November 16, 2009 - By Jonathan Rabinovitz
Ricardo Dolmetsch, PhD, assistant professor of neurobiology at the School of Medicine, last year won a National Institutes of Health Pioneer Award—a prestigious prize that recognizes creative thinking—for his research into the biological bases of autism, a developmental condition characterized by deficits in social interaction and the use of language, as well as restricted interests and repetitive behaviors. Funding for research into autism has increased substantially in recent years, as the number of those diagnosed with the condition has increased. Indeed, Dolmetsch was drawn to the subject after learning that his son has autism.
Paul Costello, executive director of the medical school’s communications office, recently interviewed Dolmetsch for the program “1:2:1.” A podcast of that conversation is available at http://med.stanford.edu/121/. Here’s an excerpt adapted from that interview.
Q. Recent reports say that the incidence of autism has increased to one in 100 kids. Are there more people today with autism?
Dolmetsch: The short answer is that we don't really know if there is actually an increase in the prevalence of autism or if there has been an increase in diagnosis. So in principle, there are two extremes. One extreme is that this is an epidemic, and many more children are affected than in the past. The other extreme is that we have always had children with this kind of developmental disability, but now we are classifying them as autistic. In my opinion both things are true.
There are a number of papers that suggest that much of the increase in autism is occurring in kids that are relatively high-functioning and that these kids might not have been detected in the past. But it is also true that at least in California, there is an increase in both children with autism and children with other neurodevelopmental disorders, like mental retardation, suggesting that it is not simply reclassification of kids with other disorders.
One mystery is that even though there has been an increase in autism, there is also pretty good evidence that there is a genetic basis for the disease. There have been studies where people have compared identical twins and fraternal twins. If you look at identical twins, the concordance is about 80 to 90 percent. So if one kid is autistic, there's an 80 to 90 percent chance that the other one will also be autistic. But if they're fraternal, the concordance is about 5 percent—much, much less. The high degree of similarity between identical twins tells you that autism is very likely to be associated with genetic mutations because two children that have the same genetic material are very likely to have the same disease. The low concordance between fraternal twins tells you that it is very likely to be caused by mutations in many genes because fraternal twins share 50 percent of the genes but the concordance between them is only about 5 percent. The more genes involved the less likely all of them will turn up in both of the fraternal twins.
So the incidence of autism is increasing but it is a genetic disease. Is it the case that we are accumulating new mutations, or is it that there is also some contribution from factors in the environment? Again, we don’t really know. Support for the idea that we are accumulating new mutations is that there is a little bit of evidence that shows that there is a correlation between parental age and autism; we know that older parents accumulate more new mutations in their sperms and eggs. Still, there are many people who think that there are environmental factors that contribute to autism though we don’t know what any of those factors are.
I should say at this point that while there have been many questions about the relationship between vaccines and autism, the correlation between them in a whole series of studies has proved to be very small. Those studies are difficult to do because most people get vaccinated, so we can't say for sure. Still, it seems as if it is very unlikely.
Q. You came to this issue in a very personal way. Can you talk about what led you to study autism?
Dolmetsch: We suspected that my oldest might have autism when he was about 18 months. He was very fussy, he didn’t talk, he didn't sleep, he threw gigantic temper tantrums and he loved to spend hours spinning things. Over time we realized that something was not quite right. He didn't talk for a long time, and then when he did talk he used language in a very stilted way. We're actually very fortunate because even though initially his autism seemed very severe, he has made a lot of progress and has become really high-functioning. Like many of these kids he is really gifted in some areas like math and science. He's in a normal school and he is a really happy kid but he still has some problems interacting with other kids and not getting lost in his internal world. When I first thought that he might have autism, I started thinking about what was going to happen to this kid in the future. It is the worst feeling in the world. You just don't know what you can do. I'm an academic so I went off and I looked at the literature. I was just horrified to discover that so little was known. And so I thought, well, I'm a neurobiologist, I don't really work on this but at least in principle I could. So I decided to turn my lab toward studying autism.
Q. How has your lab approached researching autism?
Dolmetsch: One of the big problems for autism research is that we have never really had access to the cells that control this behavior—the cells in the brain. This is very different from a lot of diseases where we've made a lot more progress. In cancer, for example, you can take tumor biopsies and study the tumor cells. That's how people have developed anti-cancer drugs. The question was, how could we get such samples for studying autism?
We thought, well, if we can't take a neuron out, maybe we could make some neurons from a patient’s other cells. At about this time, scientists in Japan found a way to turn skin cells into a kind of stem cell, known as an induced pluripotent stem cell, that can, in turn, differentiate into other cells. So what we decided to do was to take skin cells from children that had various kinds of autism. We characterized these children clinically as well as we possibly could and medically as well as we possibly could so we could get an overview of the population. We then harvested skin cells, converted them into these stem cells and then differentiated them to make a whole bunch of different kinds of neurons. We were then able to measure specific aspects of neuronal behavior, such as their ability to carry electrical signals and form connections and the expression of specific genes. This has really given us insight into the brain of a developing child with autism that we never had before.
Q. Why is your lab studying calcium?
Dolmetsch: Most people, if they know about calcium, they think about bones and milk. But it turns out calcium is this really important signaling molecule inside the cells of the brain. It is the molecule that converts electricity into long-term changes in the structure and the function of neurons. In the brain, neurons are in the business of carrying electrical signals from one part to another. When they do this, they actually change their properties. This is how we learn, this is how we develop, this is how our brain adapts to the world, this is essential.
One of the long-standing questions in neurology was how is it that these changes actually come about? Some years back, it was discovered that this occurred because there were these proteins in the membrane of the cell that would change every time there was an electrical signal. There were essentially these tubes, which would change with electricity and allow calcium to go into the cell.
Q. So what do these calcium tubes have to do with autism?
Dolmetsch: It turned out that there are these mutations in calcium channels that are associated with a devastating form of autism. We don't really know why these mutations cause autism but because we know about calcium channels and because the mutation is so strong we decided to study it to see what it might tell us about autism. We have some hypotheses about how this mutation changes the development of the brain and how it changes the reward pathways. There are these pathways in the brain that control reward and attention, and these things seem to be altered in kids with autism.
That's one relationship between calcium and autism, but there’s also more information that’s come from genetic screening. Researchers were looking at all of the genes in the genome of people diagnosed with autism, and it turned out that there were mutations not just in the calcium channels but also in a whole class of proteins that regulate the electrical activity of the brain.
Lately there has been an influx of money for research on autism, and this has been a godsend. I think it will make a very big difference in this field. Like any good scientist, I have to say that we don't really know what is going to happen in the future. It takes a long time to do things. But it takes a lot longer if you're not moving in the right direction. And we are, for sure, moving in the right direction.
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