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More than Prenatal Genetics: The Search for Autism’s Origins

Guest post by pediatric neurologist Martha Herbert, of Harvard Medical School. Dr. Herbert is the author of The Autism Revolution: Whole Body Strategies for Making Life All It Can Be.

How and when does autism start?  Unfortunately we have no way of looking directly at the disorder’s early origins. Presumably autism’s origins begin significantly before the time of diagnosis. But we have no way of reliably predicting autism before its characteristic behaviors emerge in the second or third year of life.  

This is a particular problem when we look at the cellular structure of the brain.  We can only put brain tissue under a microscope after death, when an individual or family has arranged to make a postmortem donation for research – a profoundly generous and important act. (Learn about registering your family with Autism BrainNet here.)

If the donation involves a child too young to have been diagnosed, we can’t know whether the brain was affected by autism. If the person died after diagnosis, it’s difficult to know whether or how brain differences relate to autism. What’s more, we don’t know with certainty when during brain development the differences developed.

Even so, many autism researchers have looked at brain tissue and reasoned back from what we know about brain development to draw conclusions about how and when autism might have started.  This may be the best window we have into autism’s earliest emergence in the brain. However, the stories we develop from these findings are just that— stories and interpretations — not hard facts. 

A closer look at a recent study
A recent study in the New England Journal of Medicine was widely viewed as proving that autism starts early in prenatal development. This is a huge claim to make from brain tissue collected from 11 children with autism and 11 unaffected children.  So it’s very important for the future of autism research that we understand the strengths and weaknesses of this study’s methods and how the authors interpreted their findings.

Let me summarize what I see as the key points. The researchers discovered patches of disorganization in the layering of the neocortex. That’s the gray matter on the outer surface of the brain. These patches were a bit thinner and had missing molecular markers. And they were far more common in the brain tissue from the children affected by autism than they were in the tissue from the unaffected children.

We know when prenatal brain layering develops and that genes control and guide this process. So the authors inferred that these patches were caused by genetic differences. However, these patches differed in structure and placement in different brains. In fact, they were located pretty randomly. If anything, I think this suggests that something happened to the brain tissue during the formation of the layers or more likely after the layers formed.

Environmental and physiological factors
More and more studies are revealing non-genetic influences on autism risk that can affect prenatal brain development. These include a variety of maternal health problems during pregnancy. Examples include infections, immune and metabolic disturbances such as maternal diabetes, obesity, stress and high blood pressure. Other nongenetic influences may include maternal or prenatal exposure to pesticides and other toxic substances and perhaps even exposure to electromagnetic fields. We also have research implicating inadequate supply of nutrients in the mother’s diet immediately prior to or during pregnancy.  This research includes studies on vitamin D, antioxidants, essential fatty acids and key minerals.

Such non-genetic factors, individually or in combination, could affect the developing brain by creating vulnerabilities in brain cells, membranes and tissue. Those weaknesses would make the baby’s brain more easily stressed or injured during pregnancy or infancy.

Beyond location
In the New England Journal of Medicine study I mentioned earlier, the researchers inferred that the location of the patches they found contributed to autism and to its variable symptoms between individuals. They based this claim on the larger number of patches they found in two areas of the brain frequently associated with autism (frontal and temporal) – as well as a lack of patches in the occipital lobe (related to vision).

But if one takes into account the above non-genetic risk factors, one might tell a very different story. The chemical and immune imbalances that might have injured the developing brain are likely to continue throughout pregnancy and into infancy.  These imbalances tend to be excitatory and irritating, and this irritation might disturb the function of synapses and networks in autism in an ongoing fashion after birth—and probably in many different locations.

This might explain one of the observations that the researchers made: Excitatory neurons were reduced. Perhaps the neurons were burned out by too much irritation.

More than genetics: environment and physiology are central too
In my opinion, the methods that the researchers used in their study were nowhere near strong enough to exclude the possible role of such non-genetic risk factors.  They seemed to assume that the role of environmental and physiological factors is subsidiary to genetic influences. But this is their belief, not a fact. We should not simply assume that if it is neurodevelopmental, it’s purely genetic.

We need to keep a broader perspective alive not only to explain what is driving the increasing numbers of people with autism, but also because there are things we already know about how to help reduce many of these non-genetic risk factors. This means we know enough – right now – to help reduce the incidence and severity of autism.

People with autism, their families, those suffering from chronic diseases with overlapping genetic and environmental contributors and physiological mechanisms and society as a whole would benefit from a concerted attempt by the funders of autism research to take a broader, more comprehensive and more integrated approach to science, policy, and the education of the community and public.

We need to study autism, interpret scientific findings and develop treatment strategies and policy as if not just genetics but also environment and physiology really mattered.

If you’d like to read an extended version of this blog post, with citations to the studies mentioned, please follow this link to my personal blog.