by Lone Frank
But the chances for being able to change are better the more we know about the preconditions of personality. And a good number of the preconditions are tucked into our genetic heritage. If I know about the existence of a number of gene variants that probably help pump up my stress reactions, I can use that information in various ways. I could, for instance, do as La’Tanya did and focus on dealing better with my own incapacity, to choose, with a clear conscience, to turn down the heat. Nothing wrong with that. But maybe I don’t need to avoid stressful situations. Maybe, instead, I can think my way into responding better to them. When things are too hot, I can tell myself that it is not necessarily the world that is unmanageable, but my brain which, in part because of its genetic influences, is viewing the world that way.
For this, I might take a cue from a recent study by Dina Schardt and her colleagues, of the University of Bonn, who suggest “genetically predisposed neural processing may be counteracted by willful actions.” According to their research, you can whip your hypersensitive emotional brain into submission by exerting some cognitive control. Inspired by older findings that the short, “sensitive” SERT gene variant makes the amygdala more jumpy when you confront something fearful, the team got hold of thirty-seven women who were genotyped for SERT and put them in an MRI scanner, where they were shown a set of standardized pictures designed either to be neutral or to evoke fear. Just as Daniel Weinberger and others have seen, the carriers of short SERT variants reacted much more strongly to the fear stimulus than did the others. But that was only until the next scanning session, when the women were asked not just to look at the pictures but to volitionally detach themselves from the sight – a trick they had been taught and practiced in advance. When confronted with the fear-inducing pictures, both genetically sensitive and genetically robust women were able to dampen the activation of their amygdala. In fact, the two groups became indistinguishable. The sensitive individuals more efficiently suppressed their feelings of fear, showing that even if you are predisposed to have a stronger immediate emotional reaction, you can regulate it through conscious cognitive effort, if you so choose.
So when the going gets a bit tough, I can remind myself that my genes do not directly affect behavior but the mechanisms of my nervous system. And though my genetic inheritance plays a part in setting the conditions in which my brain operates, it is an incredibly plastic organ, whose chemistry is constantly influenced by how it is used. By thinking the right way, I can develop a thick mental skin to surround and protect my hypersensitive physiology.
7
The interpreter of biologies
DNA is just a tape carrying information, and a tape is no good without a player.
BRYAN TURNER
“WHAT DID YOU say this was for?”
My general practitioner looks suspiciously at the two thick plastic cylinders with built-in needles that I have brought with me, and the detailed instructions about how they are to be filled with blood, turned slowly ten times each, and then quickly sent off for analysis to a research laboratory at Lundbeck, a Danish pharmaceutical multinational, located on the outskirts of Copenhagen.
“They want to diagnose mental illness with a blood test?” the doctor asks as she routinely thrusts one of the needles into my vein. Yes, they do, but the method is currently in development. The idea is to move away from the psychiatrist’s habit of diagnosing various ills through subjective assessments of more or less ethereal symptoms. You ask patients how they think things are going, relying on a checklist of foggy questions about emotional states, sleep patterns, and psychomotor functions to reach an overall evaluation. Depression, for example. Or social phobia. Or borderline personality disorders.
Instead, the clinicians at Lundbeck and elsewhere are pining to discover biomarkers, objective measures comparable to those doctors use when they register the quantity of sugar in the blood to diagnose diabetes, or apply ingenious electrodes to the body to see if a heart is out of whack. Biomarkers are the Holy Grail. So when I catch scent of the fact that Lundbeck is trying to test the activity of selected genes to diagnose conditions such as post-traumatic stress disorder, borderline personality disorder, and, especially, depression, I leap at the chance to become a research subject one more time.
“But you’re not feeling depressed at the moment?” my doctor asks, gazing at me with a look that says, “you know the drill, better to tell me now.”
I shake my head, because I really feel fine. None of the familiar symptoms – waking up in the morning filled with a loathing for life; experiencing the day as a wearying drudge between two periods of sleep; sensing that everyone else in the world is doing exceptionally well and that I’m the only hopeless loser. For the time being, my mood sits in the normal range, which is to say, tolerable. It’s far from the point where the film usually breaks, and I politely ask to renew my prescription for 150 milligrams of antidepressants to restore my sanity.
Reassured, she wades into the specifics of the tests, which are unlike any of the genetic tests that I’ve taken in the past. In contrast to Gitte Moos Knudsen and her fellow brain researchers, the people at Lundbeck are not interested in the particular, immutable sequence of my genes, but in how my organism chooses to interpret them. To get this information, they isolate white blood cells and calculate their number of RNA molecules, which are transcribed from a group of selected genes and provide a measure for how much of the corresponding protein can be formed.
This isn’t traditional genetics, it’s epigenetics.
“THE AGE OF epigenetics has arrived,” Time magazine solemnly proclaimed a few days before my visit to the doctor. In a similar spirit, one of my American acquaintances, who works in a lab at Harvard, characterizes the field as “hot shit.” Or as the biologist Denise Barlow of the Austrian Academy of Sciences lyrically puts it, “Epigenetics is about all the strange and wonderful things that can’t be explained by genetics itself.”
Such language is understandable, because it is presumably in epigenetics that the almost mystical encounter between inheritance and environment will be realized. It has been easy enough over the years to identify a genetic predisposition and then imagine the environment entering the picture, creating interplay and a result: a phenotype. But what does that interplay consist of, and exactly when and where does it take place? This is where things become more difficult.
Epi – that elegant little Greek prefix hints that we are dealing with something “above” or “beyond” genetics. The concept was invented in 1942, by the British biologist, Conrad Waddington, to describe how an organism’s experiences and circumstances might make its genetic material act differently. At that time, before the genetic code was even revealed, it was all ideas and theories. Today, the field of epigenetics has come to stand for the investigation of how genes are expressed – that is, how much or how little protein they are allowed to produce, at what time, and in what cells. These are changes in the function of genes that occur without mutations in the genetic sequence.
Until relatively recently, however, most scientists believed that epigenetics was not relevant for adults – it was a phenomenon largely restricted to embryos, where the genome was programmed in ways that would govern the rest of the organism’s life. After all, the purpose of developing from a single cell to a complete organism is, practically speaking, so that all cell types possess the same genome, though each uses a greater or lesser portion of that material. Depending on which genes are allowed to be activated, each cell acquires an identity, with a corresponding function, both of which are defined by the set of proteins the cell’s genes produce; rather like an orchestra in which all the musicians have the same score in front of them, but the violins, the kettledrum, the triangle, and all the rest, play a distinct part.
Take, for instance, a liver cell and a brain cell. The liver uses a battery of enzymes to break down the toxins you consume when you eat and drink, and which must be removed from the blood. There is no reason for the brawny liver cells to prod
uce the full array of complicated receptors that facilitate communication among the nervous system’s somewhat more refined cells. Thus, the genes responsible for such receptors are inactivated in the liver. Inside the cranium, however, the brain cells are free of the garbage collector function, so the genes that specify enzymes that break down alcohol or fat are relegated to eternal rest.
The body’s epigenetic program organizes this division of labor. It does so by turning specific genes on and off, in essence by making a single gene accessible or inaccessible to the whole cellular apparatus, which is necessary for copying the DNA into peripatetic RNA for production of protein. One effective way of making a gene inaccessible is to put molecular obstacles in its way. In practice, this happens when extra chemical connections – methyl groups – are attached to selected bases in the DNA strand, preventing the transcription of the relevant gene. However, accessibility also has to do with how the DNA molecule is packed. The forty-six chromosomes of the human genome do not lie relaxed and stretched out in the cell (if they did, they would run to two meters long), but are tightly wound around particular proteins, reminiscent of hair around rollers. These proteins – histones – can be modified chemically in ways that make them more or less tight and the DNA strand more or less accessible.
It turns out there are a bunch of specialized enzymes that make such modifications either to DNA or to histones, and just as many whose job it is to remove those very modifications. It also turns out that these enzymes are found in cells throughout life. Therefore, it is not strange that scientists have recently discovered that epigenetic re-programming takes place from cradle to grave and, presumably, in all of the body’s tissues.
As is often the case in genetics, a good place to hunt for evidence is in identical twins. Although twins are said to be born with the same genome, they are never entirely the same, either in the way they look or in the way they think. Some of this is due to mutations, but some is probably the result of epigenetic changes. In 2005, a group led by Mario Fraga at the Spanish National Cancer Research Centre tested this hypothesis in forty twins between the ages of three and seventy-four. The researchers looked for patterns in epigenetic modifications of blood, muscle tissue, and skin in order to compare each set of twins and twins at different ages. They found a progressive development toward more difference. As small children, the twins were pretty much indistinguishable, but the more time they spent in the centrifuge of life, the more significant their differences became, and those differences were nicely spread throughout the entire genome. Epigenetics thus explains why one twin gets more wrinkles and ages more quickly than the other. Why one is fatter than the other. Or why one gets arteriosclerosis or schizophrenia, while the other does not. Reviewing these data, it seems likely that these different outcomes come from different lifestyles, since in infancy the lives of twins are more uniform than they later become.
If you think about it from an evolutionary perspective, it is completely understandable that these sorts of ongoing adjustments can take place, the enthusiasts of epigenetics point out. Presumably, epigenetic programming is a tool we have developed because it provides better possibilities for surviving. It is an adaptive mechanism that can change the individual in accordance with the requirements of the changing environment. The ingenious off-and-on mechanisms might even be considered an individual’s personal capacity for evolution.
Of course, the changes may take an unfortunate turn and become pathological. Many forms of cancer, for example, appear to be caused by epigenetic modifications that make cells divide uncontrollably, giving birth to malignant tumors. For this reason, cancer researchers number among the vanguard in epigenetics. Recently, they have been joined by scientists searching for the roots of psychiatric illnesses in the brain.
Consider the characteristics of diseases of the psyche. They typically involve a significant genetic disposition, yet, to be realized, require some contribution from environmental effects – but no one can put a finger on what exactly those effects are. Psychiatric illnesses and syndromes also have other significant common features: they are accompanied by long-term behavioral changes; often develop gradually; and, when treated, it takes a long time for the symptoms to abate. The need for chronic medication is typical; this isn’t a case where a simple chemical imbalance can be quickly fixed, once and for all. Finally, some of the medications that seem to stabilize the mood of both depressive and manic patients actually affect processes such as DNA methylation – a central component of epigenetic programming. All signs point to epigenetics at work.
But can something as ephemeral as social experiences – indefinable influences from your upbringing and interactions with people – really increase or decrease the activity of your genes? Researchers have come across clues that these influences are real. What gave them the clue was a pack of unfit mother rats.
In 2004, Moshe Szyf, of McGill University in Montreal, observed some interesting behavior over several generations of rats in his lab. He noted that rat babies that were raised by uncaring mothers – which, in the case of rats, means mothers who licked their babies only rarely and groomed them poorly – developed changes in the way they reacted to stress. Szyf could see plainly that the mistreated rat babies grew up to display much more fear than the offspring of good mothers. When the fearful female rats in their turn became mothers, they also neglected their babies, while the daughters of good mothers grew up to be excellent and attentive parents. The behavior was not inherited, but a direct result of upbringing, because if you took the newborn babies and switched them around between good and bad mothers, the babies took after their adoptive mothers. This was proof of a direct environmental effect.
What the environment had done came to light when Szyf and his colleagues killed the adult rats, plucked out their brains, and studied them in detail. It turned out that a poor childhood left lasting traces in the area of the gene for the glycocorticoid receptor – an especially important player in both rats and people. This receptor is crucial for the regulation of the stress response, because it helps prevent the formation of stress hormones when we are under duress. Among the mistreated rats, Szyf discovered, the gene had been completely blocked off by appended methyl groups. Parental neglect appeared to turn off particular genes in the rat’s brain cells, even when the rat had otherwise robust genes.
Ultimately, the Szyf team was interested in whether the same thing held true for people, since it has long been known that children who have been subject to neglect, abuse, or violence develop abnormally strong stress reactions as adults. These same children also have an increased risk of depression and suicide, among other things. Here was the chance of a lifetime to find a direct explanation for where sensitivity to psychological illnesses comes from. The only problem: getting hold of some brain tissue.
So Szyf went to the local brain bank – the Quebec Suicide Brain Bank – and asked whether they might have some tissue from individuals who had committed suicide and who had been abused as children. They did. To begin, Szyf and his team were given tissue from twelve people who had committed suicide, all of whom had been subjected to sexual abuse, regular violence, or gross neglect, which they compared to tissue from twelve people of the same age who had unluckily died in accidents. They spotted clear differences between the two groups in the area of the hippocampus. The gene for the glycocorticoid receptor had been turned off, via methylation, in the cells of the abused – just like in the rats. There was also much less RNA from the glycocorticoid gene, which indicated that the gene was not very active.
The question was whether the genetic change was directly associated with the earlier mistreatment or with the fact that the individuals had been depressed enough to kill themselves. Szyf requested brain tissue from another twelve suicide victims who had not experienced abuse but had been depressed. And it turned out that this group did not stand out from the control group of accidental deaths. The particular epigenetic modification of the glycocorticoid receptor in the hippocamp
us was akin to a signature for mistreatment, the sordid fingerprints of abuse in the victim’s brain.
You can get a similar signature from depression – your mother’s depression, that is. It is well known that children of depressed mothers themselves have an increased risk of recurring depression and, for a long time, psychiatrists attributed this to the learning of depressive behavior. But it looks as though this sensitivity can be traced earlier, to the embryo.
According to research by Tim Oberlander of the University of British Columbia, there is an epigenetic effect on a child’s glycocorticoid receptor when a woman experiences depression during the third trimester. This is the same signature found in Szyf’s suicide victims, but this time it was measured using blood cells from the umbilical cord. When Oberlander and his colleagues later tested the three-month-old children, he found they reacted to stress by producing significantly more cortisol than the offspring of non-depressed mothers. The researchers could even ascertain that the epigenetic effect was the same whether the mothers had been treated with antidepressants or not.
Epigenetics has emerged as one of the most hopeful areas of twenty-first-century genetics research, and this is particularly due to the fact that the field seems to provide some long-desired explanations for how our environment mediates our genes. But the hope also rests on something else: that all the epigenetic changes are, in principle, reversible – something can be done about them. This stands in glaring opposition to the mutations we are so used to hearing about, which cannot be changed. Could epigenetics mark the dawn of a better world? Is it possible we can intervene with drugs and turn genes back on, or hinder the activity of those running wild?