes isolation plays a key role. This notion gets startling support from a 2004 study of 57 school-age children who were so badly abused that state social workers had removed them from their homes. The study, often just called "the Kaufman study," after its author, Yale psychiatrist Joan Kaufman, challenges a number of assumptions about what shapes responses to trauma or stress.
The Kaufman study at first looks like a classic investigation into the so-called depression risk gene — the serotonin transporter gene, or SERT — which comes in both long and short forms. Any single gene's impact on mood or behavior is limited, of course, and these single-gene, or "candidate gene," studies must be viewed with that in mind.
Yet many studies have found that SERT's short form seems to render many people (and rhesus monkeys) more sensitive to environment; according to those studies, people who carry the short SERT are more likely to become depressed or anxious if faced with stress or trauma.
Kaufman looked first to see whether the kids' mental health tracked their SERT variants. It did: The kids with the short variant suffered twice as many mental-health problems as those with the long variant. The double whammy of abuse plus short SERT seemed to be too much.
Then Kaufman laid both the kids’ depression scores and their SERT variants across the kids’ levels of "social support." In this case, Kaufman narrowly defined social support as contact at least monthly with a trusted adult figure outside the home. Extraordinarily, for the kids who had it, this single, modest, closely defined social connection erased about 80% of the combined risk of the short SERT variant and the abuse. It came close to inoculating kids against both an established genetic vulnerability and horrid abuse.
Or, to phrase it as Cole might, the lack of a reliable connection harmed the kids almost as much as abuse did. Their isolation wielded enough power to raise the question of what's really most toxic in such situations. Most of the psychiatric literature essentially views bad experiences—extreme stress, abuse, violence—as toxins, and "risk genes" as quasi-immunological weaknesses that let the toxins poison us. And abuse is clearly toxic. Yet if social connection can almost completely protect us against the well-known effects of severe abuse, isn't the isolation almost as toxic as the beatings and neglect?
The Kaufman study also challenges much conventional Western thinking about the state of the individual. To use the language of the study, we sometimes conceive of "social support" as a sort of add-on, something extra that might somehow fortify us. Yet this view assumes that humanity's default state is solitude. It's not. Our default state is connection. We are social creatures, and have been for eons. As Cole's colleague John Cacioppo puts it in his book "Loneliness," Hobbes had it wrong when he wrote that human life without civilization was "solitary, poor, nasty, brutish, and short." It may be poor, nasty, brutish, and short. But seldom has it been solitary.
Cole... spoke about how we are permeable fluid beings instead of stable unitary isolates; about recursive reconstruction of the self; about an engagement with the world that constantly creates a new you, only you don’t know it, because you’re not the person you would have been otherwise — you're a one-person experiment that has lost its control.
He wanted to add one more thing: He didn't see any of this as deterministic.
We were obviously moving away from what he could prove at this point, perhaps from what is testable. We were in fact skirting the rabbit hole that is the free-will debate. Yet he wanted to make it clear he does not see us as slaves to either environment or genes.
"You can't change your genes. But if we're even half right about all this, you can change the way your genes behave — which is almost the same thing. By adjusting your environment you can adjust your gene activity. That's what we're doing as we move through life. We're constantly trying to hunt down that sweet spot between too much challenge and too little."
"That's a really important part of this: To an extent that immunologists and psychologists rarely appreciate, we are architects of our own experience. Your subjective experience carries more power than your objective situation. If you feel like you're alone even when you're in a room filled with the people closest to you, you're going to have problems. If you feel like you're well supported even though there’s nobody else in sight; if you carry relationships in your head; if you come at the world with a sense that people care about you, that you're valuable, that you're okay; then your body is going to act as if you’re okay — even if you're wrong about all that."
Cole was channeling John Milton: "The mind is its own place, and in itself can make a heaven of hell, a hell of heaven."
"So environment and experience aren't the same," I offered.
"Exactly. Two people may share the same environment but not the same experience. The experience is what you make of the environment. It appears you and I are both enjoying ourselves here, for instance, and I think we are. But if one of us didn't like being one-on-one at a table for three hours, that person could get quite stressed out. We might have much different experiences. And you can shape all this by how you frame things. You can shape both your environment and yourself by how you act. It's really an opportunity."
Cole often puts it differently at the end of his talks about this line of work. "Your experiences today will influence the molecular composition of your body for the next two to three months," he tells his audience, "or, perhaps, for the rest of your life. Plan your day accordingly."
Illustration up top by Jeremy Dimmock.
September 16, 2013 at 12:01 PM | Permalink
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Nice article. very interesting, thanks for sharing.
Posted by: PPLIC | Sep 17, 2013 12:16:11 AM
Thank you, Joe. Nature and Nurture in dialogue. And terrifying to think how this plays out in the process of addiction.
Posted by: Marianne | Sep 16, 2013 9:18:50 PM
Wow. Great article. Such clear vision of a sea change. Thanks for posting.
Posted by: Paul D Pruitt | Sep 16, 2013 8:20:17 PM
What a fabulous article. He IS good - even I understood most of it.
"Your subjective experience carries more power than your objective situation."
from Hamlet, Act 2, Scene 2:
"...for there is nothing
either good or bad, but thinking makes it so"
"You can shape both your environment and yourself by how you act. It's really an opportunity."
from Hamlet, Act 3, Scene 4:
"For use can almost change the stamp of nature
And either curb the devil, or throw him out
With wondrous potency."
No point to this, I just thought it was interesting, being a big Shakespeare fan & all.
Posted by: Flautist | Sep 16, 2013 6:23:38 PM
G-d #*&%!!!!! All the self help books, spiritual affirmations in the inbox, cognitive emotional therapy theories, anecdotal stories about the "one great teacher", all explained. (It makes me wonder also, as economic disparity widens in this country if anyone has considered the cost in terms of disease.) Thanks for posting this Joe. It needs to be shouted from the mountain tops.
Posted by: tamra | Sep 16, 2013 4:18:08 PM
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