It Takes a Genome: How a Clash Between Our Genes and Modern Life is Making Us Sick

by Greg Gibson

  The contemporary genetic approach is to scan the entire genomes of thousands of unrelated patients for variant SNPs that associate with disease. This has worked quite well for the other diseases we’ve considered, but when the British Wellcome Trust spent a few million dollars on the venture last year, they came up with...nothing. Not even the Serotonin transporter gave more than a hint of a signal. It is a striking result.

  Taken at face value, it means that there just aren’t common genetic variants that consistently lead to chronic despair. There’s a chance that they missed one or two, and maybe if they’d studied some group other than Englishmen they’d have had better luck. But more likely, the underlying assumption that common diseases are due to common variants is just wrong in this case—at least, not common variants that increase the risk by more than 20 percent.

  There are a couple of alternatives. One is that thousands of sites in the genome contribute, but each one has a barely measurable impact—depression by 1,000 genetic pinpricks. Since morose, moody, or just plain contemplative people tend to end up marrying one another—just as tall people tend to hook up, and scientists pair with scientists, and alas white folk with white folk—these small effect variants would concentrate in families. So would the disease susceptibility, though it would be difficult to find the specific alleles involved.

  The other possibility is that hundreds of genes have rare mutations that make a big contribution, but only in occasional cases. On this model, major depression would have a different genetic basis in different people, but whatever the issue is, it would lead to similar problems as far as signaling in the brain is concerned. These mutations would not have to affect everyone who carries them. They could individually increase the risk of depression twofold, or twentyfold for that matter, but would go undetected because only every ten thousandth person has any one of them.

  Schizophrenia and Other Mental Disturbances

  Iceland would seem to be another unlikely place to find genetic studies of mental health being carried out. Nestled up there in the middle of the North Atlantic Ocean, next stop the Arctic Circle, it is famous for icebergs, glaciers, and winter days that are about as long as a soccer game and doubtless just as dull. Nights are another matter since Reykjavik is also renowned for the beauty of its women, and quite the party culture has grown up there. For the past decade, Iceland has been home to the most ambitious, controversial, and in many respects productive, human genetics study on the planet.

  The reason for this is that a prodigal son named Kari Stefansson returned from Harvard in 1996 to set up a pharmaceutical discovery company registered as deCODE Genetics. With the blessing of the government, and financial backing from Hoffmann-La Roche, the company gained sole access to the intensive medical records of most of the 270,000 citizens of Iceland, along with family pedigrees going back centuries to the Viking times. If you’ve ever read Njal’s Saga, you will know that ancient Icelandic society was very much based on brutal retribution that makes an eye-for-an-eye justice look timid. Good family records were thus a must.

  Although this right of access has since been overturned in court, the majority of the citizens have in fact granted not just medical records but also blood and hence DNA samples to deCODE. The combination is a rich treasure chest that human geneticists salivate over (while bioethicists make a living worrying about the consequences). It will really get interesting if and when the company starts churning out complete genome sequences for all of these people: Iceland may well be the first country to have the complete genome of its population determined. Out of this mix has emerged the discovery of novel genes for a bundle of common diseases, including prostate cancer, type 2 diabetes, glaucoma, psoriasis, asthma, osteoarthritis, stroke, cardiovascular disease, and even restless leg syndrome.

  The reason I mention it here, though, is because deCODE is also honing in on several strong candidates for schizophrenia. Many of the things we’ve discussed about depression are equally true of this delusional psychosis. These include an incidence around one percent of the population, typical early adult onset, and presumed origins in complex genetics and environmental risk factors. Replace serotonin with dopamine, which is another neuronal signaling chemical, and the stories show distinct parallels.

  The tale of the genetics of schizophrenia is also sprinkled with hopeful leads and heartbreaking dead-ends. Time and again a result that appears to explain some proportion of the inheritance of the disease has simply turned out to be a nonfactor in another population. This failure makes the experts wonder whether it is a factor in the initial study as well. Either the genes identified are terribly unreliable indicators, or they are specific for different ethnicities or cultures.

  Nor does it stop there. Autism has also failed to yield to genetic dissection even though we know it has a heritable component. Mental retardation afflicts a few percent of all children, but with the exception of Fragile X syndrome where a particular gene is well implicated, it looks unlikely that common variants explain the disease. As a class, then, mental illness seems to be even more complicated than other diseases.

  One reason for this may be because so much of the genome is used in the brain, well more than half of it. So there are thousands of genes that can go wrong, in each case predisposing to some sort of psychological disturbance. In fact, a couple weeks before this book goes to the printer, papers have started to appear that strongly implicate new mutations known as copy number variations in both autism and schizophrenia. It is beginning to look as though as many as ten percent of sporadic cases of these psychological diseases occur because children a born either with an extra copy, or missing a copy, of one of a handful of genes—so far—and that this disturbance alone deeply upsets the brain. That there aren’t more of these psycho-CNV surprise us. It either is a minor miracle or can be thought of as a sign that evolution has found ways to suppress the effects of potentially harmful mutations.

  The Genetic Tightrope of the Mind

  What possible good can come of genes that would plunge a person into such depths of darkness that he would want to take his own life? How can we understand why millions of housewives, having chosen to devote their best years to the hopeful raising of wonderful children, nevertheless begin each day with sheer dread at the thought of making breakfast and feel the terrible burden of sadness take over from there? Why do our genes let that happen? And why must genes be responsible for all the children who are so full of anxiety that they cannot converse with their parents, let alone the world at large? How is it that an evolutionary process that has given us Michelangelo and Beethoven, Einstein and Shakespeare, nevertheless endows so many of our most creative artists with the capacity for such debilitating depression?

  Many would have you believe that there is some benefit to despair, that it is necessary for us to be able to appreciate great joy, or to be more prosaic that it is the price we pay for possessing a contemplative consciousness. In fact, it is by now almost obligatory for anyone who offers commentary on mental health, whether in a book, on Wikipedia, in a blog, or through a 2-minute television sound bite, to pass judgment on the adaptive value of melancholy. Yet we don’t go out of our way to make such arguments to justify cancer, heart disease, asthma, and arthritis, so there is no reason to go that way for diseases of the mind. You should know that for every evolutionary theorist who promulgates these ideas, there are at least as many practicing evolutionary geneticists who daily get their hands dirty digging around the genome, who reject them as at best unnecessary, at worst just silliness.

  For a different perspective, contemplate a tightrope walker. Maybe you have seen a funambulist at a weekend fair, just a couple of feet off the ground, hands held out for balance, or if they are really good perhaps even juggling some balls. There is not much risk, but a lot of joy, and a gentle metaphor for the capacity of the mind to assimilate all kinds of tendencies that would push us into a fall. Now picture one of those maniacs traversing a high wire strung between two tall buildings, suppo
rted by little more than a long balancing pole that shifts her center of gravity to a manageable place. This is higher consciousness, a tightrope act if ever there was one, capable yet manageable given the devices at hand, but always at risk of falling into an abyss. Now give her a pole from which you’ve docked a few feet from one end, without telling her, and ask her to cross the Niagara Falls on a windy day, ferocious cascades churning away underneath for dramatic effect. This is the human mind, a delicate balancing act weakened by genetic defects we know little about, trying to cope in a hostile new environment of our own making.

  Talk about genetic imbalance and the origin of disease. The argument in a nutshell is that mood is such a complex trait that over millions of years mechanisms have evolved to buffer it from all sorts of stresses. Organisms must cope with a frightful environment, and mutations can hit thousands of genes that tend to disrupt the way the mind works. The human brain evolved in the genetic wink of an eye, fundamentally changing our mental capacities but leaving us more exposed, less buffered, than ever. On top of this, in the last few generations we have created a totally novel environment in which it is expected to act. We should be wondering why any of us are able to cope at all—but what’s that old adage, all the world’s a little strange, except for you and me, and even thee I have my doubts?

  Consider first the environmental and cultural changes. No doubt that bangle of colored balls strung across a baby’s crib, or that annoying toy piano that delivers an electronic mimic of some animal when she puts her finger on its picture, is stimulating enough. But it is not a real substitute for the visceral contact with a real world that every infant mammal has grown up with for the past hundred million years. Not that we should go back to hunter-gathering, growing up in tents, and moving our home every few weeks in search of food, but I am saying modern humanity is different from day one.

  Growing older, we increasingly inhabit a virtual world. A friend of mine told me the other day that he found his precocious two-year old not just on the computer, but playing a flight simulator game online. We all lament that our kids are more adept at hitting a baseball out of the park on a PlayStation (or, more recently, a Wii station) than they are at running the bases around the cul-de-sac at the end of the street, or that they prefer piling up thousands of hours of cell phone bills to reading 100 pages of a good book, but do little about it. Then there is the violence, sexual innuendo, and nonstop banality of television, and the in your face propaganda of talk radio, and we wonder why adolescents have a hard time adjusting to the modern world.

  On the other hand, it never ceases to amaze me how engaged and energetic college students are. The party-versity that Charlotte Simmons finds in Tom Wolfe’s novel is real, but so too are the many twenty-somethings who are putting themselves through school, studying a full 40 hours a week, putting in another 20 hours of community service, and somehow finding time to play a sport and lead a full and healthy social life. Those who aren’t in college are as often as not working two or three jobs just to pay the rent and car loan while keeping the credit card debt somewhat manageable. It is the pace of life and the enormity of the pressures this all places on us that is so different. Humans have always dealt with adversity in their daily lives, but the grind today is nothing like anything ever before. Only in the past century has every single one of us been expected to be active from dawn to midnight with so little downtime and so much peer pressure to keep up, lest we be socially outcast or thrown on the junk heap of a failed career.

  Then there is the stress on relationships. Take a walk through the airport terminals in Chicago, Los Angeles, or New York and take in the faces of the travelers. Billy Joel’s scene at the bar has become the scene at the Chili’sToo as waistlines grow ever larger and mascara runs into the stress lines of harried faces. Pursuit of the golden buck that will keep our loved ones close and happy drives businessmen to the place they call loneliness, and young people’s pursuit of a more exciting and meaningful life drives a wedge into the heart of family. Facebook and MySpace might keep acquaintances in touch, and surely we’ve just scratched the surface of virtual friendship, but the mere fact of their popularity says something about how drastically human interactions have changed. It has to be affecting the way the mind develops and carries on.

  Finally for now, but certainly not exhaustively, there is the stress of modernity. Martha Stout speaks of “limbic wars” in her book, The Paranoia Switch, arguing that Americans are so fearful in the wake of the 9/11 terrorist attacks that an almost contagious rewiring of the neural circuitry has occurred that has reshaped the way we perceive one another. By undermining our sense of tolerance and compassion, the terrorists have hurt far more people than they ever could place in direct danger. She further points out that there are maybe 1,000 times as many women suffering today in physically abusive relationships than were killed in the attacks. Marital warfare takes a far stronger psychological toll, yet the nature of it is similar to the imprint of three generations of almost constant exposure to military warfare. World War II, the Vietnam War, the Cold War, and now the War on Terror have surely placed a stress on our collective mental health.

  So much for environmental imbalance. What of genetic imbalance? Homo sapiens is by any measure one of the younger species on the planet, having been around for fewer than 10,000 generations. By comparison with the average species, we can expect to be around for at least a 100 times that long before we evolve into something else or become extinct. This is also about the length of time since we shared a common ancestor with our closest relatives, the chimpanzees.

  A lot has happened in our short time on the planet. Using new statistical methods focusing on those parts of genes that regulate when and where they are used, we can see that genes involved in brain development seem to have been particularly subject to change. Maybe as many as a quarter of our brain genes are used ever-so-slightly differently in humans, though the liver and testes are at least as divergent. It is hard to know which or how many specific changes have been key to the emergence of intelligence, and which have gone along for the ride.

  Actually, we don’t need to look at the genes to conclude that there is something different about the human brain. Our reasoning abilities are unparalleled, at least on this planet. We communicate with symbolic language that has just bare rudiments in other primates, and we use signs and tools to build cultural practices that have as profound an impact on humanity as any of our unique genetic attributes. We try to engage in monogamous relationships, for the most part, and live in extended family relationships that are definitively human, typically extending the trust we share with family to friends as well. We have a spirituality that is undetectable in other creatures but seems to be at the very core of what it is to be human, though it is often allied with a sense of wonder that can create a sense of emptiness that is at the heart of depression.

  A Kindling Theory in the Modern World

  The final piece of the puzzle is to realize that the mechanisms that regulate mood have been exquisitely fine-tuned and genetically buffered, or canalized, ever since the dawn of animals. All the major brain signaling mechanisms, including serotonin, dopamine, and a half dozen others, are in place and working pretty much the same way in flies, pythons, and piranhas. I’m not sure what a depressed python or a manic piranha looks like, but just like us, their mood is regulated within strict bounds that enable the animal to function, and it would not surprise me if some of these animals also have mental health problems.

  The buffering is the key here. Just like blood glucose levels that rise and fall with the day and with the stages of your life, serotonin levels adjust to a person’s circumstances. Whether you are fighting or fleeing, sleeping or waking, angry or amorous, comes down at some level to this chemical. Despite the wide daily variation in activity, it is crucial that the basal levels remain within certain bounds, lest your whole mood system gets out of whack.

  This is why addictive drugs are so dangerous over the long haul. Cocain
e inhibits the reuptake of dopamine, nicotine prevents another signal called acetylcholine from finding its receptors, and hallucinogens mess with your serotonin function. The brain responds to all these drugs by modulating the levels of the receptors: Constantly firing in a bath of elevated serotonin, the logical response of a neuron would be to desensitize itself by turning down the number of receptors. This is what it does, but it means that without the drug an addict is left desperate for more of the signal to overcome the lack of reception. Over time levels can return to normal, but often, heavy drug users are left with a state of chronic low-level depression.

  Another sign that the brain modulates itself is seen in the phenomena of sensitization. A fly that is fed volatile cocaine will go a little crazy, buzzing all over the place. As the procedure is repeated, it becomes progressively wilder, crashing about its home like a pinball. Stimulate a rat’s brain with electric shocks at low intensity, and after a couple of weeks it starts convulsing, having become more sensitive to the shocks. In humans, over time, the frequency and intensity of epileptic seizures generally increases, and lately many physicians have begun to wonder whether the same is true of bipolar disorder.

  The hypothesis is called the kindling theory. Kindling is the dried small sticks and twigs that we used to use in the days before MatchLight inflammable fluid-soaked charcoal meant that fires could be guaranteed at the strike of a match. So perhaps we should rename this the Match-Light theory, reflecting the idea that we’re all primed for mental disturbance in today’s fast-paced world. In any case, the idea is that once one episode of depression occurs, the changes in the circuitry between the neurons that ensue leave a person prone to another episode.