Autism: Where Do We Go From Here?


In the last 5 years, there has been an absolutely profound transformation in the ability to identify genes that contribute to autism and schizophrenia.

For the last 20 years or so, my laboratory has been searching specifically for genes involved in autism and Tourette syndrome. The reason that we started doing that actually stems from my experience and training. I did not have much of a scientific background and went to medical school, and then I was on the wards and became trained as a child psychiatrist.

I was really frustrated toward the close of my training when I was taking care of [children] with very serious psychiatric disorders about how little we knew as a field; about what the causes their problems were and how little we could tell parents about what to do. And so I decided to go back to school and ended up doing a PhD at Yale University, studying human genetics.

[[{"type":"media","view_mode":"media_crop","fid":"34516","attributes":{"alt":"Autism","class":"media-image","id":"media_crop_7786539615551","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3680","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","title":" ","typeof":"foaf:Image"}}]]And my lab for the last 20 years, since I completed that, has been entirely focused in the idea that if we can find genetic mutations that contribute to autism, or Tourette syndrome, or childhood-onset schizophrenia, [we will then have] an understanding at the molecular and cellular level about what’s going wrong.

It is that kind of understanding in other areas of medicine that have led to truly dramatic advances in thinking about treatment and intervention. So we [have] been on that hunt for a long time, and I have to say for the first, say, 15 years that it was extremely frustrating. We were having a very difficult time-all laboratories were-in trying to identify the genetics of these conditions.

We realize in retrospect it is because those genetics are very complex. They involve many genes. They involve interactions with genes in the environment. And frankly we just didn’t have the tools necessary in order to be able to detect the changes in the genetic code in [children] or families that had autism, until about 5 years ago.

Since that time though there has been an absolutely profound transformation in the ability to identify genes contributing to autism. We have learned a remarkable amount in the last 5 years, and now have a growing list of genes that the entire field agrees are significant risks for autism, carrying many times the increased risk.

The reason that [this is] important is because the bigger the biological effect that that mutation has, the more likely it is, we think, to lead to clues about what the underlying problems are in brain development and functioning. So right now we have learned both things about specific genes that contribute to autism, and other disorders. And we have also learned a lot more about the kinds of mutations that  contribute.

One thing that we learned relatively early as we began to make rapid progress was that for a substantial minority of children, say 15% to 20%, the mutations are actually arising spontaneously, right before conception. So they are not being transmitted from the genetic material of the mother and the father, in terms of what makes up their entire genome.

What happens is just prior to conception, either sperm or egg has a spontaneous mutation. That is called the de novo, or new, mutation. We find, as I said, that maybe 15% to 20% of children who will come to our clinics with a diagnosis of autism will have a de novo mutation that is contributing to their condition.

That was a very important observation. It does not mean that there are not genetic signals that are transmitted from generation to generation. But it did begin to identify for us a particularly important set of mutations. [It also] began to explain something about why we were seeing, in some families that had no history at all of autism, the [sudden] presence in the children of autism.

I think broadly, as I said at the start, the search for these genes was really aimed because of my experience toward trying to get an understanding of the basic mechanisms of brain development, and less about understanding the diagnosis, or how to use genetics, to diagnose autism.

It still turns out today that probably the best way, or actually the best way, to determine what the risk for a child is for getting autism is to rely on family history and whether or not there is anybody else (a first-degree relative) that is affected. It turns out to be more effective than sequencing the genome of a child . . . so the progress that we have made in identifying particularly these de novo mutations, the most impact that is going to have . . . on understanding basic mechanisms of autism now, and other disorders we hope soon.

What we have learned is that the functioning of the neuron is tremendously important, particularly at the synapse. We have also learned that the global regulation of how genes are turned on and turned off by something called cromatin modification is tremendously important. [Furthermore], the creation of proteins, or local protein synthesis, which means protein synthesis that is taking place right at the synapse where neurons can connect, is tremendously important.

We have also been able to use the clues that we have found from genetics to begin to pinpoint for subsets of those mutations-when and where in the human brain these are taking effect, or having their effect, or at least beginning to have their effect.

We, and many other laboratories now, have found that it [happens] during fetal development, particularly in the middle of fetal development, in a part of the brain called the prefrontal cortex-in particular sets of cells in the prefrontal cortex, excitatory neurons, deep layer cortical glutameturgic neurons, to be specific. That again, [is] for just a subset, but an important subset, of mutations [that] seem to be carrying risk.

Overall, we are really at a point of major transition. We were searching for a tremendously long time without finding [anything]. Now we have found [something major and] we know how to find more.

The list now is nearing 60 genes that we have strong confidence are contributing risk to autism. We can begin to take the next important step, which is to narrow in on those processes again at the cellular, molecular, or circuit level that will begin to tell us about pathophysiology. We hypothesize, more than that we hope, that those clues about pathophysiology will be a critical next step to developing much better treatments than we currently have available.

Further readingDozens of Genes Associated with Autism in New ResearchAutism and Schizophrenia


Dr State is Oberndorf Family Distinguished Professor and Chair of Psychiatry, University of California, San Francisco.  His lab focuses on gene discovery as a launching point for efforts to illuminate the biology of these conditions and to develop novel and more effective therapies.

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