by Lone Frank
At the other end of the spectrum are people with two copies of the methionine variant. These “met-met” individuals are cognitively more precise and, correspondingly, better at various memory tasks, but they handle emotional stress poorly. These are the world’s worriers.
“I myself have two copies of the met variant,” I note, because, of course, I checked this particular SNP in my Promethease report. “And I do worry. All my life, in fact… “
“Yes, well,” answers Weinberger with a polite lack of interest. Personal twaddle is not his business. As a scientist, he must take a larger perspective – evolution and the human condition itself. He stresses that it is not as though one COMT variant is the right and righteous one, the other an evil, debilitating mutant. No, when it comes to behavioral genetics, we’re talking about trade-offs between one area – emotional reactions – and another – cognitive tuning.
“You can show that, in evolution, there has been a genetic balance between effects that provide cognitive advantages and effects that provide emotional advantages. For every variant, there will be certain environments or niches where it is best suited. In our historical past, warriors were probably much better at hunting mammoths, while worriers stayed home in the caves and discovered fire.”
Stories from old days and far climes are always pleasant, but I know there are meta-analyses that conclude that the different COMT variants provide no effect. It’s a pet peeve of Weinberger’s. His face puckers in response to my needling.
“Meta-analyses,” he says as if he just bit into a lemon. “What’s wrong with them is that they are mixing apples and oranges! Meta-analyses of COMT just smack together all the studies where they’ve done cognitive tests, even where the cognitive tests are not at all the same. And the other problem is that the analyses are strongly colored by one bad study that just happens to have a large number of participants. They don’t take the quality of the various studies into consideration.”
Weinberger asks whether I have heard about the new meta-analysis that, apparently, refutes Avshalom Caspi and Terrie Moffitt’s study of SERT and depression. “Of course,” I say with a clear conscience.
“This is a classic example. A meta-analysis that was ruined by one British study that did not find the effect Caspi had observed. They had over eight thousand participants, but the data were superficial, based on a single telephone interview. You can’t compare work like that with a study like Caspi’s, which followed a group over many years and where the researchers interviewed the participants repeatedly and face to face.”
He bursts out again in his vigorous laugh.
“Know what? It’s like what one of my geneticist colleagues says: if you check the Nobel Prize winners for the last hundred years, none of them worked with meta-analyses.”
With that, I’ve run smack into the war between epidemiologists and molecular researchers, a long-standing enmity that Kenneth Kendler had mentioned to me in passing. One school thinks in terms of populations and percentages – in short, statistics – and they need data from groups, the bigger the groups, the better. The other side looks to the individual, trying to understand processes at the microscopic level that can be expressed in the differences observed across populations. For the molecular researchers, the point is to think small, to design well-planned studies that test a scientific hypothesis.
“If we are to understand anything about genes and behavior, we can’t start from enormous population groups,” Weinberger says dismissively. “Here’s a good analogy you can put in your book.”
I say thanks, but he doesn’t seem – or choose – to hear me.
“Do you know why the big association studies have a hard time finding genes that have to do with behavior? Because they treat a particular example of behavior that covers many things as if it were a clearly delimited phenomenon. To think that ‘anxiety’ is a single phenomenon, biologically speaking, is … silly. It’s like studying the cause of car accidents in the United States and just defining it as accidents with cars. The only thing you know is that the car is destroyed. You collect all the information you can – alcohol in the driver’s blood, the driver’s age, whether there was a woman next to him, how many years he had driven, the state of the tires, how old the car is, and so on.”
Weinberger finishes the last of his soda and throws the can nonchalantly across the room, hitting it right into the trashcan.
“You conduct measurements all over the US. But because you are an epidemiologist and not a biologist, you look at a car accident as one thing and overlook the fact that there are many types of car accident. In Florida, where the average age of the driver is sixty-five, it’s about elderly motorists; in Seattle, it’s bad weather; down in the South, it’s about the driver’s alcohol level; and up in the northeast, accidents are caused by your girlfriend sitting next to you, screaming at you and chewing you out. In the northwest, poor tires make the weather effect worse, while the same bad tires protect you in the southwest, where the roads are hot and sticky. A risk factor in one place may be a protective factor in another place. And what do you end up with when you control in this way for five hundred different factors?”
I shrug my shoulders.
“That the primary cause of automobile accidents in the US is: a driver’s license. Driver’s licenses are the only common factor you can find in all those people, but this does not in itself have any predictive force. This is what the gene studies are coming up with for behavior and mental traits. The same for diabetes. Here, they always say that they have so much success, but they really don’t; they have explained four percent of individual variance with their genetic risk factors. Four percent!”
Weinberger has just rehabilitated his colleague Caspi’s controversial study of depression. But I would like to know what other findings they have for a connection between genes and behavioral traits. Are we talking about a lone swallow here?
“We have robust effects for brain systems. And brain systems are the foundation for behavior. We know from many studies that, under many conditions, SERT has an effect on how sensitive your amygdala is. It is a foundation for emotional engagement; in order to feel threatened or to feel anxiety, you have to have this activation of the amygdala. There are stimuli – sounds, strange faces, and that sort of thing – that must be there in order to stimulate your brain to produce some particular behavior. Genes are biological toolboxes that work on the configuration of your nervous system. They influence molecules and cells and thereby the whole structure of the brain, and the structure of your brain and its synapses determine how your environment is experienced and feels for you.”
DURING THIS LITTLE sortie, Weinberger has acquired some color in his cheeks and looks ten years younger. His voice has become warm and well-oiled. And I know why. We have reached the point where he can explain how you can move beyond these despised genetic association studies.
“We need to focus on how the brain functions,” he says triumphantly.
It cannot be denied that fascinating findings come out of looking at brain function. In a forthcoming study Weinberger’s group examined the brains of one hundred normal volunteers to see if the COMT gene is linked to any distinguishing characteristics in the brain. They discovered that those individuals who carry two copies of the met variant exhibit a greater density of synapses between nerve cells in the anterior part of the brain than do others. Weinberger believes these extra synapses make a person more capable of concentrating – and may explain better results in various memory tasks. But there is a price: a psyche with rigor mortis. “They have a harder time shifting focus quickly and presumably also have a tendency to brood more on the ideas they have – including sad and negative thoughts,” he explains.
Another conspicuous example of how the brain’s function can be altered considerably by small genetic idiosyncrasies comes from research at the University of California, Los Angeles, led by psychologists Naomi Eisenberger and Matthew Lieberman. The researchers, who happen to be married,
are investigating the neurology of social relations, and they have a hypothesis for why people with two copies of the less efficient MAOA variant may be more aggressive: the travails of this world hit them harder.
After identifying the MAOA variant for each of the volunteers in their study, Eisenberg and Lieberman put them into a brain scanner and subjected them to a computer game designed to make the player feel like an outsider, the equivalent of social rejection. The researchers then measured the activity in an area of the brain, the dorsal anterior cingulate cortex, which is central to assessing social situations involving psychological pain. In those who were endowed with the “aggressive” MAOA variant, the dorsal anterior cingulated cortex lit up like a firecracker when the player was rejected. Aggression was not, as had been assumed, the result of a lack of self-control. These were not insensitive brutes. They were super-sensitive, and their aggression rather an expression of psychological thin-skinnedness.
“MAOA is a really interesting gene,” Weinberger remarks, leaning back in his chair. “The first studies concentrated on aggressive behavior, which is just a reaction. But we gradually uncovered a picture that variants of MAOA more generally play a part in adjusting our social sensitivity.” He sits up with a start. “We mustn’t forget BDNF.”
Hearing the words brain-derived neurotrophic factor is like encountering an old acquaintance. My PhD project looked at how the BDNF protein work in the brain. Of rats, that is.
“Sure, but it’s the same thing,” says Weinberger with a wave of his hand.
Whether in rats or people, BDNF is a growth factor, a protein that tells brain cells to divide or grow or create new synapses. Scientists have ascertained that BDNF exists in two versions and, just as with COMT, the difference comes down to one little amino acid, namely the one at position 66 in the protein chain, which can be either a valine or a methionine. When the BDNF gene codes for a methionine, the BDNF protein is pumped out of the producing cells at a slower rate, which means there is less growth factor available to the brain tissue. That must have significance. Yet scientists are still trying to discover precisely what that significance is.
One avenue of attack is to place subjects into situations that require different cognitive capacities. For example, researchers at the University of California, Irvine, looked at how driving ability corresponded to BDNF variants. A group of volunteers, all of whom had undergone genetic tests, were put into a driving simulator. Those with a BDNF gene with the methionine variant not only made the most mistakes, they also displayed a poorer ability to learn from those mistakes. Other studies claim that the variant is linked to negative effects in certain aspects of memory, not least what is called episodic memory, in which you recall autobiographical events. Weinberger’s group has found indications that people with this same variant perform more poorly in tests in which they have to recognize words –” subtle effects, but measurable,” as he terms them.
BDNF also appears to interact with SERT. In fact, in 2008 Weinberger and his colleagues published a report in the journal Molecular Psychiatry showing that a slow-release methionine variant of BDNF protects against some of the effects that are known to go with the short variant of SERT. If you are born with two short SERT variants, you typically have a harder time suppressing any negative emotional signals that are pumped out from the amygdala. These negative emotions loom large and, presumably, cause you to slip more easily into a depression. But if, in addition to your short SERT variants, you are lucky enough also to carry a defect in your BDNF genes, this effect is somewhat dampened. In other words, a variant that increases a certain risk in one genetic background can work protectively in another.
“E-p-i-s-t-a-s-i-s,” says Weinberger, so everyone can follow along. “Interplay, you know, mutual control. We’re sitting here talking about individual genes, right? And we are because the research typically looks at one gene at a time. But, ultimately, it’s all about the interplay. I know Ken Kendler doesn’t like this, but that’s because he doesn’t understand it. He keeps on claiming that data from population studies do not support epistasis, but it’s not true.”
Indeed, this may be the case with MAOA and testosterone. In one study, a team of American and Swedish researchers, led by Rikard Sjöberg at NIH, compared ninety-five Finnish alcoholics who had been convicted of violent crimes with forty-five law-abiding non-alcoholics. All the participants were psychologically assessed, completed a questionnaire designed to reveal their level of aggression, and had their testosterone levels and MAOA genes tested. The results indicated that those individuals with high testosterone and at least one MAOA variant with low activity had a greater tendency for antisocial and violent conduct. For those without this MAOA variant, testosterone levels did not seem to influence aggression levels.
Furthermore, a surprising study from the Caspi and Moffitt lab focused on attention deficit hyperactivity disorder. Though the ailment is known to be partially heritable, it can also express itself very differently in different people. Some hyperactive children not only have problems with attention but also with grossly antisocial behavior – they fight, they steal, they set fire to things. Caspi wanted to see whether there was a connection between such an antisocial element and the variants of the COMT gene. There was. The young people who had an ADHD diagnosis and also showed “early and consistent antisocial behavior” had, in the vast majority of instances, two copies of the “warrior” valine variant.
“It is probable,” said Caspi when the study came out, “that the role COMT plays in relation to antisocial behavior touches on an interaction with other genes or behavioral factors in ADHD.”
What happens when we can discover these sorts of connections, and more besides? Soon, when every child has a complete genetic map made at birth, these connections won’t be the stuff of somewhat obscure scientific journal articles but everyone’s everyday life. Would having this knowledge be good for us as individuals, or for society? If you knew from your earliest moments that both your copies of the COMT gene belonged to the met variant, making you predisposed to worrying and rumination, would it change the course of your existence?
Daniel Weinberger looks down at the table and squirms.
“Ah,” he says at last. “You can’t predict anything for the individual, because these are small buttons that are finely adjusted; the effect is not great from one single gene.”
Of course, that is correct. You ought to be able to look at your genes and say, “Oh, perhaps I should do X out of consideration for Y,” but how many of us can do that when confronted with our family history of cancer or some other disease? Honestly, I think he’s avoiding the question. Because what scientist wouldn’t want to be able to claim some benefit from his or her research, despite all the possible harms?
“Look at psychiatrists, you know, good, old-fashioned psychiatrists,” he scoffs. “They used to ask people endless questions about their mothers, as if we could make good predictions on that basis. So, the profession really went off the rails by giving advice and making predictions on the basis of information that is completely subjective. At least, genes are objective. But, honestly, I don’t know whether it helps you to know that you have a genetic disposition to be more fearful. That is something you already know about yourself from your own life.”
“You mean it can become a self-fulfilling prophecy?”
“I just don’t know whether you’re served well by that information,” says Weinberger, smoothing the bags under his eyes. “I believe, at any rate, that it is wrong to treat human behavioral variation as disease.”
ON MYWAY out of the vast parking cellar, one of the guards lifts his hand from his weapon, and I can’t help but wave back at him enthusiastically. I’m buoyant from my visit to Daniel Weinberger. Not least because his final remark runs so well with one of my own hobby horses.
It has long irritated me that our relationship to behavior and psyche is so deeply influenced by the concept that you can divide humanity into the sick and the well. Th
is is a medical way of thinking. In a biological sense, you talk about variation, as Weinberger emphasizes. There are no healthy and unhealthy genes; variation is the modeling wax that evolution uses to create diverse forms. Mutations and their random alterations of the genome are a guarantee that evolution and adaptation occur. And variations that are not adaptive and impractical in one context may do quite well in another.
Asperger’s syndrome is a superb example from the lived world of human experience. Aspies, as many call themselves, have a hard time automatically and intuitively understanding the emotions of others. They do not express their own feelings in the regular and accepted ways. They may seem awkward, volatile, strange. People with Asperger’s syndrome are today classified as falling on the autistic spectrum; they display some of the typical autistic patterns of behavior and character traits, but in a high-functioning version. Those with Asperger’s are poorly adapted to the furiously paced network economy, which seems to insist on constant, effortless social interaction and readiness for change.
On the other hand, other behaviors can accompany Asperger’s syndrome. These include a tendency to nurture powerful personal interests, a drive to acquire an immensely detailed knowledge about them, and the ability to maintain an extraordinary mental focus. This aspect of being and character makes some Aspies brilliant at tasks that require contemplation and sustained concentration, especially if they are in an environment that provides the space for both and which ratchets down the need for social finesse. In this sense, the behavioral variation we call Asperger’s syndrome is in no way“diseased.”
Research in behavioral genetics has made it clear that genes do not exist in a vacuum but develop more or less advantageously depending on our circumstances. Such thinking is sure to change the way we see ourselves and one another. For instance, we often hear concerns about how more and more behaviors are labeled “sick.” And if you look at the professional manuals on psychiatric illnesses, it’s true that every new revision contains more and more specialized diagnoses. You could call it the clinician’s diagnostic itch. Behavioral genetics stands in contrast to that trend: it shows us that the concept of “normal” must be expanded, not constricted, and that biological variation at the genetic level provides a broad palette of behavior and psychology. By demonstrating that genes do not code for behavior but act by adjusting and shaping our complex and dynamic nervous system, the pioneers who are combining genetics with brain research are uncovering how external influences and environmental factors create different outcomes for the brain – and thus for the person.