Post by Former NIMH Director Thomas Insel: Summer Science
The last days of this long, hot summer are a good time to catch up on a few of the season’s scientific breakthroughs, which have been coming fast and furious during what has been a down time for many people outside of science.
What about this week’s story of an increase in spontaneous mutations in children of older dads? We already knew that children with autism and schizophrenia were more likely to have been conceived by fathers over 40. And we knew that people with schizophrenia or autism, especially those without a family history of developmental disorders, had a higher number of spontaneous mutations – mutations not found in their parents. The new story, from Kari Stefánsson and colleagues of deCODE Genetics in Iceland, reports that, as men age, they collect spontaneous mutations in their sperm.1 Sperm, which divide every 15 days, collect mutations at a rate of about two per year, with the number of mutations doubling over a 16-year period. Along with a report last month that demonstrates the very high rate of mutations in individual sperm cells,2 we now have a mechanism to explain why paternal age is a risk factor for neurodevelopmental disorders. But the risk is still small, in the range of 2 percent for a man above 40 years of age, and the vast majority of these mutations have no effect. While there has been over a 30 percent increase in birthrates for men over 40 during the past 30 years, increasing paternal age is still a minor factor as a driver for the increased prevalence of autism, certainly not a reason to forego fatherhood.
The strangest discovery of the summer may be the report of bone marrow transplants resolving the symptoms of autism…in mice. Paul Patterson and his colleagues at California Institute of Technology created an autism-like syndrome in mice by exposing them to immune challenges during mid-gestation.3 Once grown up, these prenatally exposed mice showed immune changes but also increased anxiety, decreased social behavior, and repetitive behaviors. A bone marrow transplant, which replaces the immune system, corrected both the immune response and the behavior. This finding, which was unexpected, is surprisingly similar to another recent paper reporting disappearance of the symptoms of Rett syndrome in mice following a bone marrow transplant.4 Both studies suggest that abnormalities of the immune system may underlie some of the symptoms of these neurodevelopmental disorders.
But for me the most disorienting discovery of the summer came from the score of papers in July and August on the microbiome. In the same way that cognitive psychology has redefined how we think about our minds, the microbiome must now redefine how we think about our bodies. Actually the term “our bodies” is no longer accurate. Only 10 percent of our bodies’ genetic material checks out as human DNA: some 90 percent belongs to the trillions of microbes that live on and inside us. If all the cells in our bodies were to take a vote, human cells lose. The reports from the last month begin to map the biogeography of the human body, revealing that we are really a complex ecosystem with regional variation and completely unexpected individual variation in the microbes that make each of us a super-organism. How does this variation influence brain development? What does this variable ecosystem of our bodies mean for the individual differences in our minds? Will the microbiome help us to understand or treat mental disorders? All questions that we can begin to address in the fall.
Lest the microbiome leaves you feeling less impressed about being human, a paper just out from Dan Geschwind and his colleagues at UCLA shows us that the human brain, at least the human frontal lobe, is quite unique in evolution.5 Comparing patterns of gene expression in the human frontal lobe to corresponding areas from chimpanzee and monkey brains, the human expression patterns are not only markedly different but markedly more complex. Certain gene networks, such as the network linking to FoxP2 (a gene implicated in language), appear unique to the human brain.
Of course, there has been much more. New targets for medication development were reported for psychosis6 7 and depression.8 9 10 New findings confirm the role of epigenetics in memory. These tantalizing findings suggest that age-related declines in memory may not be irreversible and suggest new targets for enhancing cognitive function.11 Kurita et al even identify an epigenetic mechanism through which atypical antipsychotic drugs exert their effect, suggesting ways to improve these drugs.7
While this summer may have felt like the doldrums, for science related to mental disorders, it has been tough to keep up.
6 Law AJ, et al. Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy. Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):12165-70.