Baboons are nasty and brutish*.*They have a long muzzle and fangs designed to inflict deadly injury, and are largely defined by their social habits -- they live in groupings of several dozen and have a strict hierarchy. Whereas female rank is hereditary, males compete for dominance. These fights are bloody and the stakes are immense: a higher rank means more sex. The losers face a bleak array of options -- submission, exile or death. In 1978, Robert Sapolsky was a college graduate with a degree in biological anthropology and a job in Kenya. He set off for a year of fieldwork among baboons before returning to the US for grad school and lab drudgery.
His wilderness experience consisted of backpacking trips; he had lit a campfire only once. On making his way to the bush, he discovered a sprawling savannah filled with zebras and wildebeests and elephants. “I couldn’t believe my eyes,” Sapolsky remembers. “There was an animal behind every tree. I was inside the diorama.”
Sapolsky slowly introduced himself to a troop of baboons, letting them adjust to his presence. After a few weeks, he began recognising individual animals, giving them nicknames from the Old Testament. It was an act of rebellion against his childhood Hebrew-school teachers, who rejected the blasphemy of Darwinian evolution. “I couldn’t wait to record that Nebuchadnezzar and Naomi were off screwing in the bushes,” Sapolsky wrote in A Primate’s Memoir. “It felt like a pleasing revenge.”
Before long, Sapolsky’s romantic vision collided with the dismal reality of living in the bush. His feet itched from a fungal infection, his skin was covered in insect bites, the Masai stole his stuff, he had awful diarrhoea, and he was terribly lonely. Sapolsky’s subjects gave him no glimpse of good fellowship. They seemed to devote all of their leisure time – and baboon life is just that – to mischief and malevolence. “I discovered that I didn’t like them very much,” he says. “They’re awful to one another, scheming and backstabbing.
They’re likechimps without the self-control.” Although Sapolsky was disturbed – this was nature, red in tooth and claw – he realised that their cruelty presented an opportunity to investigate the effects of social upheaval. He noticed that the males at the bottom of the hierarchy were thinner and more skittish. “They just didn’t look very healthy,” Sapolsky says. “That’s when I began thinking about how damn stressful it must be to have no status. You never know when you’re going to get beaten up. You never get laid. You have to work a lot harder for food.”
So Sapolsky set out to test the hypothesis that the stress involved in being at the bottom of the baboon hierarchy led to health problems. At the time, stress was mostly ignored as a medical subject. It was seen as an unpleasant mental state with few long-term consequences. “Studies had linked stress to ulcers, but that was about it,” he says. “It struck most doctors as unlikely that your feelings could affect your health. Viruses, sure. Carcinogens, absolutely. But stress? No way.”
Sapolsky, however, was determined to get some data. He wasn’t yet focused on human beings or public health. His transformation into one of the leading researchers on the science of stress would come later. Instead, he was busy learning how to shoot baboons with anaesthetic darts and then, while they were plunged into sleep, quickly measure their immune-system function and the levels of stress hormones and cholesterol in their blood.
In the decades since, Sapolsky’s speculation has become scientific fact. Chronic stress, it turns out, is an extremely dangerous condition. And not just for baboons: people are as vulnerable to its effects as those low-ranking male apes. Although stress doesn’t cause any single disease – in fact, the causal link between stress and ulcers has been largely disproved – it makes most diseases significantly worse. The list of ailments connected to stress is staggeringly diverse and includes everything from the common cold and lower back pain to Alzheimer’s disease, major depressive disorders and heart attack. Stress hollows out our bones and atrophies our muscles.
It triggers adult-onset diabetes and is a leading cause of male impotence. In fact, numerous studies of human longevity in developed countries have found that psychosocial factors such as stress are the single most important variable in determining the length of a life. It’s not that genes and risk factors like smoking don’t matter. It’s that our levels of stress matter more. Furthermore, the effects of chronic stress directly counteract improvements in medical care and public health. Antibiotics, for instance, are far less effective when our immune system is suppressed by stress; that fancy heart surgery will work only if the patient can learn to shed stress. As Sapolsky notes, “You can give a guy a drug-coated stent, but if you don’t fix the stress problem, it won’t really matter. For so many conditions, stress is the major long-term risk factor. Everything else is a short-term fix.”
The emergence of stress as a major risk factor is testament to scientific progress: the deadliest diseases of the 21st century are those in which damage accumulates over time. (Sapolsky refers to this as the “luxury of slowly falling apart”.)Unfortunately, this damage is exacerbated by stress. Although medicine has made astonishing progress in treating the fleshy machine, it is only beginning to grapple with those misfortunes of the mind that undo our treatments. The power of this view – that health is linked to our emotional state – connects with a range of observations, from the sociological to the molecular. On one hand, stress can be described as a by-product of a society that leaves people in a state of unease. But that feeling can now be measured in blood and urine, quantified in terms of glucocorticoids and adrenal hormones. And we are starting to see, with scary precision, the devastating cascade unleashed by these chemicals. The end result is that stress is finally being recognised as a critical risk factor, predicting an ever larger percentage of health outcomes.
To Sapolsky, the next step was obvious: attack the condition head-on. In 2003, he proposed a vaccine-like treatment that protects people against stress. It’s an ambitious attempt to combat a societal scourge at the level of our DNA. Although years of work remain, Sapolsky now insists that, given the public-health consequences, it’s time to take the problem seriously, to move our treatments beyond talk therapy and Valium. “Sometimes it’s not enough just to tell people, ‘You should really learn to relax,’” Sapolsky says. “If stress is as half as bad as we think it is, then we need to stop treating the side effects and go after stress itself.”
After his trip in 1978, Sapolsky began spending every summer in Kenya. In the early 80s, he happened upon a rare event: the highest-ranking female and a low-ranking one gave birth to daughters just days apart, and these newcomers allowed him to compare the effects of status on development. The first thing he noticed was that the high-ranking daughter hit every developmental landmark faster. She walked first, ate solid food earlier and interacted more with other baboons. The lesson, Sapolsky says, is that “status comes with privileges”, which are present from birth.
Sapolsky describes a poignant scene that took place when the newborns encountered each other for the first time. “They can barely get around, but they’re both so excited to see another baby,” he says. “And so the low-ranking kid goes wobbling over to say ‘hi’. But then, just as she gets near, the low-ranking mom grabs her daughter and drags her back. The poor kid has no idea what’s happened, but she’s just received her first lesson in the social hierarchy. The high-ranking kid is not somebody she can play with.” For Sapolsky, the tragedy of such interactions is their lasting legacy. “I can come back 25 years later, when these kids are old matriarchs, and they’ll be acting out the same dynamic. When they meet, the low ranking baboon will just stare at the ground. That’s what her mom was trying to teach her. She was being taught how to live with low rank. She was learning how to cope.”
That coping comes with a steep cost. In a controlled lab experiment led by Jay Kaplan at Wake Forest University School of Medicine in North Carolina, a study involved macaques, small primates who, like baboons, live in a rigid social hierarchy. The scientists quickly discovered that macaques of high rank were less likely to develop heart disease, despite the fact that all of the animals were fed a diet high in saturated fat and cholesterol.
They also conducted experiments in which monkeys were put into a new enclosure, a move that forced them to struggle to maintain their status. This led to increased heart rate and blood pressure. (In fact, Kaplan saw a rise in arterial plaque even when the stressed monkeys were fed a low-fat diet.) The effect was more pronounced for females. Normally, male primates are twice as likely to suffer from heart disease. This difference between the sexes disappears, however, when females lose their rank. A similarly destructive process is at work in humans. Doctors speculated that increasing rates of cardiovascular disease in women might be linked to the rising number employed outside the home, but that correlation turned out to be nonexistent. There were, however, two glaring exceptions to the rule: women were more likely to develop heart disease if they performed menial clerical work or when they had an unsupportive boss. The work wasn’t the problem. It was the subordination.
One of the most tragic aspects of the stress response is the way it gets hard-wired at a young age – an early setback can permanently alter the way we deal with future stressors. The biological logic of this system is impeccable: if the world is a rough and scary place, then the brain assumes it should invest more in our stress machinery, which will make us extremely wary and alert. There’s also a positive feedback loop at work, so that chronic stress actually makes us more sensitive to the effects of stress.
The physiology underlying this response has been revealed in the laboratory. When rats are stressed repeatedly, the amygdala – an almond-shaped nub in the centre of the brain – enlarges dramatically. (This swelling comes at the expense of the hippocampus, which is crucial for learning and memory and shrinks under severe stress.) The main job of the amygdala is to perceive danger and help to generate the stress response; it’s the brain area turned on by dark alleys and Hitchcock movies. Unfortunately, a swollen amygdala means that we’re more likely to notice potential threats in the first place, which means we spend more time in a state of anxiety. (This helps to explain why a more active amygdala is closely correlated with atherosclerosis.) The end result is that we become more vulnerable to the very thing that’s killing us.
This acute sensitivity also makes us more vulnerable to stress-related diseases. Just ask Michael Marmot, a professor of epidemiology and public health at University College London. For the past 25 years, he’s been running the Whitehall study, an exhaustive longitudinal survey launched in 1967 that has tracked some 28,000 men and women working in London. What makes the study so compelling is its uniformity. Every subject is a civil servant, a cog in the vast governmental bureaucracy. They all have access to the same healthcare system, don’t (generally) have to worry about getting laid off and spend most of their workdays shuffling papers.
The British civil service comes with one other feature that makes it ideal for studying stress: it’s hierarchical, with a precise classification scheme for employees. At the bottom are messengers, porters and security guards. Just above them are the clerical officers, followed by staff scientists and other professionals. This last group implements the policies dictated by powerful administrators who run the governmental agencies. Marmot wanted to investigate how differences in status “in people who are neither very poor nor very rich” might lead to measurable differences in health.
The differences are dramatic. After tracking thousands of civil servants for decades, Marmot was able to demonstrate that between the ages of 40 and 64, workers at the bottom of the hierarchy had a mortality rate four times higher than that of people at the top. Even after accounting for genetic risks and behaviours such as smoking and binge drinking, employees at the bottom still had nearly double the mortality rate of those at the top.
What, then, determines our health? Why were people in the lower ranks of Whitehall dying at a younger age? Marmot was forced to conclude that the significant majority of variation is caused by psychosocial factors, most notably stress. People of lower status in the Whitehall study experienced more negative stress, and this stress was deadly. (To take but one data point: fully two-thirds of an individual’s risk of stroke was attributable to the person’s socioeconomic status.) In fact, we’re so sensitive to the effects of status that getting promoted from the lowest level in the civil service reduced the probability of heart disease by up to 13 percentage points. Climbing the social ladder makes us live longer.
However, the Whitehall results aren’t a straightforward analysis of stress, at least not as it’s usually defined. After all, people in leadership positions often describe their jobs as extremely stressful. They work longer hours and have more responsibilities than those at the bottom of the bureaucratic hierarchy. Consider the self-report of Nigel, a high-status administrator: “There were 2,000 people, and I was responsible for all the personnel aspects, contracts and all the common service… It had every sort of challenge that you could ever wish to meet. A very active job and a lot of stress, but a very enjoyable job – and you got a tremendous amount of satisfaction from doing a good job.”
Notice the reference to stress; undoubtedly Nigel thought of himself as under lots of pressure. In contrast, here’s the self-report of Marjorie, a typist: “I went to the pool and sat there typing documents. Which was absolutely soul-destroying… The fact that we could eat sweets and smoke was absolute heaven, but we were not allowed to talk.” Researchers refer to the “demand-control” model of stress, in which the damage caused by chronic stress depends not just on the demands of the job but on the extent which we can control our response. “If an employee has a high degree of control over work, it is less stressful and will have less impact,” Marmot writes. (This helps to explain why the women with the meanest bosses showed the highest incidence of heart disease.)
The moral is that the most dangerous kinds of stress don’t feel that harmful. It’s not the late night at the office that’s going to kill us; it’s the feeling that nothing can be done about any current stressful situation. The person most at risk of heart disease isn’t the high-powered executive anxious about their to-do list – it’s the frustrated office cleaner stuck suffering from existential despair.
Stress is a chemical problem. When it occurs, a tiny circuit in the brain triggers the release of glucocorticoids, a family of stress hormones that puts the body in a heightened state of alert. The molecules are named after their ability to increase glucose levels in the blood, thus providing muscles with a burst of energy. They also shut down all non-essential bodily processes, such as digestion and the immune response. “This is just the body being efficient,” Sapolsky says. “When you’re being chased by a lion, you don’t want to waste resources on the small intestine. You’ll ovulate some other time. You need every ounce of energy just to get away.” But glucocorticoids have a nasty side effect: when they linger in the bloodstream, as they might due to chronic stress, damage accumulates. It’s the physiological version of a government devoting too many resources to its defence department, Sapolsky says. The body is so worried about war that it doesn’t fix the roads or invest in schools.
Interestingly, the effects of stress appear particularly toxic to the brain. Elizabeth Gould, a neuroscientist at Princeton, is best known for demonstrating that the birth of new neurons – a process known as neurogenesis – takes place in the adult brain. For the past several years, Gould has been studying the relationship between neurogenesis and stress in primates. She has found that when stress becomes chronic, neurons simply stop investing in themselves. Neurogenesis slows and dendrites (the branches of a neuron) shrink. Neuronal arbors then retreat. In fact, the very act of keeping primates in standard lab enclosures – often just bare wire cages – is so stressful that for years scientists had a warped understanding of the primate brain. Gould has become an ardent advocate of “enriched enclosures”, which provide the animals with things to play with and social interaction.
These cellular alterations help to explain why, as researchers noted in a recent review article, a “large part of the changes in brain structure and function (induced by chronic stress) have similar characteristics to those observed in neurodegenerative diseases, most notably Alzheimer’s.” And the higher the level of stress hormone, then the greater the level of cognitive decline.
One of the most disturbing aspects of these effects is the way they’re transmitted across generations. Gould has demonstrated, for instance, that if a pregnant rhesus monkey is forced to endure stressful conditions, like being startled by a horn, her offspring are born with reduced neurogenesis, even if they never actually experience stress after birth. This prenatal trauma, like any other endured in infancy, has lifelong implications. The offspring of monkeys stressed during pregnancy have smaller hippocampi, and suffer from elevated levels of stress hormone and anxiety. Look at humans – a recent study found that children abused in childhood by parents showed epigenetic changes to their DNA, which altered how their genes were read. The most prominent changes involved genes encoding glucocorticoid receptors, which led to a magnified stress response. So although the abuse might be temporary, the damage inflicted is permanent – a wound that never heals.
Not every bout of stress is so devastating. As the Whitehall data demonstrates, the executives in the corner office reported high levels of stress and yet seem to survive just fine. Other experiments show that intense exercise – such as running for hours on a treadmill in a gym – can lead to the release of glucocorticoids. And yet physical exercise is reliably associated with all sorts of positive effects.
These anomalies have led scientists, including Gould, to search for additional molecules in the brain that might serve as buffers for the stress response. Gould’s short list of candidates focuses on neuromodulators such as dopamine and oxytocin that are released when we experience pleasure. She argues that these feelings of enjoyment – the ability to find meaning in our work, even if it’s stressful work – may counteract the effects of glucocorticoids. These molecules might also explain why not every cleaner dies of heart disease at a young age and why enjoyable forms of exercise are good for us. “There are important individual differences in how people respond to stress,” Gould says. “Soldiers experience lots of stress in war, but most of them won’t get post-traumatic stress disorder. What accounts for those differences? And how can we help the most vulnerable?”
Robert Sapolsky looks out of place on the Stanford campus*.*He’s surrounded by manicured lawns and preppy students, but his appearance is deliberately untamed. His face is hidden by a bushy beard, which extends below his neck in the style of late Darwin. All that remains visible are pale blue eyes and the Sun-worn wrinkles that tell you he’s smiling.
In recent years, it has been harder for him to study primates in the wild. The main problem is the intrusion of humans. “The original beauty of studying stress in baboons was that they didn’t act like people,” Sapolsky says. “The animals don’t smoke, they don’t lie on questionnaires and they all eat the same basic diet.” Unfortunately, the increasing sprawl of human settlements means the baboons now supplement their natural menu of fruit, seeds and small antelopes with human trash. As a result, it has become all but impossible to disentangle the negative effects of stress from the negative effects of bad diet.
The difficulty of conducting research has led Sapolsky to focus on lab work. The theme remains the same – he is single-minded about stress – but the tools are different. Instead of tranquilising baboons, he oversees a molecular-biology lab, its shelves and counters cluttered with fridges, notebooks and salt solutions. “It kills me that I can’t spend more time in Africa,” he says. “But you take what you can get. And right now, it’s this lab.”
This doesn’t mean Sapolsky has stopped thinking big. His main project is absurdly ambitious: he wants to create a vaccine-like treatment for stress, a genetic therapy that can prevent struggle from wrecking brain and body. He started thinking about the treatment in 1992, during the early days of gene therapy. At the time, it seemed simple: if the chronic drip of glucocorticoids is toxic, then why couldn’t these chemicals be stopped before it’s too late?
That straightforward goal concealed a series of technical challenges. The first was that Sapolsky couldn’t just eliminate glucocorticoids from the bloodstream, because they are involved in all sorts of important functions, such as helping you run for your life. Second, Sapolsky needed to get his treatment past the blood-brain barrier – the specialised capillaries that prevent blood contaminants from entering the brain. Sapolsky’s vaccine-like cocktail needed to deliver a potent mixture of genes to the cortex – these genes would counteract the stress response – but the most common mechanisms of delivery, such as free-floating strands of DNA called plasmids, were denied entry. There were a few years of false starts, but Sapolsky and his post-docs continued to play around with the herpes simplex virus, which has been used as a viral vector in gene therapy research for decades. Herpes was a good candidate because it slips easily into brain cells. Sapolsky set about deleting all the dangerous genes in the virus, replacing each of them with an assortment of “neuroprotective” ones, which increase the production of growth factors, antioxidants and substances that mimic oestrogen (it counters many of the deleterious effects of stress on the brain). Brain cells infected by the virus would then be protected rather than get subjected to stress.
The question was how to get the herpes to turn on at key moments. Fortunately, natural selection solved the problem. “Viruses aren’t dumb,” he says. “They don’t want to become active until we’re vulnerable and our immune response is suppressed.”How does the virus know we’re stressed? To Sapolsky’s pleasant surprise, the virus already had the necessary genetic machinery: it automatically monitors glucocorticoids in the bloodstream. It had evolved to start expressing its genes whenever its host felt overburdened by the world. After several years of genetic engineering – it’s not easy to substitute all the dangerous genes with their therapeutic replacements – Sapolsky began introducing the modified herpes virus into rodent brains. Then he induced a series of tragedies, such as a massive stroke or an extended seizure, which would trigger the release of glucocorticoids (chronic stress is like a slow-motion stroke). Within minutes, the virus began pumping out neuroprotective proteins, which limited the extent of cell death. As a result, the damage was contained. For instance, rats given the herpes treatment were able to stave off practically all cell loss, while control rats lost nearly 40 per cent of neurons in a given region. In the hippocampus, neuronal death was reduced substantially. “To be honest, I’m still amazed that it works,” he says. “It’s not going to help anybody soon” – the research is still years away from clinical trials – “but we’ve proved that it’s possible. We can reduce the neural damage caused by stress.”
The power of Sapolsky’s vaccine is that it can rescue us from ourselves, in theory. Like those baboons in the bush, we live in a stratified society that comes with costs, which make us depressed, give us back pain, shrink the brain, clog the arteries and weaken the immune system. They shorten our already short lives.
The science of stress illuminates the damage. It documents the chemistry that unravels us from the inside. One day, it might give us options for preventing the damage, silencing the stress response at its source. But these are mere fancy fixes for what remains a societal problem. We tell our kids that life isn’t fair, but we fail to mention that the unfairness can be crippling, that many of us will die because of where we were born. This is the cruel trick of stress: if it were only a feeling, if there were only the despair of having no control or the anxiety of doing without, then stress would be bad enough. But the feeling is just the trigger. We are the loaded gun.
This article was taken from the September 2010 issue of WIRED magazine. Be the first to read WIRED's articles in print before they're posted online, and get your hands on loads of additional content bysubscribing online.
This article was originally published by WIRED UK
