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Working around the Mendelians: A Q&A with Michael Wigler

By looking at large genetic events, Michael Wigler developed a unified theory of autism that would recharge the field.
MICHAEL WIGLER



BRIAN MARANAN PINEDA

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When Michael Wigler saw researchers using classical genetic methods "breaking their teeth" on the underpinnings of autism, he took a different approach. By looking at large genetic events, he developed a unified theory of autism that would recharge the field.

The search for single nucleotide polymorphisms (SNPs)—substitutions, deletions or additions of a single base along the genetic code—associated with autism has yielded minimal insight into the genetic footprint of the disorder. Drawing on his work with cancer, Michael Wigler thought that by looking at bigger events—specifically copy number variations, where large segments of DNA are duplicated or deleted—that arose spontaneously in a child (without appearing in a parent) could help jump-start the field. In a study published last March in Science, he and colleagues showed that these larger genetic rearrangements could account for more than 30 percent of autism cases. He followed that up in July with a second paper, appearing in Proceedings of the National Academy of Science USA, which rolled out a unified theory for the genetics of autism, ascribing 75 percent of the disorder to spontaneous mutation.

For the Insights story, "A Maverick against the Mendelians," appearing in the February 2008 Scientific American, Nikhil Swaminathan talked with Wigler about the reception to, the genesis of, and the effect he hopes to have with his controversial theory. Here is an expanded interview.

SciAm: How has your unified genetic theory of autism been accepted by colleagues and the general public?

Wigler: At a personal level, I haven't gotten any death threats. I haven't had any colleagues calling me on the phone and telling me that they think I am an idiot. I've gotten a few colleagues sending me e-mails congratulating me on a marvelous integration of facts. And I've gotten a number of calls from journalists who wanted explanations of things. And, in general, I have been more or less disappointed by the media coverage because it doesn't really capture what we're saying, but what we're saying is kind of complicated. So that's excusable, I guess. Some of the worst offenders were saying that we were blaming mothers. That was a little horrifying.

In general, I don't think the publication has had the impact that I would have liked to have had. I think that there should have been more controversy about the implication of these certain mixed de novo mutations and inherited models on other disorders like schizophrenia. I don't think it's really penetrated very far. I think its penetrated pretty far in the autism community among geneticists. But there's really no other game in town right at the moment besides our approach.

So, it doesn't matter if the model is right. Because everybody is looking at copy number variation because the methods for looking for SNP associations are pretty much acknowledged as … worthless. The other kinds of approaches in autism that show promise are in families with a lot of inbreeding where you can use more classical methods. The fellow who's doing that is Chris Walsh. He's gone off to the Middle East where there's still a lot of consanguineous marriages and tried to use those families.

But, ultimately, looking at marriage within the same bloodlines has a limited scope, right?

Well, yes and no. Our major hypothesis is in fact that there are up to a hundred or perhaps even more loci. There isn't any one locus that's going to be the common etiologic factor. So, any particular gene that tells us something is valuable.

Basically, we divide the genetic task into two parts: Part one is finding genes at very high penetrance—that is, when those genes are mutated, then your odds of getting autism are very high, if you're a boy. Those will tell us something about the underlying basic mechanisms. There are another class of genes that are modifiers and the evidence that they exist comes from the observation that girls don't show autism with the same frequency. Those could be of small effect, that they change the odds of you being autistic—each one may be a minor thing, but, in total, they add up to a lot. They're harder to find.

So, essentially, mutations to transcription factors?

Yeah, things that change the balance of connectivity in the brain, for example. They're important to find because they hold promise of being able to modify the outcome of the disorder, if you can detect it early enough.

Things that are modifiers are likely to be, in my opinion, common polymorphisms. The things that are strongly contributory, I don't think are going to be common in the genome. They're going to be things that arose from mutation and survive in the human gene pool for one, two or three generations before getting eliminated because they're really nasty.

Is that why spontaneous mutations would most likely result in autism for males?

The model is that most sporadic cases are in fact these lightning strikes, which nobody likes to think about. I'm used to thinking about it because I'm a cancer researcher and when you get cancer, it's a lightning strike. You hear people say, "Oh I eat all the right things, I exercise, I don't smoke," and they still get cancer. I think it's natural for people to want to finger some cause that's controllable, but random processes are not controllable. People are very reluctant to accept randomness as a factor in their lives.

How confident can you be attributing a large part of your theory to randomness with all the reports of increased incidence of autism in recent years?

There are a couple of things that draw a lot of attention. One of them is the apparent increased incidence. Another is the sense of many parents that there child is doing well and developing normally and then fairly suddenly seems to develop symptomatology. Those are the two things that I think are driving people to think in terms of models that are not genetic. So, we should probably talk about them separately.

On the increased frequency, I am not an epidemiologist, but I have heard a very convincing talk by a Canadian epidemiologist, who did a very careful analysis and came to the conclusion that there was no real measurable increase in frequency—that it is largely a factor of more people being diagnosed. And I have heard this theme in other people's talks who are not professional epidemiologists, but there seems to be a general consensus that when the diagnostic criterion was solidified in the mid-'90s, that more or less correlates with the sudden change in slope of diagnoses—that the rate of diagnoses started to rise.

And with regard to the increased incidence being caused by thimerosal in vaccines, the rate has continued to climb, even with the chemical being removed from immunizations more than six years ago.

I am not familiar with data on vaccines and what people have done with that. I can tell you that my own bias—and it's really a bias—is that there's nothing in that. But you can't print that without also printing that I haven't seen the data, that's just my intuition. So, in that sense, I am just like an ordinary citizen.

So, the increased incidence is largely increase in diagnosis. There could be reasons why there could be small increases. That could have to do with the age at which couples are having children. There could be something about the pattern of marriages that somehow increase the rate, but then we start getting into dangerous terrain.

Then, regarding the unified theory, where do environmental factors come in?

Just because something is genetic doesn't mean it's not environmental—that's number one. If you have 100 people and they're all exposed to the same environment and one reacts badly to it, that's genetics and environment. So, just by saying something is genetic says nothing about that it might not be also environmental. That's the main point. The secondary point, we said our model assumes that—the population genetic analysis that we did makes an assumption that—it's genetic. You can't turn around then and say it proves that it's genetic.

There's nothing in the paper that puts us at odd[s] with people that do want to think there's something wrong in the environment.

You mentioned seemingly normal children suddenly showing symptomatology. Wouldn't that be triggered by something environmental?

There is a subjective sense that the child regresses in about 25 percent of the cases, but it's not really that the child is regressing, but the subjective experience of it. In fact, I've met scientists who told me a story about their three-year-old child who was developing very well, and then the child did regress. And this was from a trained observer, so I think there is little question that there are cases where little children regress. And that doesn't necessarily mean that something is environmental, although that would seem to be the logical conclusion, because I think in many cases, for example, where there are storage diseases. The body's buffer can accumulate. The child continues along normal development. The buffer gets filled and then catastrophe strikes.

The cases where there is regression are extremely interesting. It suggests a different molecular mechanism, but it doesn't necessarily suggest that a kid has been vaccinated and he's having an immunological reaction.

So, do you see the new theory of autism as a plan of attack for figuring out the disorder?

It says, "If you want to solve this disease at a genetic level, here's a reason to think that it can be done this way." It does have clinical application—not presently, but it will. The techniques that are developed to search for the causes will create more robust technologies, higher resolution technologies, cheaper technologies that then can be applied when parents walk in the door of the pediatric geneticist and ask them what's wrong with their son or daughter.

Are you getting the impression that people are going to follow the ideas you've laid out?

Oh, people already have done that. The PNAS paper, it doesn't matter if people believe it or not. If it's correct, it will guide research whether you believe it or not. Because the breakthroughs will come by seeing spontaneous mutations. So it doesn't matter if people believe it or not. If people know that you can find spontaneous mutations in autistic children, nobody knows for sure how much of autism that will reveal, but lots of groups are looking using this method both in autism and in schizophrenia. We are doing congenital heart disease. Certainly mental retardation

The general approach of looking at copy number variation as the cause for genetic disease has probably taken one of those exponential—it's probably hyper—exponential leaps. So, in 2003, we published the Science paper [which showed that there is relatively large amounts of copy number variation among normal, healthy people]. And I think already in 2005 or 2006 there was an American Genetic Association meeting that I didn't go to, but people came back and said that the whole thing about copy number variation. There's a flood of descendants of that approach.

Well, what does the theory accomplish socially?

Well, first of all it challenges the existing dodge. That is, if you're not able to solve a particular genetic disease, it gives you an alternate way of thinking about it. It also provides close to a rigorous analysis of how we should use population data to infer genetic models. The methodology based on how to use the data on sibling recurrence, I don't know if there's any paper like in the last 15 years that looks at the data and makes a genetic model that combines Mendelian and spontaneous. It may be unique that way. There are probably other things such as schizophrenia, depression, maybe even diabetes, which could yield the same kind of population genetic analysis. It does sort of open conceptually the door to maybe the unknown cause of spontaneous mutation.

The real workhorse is the April 2007 paper [published in Science], which says spontaneous mutation is higher in autism.

What percent of autism cases did you predict were due to spontaneous mutation in that paper?

In PNAS, we said 75 percent; in the Science paper, we said that 30 percent would be spontaneous mutations of the copy number variety. The PNAS paper says that 75 percent of autism may be caused by spontaneous mutation, not necessarily by the copy number variant. It could be a new SNP.

Going back to the issue of what does the theory do to scientific practice: It makes a boast in some sense. It says just stay doing this sort of stuff, looking for spontaneous mutation and you'll find your answers. You can believe it or not believe it. if it's correct, those who believe it will win. If it's incorrect, those who believe it will lose.

It provides a way of developing models that incorporate spontaneous mutation and Mendelian inheritance, but it also does something which says: How do you look for modifier genes? So, at the end of the paper, we're left with this really outstanding, unexplained fact, which is: Girls don't get it with the frequency of boys. It suggests that there must be genetic modifiers of that. It might be merely estrogen. Even it were estrogen, it's not going to be all in the effects of estrogen; it would have to be something specific. It really raises the most profound questions about what is different about the male and female brain[s]. To me, it suggests that there are going to be simple, genetic modifiers and suggests if you read into it, how to look for those.

In earlier versions, we stated how to go looking for these things. If you have this model in mind, you want to compare mothers and daughters; mothers that you think are carriers and daughters who have the disease. That gives you a pair to compare with classical genetics.

Everything is a signal-to-noise game. If you're looking at the whole world, your signal is submerged in things other than what is going to show up as a strong genetic signal. If you focus on the right population subclass, these methods might work. So, one is to look at mother–daughters. And the other is to look at brothers both of whom have autism—one who has it severely and the other who doesn't—which I don't think the geneticists were doing. If you're a Mendelian, and you have two brothers who have autism, what do they have in common, because that's causing their autism. But, I am asking, "How do they differ, if they are at different ends of the spectrum?" That's going to yield you the heritable genetic things—because presumably they have inherited the same major causative allele.

The people who really should be paying attention to this model, if they think it's correct, are the people who are interested in leveraging the Mendelian approaches to find modifying genes.

And you got to this point thanks to your work on cancer?

I don't think that we have had the model that we have or the approach to autism that we had without being conditioned by our experience in cancer. My first experiments when I came to Cold Spring Harbor were isolating oncogenes. These oncogenes were activated by point mutations. The laboratory that I came out of before that, everything was directed to mutational hypotheses. How is it that mutations cause cancer? And one of the first, big biological hypotheses that I was in relationship to was the idea that point mutations in normal genes have the potential to create cancers.

So, my orientation to begin with was not Mendelian, but more oriented towards the effects of spontaneous mutation. And then as we began to analyze, as our tools became more powerful, it was clear that there a lots mutations in cancers, but some of these mutations go away when you compare the cancer to normal. So the person was abnormal relative to what was then thought of as the standard human genome. And that was actually the first indication that there was more variety of the type that we subsequently went after directly, resulting in the Science paper of 2003. But, the way we first saw that was in cancer.

So, did you jump from looking at the genome from a SNP level to this more macroscopic view?

We were never looking at the genome from a SNP level. We were looking at cancers and we were comparing cancers to sometimes unrelated people—normal tissue from unrelated people and sometimes normal tissue from the same person—and we saw more differences when compared to an unrelated person than when compared to a normal person. And that was really our first indication.

Nobody was paying attention to variation of copy number. There was a lot of talk about SNPs. There was this sub, almost below the ground, discussion of the concept of an "in / del," so when the sequencers were trying to assemble the genome, they were having a great bit of difficulty at certain places and they developed the concept of an in / del. An in / del is either insertion or deletion, they don't know which, they don't know which version of the genome to believe, so they postulated a small insertion or deletion. It was always small, because again in sequencing, you can't see the bit. So, there was this vague sense that the genome had types of variation that were not simply SNPs.

Nobody was studying that seriously and nobody had a sense of how common it was and whether it would be easy to study. And it was through our comparative cancer work that we realized it would be easy to study, that it was fairly common and then we devoted a study to it that resulted in the 2003 Science paper. That's its historical route.

And then how did this move to autism?

Autism was an example of what people call a complex, genetic disorder that was failing to be conquered by Mendelian SNP association studies. People were really breaking their teeth on this. To groups would rarely come up with the same conclusion. And it was fairly easy for me to believe that this was not the right approach to autism or to other complex genetic diseases, like schizophrenia or obesity—any large number of things. There were two things that I thought were being missed: one was the possible role of spontaneous mutation. There were really three things: the possibility of spontaneous mutation; the possibility of rare variants that don't exist in the population for very long because they're eliminated quickly; the possibility of there being many loci that could contribute to the disorder. And those three things were generally missed, and the way the Mendelians tried to deal with this was to say: "These are complex disorders caused by the alignment of the planets;" that there would be four or five loci and that if you got the wrong allele configuration at these four or five loci, you would have the disorder. This was sort of the hypothesis you heard to explain why they had failed.

And it was a very unsatisfying hypothesis because first of all it's not testable. Second of all, it gave them reason to hope that they could continue to use their methods, just scale them up and eventually they'd get [a] signal. So, it was sort of self-serving. So, I really didn't like it. I really disliked it. There were huge amounts of money that were going into supporting giant efforts of that type.

So, it seemed to me that there were simpler hypotheses. All we had to do was admit to the possibility that there multiple loci and multiple mutations, each one of strong impact and high penetrance, and you could still get the failure of the Mendelian methods.

Given that schizophrenia, diabetes and other diseases may also work in this manner, was there something that tipped the scales in favor of autism?

I thought for a long time that autism was the right disease to do this on, but didn't have the funding for a study of the size that would be needed. So, it was just a hypothesis.

How long had you had the idea to train your methodology on autism?

At least since 1992, I think. We only had the methodology in a robust form in about 2001. It started with RDA [representational difference analysis, a microarray method for quickly scanning for differences between two genomes] and it was still too painful to do. And when it became ROMA [representational oligonucleotide microarray analysis, the next generation of the technology], it was feasible to do, but we didn't have the funding. And I didn't have any real hope of getting funding.

But by a marvelous coincidence, there was a philanthropist that was interested in supporting us, Jim Simons, who I knew through some completely different interaction. Jim called me to get my advice on a grant he was going to give to deCODE [the Icelandic genetic research company]. So, I gave Jim a phone call and I said "Autism, autism! We'd love to study autism!" So, I explained to him what our approach was and he liked it. And he gave us a small initial grant, which was actually, for us, a lot of money at the time. I think his funding started prior to the 2003 paper; we were already driving to that.

And then through another lucky coincidence, I had a colleague at Columbia, Conrad Gilliam [now at the University of Chicago]. He was part of the AGRE [Autism Genetic Resource Exchange] consortium, and so we had access to the AGRE samples and his enthusiastic backing. There is sort of an irony there because the AGREs were multiplex, and I actually wanted to study simplex because we're less likely to see spontaneous mutation in multiplex families, more likely to see them as the cause in simplex families. Conrad felt that we would see what we would see with the multiplex. Finally, I came to him and said we really want to study simplex. Conrad told us about Jim Sutcliffe [a molecular physiologist at Vanderbilt University, who had a collection of simplex families]. So, Conrad was really instrumental in connecting us to the community.

Had you had any experience with any autism sufferers that stoked your interest in the disorder?

I was aware of it because my [high school] girlfriend's brother had autism. I didn't know it was autism at the time. And then, through our kids, I met friends in the neighborhood who had autistic children. So, I was very aware of its devastating consequences to a family. Since much of my last 20 years has been spent raising a family, I am very sensitive to family issues

If you're a biologist, if you're a geneticist, you are in a culture where you hear repetitively the problems that people are being frustrated by. And if you're at all sensitive to the culture that you live in, these things are like neon signs; they're not obscure things. And it was clear that there are a host of genetic problems that were not getting solved by the classical methods, and some of them were socially devastating. Schizophrenia was the most obvious but autism was just as abundant as schizophrenia and it's probably socially more devastating. Probably the most devastating of all is alcoholism.

Unless you're tone deaf, you're aware that autism is a large, unsolved problem. Also, if you're at all sensitive to the public support for biomedical research, you realize the public's been disappointed. It's a little bit like solving multiple equations in one fell swoop. Number one, there's a crying unsolved problem. Number two, the public has been losing faith in the return for investing in molecular biology, in particular, in the Human Genome Project.

And then, I'm an opportunist. To be alive is to be an opportunist. And we had a methodology that could be used for cancer and we were doing that. But we also had a methodology that could be used for genetic disease. And so, there's kind of an inevitability to work on this glaring problem that no one's making progress on. And people were not making progress on it because I think you need to have a genetic understanding of a disorder before you can go anywhere. Unless it's some sort of thing you can correct surgically.

So, it wasn't a leap. I had been talking about working on autism at least since '92 or '93. I think that there's still a very real need for the public to support research. It's suffering tremendously under the Bush administration for at least two reasons: one of them, objectively, is that funding has been cut back. And also the fellow is such an anti-intellectual that the good people in government that are needed to manage the research dollars have either become cynical or they've fled. So, I think, the country has taken a real double hit from this administration.

There's clearly a need for the public to see that scientists care about their concerns and can yield things that don't bankrupt them, but that can improve their lives and their children's lives.

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