My Beautiful Genome

by Lone Frank

  Kendler shakes his head slightly.

  “But the idea that we are all equally sensitive is unrealistic. Human experience is a subtle, nuanced system in which we come to the world with some very substantial dispositions with respect to intellectual capacity and personality traits. Dispositions that we can only shape to a certain degree.”

  He remains quiet but rapidly brightens up.

  “Let me give you an example where the evidence is quite good: a child with a moderate case of ADHD, and behavioral problems. You know, a child who shows highly impulsive behavior, can’t sit still, and so on.”

  I try to imagine this hypothetical brat. I raise a hazy picture of Niels, an acquaintance from my early childhood. He was a particularly restless boy, who bit and kicked and threw scissors at people until he was finally expelled from nursery school. A seemingly archetypal case of attention deficit hyperactivity disorder. Later, I heard, he became an experimental psychiatrist.

  “Some parents can shape these children in a positive direction by being a sort of buffer for their propensities. These parents, in fact, reduce the heritability. But other parents exacerbate the same conduct. But people cannot stand the complexity of a nuanced problem. I notice this when I’m out speaking about this subject in public – there is a huge desire to be able to lean back and say, ‘It’s my genes, it’s not my fault.’”

  The fact of the matter is that, by knowing more about inheritance, we can learn more about how we shape an environment – or engage in an “intervention,” as therapeutic lingo would have it – to nudge our genetic background in a desirable direction.

  “That is partly correct,” says Kendler.

  So, what can you do about a person with an early tendency toward depression, just, you know, hypothetically speaking?

  “Relatively little, I would think, but I don’t know the intervention literature very well.”

  Don’t they at least know what type of environment or circumstances depressive people typically seek out?

  “They know a little, in an indirect way. We’ve done twin studies that look at neuroticism as a trait closely associated with a vulnerability to depression. Neuroticism increases your risk for having a lower degree of social support, for having a poor network, and generally meeting with negative events. This indicates, in other words, that the component of the genes that increases your risk of depression has the effect of giving you a tendency to have difficulties with human relationships.”

  But, he stresses, you can’t provide a gene test for that.

  “We find ourselves at a stage where there are some research findings – interesting research findings, at that – but these don’t yet constitute enough of a basis to form a conclusion.”

  People want conclusions, I argue, dumping all my expectations for a bit of progress on my host. Doesn’t he think that genetics, now that it is accessible to everyone, will appeal to the human need for prediction? We want so much to optimize this one little life we have. We want so much to have some guidelines and directives that make sense and that can, in some way, guarantee that we exploit our potential to the max. Is he really saying that things will never be certain, nothing will ever be on solid, scientific ground?

  “I say,” Kendler replies slowly, “that it is difficult to know.”

  I GET NO more answers. Sue Kendler has put homemade brownies and some fruit on the table, and I take the seat below the daughter’s self-portrait while the crazy cat with her grape-like eyes glowers from the nearby fireplace. We chat about this and that, until I think it’s time to get back to my hotel bed in Washington, if I could just call for a taxi to take me to the train. The couple looks shocked.

  “Train? There’s no train now, it’s almost nine o’clock,” Sue says, explaining that the train traffic in and out of Richmond stops around mid-afternoon. My palms go clammy. I don’t get it. Washington is the nation’s capital, and the train ride takes just over an hour – how is it possible that you can’t leave this small town after mid-afternoon?

  “This isn’t Europe,” Kendler says with a smile. But Sue immediately invites me to stay overnight. Two of the children are home on vacation at the moment, taking up the guest rooms, but they have a comfy sofa I can sleep on.

  “Please, stay and take the train back tomorrow.”

  I feel shy and awkward at their invitation, incapable of accepting. I mumble something about finding a hotel, and it ends with Kendler driving me to the local Holiday Inn, which is nearby and within my discount budget. It is a sad place. One of those motels where the buildings have two floors, and the doors all open onto a concrete balcony. Everything is brick and avocado-green wood, reminding me of a cheap university dormitory, circa 1970.

  I’m pretty much the only guest and wind up sitting in my room drinking tap water – which tastes of chlorine – and wondering why in the world I did not accept the Kendlers’ hospitality. It’s crazy to sit here completely alone in a semi-dark motel room with tasteless decorations on the walls and watch bad television. Instead, I could have got to know some intriguing people better, and I might have been able to learn something about the complicated connections between the human mind and DNA. After all, that is what I traveled all the way from Europe for.

  This may be precisely the type of situation Kendler was talking about. This is not unfortunate circumstances but me, the neurotic, actively seeking out situations and shaping my environment. I am isolating myself and boring myself – fertilizing the soil of melancholy and self-pity. Depression, if I’m fortunate. Maybe it’s the chlorinated water and the quiet, but I now see myself as a behavioral geneticist might, the result of a long series of self-selected circumstances.

  Even as a snotty-nosed kid, I would trip myself up socially. For instance, I loved to go to my two cousins’ house. They lived far away, were a few years older than me, and were, therefore, endlessly attractive. But what did I do when I finally got there and my cousins had been told to look after me?

  I would let them know straight away that I only wanted to play chess, a pastime they did not care for, and they would respond by locking me in the guest toilet and telling me to stay there until they gave me permission to leave. And there I would sit until some merciful adult happened by and let me out.

  Ever since, I have regularly felt banished to the loo, metaphorically speaking, but have never really considered whether I might have put myself there. Is that my genome sneaking out in subtle ways? My conversation with Kendler about the weird tango between immovable DNA and our dynamic psyches has given me a new, intimate understanding of myself.

  FAR FROM THE Holiday Inn and safely back in Washington, I think again of Dean Hamer, the discoverer of the “gay gene.” Or, more precisely, I think of something Hamer said several years ago about what will be required for behavioral genetics to match the complexity of twin studies.

  “Geneticists have to start working together with brain researchers who are using more and more sophisticated scanning techniques to analyze the functions of the brain,” he said. “Instead of trying to make a leap directly from gene to behavior, we need to take small steps. From gene to biochemistry, from biochemistry to what happens in the brain, from the brain to behavior.”

  One of the people taking these steps is Daniel Weinberger, of the US National Institutes of Health. For all practical purposes, he has invented the field of imaging genetics. As that name implies, Weinberger aims to create pictures of the genetics under investigation. He couples advanced forms of brain scanning, which capture what is going on in the living, thinking, and feeling brain, with knowledge of which gene variants exist in that brain. The approach allows scientists to look beyond behavior and directly at the processes occurring in the brain.

  Take, for instance, imaging studies of our old friend SERT. After debating for years how – or whether – the gene was involved in shaping susceptibility to depression and neuroticism, Weinberger decided in 2002 to put it under the microscope. He got hold of research subjects who had either
two copies of the long SERT variant or two copies of the “sensitive” short SERT variant. Everyone took a trip through an MRI scanner, which was set up as a cinema for the occasion. The volunteers didn’t have to do anything but lie completely still while they were shown a series of pictures of unknown faces with different emotional expressions, from the funny, to the fearful, to the furious. The imaging showed a distinct difference in the activity in the amygdala. This minute brain area, which is involved in signaling negative emotions such as fear, disgust, and loathing, lit up when researchers showed pictures of fearful or angry faces.

  The “sensitive” ones – those with two short SERT variants – reacted with a significantly higher amygdala activity than the others. Presto! Here was something you could put your finger on. Instead of a vague statistical connection between a gene variant and a complex condition such as depression, Weinberger and his colleagues had identified a concrete biological mechanism arising from a tiny genetic difference. It was a first glimpse into the mysterious black box that lies between genes and behavior.

  To meet Weinberger, I’ve rented a car, but as soon as I arrive at the NIH campus in suburban Maryland I realize this was a dumb idea. I feel as though I’ve arranged a meeting at a military camp, not a research institute. The safety inspection rivals anything I’ve experienced at an airport; if you are unlucky enough to be in a car, as I am, you are summarily escorted out of it so that a bomb detection dog – a friendly yellow labrador – can check out every inch of the interior. While the dog’s sensitive nose conscientiously explores the garbage I’ve thrown on the floor of the passenger side and lingers over a sock that has somehow landed on the back seat, I am scanned for hazardous substances in a small glass cage. My passport data is typed into a database and, when I complain, the security officer at the computer flatly replies, “These are the safety precautions since September 11.” He then looks me up and down before adding “ma’am,” which makes me furious.

  “You should probably calm down,” advises another guard. They are an interesting crew: all very dark-skinned, and boasting identical African accents and handguns – presumably loaded. I get the absurd impression that an African competitor of the Blackwater security firm has won the concession to guard NIH’s scientists. I manage not to blurt the idea out, and one of the kind gentlemen sends me in the direction of Building 10, a vast, burgeoning structure on campus that proves to be a modern labyrinth.

  “Weinberger? Is he a patient here?” asks a sullen woman at reception and, when I explain that he is a professor, the head of a research group in the neurogenetics department, she frowns and looks disappointed.

  “Then I really can’t help you.”

  I ask at five different desks and get sent in five different directions – all wrong. Not until a local woman takes pity on me and takes me by the hand do I make any progress.

  “Just calm down,” she says in a tone that indicates that I’m behaving like a spoiled child. “It took me a month to be able to find my office without getting lost.”

  With her experienced guidance, we find it. An insignificant door in a distant corner opens onto Daniel Weinberger’s department and shuts out the bustling lab coats and impatient hospital patients. A secretary welcomes me and gestures me to a comfortable chair. On the wall facing me are pictures from international conferences in which Weinberger’s research group has participated, and which, interestingly enough, all seem to have taken place at ski resorts or on the beach. One looks to be the Alps, and several – to judge from the apparel and the many tiny umbrellas hugging the lips of long drinks – must have been in Hawaii.

  Weinberger is grinning widely in all the pictures. And when he comes out to greet me, he looks like a man who doesn’t go out of his way to avoid a party. His face is slightly worn and the bags under his eyes appreciable, his voice sounds like no small amount of cigarette smoke has passed through his throat, and his accent is the broadest Brooklyn. He belongs to that part of humanity that you immediately want to drink a beer with.

  “Would you like a soda?” he asks. “It’s diet.”

  While he procures the yellow drink, I glance around his office: cluttered, with the usual family photos and, on the windowledge, a row of volumes squeezed between bookends shaped like the two hemispheres of the brain. I wonder why scientists almost always have a weakness for that kind of junk. They always seem to have small monstrosities that you’d never find in the office of an architect or an investment banker.

  “What can I do you for?”

  Weinberger’s manner is about as far from the reserved Kenneth Kendler as you could get, but the two have the same point of departure – that is, they are psychiatrists with an interest in schizophrenia. In the 1980s, Weinberger studied dozens of twins of which one was schizophrenic and the other was healthy, because he hoped it would yield some insight into what in the disease was genetic and what wasn’t. He was particularly interested in whether, beneath the illness itself and its symptoms, there were any ways of thinking or functioning that those with the disease shared with the healthy. Things were going swimmingly until a powerful new model arrived unexpectedly.

  “I’ll never forget it,” Weinberger says hoarsely. “It was 1992, and I was at a meeting with Harold Varmus, who headed up NIH at that time. ‘Hello!’ he said to all of us, sitting there with our big egos. ‘You’ve been researching schizophrenia for twenty years without finding anything at all of significance. From now on, you’re going to be doing genetics, folks. The mapping of the human genome is going full steam ahead, and the project will identify genes that are involved in disease and every kind of human conduct. If you don’t study genes, you’ll very soon be like a flock of dinosaurs caught in the age of mammals’.”

  Weinberger’s laugh is unvarnished and hearty. Liberating.

  “I knew it at once – the man was right. Here I was studying the symptoms of schizophrenia, but it was suddenly clear that genes represent the underlying mechanism for the causal connections. I have to get into the lab, I thought, and I spent the next ten years there. It was like the Cultural Revolution in China – all of us refined intellectuals had to go out into the field and learn some genetics.”

  Some interviews are easier than others. This is one of those interviews driven by the interviewee, because he has a story to tell, and my greatest contribution is to put the recorder on the table between us and nod understandingly at the right places.

  “Strange,” Weinberger says abruptly. “It is so strange to think that people just a couple of decades ago would not acknowledge that genes help determine the way we are. Everybody was fine with the fact that genes shape physiology and the body, but they repress the fact that the brain is also a part of the body – even traditional geneticists have a hard time with it. But, hell, we all look different, how in the world can we imagine that our differences only take a physical form?”

  He shrugs his shoulders and screws up his eyes behind his rimless glasses.

  “The reason we are a little afraid of individual genetic variation is because it is easy for value judgments to come into play. People will say that one variant is good, while another is bad. Good genes and bad genes – it sounds unpleasant, right?”

  Perhaps it does, but at the same time it is impossible to get around the fact that there are human variations that are good to have in certain contexts and not good to have in others. When we look at different types of personalities, for example, is there is a natural repertoire?

  “Yes, that much is obvious. It is also obvious that some variations in this repertoire are better in certain situations than others. And when we have spent a whole lot of time researching a particular gene…” He considers me with a certain expectation in his eye.

  “You mean COMT?” I ask.

  He nods like a smug schoolteacher.

  THE GENE FOR catechol-O-methyl transferase, COMT, is and will remain Daniel Weinberger’s signature object of study. It has become almost synonymous with his name and, again and agai
n, his group publishes fresh findings about how variants of COMT work in the brain and influence the psyche. The gene codes for an enzyme that, among other things, breaks down the neurotransmitter dopamine in the frontal areas of the brain. These regions are central to cognition – everything involved in planning, reasoning, and conscious thinking.

  The quantity of dopamine available to these areas of the brain is directly connected to the COMT enzyme. Greater enzyme activity leads to less dopamine production. The exact level of the enzyme’s activity is determined by the specific sequence of COMT gene producing the protein. The version of the gene that has the amino acid valine at position number 158 in the chain imparts higher enzyme activity, in fact, four times higher than if the same position is filled by the amino acid methionine. This small difference has surprising repercussions, including, perhaps, to whether we live our lives as “warriors” or as “worriers.”

  “It’s a question about the dose of dopamine in the cerebral cortex, and you can say that there are three settings,” Weinberger explains. At one end, you find people with two copies of the valine variant, and they have the least dopamine available. This is reflected in physical effects that can be measured directly from brain scans. In general, these are people who function slightly worse cognitively – among other things, they do somewhat less well in certain memory tests. On the other hand, they are better at handling emotional stress. They have a higher pain threshold and go more directly after rewards in the form of activities that trigger increased dopamine in the brain. These are the warriors. They need more dopamine to feel alive. Weinberger clarifies: “The sorts of people who, in war, are up for attacking the enemy’s machine gun nest and who look forward to the next stimulating battle.”