I know that doesn't sound all that exciting, but everyone who is anyone will pull a graph from this 4-page seminal Caspi work and ooh and aww over it. In fact, as of this week, the article has been cited by 2022 other articles. This paper links nature and nurture and depression in one elegant demonstration - so without further ado�
Caspi used subjects from a lifelong observational study, the white New Zealanders known as the Dunedin Multidisciplinary Health and Development Study. This cohort of 1037 children was studied at ages 3,5,7,9,11,13,15, 18, and 21, and 96% of the subjects could still be found at the age of 26. This careful observation meant that Caspi could not only rely on the lifelong memories of the subjects about history of trauma and medical/depressive issues (which can be to some extent unreliable), but also what was studied at all the data points in the subject's lives.
847 members of the cohort were divided into three groups based on 5-HTTLPR genotype - l/l, s/s, and s/l. No need to scratch your head - let me explain!
Basically, we are talking serotonin here. Serotonin is an important neurotransmitter in regulating our emotional state. Like any neurotransmitter, serotonin is made by one neuron, which then spits it out into the synapse in between neurons. Then the serotonin floats over to the second neuron and activates the receptors over there. On the first neuron, there is a serotonin reuptake transporter that sucks serotonin back into the first neuron to be recycled and used again. See the picture below:
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| Image Credit |
So peer at that reuptake transporter (yellow) and have a look. All of us have genes that code for the making of that transporter. And this gene happens to have a special promoter (called the 5HTTLPR) that directs how much serotonin reuptake transporter we make. People (and rhesus monkeys, as it happens) that have two LONG (l/l) copies of the promoter have higher levels of serotonin in the spinal fluid. People (and monkeys) with two SHORT (s/s) copies of the promoter have lower levels of serotonin in the spinal fluid. People with a short and a long (s/l) are, predictably, intermediate. Got it? Serotonin-speaking, s/s is the short end of the stick, s/l is in the middle, and l/l is protective.
Back to New Zealand, where it was found that 17% of the young adults in the Dunedin cohort were s/s, 51% were s/l, and 31% were l/l. Caspi and his crew collected information about previous depressive episodes, suicide attempts, previous traumatic events (employment, financial, housing, health, and relationship stressors), and current psychological state. It turns out that when you look at current or previous depression or suicide attempts, the link between the type of promoter you have and those findings are non-significant. Uh oh. That sounds like a big bust! The type of serotonin transporter gene promoter you have doesn't seem to matter�
Then Caspi's team ran the numbers backwards and forwards, plugged in number of stressful life events and generated this remarkable finding:
As you can see, if you've had no stressful life events, your likelihood of having a depressive episode is around 10%. If you have the protective l/l version of the promoter, even if you have 4+ major stressful events, your chance of having a depressive episode only climbs a little. But if you have the s/s "short end of the stick" promoter, add stress and your risk of developing depression climbs very quickly. When you plug in severe childhood maltreatment as a variable, the s/s folks have a 63% chance of having a major depressive episode by age 26. The l/l severely maltreated children had a 30% risk of having a major depressive episode by age 26. The s/s folks with 4 or more stressful life events accounted for only 10% of the cohort, but 23% of the cases of diagnosed depression in the cohort.
So what we have found here is that this particular genetic lottery can tell us to some extent which of us are more resilient to stress, and which of us are less so, at least with respect to depressive episodes and suicide attempts (plotting suicide attempts against number of stressful life events generates a similar graph). These percentages (roughly 20% s/s, 50% s/l, and 30% l/l) are pretty much the same as those in Europe and America. The yearly incidence of Major Depressive Disorder is right around 20% too, by the way.
Back to New Zealand, where it was found that 17% of the young adults in the Dunedin cohort were s/s, 51% were s/l, and 31% were l/l. Caspi and his crew collected information about previous depressive episodes, suicide attempts, previous traumatic events (employment, financial, housing, health, and relationship stressors), and current psychological state. It turns out that when you look at current or previous depression or suicide attempts, the link between the type of promoter you have and those findings are non-significant. Uh oh. That sounds like a big bust! The type of serotonin transporter gene promoter you have doesn't seem to matter�
Then Caspi's team ran the numbers backwards and forwards, plugged in number of stressful life events and generated this remarkable finding:
As you can see, if you've had no stressful life events, your likelihood of having a depressive episode is around 10%. If you have the protective l/l version of the promoter, even if you have 4+ major stressful events, your chance of having a depressive episode only climbs a little. But if you have the s/s "short end of the stick" promoter, add stress and your risk of developing depression climbs very quickly. When you plug in severe childhood maltreatment as a variable, the s/s folks have a 63% chance of having a major depressive episode by age 26. The l/l severely maltreated children had a 30% risk of having a major depressive episode by age 26. The s/s folks with 4 or more stressful life events accounted for only 10% of the cohort, but 23% of the cases of diagnosed depression in the cohort.
So what we have found here is that this particular genetic lottery can tell us to some extent which of us are more resilient to stress, and which of us are less so, at least with respect to depressive episodes and suicide attempts (plotting suicide attempts against number of stressful life events generates a similar graph). These percentages (roughly 20% s/s, 50% s/l, and 30% l/l) are pretty much the same as those in Europe and America. The yearly incidence of Major Depressive Disorder is right around 20% too, by the way.
We've learned also that trauma changes our brain. Years later, if we have endured trauma, we are more vulnerable to having a major depressive episode and to make suicide attempts, modulated in part by how many serotonin reuptake transporters we have.
How does trauma change the brain? Our genes are pretty much set in stone from the moment 23 chromosomes from Mama meet 23 from Dada (except for random mutations). However, gene expression can change throughout life (and over generations). How does that happen? Well, that's (in part) what we mean by the word epigenetics.
A lot of our DNA spends its life wrapped up like candy. Proteins called histones wrap around the DNA and prevent it from being transcribed into RNA (RNA is the stuff that is eventually translated into proteins). Histone wrapping is entirely necessary - after all, all of our cells (except sperm and eggs) have the same DNA, and yet it is patently obvious that a skin cell is quite different from an eyeball cell which is different than a neuron. So in some cells, certain DNA is expressed, but not in other cells.
Histones that are highly methylated hang on tight to the DNA and keep it from being transcribed. Once you demethylate the histones, the DNA is set free to be expressed. A practical example - certain species of rodents called voles have species that have very attentive mothers, and less attentive mothers. The baby voles raised by the less attentive mothers seem to be more vulnerable to stress later in life. But put a less attentive species vole with a high attentive species mother, and the baby vole grows up resilient to stress. Decreased methylation of the attentive (oxytocin) gene results in a genetically inattentive vole becoming more like an attentive vole.
How does trauma change the brain? Our genes are pretty much set in stone from the moment 23 chromosomes from Mama meet 23 from Dada (except for random mutations). However, gene expression can change throughout life (and over generations). How does that happen? Well, that's (in part) what we mean by the word epigenetics.
A lot of our DNA spends its life wrapped up like candy. Proteins called histones wrap around the DNA and prevent it from being transcribed into RNA (RNA is the stuff that is eventually translated into proteins). Histone wrapping is entirely necessary - after all, all of our cells (except sperm and eggs) have the same DNA, and yet it is patently obvious that a skin cell is quite different from an eyeball cell which is different than a neuron. So in some cells, certain DNA is expressed, but not in other cells.
Histones that are highly methylated hang on tight to the DNA and keep it from being transcribed. Once you demethylate the histones, the DNA is set free to be expressed. A practical example - certain species of rodents called voles have species that have very attentive mothers, and less attentive mothers. The baby voles raised by the less attentive mothers seem to be more vulnerable to stress later in life. But put a less attentive species vole with a high attentive species mother, and the baby vole grows up resilient to stress. Decreased methylation of the attentive (oxytocin) gene results in a genetically inattentive vole becoming more like an attentive vole.
Y'all remember Lamarck, right? He's the guy who postulated that giraffe's necks got all long because they stretched them to reach the high leaves, and the stretchiness-length was passed on to baby giraffes. Well, it turns out that in some respect, Lamarck had it right - what we do, what we eat, what we experience, how we cope - all of these things can affect the expression of our DNA. So Lamarck gets the last laugh - to some extent. You want to change those brown eyes blue - don't wait for Lamarck - get some contacts. And don't expect the kids to inherit the faux color.
And so at last we come around to Evolutionary Psychiatry. Our gene expression has been modulated by selection pressure for thousands and thousands of human generations. Live and eat and sleep more like a hunter-gatherer, and it seems to me you are more likely to deactivate the histones for the genes for survival, strength, resilience, and happiness. When you are the most resilient you can be, presumably you raise little resilient humans to take your place.
And some things we cannot change. If I'm a l/l, theoretically I can deal with more stress than an s/s without being depressed - but of course, many of the s/s cohort had no depressive episodes, despite having 4 or more stressful life events. But why has s/s been maintained in the population despite serving up a higher risk of suicide and depression in combination with stress? Well, the most likely explanation is that the short allele of the serotonin reuptake transporter promoter gives us some sort of resistance to disease (1). But who knows. In the mean time, I'll try to limit my stress and eat more like a hunter-gatherer.
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