My Beautiful Genome

by Lone Frank

  “You must have seen today’s New York Times?”

  I show him the front page of my Washington Post.

  “Yes, it’s the same story, and I already have twenty e-mails about it.” We stare at the headline: “Report on Gene for Depression Is Now Faulted.”

  “Excellent, excellent,” says Kendler, mostly to himself, “let’s go inside.”

  From my chair tucked into the front window’s bay, I notice all the signs that a cultured family lives here. The rooms are decorated with antique furniture and aged, original prints from India. Above the dining room table hangs a large, color photograph of a young woman who clearly belongs to the present but is posed as a Renaissance figure from seventeenth-century Holland. It is a strangely brooding portrait.

  “My daughter,” explains Kendler. “She’s an art student. It’s a self-portrait.”

  More conventional pictures of her and his two grown sons fill the landing, where I also notice a photo of the parents, when they were young. It seems to be from the ’70s, but Kendler looks nearly the same today. The only difference is that his hair and beard are no longer black but grey. Just like the last time we met, he reminds me of a thoughtful rabbi. Perhaps, it’s the gaze behind his round, owlish glasses or the way he speaks with a low, penetrating voice and an almost exaggeratedly clear diction. Kendler is a very calm, polite man. The strongest expression ever to pass through his lips is “bullshit,” and that happens only very rarely.

  “I grew up in a Jewish community on Long Island, outside New York,” he says at one point. “It was all very traditional until I moved to California as a teenager, where there was a different pace with drugs and …”

  Unfortunately, he doesn’t go into detail. We are interrupted when a very reserved tabby cat with pale green eyes comes slinking in. The cat glances at her guest before creeping up the last few inches to sniff my outstretched hand.

  “She is very particular and doesn’t take to just anybody,” remarks Kendler. Today it’s not a problem, because I’m very good with animals. They love me, I explain, and I speak to the cat in the manner I use with my black tomcat at home. “Such a sweet little pussycat, come here.” The cat draws nearer, but when I try to scratch behind her ear, she bites aggressively at my hand and plants a single cuspid into the soft flesh between my thumb and forefinger. Then, she slowly curls into a ball on the floor and fixes me with a malicious stare.

  Meanwhile, Kendler returns to that day’s big news, in which he is cited several times. The story involves Avshalom Caspi and Terrie Moffitt’s famous Dunedin study that showed the gene for SERT increases the risk of depression if the person experienced traumas and abuse as a child. Now, however, a group of psychiatrists and statisticians have produced an analysis of fourteen other studies using the same type of data and, when all this data is put together, they cannot see any connection between SERT and depression.

  “I should think that would take the wind out of the sails for Caspi’s studies,” says Kendler. He hurries to add that Avshalom’s father was his Hebrew teacher in school and that, no doubt, the younger Caspi is a fine fellow. The two iconic studies of the young men of Dunedin and the interplay of the genes for SERT and MAOA in their childhood remain, in their way, an excellent starting point. The studies have simply, in Kendler’s opinion, acquired influence far beyond what they deserve.

  “My explanation is that these two findings represent an ideal answer to the old question of nature versus nurture. You can almost say it is ‘feel good’ research. The results provide a sense that everyone is a winner. It is very intuitively appealing, and when it was published in 2003, everyone who had done studies with the SERT gene immediately went to their own data to see whether they could find the same effect if they asked the research subjects about their childhood.”

  “And…?”

  “Some could. Others couldn’t. And the new meta-analysis takes them all into consideration.”

  Meta-analyses. These are statistical exercises based on testing a connection that is shown in some studies but not others. They work by merging all the studies together and treating them as one. Meta-analyses are often thrown on the table as a sort of trump card in research. Smack! Take that. We have more data than you, so we’re right.

  Nevertheless, many people in the field have a hard time accepting this as the end of the entanglement of SERT with depression. After all, the “Woody Allen gene,” as it has been called, has repeatedly been linked to a sensitivity to stress – the short version of the gene makes you worse at dealing with stressful situations and events. In 2007, a team of British researchers reported that a timid temperament in children linked up nicely with the short version of SERT, and that same year another group saw a connection between the variant and suicide. At the same time, stress is frequently indicated as a triggering factor for depression. If I remember correctly, Kenneth Kendler and his group were among the first to show, back in the 1990s, that people react differently to influences associated to depression. That is, sensitivity is not uniform.

  “Mind you,” he says very evenly, “I, too, believe the general phenomenon described by Caspi exists. There is just not enough effect in each gene to see – statistically – interplay with environmental factors such as upbringing. But it is also a fact that psychiatry is an immature science. People get wildly enthusiastic about one idea and then another – it looks almost like infatuation. Psychiatry is influenced by fashion, and it was fashionable to study the environment and individual genes in the way they did in the Dunedin studies. My hope is that people will cool down and look more soberly at the data.”

  I mention that my personal interest in depression comes from my family background, and I am curious to know how genes and upbringing interact.

  “Yes, of course,” he says sympathetically, like a funeral director. “Let me tell you something. My own starting point in psychiatry was a deep interest in schizophrenia. But schizophrenia research has gradually moved in the direction of genetics, and one of the reasons I later worked so much on depression is that schizophrenia is simply too hereditary – so genetically determined that it is too difficult to study many of the interesting questions around the significance of external influences. In depression, on the other hand, there are stronger environmental variables. We know, as you yourself say, that stressful events such as death and divorce are clearly a factor in triggering the disease.”

  Just a minute. Is a professor of psychiatry and genetics actually telling me that there is too much focus on genes?

  “I can see a sort of fixation on genes, yes.”

  But is it unhealthy?

  “I don’t believe for a moment that we even can find genes that solely and in themselves have a major influence on whether you develop a psychological illness or not. In other words, we won’t see a parallel between depression or anxiety and Alzheimer’s in which a single gene – ApoE – actually says it all.”

  That, I think, is interesting, and perhaps a bit peculiar to hear from a man who was recently appointed the head of a gargantuan genetics project. Together with researchers from Oxford University and Fudan University in Shanghai, Kendler is gathering data from six thousand Chinese women with repeated depressions in order to use gene chips to study a half million genetic markers, much like Robert Plomin’s protocol for investigating the heritability of intelligence. So, the man who apparently does not believe in the discovery of decisive genes is doing a traditional genetic association study to find new genes.

  “Correct. But note that we are not just studying the genetics of the women; we’re also assessing their environment very thoroughly.” Kendler breathes deeply and looks over his glasses.

  “Even though the genes we are finding are not in themselves decisive – rather, each plays only a quite small role – they point in the direction of some concrete biological pathways. They give us a key to open the door to the underlying mechanisms for illness about which we are still fundamentally ignorant. We believe, however, that neurotransm
itters such as serotonin are involved in depression, because the drugs that inhibit symptoms act on serotonin. But, in reality, we are very far from knowing what is going on.”

  The serotonin hypothesis is the one everybody has heard of. “You’re depressed? Well, then, you have too little serotonin,” they say, or, “Your serotonin balance is off” – whatever that means. A few years ago, Jeffrey Lacasse of Arizona State University and Jonathan Leo of Lincoln Memorial University pointed out in the periodical PLoS Medicine that this is a message we particularly hear from the pharmaceutical industry. The duo had studied advertisements for SSRI drugs and found that they consistently play up the claim that well-known brand names such as Zoloft, Paxil, Prozac, and Lexapro normalize the brain’s serotonin balance. But there is no scientifically established “balance” for serotonin, Lacasse and Leo assert. In other words, no one has measured how much serotonin there should be in various places in the brain to keep someone free of depression. Or, as the British psychiatrist David Healy, a specialist in antidepressive remedies, once put it to me in an interview: “The theory that serotonin levels are the cause of depression is as well founded as the theory of masturbation causing insanity.”

  But then we are back to how you are supposed to study environmental influences.

  “We’ve only just begun to look at what happens during the development from child to adult,” Kendler says. “I bet you there is something very interesting there. There is a conception that our genes are immutable – we inherit them and that’s that, nothing happens after that. But that is far from the truth. You can see that the genome is very dynamic over time in the way that genes associated with certain traits at the age of seven do not show the same association if you check at the age of sixteen. Some kind of rearrangement of genetic effects occurs at puberty.”

  Gender differences are another area.

  “Take something like the frequency of depression: it is the same for girls and boys until the age of fifteen. Then, women take the lead for the rest of life. Adult women suffer from clinical depression twice as frequently as men do.”

  Depression is heritable – on the average, in the vicinity of forty percent – but if you focus on the hereditability, it looks as though genetic factors play a larger role in women than in men. That is, the heritability is greater in women.

  “You can ask whether the same genes always give the same effects in men and women and, for depression, we can say that they don’t.”

  But as soon as you get into gender differences, you inevitably also think of hormones. Just take premenstrual syndrome, the recurring monthly symptoms that, for some women, approach a depressive mood. So, couldn’t it be estrogen that makes the difference?

  “Hormones are certainly a part of the story,” says Kendler affably, but with a hint of indulgence in his voice. “But doesn’t that also mean that society should treat women differently as soon as they are sexually mature?”

  I don’t quite get what he’s aiming at.

  “Wouldn’t all the hullabaloo around body image and self-esteem play into this?”

  I really couldn’t say.

  “For example, studies show that early menstruation is a very bad thing for girls who are in mixed gender classes. Early maturity makes for early older boyfriends, an early sexual debut, more instances of drug abuse, and mental illnesses over a lifetime. If the same girl, on the other hand, goes to an all-girl’s school, you don’t see the same connections.” Kendler enunciates his next sentence very slowly and carefully. “This is very much due to the reaction of those around her to something biological. There is nothing so inviting for an older boy as a physically well-developed thirteen-year-old girl who is mentally too young to defend herself.”

  I ask whether this might be genetic to men, and Kendler smiles slightly wearily. “I’ll dodge that question,” he says.

  On the other hand, there’s another promising research area that he’s happy to discuss: the interactions between genes and environment. “We have to understand the field of probability in which genes increase the risk of developing a psychological condition if we are subjected to certain stress factors,” he explains. “One of the challenges is what I call genetic control of environmental exposure. It is particularly important in conditions such as anxiety and depression.”

  KENDLER IS CONVINCED that one way in which genes work in relation to psychological illness is by changing the environment around us. How in the world would that occur? In 1997, he demonstrated through a twin study that the psychological concept of a social network, which details the interpersonal ties and support systems available to an individual, is not only socially determined but also highly heritable. This finding encouraged him to speculate that partially genetic traits, such as temperament, might cause people to build their own social environment.

  “As we go through life, we actively create our own environment through the way we interact with other people. And the quality of this environment, in turn, affects our psychological state. There are circles that run into each other – the genes that make us inclined to develop depression are also the ones that make us more difficult to be married to or work with.”

  When people say “environment,” most of us think of things that just happen. The music of chance, so to speak.

  “Shit happens, they also say. Of course, chance and bad luck are part of the game, but if you look closely, many negative life events have to do with human relationships – especially when it comes to couples. We’re not just victims, we’re accomplices. We have done long-term studies of neurotics that illustrate my point. By following a group of people and their lives over many years, we have shown that if you measure how neurotic – that is, how nervous, sensitive, and so on – a person is, you can predict future life events with respect to personal relationships and the ability to have a social network.”

  The more neurotic, the more problems, the smaller the network, and the greater the risk for depression and anxiety.

  “When we began to publish this stuff, we got a lot of resistance from colleagues in psychiatry. It just couldn’t be true! But, funnily enough, it was an entirely natural thought process for evolutionary theorists. Everywhere in nature, genes work by changing the environment around them. Genetically different weaverbirds weave different nests and thus attract different types of females. And certain genes in a cold virus try to irritate the mucous membranes in our noses to make us sneeze and thus spread virus genes.”

  It reminds me of a column that ran on the New York Times website under the headline “Mugged by Our Genes?” The writers were probably inspired by the Florida State University criminologist, Kevin Beaver, who had come to the conclusion that being the victim of a violent street mugging was actually partially heritable. What? Isn’t being the victim of a crime just a question of bad luck? But after poring over data from a major twin study that followed young Americans over part of the 1990s, Beaver calculated that almost half of the variance in relation to whether they were mugged had to be ascribed to genetic factors.

  Upon closer consideration, this is not as absurd as it sounds. Beaver’s thesis is that genetic effects work indirectly. They help shape behavior that increases the probability that a person’s path will cross that of a mugger – perhaps because he seeks environments where criminals are more likely to hang out.

  “This effect presumably explains why the heritability of mental traits seems to increase with age,” says Kendler. “After childhood, we have more freedom to go where we want to, and genetics plays a role in our preferences.”

  Isn’t it like a snake eating its own tail? And if genes also help determine our environment, doesn’t this suddenly leave less room for free will?

  Kendler leans back and chuckles mischievously.

  “I’ve been thinking about all that free will stuff, and I believe you are falling into a classic trap,” he replies. “People always think that genetics and inheritance are about determinism, while environmental influences aren’t. But thi
nk about it: if the protein content of your diet in your first three years of life influences your brain and, thus, your intellectual potential and your personality, isn’t that also a loss of free will?”

  His question, of course, is rhetorical.

  “If we accept that our behavior comes from the brain and that the brain is a biological system in which there are causes and effects, then this is, in reality, the only problem we need to concern ourselves with. Whether depression is sixty percent or ninety percent heritable, the behavior comes from the brain. There are biological limitations. The extent to which they are created by genes or environment, or both is, in fact, immaterial.”

  The conversation has taken a somewhat dispiriting turn. It’s difficult not to get a little discouraged when the topic of free will comes up, because nothing ever seems to come of it. Purely subjectively, we all feel as though we have free will. We could, after all, say “no” to that third glass of wine during happy hour, just as we could keep within the speed limit on the highway. It’s just a matter of choice, right?

  When you think about it, though, it’s clear we are just fooling ourselves. Obviously, no one is completely free in the classic sense of being able to choose anything, in any situation. Such freedom does not exist. We all find ourselves in cages limited by our being, our history, and our experience. But the challenge is whether there are any tools for expanding the cage. Could possessing all this genetic knowledge change the way we think about ourselves? Do we ultimately gain a little more free will by knowing our biological limits?

  “That is, of course, a very interesting question,” says Kendler, who then falls silent. I can’t quite judge whether there is a slight tinge of sarcasm in his tone but, fortunately, he continues in an obviously serious vein.

  “It also says a lot about our image of ourselves and the peculiarity of Western culture, which has to do with the desire to relate biology to responsibility. But whether we can unite knowledge of biological causality with the concept of free will is not a scientific question at all. It is a philosophical problem. As soon as biology gets into the debate, it actually has to do with the omnipresent idea that we can shape ourselves, that we can make a stressed-out, maladjusted person completely calm if he just takes a course of transcendental meditation. Or that a navel-gazing, introverted person can be transformed into an exuberant extrovert if he gets a little therapy and engages in positive thinking.”