NEWSWEEK: What does the MET gene do? How does it work, or in cases of autism, not work?
Pat Levitt: The gene does a lot of different things. First, for the architecture of the brain to develop properly, there are genes whose function is to help put it together starting before birth. They promote the building of healthy brain architecture development of connections in the brain that help it to process complex information—language, vision, emotions, all sorts of things. The MET gene is active both before birth and after, and it helps with the development of those circuits in the cerebral cortex. It also helps build the cerebellum. And both of those brain regions are disrupted in autism. So the idea is that this version of this gene is less active in individuals with autism, and that changes the way their circuits grow. Also, there are groups of children with autism who also have digestive disorders and immune disorders like hypersensitivity, and MET is involved with the function of those systems, too. For example, the gene normally controls how the immune process takes place, helping to shut it down after a response. One hypothesis to test is whether you might not be able to shut the immune response down in an appropriate way if you have autism and the MET variant that is associated with autism. As for healthy adults that carry this variant of the gene, no one knows what effect, if any, the autism-associated MET variant has on them. It’s not disease-causing—it might not mean anything.
Earlier this week, another team announced that some parts of autistic adults’ brains don’t communicate very well with other parts. Is your discovery related to that finding?
It might be. This is called the “disconnect hypothesis.” The term “disconnect” makes it sound like pulling a plug out from a wall, and that’s not exactly what we’re talking about. It’s not that there’s no connection in key brain areas—it’s that the architecture of the circuits may be different—that is, fibers running between those brain areas might be formed in a different way. The MET gene is involved in the formation of some of these circuits, but it’s not the only gene—it could be one of five or 10 genes that come together to build the circuits. It’s mind-bogglingly complicated. It has been estimated that babies from just before birth to three years of age are adding something like 40,000 nerve connections per minute in the cortex, which is amazing—so it takes a lot of effort on the part of the system to build the circuits.
How many other genes might be involved in autism?
There’s definitely not a single gene that causes the disease. One faulty variant alone is going to reduce the levels of protection you might have against developing autism—our gene increases the risk by about 2 to 2.5 times—but alone, it’s not enough to put a person over the edge. There are probably between five and 15 genes that increase the risk for autism. There are some smaller studies that have reported on other genes that might be involved, but the possible impacts the variants might have on gene functioning haven’t really been identified. But I can tell you that probably in the next year, there will be at least two or three more studies that will report other genes involved in increasing risk, and we will begin to solve the mystery of what aspect of brain development is actually disrupted in autism.
Some scientists also suspect that environmental factors might increase the risk of autism. What does your discovery mean for that theory? And how much of the risk do you think is genetic versus environmental?
This is a disorder with a very large genetic component. If you look at identical twins, if one has autism, the chance that the other twin will also develop autism ranges between 70 to 90 percent. And scientists have done a lot of large population-based studies on environmental factors—that includes vaccines and mercury—and so far, there’s no evidence that any of these factors really increases the risk of autism. But that’s just for the population as a whole. It doesn’t mean that at an individual level, there might not be people who are sensitive to those or other hypothesized environmental factors because of their genetic makeup. If we had a way of separating out people who are more sensitive, then we could figure out whether a certain environmental factor could be part of the trigger in them. And that’s where the genetics are going to help. Until now we’ve been kind of stuck because we didn’t know who was more vulnerable, but we can do studies now to see whether exposure to certain agents in the presence of this MET variant (and other variants to be discovered) reduces the levels of activity in the gene even further. There are theories about heavy exposure to compounds in fertilizer or form-manufacturing plants, or prenatal infection of the moms—there are all sorts of reasonable hypotheses, but they have to be tested in the context of genetic vulnerability.
Also this week, a team of economists made a tentative link between autism and TV viewing. It wasn’t a scientific study, but is it something parents should be concerned about?
I didn’t read the study, but I will say that that we know from research in younger siblings of autistic children and from studying the medical histories of individuals with autism that there are early signs of autism before kids watch a substantial amount of TV. There’s evidence that atypical things are starting to occur early in terms of brain development and function, measured in the baby siblings of children with autism, even before one year of age. There’s also very solid data from head circumference and brain-imaging studies where the size of the brain is larger in autistic kids by one year of age. That doesn’t guarantee autism, of course, but the data about early differences in head circumference have been reproduced over and over again.
Why do autistic children have bigger brains at that young age?
We don’t really know, but it seems that typical children have parts of their brain that continue to grow for an extended period of time, right up through puberty. In children with autism, there’s a growth rate that’s faster at first, and then it kind of flattens out. Why that is, at the level of the brain cell and the developing brain architecture, we have yet to find out.
How long might it be before there’s a test for this variant of the MET gene?
Well, we can already test for whether you carry it or not, but 47 percent of people in the general population have this variant, so the test for the MET gene variant by itself doesn’t tell you much, other than possible increase in risk. Genetic testing in terms of finding people who are at very high risk is only going to work when we have better information about what the other genes are.
Is there any potential for gene therapy here, or any reason to think that the faulty gene’s effects might be preventable or reversible?
Gene therapy, no, I don’t think so. Even with diseases caused by single genes, such as cystic fibrosis, researchers have struggled to develop effective gene therapies. Here we’re talking about five to 20 genes that together increase vulnerability. What this is useful for, though, is that once we identify some of the other genes, we’ll be able to look at ways in which we can intervene to boost the functioning of those genes whose activity is being disrupted. They could be targets for either drugs or behavioral intervention—it doesn’t necessarily have to be a pill. If somehow we can tap into that process, we’re going to be able to improve the situation for children for autism and their families.
