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Director’s Blog: What Caused This to Happen?

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“What caused this to happen?” is usually one of the first questions asked by patients and their families following a psychotic episode, suicide attempt, or manifestation of any serious mental illness. In earlier times, the explanations ranged from an imbalance of the “humours” to demonic possession. More recently, there have been “schizophrenogenic” or “refrigerator” mothers and “abusive” or “toxic” fathers. Modern scientists and clinicians point to a mix of genetic and environmental factors but these explanations are rarely satisfying and do little to stem the tide of guilt, shame, and blame that surrounds mental illness as much today as during the witch hunts of centuries past.

Of course, genetics and environment are important. But their effects are probabilistic. With the exception of a few rare mutations that appear causal for autism, genetics confers a tendency for height, personality, and risk for mental illness through the aggregate effects of hundreds of common variations in the genome. This information may be useful in populations, but it is of little help in explaining cause for any individual.

Environment or, more accurately, experience is undeniably a factor for PTSD, but for most other forms of mental illness the link is difficult to prove. We use terms like “adversity,” “toxic stress,” or “trauma,” recognizing that our assays of these experiences are woefully imprecise and knowing that subjective experience, especially memories of childhood experience, may trump any objective measure of the event. None of these factors have prevented patients and clinicians from assuming that “trauma” is the cause of most mental illness, perpetuating a culture of blame that has permeated mental health care for a century.

The scientific answer to the question of “what caused this to happen?” is to cite a mixture of genetic and environmental factors, often expressed as a gene-environment interaction. The honest answer to the question of cause is that we don’t know. Gene-environment interaction is a multi-syllabic way of saying “we don’t know.” Our minds seek explanations to reduce the mystery and pain of mental illness, but in truth, we are early in our search for understanding how, when, and where these disorders develop.

I found myself thinking about all of this after reading a recent paper on cancer. In last week’s Science, Tomasetti and Vogelstein describe a very simple approach to the cause of cancer.1 We have known for a century that some tissues (skin and colon) have more cancers than others (bone and brain). Tissues differ in the rate at which cells reproduce normally. Skin and gut cells, for instance, are constantly self-renewing at a high rate whereas cells in bone and brain show little replication. Because cancer happens when cell replication goes berserk, perhaps we should not be surprised that the lifetime risk of cancer in any particular tissue can be predicted by the normal rate of cell replication in that tissue. Replication is imperfect with mutations happening “by chance” all of the time. Cancers develop when mutations hit genes that regulate the cell cycle and this is statistically more likely in tissues with high rates of normal cell replication.

What is stunning about the paper by Tomasetti and Vogelstein is the strength of this prediction. I can’t do better than their summary:

These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to “bad luck,” that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes.

There are exceptions – lung cancer and smoking, skin cancer and sun exposure – but for most forms of cancer, the data suggest the “cause” is “bad luck”.

What does this have to do with mental illness? Outside of a few areas of the brain, adult neurons don’t divide and exuberant cell replication is unlikely to be the cause of schizophrenia or depression. The link starts much earlier. In fact, between weeks 4 and 24 of gestation, the human brain is generating 100,000 cell divisions every minute – arguably a faster rate of cell division than any other organ at any other time in the lifespan.2 Curiously, cancer is not an outcome except in rare cases, presumably because mutations hitting cell cycle genes are quickly suppressed. But could other mutations that influence excitability or connectivity or even survival be affected, leading to changes in brain architecture that years later emerge as psychopathology? A new NIMH program on somatic mutations  will investigate this question as a potential cause of mental illness.

President Lincoln’s famous line that “a tendency to melancholy is a misfortune not a fault” comes to mind. We need explanations. “Bad luck” is not particularly satisfying as an explanation of cause, but that does not make it wrong. Of course, genetics and environment influence brain development during gestation. And we don’t know that this new explanation, which seems so attractive for cancer etiology, has any relevance at all to autism or schizophrenia. But this new report for cancer serves as a useful reminder that we really know too little about “what caused this to happen” when someone we care about develops a mental illness. And the real cause may be something that is, unfortunately, out of our control.


1 Tomasetti C, Vogelstein B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions.  Science. 2015 Jan 2;347(6217):78-81. Doi: 10.1126/science.1260825.

2 Insel TR. Brain somatic mutations: the dark matter of psychiatric genetics?  Mol Psychiatry. 2014 Feb;19(2):156-8. doi: 10.1038/mp.2013.168. Epub 2013 Dec 17.