His name was David. He was 10 years old and, to put it bluntly, compellingly weirdespecially in the buttoned-down, groomed normality of suburban Long Island in the early 1960s. At the time, Michael Wigler was a ninth-grade student in Garden City, and he liked to hang out at the home of his girlfriend. Thats where he encountered David, her younger brother. Half a century later, he still cant get the boy out of his mind.
He was just like from another planetit was like meeting an alien, says Wigler, who ended up a little further east on Long Island as a geneticist at Cold Spring Harbor Laboratory. He was so different from anybody I had ever met before. First of all, he threw his arms about a lot. And then he moved his head around a lot and would never look at you when he talked to you. And he had an uncanny knowledge of baseball statistics. And I just thought, you know, Boy, this guy is really different. I mean, hes not just a little different. Hes very different.
In the 1950s and 1960s, children like David were pretty much anomalies without a name. Long after becoming a prominent cancer researcher, Wigler would mention him to colleagues, students, postdocs, writers, almost anyone. As one of those postdocs later recalled, At the time, autism existed; they just didnt call it autism, so Mike didnt know this kid had that particular disorder. Nonetheless, Wigler had become fascinated by the biological mystery that might explain such aberrant behavior. I think its probably what got me interested in genetics, he says.
Wigler, now 67, indeed devoted his career to genetics, establishing a reputation as one of the most original and productive thinkers in cancer research. So it was a bit of a surprise when, about 10 years ago, he jumped into autism research. Even more surprising has been what he and a few other maverick geneticists began to find.
Nicole Appel Vintage Tools 2013
One of the things Wigler had seen in cancer is that the disease usually arises because of spontaneous mutations. Rather than lurking in the population for generations and passing from ancestors to descendants, as in classic Mendelian illnesses like Huntingtons disease, these noninherited mutations popped up in one generation. They were fresh new changes in the DNAde novo mutations, in the jargon of geneticists. As a cancer researcher, Wigler developed new techniques for identifying them, and that led to another surprise. Some of these new mutations were often stunningly complexnot just little typos in the DNA, but enormous chunks of duplicated or missing text, which often created unstable, mistake-prone regions in chromosomes.
All thatthe memory of David, his successes in understanding cancer genetics, and the resulting realization that a focus on inheritance might miss some of the most significant disease-causing genesserved as background when, in the spring of 2003, Wigler received a phone call from James Simons, a wealthy hedge fund manager and cofounder (with his wife) of the Simons Foundation, whose daughter had been diagnosed with an autism spectrum disorder. The foundation had received a grant proposal for a research project, and Simons asked Wigler if he would be willing to evaluate it.
The researchers had proposed hunting for autism genes using conventional methods to look for inherited mutations passed down through families. Wigler didnt mince his words. I thought they were looking the wrong way, he says now. And I didnt want to see all this wasted effort.
Wigler, still fascinated by the boy hed met some 40 years earlier, threw his own hat in the ring. Autism? he recalls telling Simons. Autism? Iwant to work on autism.
Beginning with a paper in Science in 2007 and culminating with a report published in Nature last October, Wiglers group and its collaborators have written a dramatically different story about the genetic origins of autism spectrum disordersa story so unexpected and out of left field, as Wigler puts it, that many other genetic researchers refused to believe it at first. Wigler and his colleagues have shown that many cases of autism seem to arise from rare de novo mutationsnew wrinkles in the fabric of DNA that are not inherited in the traditional way but arise as last-minute glitches during the process in which a parents sperm or egg cells form.
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Solving the Autism Puzzle