A "Unified Theory of Autism"
Early in his career, Dr. Wigler developed methods for engineering animal cells with his collaborators at Columbia University, Richard Axel and Saul Silverstein. These methods are the basis for many discoveries in genetics, and the means for producing medicines used to treat heart disease, cancer, and strokes. Dr. Wigler continued his genetic explorations, and in the early 1980s isolated the first human cancer genes. In the mid 80s, Dr. Wigler and his collaborators demonstrated conservation of cellular pathways in humans and yeast, thereby providing deep insights into the function of the cancer genes.
In the early 1990s, Drs. Wigler and Clark Still developed a method for building vast chemically indexed libraries of compounds, an approach that is still in use for drug discovery. During the same period, Wigler’s group developed the concept and applications of representational analysis, RDA, which led to identifying new cancer genes and viruses. He later enhanced this concept through use of microarrays, a method now widely used commercially for genetic typing.
Dr. Wigler’s research is presently focused on the genomics of cancer and genetic disorders. He expects this work will eventually improve the targeting of cancer treatment and lead to early detection tests for cancer. His studies in human genetics led to the discovery of a vast source of genetic variability known as copy number variation (CNV), and to the breakthrough that spontaneous germline mutation is likely to be a contributing factor in autism. His genetic theories and methods suggest to new approaches to understand many other cognitive and physical abnormalities.
For his fundamental contributions to biomedical research, Dr. Wigler is a recipient of numerous awards and honors and is a member of the National Academy of Science and the American Academy of Arts and Sciences.
Question: What is the “unified theory of \r\nautism” that you’ve\r\ndeveloped?\r\n\r\n
Michael Wigler: The unified theory of autism\r\n attempts to\r\nreconcile several observations. \r\nThe first observation is that having siblings with autism is more\r\n common than\r\none would expect if each incidence of autism was random. \r\n So, if a child is born has autism, a\r\nbrother is born, the chances that that brother has autism are much \r\nhigher than\r\na male born to another family.\r\n\r\n
And twins, identical twins have an extremely high\r\nconcordance. Something like\r\n90%. There is no other cognitive\r\ndisorder whose concordance among identical twins is as high.\r\n\r\n
So, those two facts tell you that there is a \r\ngenetic\r\ncomponent to autism. However,\r\nthere are families that have autistic children and there are large \r\nfamilies and\r\nonly one child will have autism. \r\nSo, the genetics would look to be complicated. There’s\r\n an inherited component because siblings have a higher\r\nrate of concurrence, but there might also be a sporadic component. So, the issue is how to reconcile\r\nthat.\r\n\r\n
I think that prior to our serious involvement in \r\nthe\r\nfield, people assumed there was what was called this complex inherited\r\nmodel. That there are many genes\r\nthat may be in the wrong state in the parents that come into some \r\ncombination\r\nin the child, so the children of these parents have a higher chance of \r\nhaving\r\nautism. But it’s not a classical\r\nMendelian pattern where half of your kids have it, or a quarter of your \r\nkids have\r\nit. Half will have it if it’s a\r\ndominant, a quarter if it’s recessive. \r\nThe pattern seems more complicated than that.\r\n\r\n
What we did was come in and say, well, you know, it\r\n could be\r\na combination of both. In some\r\nfamilies, it is perhaps simple Mendelian and in other families it’s \r\nspontaneous. And if you assume that there are a\r\nlarge number of genes that can give you autism, then you could have a \r\nvery\r\nlarge proportion of autism being generated by spontaneous mutation. But if the mutations don’t all have\r\ncomplete, what’s called complete penetrance, that is, you can pass on \r\nthe\r\nmutation and the child can carry it and not show the disorder, then his \r\nor her\r\nchildren could then be at risk in a Mendelian way of inheriting that \r\ngene.\r\n\r\n
So combining these two ideas that the sibling risks\r\n is\r\nreally a combination of simple Mendelian in some families with other \r\nfamilies\r\nbeing spontaneous mutation unifies these two observations and does so in\r\n a\r\ncoherent model. So, the coherent\r\nmodel is that humans are mutating, the rate of new mutation giving rise \r\nto\r\nautism is perhaps on the order of 1 in 200 kids, and something like half\r\n of\r\nthose kids actually don’t come down with a diagnosis, they mature, they \r\nget\r\nmarried, they have children and those children are then at risk from the\r\n carriers.\r\n\r\n
Now, one of the very important clues that is \r\ncompatible with\r\nthis model is that the risk of autism is much higher in boys than in\r\ngirls. If the model, almost any\r\nmodel would predict that whatever genetic abnormalities exist in the \r\nboy,\r\nthose abnormalities will exist in the girl. So \r\ngirls have something that makes them resistant. So\r\n girls, in fact, could be natural\r\ncarriers of genes that in the boy would give the boy autism. And that girl might grow up and be a\r\nhealthy and desirable mate and have children and her children, \r\nparticularly her\r\nmale offspring might be at high risk because they might inherit the gene\r\n that\r\nshe safely carries. That’s the\r\nessence of unified theory. It does\r\nnot explain why autism, why boys are at higher risk than girls. But it does suggest that you can have\r\ntwo forms of genetic involvement; an inherited involvement from a \r\ncarrier\r\nparent and also those rare mutations that destroy a gene in the germ \r\nline.\r\n\r\n
Now, I should say, and I really have to mention \r\nthis, that\r\nin the model we’re not saying that only women are carriers. In fact, there’s well-known example\r\nthat’s been in the news of a male sperm donor who had something on the \r\norder of\r\n20 male offspring and half of them had autism. So,\r\n that’s clearly a case where the sperm donor, who I guess\r\nwas judged to be normal, probably maybe even brilliant or even genius, \r\nwas a\r\ncarrier of a simple dominantly inherited Mendelian trait.\r\n\r\n
Question: Why do older parents tend to \r\nhave more autistic\r\nchildren?\r\n\r\n
Michael Wigler: \r\nThe incidence of autism goes up with the age of the parent, and \r\nthat’s\r\nentirely consistent with the new mutation idea. Because\r\n it’s already well established in males that the\r\nnumber of point mutations found in the male’s offspring go up with the \r\nage of\r\nthe father. And there’s also a\r\ncorrelation with the age of the mother. \r\nSo, there may be a mild increase in the rate of autism in those \r\ncultures\r\nwhere having children is differed and delayed. The\r\n magnitude of that effect is not going to explain the\r\noverwhelming explosion in the number of diagnoses, but there may be a \r\nmild increase in the\r\nrate of autism due to that. And the age\r\ndependence on the parents is consistent with the new mutation \r\nhypothesis.
Recorded April 12, 2010
Why is the risk of autism higher in boys than girls? Why do older parents tend to have more autistic children? New genetic research attempts to answer some of the major questions surrounding the disorder.