TOPICS > Health

Autism Now: Dr. Craig Newschaffer Extended Interview

April 20, 2011 at 12:00 AM EDT

ROBERT MACNEIL: So, Dr. Newschaffer, how close are we to finding the cause of autism?

DR. CRAIG NEWSCHAFFER: To begin with, I think there probably is no cause of autism. We’re probably talking about multiple causes. And I think we already have identified some causal components on the genetics front. But if I can interpret your question as a complete understanding of all of these complex causes of autism, I think we’re still quite a ways away.

ROBERT MACNEIL: Where do you think we’re going to find the causes?

DR. CRAIG NEWSCHAFFER: Well, I think it’s going to be a combination of continued good work on the genetic side of things. As I just said a second ago, we have discovered some genes that are causal components of autism. But there’s more explanation to do on that front. I also believe, however, that there are going to be causal components that are nonheritable genetics, things that we refer to as environmental causes, with a capital E, environment encompassing lifestyle factors — exposures, things of that nature. And those were, by the way, we’re still at the very beginning stages.

ROBERT MACNEIL: Such factors as?

DR. CRAIG NEWSCHAFFER: Well, it could range from things like nutritional components, dietary components. In particular dietary components among pregnant mothers. Something that I think is important in thinking about these complex causes is thinking about the window of vulnerability. When are these causes most likely to act?

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And again, I believe that that prenatal, intrauterine period is gonna be very, very important. So things from maternal diet, infections that mothers may be exposed to in pregnancy — exogenous chemicals, chemicals in the environment that could be neurodevelopmentally significant.  I think these things are likely to play a role. How large, how small, I think is yet to be determined.

ROBERT MACNEIL: There is in some quarters a belief that so much emphasis and funding has been put into genetic research that the potential environmental factors have not been as thoroughly looked into. Do you believe that?

DR. CRAIG NEWSCHAFFER: Well, I think it’s true that the environmental factors have yet to be as thoroughly investigated as the genetic factors, no doubt. But I think the emphasis on genetics probably has been correct, at least as we think about the unfolding of our understanding of what causes autism. In the early 1980s, there were strong signals that autism was a genetic condition.

And the measures that are used to sort of, in a rough sense, figure out whether or not a condition is in heritable or not, the needle pointed very strongly towards heritability. So I think  the resources that were devoted to follow up on that made some sense. What happened, though, is the story became complicated.

There was no easy answer on the genetics front. And I think over time, we realized that in addition to these genetic components, there is room for and probably just cause for investigating the environmental. So we’re swinging around.

ROBERT MACNEIL: Is there scientific interest or ambition and research direction and funding in the environmental area?

DR. CRAIG NEWSCHAFFER: Asking an academic about if there’s enough funding in their area, they’re always going to say no. But I do think  that things are a little bit imbalanced. And we do need to put a little bit more  attention on studies that can look at the complex causal factors. So I think that focusing only on a particular environmental component by itself is probably not the way to go either. The right way to go is to try to build comprehensive studies that can consider genetic background, but can also look at some of these other factors in concert. And I do think that that’s the way we’re heading now.

ROBERT MACNEIL: How do you organize a study of environmental factors when there are hundreds, thousands of things in the environment, and where do you start? Whereas in genetic studies, once the human genome was worked out, you could target more specific areas of research.

DR. CRAIG NEWSCHAFFER: It’s interesting, and I think there are some analogies. How to begin at this? You know, scientists, their favorite way of going about something is to develop a hypothesis that builds upon something that came before, that builds upon some nice evidence and a nice story before. And try to test that hypothesis in their discipline.

So if we’re thinking about environmental factors, it would be most wonderful if we had, say, neurobiologic evidence of the organic deficit underlying autism. We understood that. We knew that along this pathway. Here’s a point where a particular environmental agent could potentially act. It makes biological sense. Let’s do a nice study and focus on that. That’s sort of a hypothesis-driven approach. We’re lacking that in the environmental risk side of that–

ROBERT MACNEIL: The hypotheses are not there?

DR. CRAIG NEWSCHAFFER: Well, there are lots of hypotheses. But the hypotheses that are supported by the level of evidence that gets us truly excited about building a study to confirm that. And there are a lot of speculative hypotheses. And so that’s an issue with going that direction.

Now jumping to the genetic side, there have been some hypotheses about candidate genes, specific genes. We know what they do to the developing brain. It makes some sense that perhaps this pathway that this gene acts on might be involved in autism. And those candidate genes have been investigated.

And there’s been some confirmation but there’s been a lot of stories that haven’t panned out. Now the molecular biology revolution on the genetic side. What that actually did was it enabled us to say, “All right, well, we don’t have a candidate gene, but we can look at all the genes. and we can develop techniques that are gonna allow us to parse through the signal that we get through looking at this huge, dense genetic information and try to find some leads.”

And that’s really where the genetics is right now. On the environmental exposure sides, you sort of have this similar dilemma. It wouldn’t be a bad thing to be able to assess these thousands, maybe hundreds of environmental exposures of interest simultaneously. But we don’t have an analogous technology to a genome-wide screen on the environmental side.

But what I think we’re trying to do in the larger epidemiologic studies is to at least collect information and collect samples that are gonna allow us to explore many different pathways on the exposure side of things. And hopefully, as genetics work develops, as research in neurobiology develops, maybe we will get some of those stories to start making sense. And we can follow up on this.

ROBERT MACNEIL: You studied the etiology, which is the history of the development of a disease, correct? The underlying pathway towards that disease.

DR. CRAIG NEWSCHAFFER: The series of causal events.

ROBERT MACNEIL: Series of causes. So is it as simple as looking at a lot of people with autism then looking at particular environmental exposures that child in development or its parents had and things they might have been exposed to in particular?

DR. CRAIG NEWSCHAFFER: Well, the science of epidemiology is a science of making observational comparisons. So in essence, it is that simple. We define nice samples of individuals with autism. We define contrast groups of kids who do not have autism or maybe free of any neurodevelopmental problems. And we compare information on exposure.

Where it gets complicated is doing that in a high-quality way, where our studies are going to be robust and are not going to be biased. So for example, if we want to study environmental exposures in a sample of kids with autism and controls, the average age of diagnosis right now in the United States based on the CDC data is somewhere in the fourth year of life, give between four and five. So we can find kids at that age, confirm them with autism, find some controls.

But the exposures that may matter may have occurred many, many years earlier. And in fact, as far back as in utero. So figuring out how to accurately measure those exposures through the retroscope, looking backwards, is tough. So that’s where the challenge is. And I think a lot of the direction of my field is moving towards trying to figure out ways to do prospective studies, where we’re trying to measure exposures in real-time moving forward. And there are a couple of different ways of doing that. And there are different types of initiatives trying to accomplish this.

ROBERT MACNEIL: Describe those initiatives, if you can.

DR. CRAIG NEWSCHAFFER: Sure. For prospective studies, I think there are basically two approaches. One is a general population approach. So that essentially means you’re trying to follow forward a representative sample of pregnancies or new births forward in time for different health outcomes, autism being, you know, one of very much interest these days.

These studies have to be quite large, especially when the outcome of interest, even though autism’s much more common than we thought it was, it still is relatively rare. One in 110 is relatively rare. So to study autism in these kinds of general population cohorts, you need hundreds of thousands of kids. A daunting task, but the good news is, there are initiatives like this underway.

There’s something called the National’s Children’s Study, underway here in the United States. There are analogous efforts going on in Europe. Japan is starting a similar study. These will be excellent tools for studying autism and also other childhood health conditions.

The other approach, prospective approach, would be to study high-risk population. And some of the work that I’m doing takes this approach. What we try to do is we try to define a cohort of pregnancies and the ensuing babies who are at higher than expected risk for autism. So what we’re doing in our studies is we’re looking at mothers who already have an affected child. So we’re using what we know about autism being heritable, because the risk in other siblings in those families is higher than the population average. And we’re assembling a cohort of those high-risk babies and following those babies very closely forward in time until they’re around age three. And we can make a confirmatory diagnosis.

ROBERT MACNEIL: So you’re following those babies from the moment the mother becomes pregnant–

DR. CRAIG NEWSCHAFFER: As close as we can.

ROBERT MACNEIL: As close as you can.


ROBERT MACNEIL: Does that mean additional tests during pregnancy or monitoring how the mother behaves, what she eats, what she drinks, what she…

DR. CRAIG NEWSCHAFFER: Yeah, essentially we do fairly comprehensive data collection during the pregnancy period, and we do it a variety of different ways. We have mom self-report through regular diaries, things like lifestyle exposures and dietary exposures. We also collect biologic samples. We’ll collect blood samples, urine samples from mom. And we also collect some environmental samples from the home. For example, we go in and take a sample of household dust. And there’s certain things that we can assess, levels of chemicals, exogenous chemicals that can be assessed. And it’s things like a dust sample.

ROBERT MACNEIL: And you have large numbers of mothers who have volunteered to be followed this way?

DR. CRAIG NEWSCHAFFER: Well, we’ve cracked the 100 mark. And we’re on our way to 1,000. We’ve only been doing this for a year or so, and we plan to recruit moms for about eight years. And the study is built this way to recruit over a long period of time, precisely because we knew that it’s a bit of a challenge recruiting this type of sample.

These are families that are dealing every day with the challenges of autism, because they have an affected child. And it’s really, you know, a tremendous gift that they give to research to be able to participate in a study like this. So we’re building that cohort.

ROBERT MACNEIL: And of course, there’s an emotional factor too. They probably dread that another child may be affected and…

DR. CRAIG NEWSCHAFFER: There’s no doubt there’s a certain amount of concern about that. One of the things that this study can do is confer some direct benefit on these families, because we do follow those babies so closely. So through our research assessments, we may get some indications that are useful for the family that there are things developmentally out of mind that can allow them to pursue resources in their community for this case.

ROBERT MACNEIL: And early intervention.

DR. CRAIG NEWSCHAFFER: And early intervention, yeah, absolutely.

ROBERT MACNEIL: So is that your principal focus of research now? Personally your focus?

DR. CRAIG NEWSCHAFFER: This study, which is called the EARLI study, is my major research initiative right now. But I am involved in a series of other projects.

ROBERT MACNEIL: What else is of particular interest to you, right at the moment, that you’re researching?

DR. CRAIG NEWSCHAFFER: Well, I’m also involved in a study that is of the other design I talked about, the retrospective design, where we have existing kids who are diagnosed in a large comparison group. This is a collaborative study with multiple sites around the country funded by the Centers for Disease Control and prevention. While we do have the challenges of looking at exposures retrospectively, it’s a very large study. And what we have been able to accomplish is we do have the genetic samples.

So that is a large sample where we have both the genetic information on the families and environmental information. And that’s going to allow us to do some very exciting things, looking for how genetic susceptibility and environmental exposure interact. So it’s another initiative that I’m involved in.

And then I mentioned the National Children’s Study, which was a prospective study, general population sample. We’re working with the National Children’s Study, which is just in its early stages, to try to help them figure out how in this sample, 100,000 families all around the United States — how are we going to most efficiently and effectively follow the kids in that general population sample for autism-spectrum disorders? It’s a challenge because the way we diagnose autism in research studies is very intensive, requires a lot of time, a lot of careful interviewing and direct observation. So we’re trying to see whether we can find a more efficient way for a study like that to identify autism cases. And those methods would be useful for other large birth-cohort studies like that around the world.

ROBERT MACNEIL: So you’re looking, really, ahead a decade or so before these large studies can produce usable results.

DR. CRAIG NEWSCHAFFER: Well, I think the high-impact, fully powered meaning that we have enough subjects that maximize our statistical ability to detect real effects are down the line. I do think though that there are going to be some things that we can do that are going to inform our thinking about the mechanisms underlying autism.

In the EARLI study, which is the study of the high-risk siblings, where we’re actually doing the data collection during pregnancy. As mentioned, I said we do biologic samples. So we get things like blood and urine from them at multiple time points. Well, in the blood samples, we can obviously look at maternal DNA. And one area of research that’s of a lot of interest in autism is this area called epigenetics. May have been mentioned by other folks–

ROBERT MACNEIL: Beyond the genetics?

DR. CRAIG NEWSCHAFFER: Beyond the genetics. When we think about genetic risk factors, we tend to think about that alphabet, that DNA alphabet, that code in our genes that programs what our cells do. Critically important.

But it turns out there’s another sort of system overlying our DNA that influences how our genes are expressed. And that’s epigenetics. There are actual chemical groups that are attached to our DNA that may turn off, turn on how those genes are expressed. And there’s much interest in a lot of complex diseases. There’s a lot of interest in these epigenetic mechanisms.

And one of the things about epigenetic mechanisms that’s really interesting is while the DNA code is mutable, you have epigenetic marks that can change over the course of a lifetime and may affect gene expression and the way our genes influence who and what we are, and what diseases we have differently over time. So one of the things that we can do in the EARLI study with smaller samples and even before we’ve necessarily followed the babies fully to outcome is we’re going to look at whether or not we see the epigenetic patterns in the mom changing over the pregnancy period. It’s an unknown.

If it does, it might suggest that there might be certain periods in pregnancy where epigenetic patternings might make mom more or less susceptible to environmental exposures. And also environmental exposures may influence the laying down of this epigenetic pattern. So that sort of descriptive work on those samples over pregnancy is something that we plan on doing this year, as a matter of fact. And while it doesn’t directly address an autism risk factor, yes or no, per se, it’s important work for developing leads for this field of epigenetics and autism.