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Big Think Interview With Michael Wigler

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Michael Wigler: Michael Wigler.  Professor of genetics at\r\nCold Spring Harbor Lab.

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Question: What does your research consist of on a day-to-day\r\nbasis?

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Michael Wigler: Our lab studies the genome of organisms and\r\nalso the genome of cancer cells. \r\nAnd we work on two kinds of problems: the evolution and outcome of\r\ncancers, and also on genetic disorders of a spontaneous sort, that is,\r\nnon-heritable genetic disorders. \r\nAnd those are two very—it sounds like two very different things, but\r\nthey’re related by our methodology, which is genomic analysis.

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What we do is called difference analysis, for example, if\r\nwe’re looking at a cancer, we’ll want to see where that cancer has mutated\r\nrelative to the genome of the person who gave rise to that cancer.  That’s differential genomic\r\nanalysis.  And it tells us where\r\nthe cancer has mutated.  And from\r\nthe types of mutations, the number of mutations, we can infer a lot about\r\ncancer etiology. 

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Question: Is biology becoming a more quantitative than\r\nqualitative science?

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Michael Wigler: Well, biology has always been influenced\r\nstrongly by quantitative types. \r\nMany physicists in the late ‘30s, early ‘40s, ‘50s, came into biology,\r\nstrongly influenced it.  There was\r\na period, I would say, from the time I was a graduate student in the mid-‘70s\r\nuntil the mid- to late-‘90s, where it was not particularly quantitative, and that was\r\nlargely because of the revolution in recombinant DNA.  So, really all you needed to be a good biologist was a good\r\nsense of logic and a good imagination. \r\nAnd mathematical and statistical skills weren’t really that necessary\r\nfor much of biology.  And I was in\r\nthat group actually.  I had studied\r\nearlier on as a mathematician but I used almost none of those mathematical\r\ntools when doing biological research. \r\nOf course, the logic comes in handy, but the tools were not very\r\nvaluable.  There was no place for\r\nthem because the kind of data that we were getting was very individual data and\r\nI actually had a rule of thumb. I actually disliked statistics early on in my\r\nlife and I felt that if I needed to do statistics to see what I was observing,\r\nthen I wasn’t really observing anything. 

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But that changed with the advent of the sequencing of the\r\nhuman genome.  That changed\r\neverything.  And the development of\r\nnew high throughput methods of extracting data, it forced biologists to\r\nreconsider the value of statistics and mathematics in the analysis of their\r\nsubject.  So, a number of\r\nbiologists moved in that direction. \r\nNot a lot, but quite a number did. \r\nAnd I was one of those who moved in that direction.

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Question: How has the sequencing of the genome “changed\r\neverything”?

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Michael Wigler: You know, we are so close, historically, to\r\nthat period, and the data that’s coming out of that effort is still being\r\ngenerated.  I think it’s very hard\r\nfor any of us to really judge the impact that it has had.  It was a huge revolution in terms of\r\nthe kinds of experiments one can conceive of doing.  The only thing comparable in my lifetime was the recombinant\r\nDNA revolution which changed entirely the kinds of experiments people did.  

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Since sequencing methods are changing so fast, the cost of\r\nsequencing has dropped enormously. \r\nAnd with each drop in the cost, it changes entirely how you think of\r\nattacking the problem.  So, in a\r\nfew years from now we’ll be in a position to have DNA sequence of a very high\r\nquality for a million people and know the medical history of these million\r\npeople.  And there’ll be—I don’t\r\neven think our computers are yet to a stage where they will be able to handle\r\ndata of that type and the kind of analysis tools that will be needed to analyze\r\nthat haven’t been developed yet. \r\nSo, we’re in a really a strange point in the history of biology where\r\nthings are changing so rapidly, we can’t quite see the shape of the future\r\nyet. 

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Question: What has your research revealed about the genetic\r\ncauses of cancer?

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Michael Wigler: Yeah. \r\nWell, the first observation was that there was a very strong correlation\r\nbetween the extent to which the genome in a cancer cell has changed and the\r\nlethality of the cancer.  So that,\r\nif one’s looking at cancer and there’s lots of changes in the genome, that\r\npatient is less likely to survive than a patient whose genome has just begun to\r\nevolve.  That was the first major\r\nobservation. 

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There were a lot of particular details that emerged from\r\nthose studies, that is, we found the locations of genes that are called uncA\r\ngenes and tumor suppressor genes. \r\nThe individual genes at these places, many of the changes are what we\r\ncall recurrent.  They happen over\r\nand over again in different people with the same cancer, and there are genes in\r\nthose regions that one can show functionally alter the capacity of the cancer\r\ncell to grow, divide, or spread in the individual.  So this has been an engine also for the discovery of new\r\ncancer genes. 

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We weren’t the first ones to do this.  People have been using these techniques\r\nfor a while, including ourselves, for a period of 10 years or more.  Sometimes particular drugs that are\r\ngiven to a patient are determined by whether that patient has a particular gene\r\namplification in their cancer.  The\r\nmost well-known example of that is patients with amplification of the HER2\r\ngene will likely respond to Herceptin. \r\nSo, our review has been that specific amplifications will correlate with\r\ndrug sensitivity, we’re in the middle of exploring that, and we’ve also begun\r\nto look at single cells within cancer. \r\nSo that we can now actually look at the genome of an individual cell\r\nwithin the cancer and that’s giving us a much more detailed picture of how the\r\ncancer has evolved. 

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So, we think we’ll be able to identify, for example, the earliest\r\ncells, the earliest mutations in a cancer that will tell us how the cancer\r\nbegan to grow in the first place. \r\nIt will also tell us what you might call the tribal, or population\r\nstructure of the cancer, and that tells us about how the cancer is... how the\r\nindividual cancer cells are interacting with each other, interacting with the\r\nhost, and migrating through the cancer, and possibly migrating throughout the\r\npatient.  So that we think that by\r\nlooking at the individual cells of the cancer, we’ll be able to improve\r\nclinical staging and drug treatment enormously.  But this is a long-term project.  This will take us five years, 10 years.

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Question: How might this research impact clinical cancer\r\ntreatments?

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Michael Wigler: Well, I can give you two ways—there are many\r\nways this research could impact the clinic.  I can give you two very concrete examples.  If a new drug is being tested in a\r\npopulation with a particular type of cancer, one might look for correlations\r\nbetween response to the drug and the genome profile.  That could tell you which patients are likely to respond to\r\na drug so that patients don’t have to take a drug that’s not going to benefit\r\nthem and don’t have to suffer the side effects of a drug that’s not going to\r\nbenefit them.  And that will\r\nultimately lead to the design of better drugs.  

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A second way—and this next way is not quite science\r\nfiction, but we’re looking a little bit into the future—when we can examine\r\nthe genome of individual cells, and can do that cheaply, we can develop early\r\ndetection tests for cancer that are based on blood.  So, it’s now being appreciated widely that even cancers that\r\nperhaps have not yet metastasized release their cells into the bloodstream and\r\ndo so in fairly large numbers so that you can collect cells from the blood and\r\nidentify them as a kind of cell that shouldn’t be in the blood.  But people haven’t yet been able to\r\nlook at the genomes of these individual cells.  So, some of the methodology that we are developing will\r\nenable us to do that.  So you can\r\nimagine that at some time in the future, you can draw blood in the doctor’s\r\noffice and just like the doctors now do what’s called a blood count to\r\ndetermine how many white blood cells you have, whether it’s likely that you’ve\r\ngot a fever, they’ll be able to sort out from the blood this small proportion\r\nof cells that might be being spun off by a cancer somewhere undetected in the\r\nbody.  And by looking at the genome\r\nof those cells, and possibly by also looking at the RNA that those cells are\r\nmaking, I'll be able to say "This person has malignant bone cancer," and then you\r\ncan look for that. 

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So, this technology can ultimately lead to early detection\r\nfor cancer.

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Question: How did you become interested in autism?

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Michael Wigler: My personal interest in autism dates\r\nfrom when I was a child, and I had a friend whose brother was quite\r\nstrange.  And when I was in medical\r\nschool, I realized that he had autism. \r\nIt was actually Asperger’s. He was a very bright kid, never looked you\r\nin the face, constantly was throwing his arms up like that as though he had\r\nmade some great discovery; and knew everything about baseball statistics. And so it made an imprint on me at an\r\nearly age. And it’s sort of a\r\nwonderful, it was sort of a wonderful thing to see this fellow who actually\r\ngrew up to, I think he had a successful career as a disc jockey.  So, I was always interested in autism\r\nand because I come from a family that’s somewhat left-wing, always looking for\r\nways I can do something that is a benefit to society.  And it struck me that autism was not a disorder that was\r\nstudied by the scientific community very deeply.  But in the worst cases, it was tragic for the families that\r\nhad an autistic child. 

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So, I was motivated by both of those things to have an\r\ninterest in autism.  And when we\r\nbegan to study cancer, which was in the early 1980’s, I knew at the time they\r\nwere studying cancer that the tools that we were developing could later be\r\napplied to genetic disorders.  Not\r\nthe kind of genetic disorders where you inherit something from your parents,\r\nbut the kind of genetic disorders that arise spontaneously because of mutation\r\nin the parent’s germ line. 

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An example of those kinds of mutations that everybody’s\r\nfamiliar with is Down syndrome; or Trisomy 21 I guess is the clinically\r\ncorrect way to refer to it.  These\r\nare new mutations.  You don’t\r\ninherit it in the classical sense, but it was obvious to people who thought\r\nabout it that human genome is not static; it changes over time.  That’s how we evolve.  And most of those changes are not\r\ngood.  They result in some disorder\r\nor another, but they’re hard to study. \r\nMost people who study genetic disorders study inherited kinds of genetic\r\ndisorders.  I was interested in the\r\nother kind of genetic disorders that result from new mutation.  And new mutations are what we study\r\nwhen we look at cancers.  When\r\nwe’re comparing a cancer to the normal person’s genome, the cancers differ by\r\nnew mutation.  That’s called\r\nsomatic mutation. 

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The same tools that find somatic mutation can find germ line mutations if you compare the child to the parents.  The incidence of autism being relatively high—and by and large, these children are so different from their parents—it seemed to me that it was likely, just a priori, that autism was the result of new mutation in the germ line\r\npossibly affecting many, many, many genes that result in the same end behavior,\r\nor similar end behaviors, and that was being ignored by the community. 

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So, when we had the tools to go look at this, we did\r\nso.  And so it was a combination of\r\nopportunism because we had developed the tools, and intrinsic interest from\r\nboth a social point of view, the social good, and also from a personal point of\r\nview.  That is, I had a personal\r\ninterest in how does the brain go from being what we would recognize as\r\nbelonging to a normal person to somebody who is, in wondrous ways, very\r\ndifferent from us.

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Question: What is autism?

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Michael Wigler: Well, there are a triad of behaviors that\r\nare the earmarks of autism.  The\r\ninclude difficulty in social interactions, delay in the development of speech\r\nand communication.  And those are\r\ndistinguishable and repetitive behaviors, almost obsessive-like behaviors.  

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The recognition of this triad as a condition we call autism\r\nbegan only in the late ‘30s, and as the diagnostic criteria began to be more\r\nwidely applied, more and more children were being called autistic.  And the definition, I think, I mean,\r\nwhen people now talk about autism spectrum disorders where a child has varying\r\ndegrees of these abnormalities.  It\r\nis not, in fact, an extremely well-defined disorder.  It has sloppy boundaries to normal behavior.  We all know people that are awkward\r\nsocially, there are many people who learn language late in life, and we all may\r\nknow people that have stutters, or have obsessive behaviors, or even hang\r\nwringing.  So there is something of\r\na continuum of all three of these things. \r\nThat’s not a condition whose boundaries are well-defined.  Yet, if you meet a child with autism,\r\nyou can generally say that there is something profoundly wrong here. 

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But it’s a hard disorder to define better than that.  And probably the reason it’s harder to\r\ndefine better than that is that the number of genes involved.  The number of underlying causes that\r\ncan create this triad is very great. \r\nFor example, the syndrome itself is enormously varied.  And if you have listened to somebody\r\nwho studies autistic children—children with autism, you’ll frequently hear them\r\nsay that each child that they see is different than the next.  It’s not really a syndrome in the way\r\nthat Down syndrome is a syndrome. \r\nThere are a variety of genetic disorders that are frequently—you can\r\nalmost tell that the children who have these disorders have the same underlying\r\ncause, because they’ll actually look alike.  It’s not just Down syndrome that has that property, Progeria\r\nhas that property.  There are a\r\nnumber of childhood disorders where\r\nthe children who have these disorders actually look alike.  

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That’s not the case in autism.  Each child has—is sort of wonderfully different than the\r\nnext child, so there’s a huge amount of variability.  And I think this has confounded the general public because\r\nit appears that the rate of autism has been going up so dramatically.  In fact, I think that’s mainly due to\r\nincreased diagnosis.

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Question: What is the “unified theory of autism” that you’ve\r\ndeveloped?

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Michael Wigler: The unified theory of autism attempts to\r\nreconcile several observations. \r\nThe first observation is that having siblings with autism is more common than\r\none would expect if each incidence of autism was random.  So, if a child is born has autism, a\r\nbrother is born, the chances that that brother has autism are much higher than\r\na male born to another family. 

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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. 

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So, those two facts tell you that there is a genetic\r\ncomponent to autism.  However,\r\nthere are families that have autistic children and there are large families and\r\nonly one child will have autism. \r\nSo, the genetics would look to be complicated.  There’s 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. 

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I think that prior to our serious involvement in the\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 combination\r\nin the child, so the children of these parents have a higher chance of having\r\nautism.  But it’s not a classical\r\nMendelian pattern where half of your kids have it, or a quarter of your kids 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. 

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What we did was come in and say, well, you know, it could be\r\na combination of both.  In some\r\nfamilies, it is perhaps simple Mendelian and in other families it’s spontaneous.  And if you assume that there are a\r\nlarge number of genes that can give you autism, then you could have a very\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 the\r\nmutation and the child can carry it and not show the disorder, then his or her\r\nchildren could then be at risk in a Mendelian way of inheriting that gene.

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So combining these two ideas that the sibling risks is\r\nreally a combination of simple Mendelian in some families with other families\r\nbeing spontaneous mutation unifies these two observations and does so in a\r\ncoherent model.  So, the coherent\r\nmodel is that humans are mutating, the rate of new mutation giving rise to\r\nautism is perhaps on the order of 1 in 200 kids, and something like half of\r\nthose kids actually don’t come down with a diagnosis, they mature, they get\r\nmarried, they have children and those children are then at risk from the carriers. 

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Now, one of the very important clues that is compatible 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 boy,\r\nthose abnormalities will exist in the girl.  So girls have something that makes them resistant.  So 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, particularly her\r\nmale offspring might be at high risk because they might inherit the gene 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 carrier\r\nparent and also those rare mutations that destroy a gene in the germ line. 

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Now, I should say, and I really have to mention this, 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 order of\r\n20 male offspring and half of them had autism.  So, 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, was a\r\ncarrier of a simple dominantly inherited Mendelian trait.

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Question: Why do older parents tend to have more autistic\r\nchildren?

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Michael Wigler: \r\nThe incidence of autism goes up with the age of the parent, and that’s\r\nentirely consistent with the new mutation idea.  Because it’s already well established in males that the\r\nnumber of point mutations found in the male’s offspring go up with the age 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 cultures\r\nwhere having children is differed and delayed.  The magnitude of that effect is not going to explain the\r\noverwhelming explosion in the number of diagnoses, but there may be a mild increase in the\r\nrate of autism due to that.  And the age\r\ndependence on the parents is consistent with the new mutation hypothesis.

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Question: Do you believe that environmental factors such as\r\nvaccines increase the autism rate?

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Michael Wigler: Well, any genetic disorder is an interaction\r\nwith the environment.  So, I don’t\r\nexclude environment.  I just don’t\r\nsee yet any strong evidence for a particular environmental factor.  I think that one could do studies.  For example, one could go to third world countries and do a study and ask is the rate of autism there the same as\r\nit is in the developed countries. \r\nNo one has done a study, that I know of, of that type, but it certainly\r\ncould be done.  That would answer\r\nthat question. 

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But certainly anything to have to do with the development of\r\nan organism has an environmental component to it, but you can only study that\r\nwhen there’s some evidence which enables you to isolate that environmental\r\ncomponent.  I think the vaccine\r\nstudies have been now largely discredited.  They took mercury out of the vaccines and the rates of\r\nautism didn’t change.  And now of\r\nthe 12 authors of the original paper that got some people very excited, I think\r\n11 of those 12 authors have now withdrawn their backing for that paper and the\r\nmethods used in that paper are really in doubt.  

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So, I don’t take it as there being any evidence that\r\nvaccines are such an environmental factor.  It’s unfortunate that at the age at which parents begin to\r\nrecognize autism in their children often correlates with the age at which they\r\nreceive vaccinations.  That’s an\r\nunfortunate thing. 

There is a\r\nportion of autism, probably the majority of autism that you can detect it very\r\nearly once the child is... almost after the child is born.  Many parents of autistic children say\r\nthey could tell very early on that there was something wrong with their\r\nchild.  There are about a quarter\r\nof the cases of autism where it looks like the child, in the parents’ opinion,\r\nhas been developing normally and then, to their mind, suddenly goes off course.  And I think at least five percent of\r\ncases, it’s been very well documented that actually, a child has begun to lose\r\ngains that they have made.  So,\r\nthere is this component that’s very tragic when a parent feels relieved that\r\nthey’ve gotten through, and I think every parent who has a child suffers through\r\nnightmares that, you know, hoping that their child will be healthy and they give birth to a healthy child and then at age two or three, the child suddenly\r\nstops developing.  That’s a tragedy\r\nof horrendous proportions, and it’s natural for the parents of such children to\r\nlook around for the possible causes; something external. 

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However, it should be borne in mind that our brains\r\ncontinuously are developing at that age, and it is well-known that there are\r\ngenetic defects whose onsets can occur at almost any particular age.  For example, there is a class of\r\ndisorders that are called Storage Disorders where the child develops normally,\r\nbut because of the buildup of some compound due to the faulty metabolism of\r\nsome essential thing that they eat every day, builds up to a point and then\r\nbegins to poison the brain.  And in\r\nthese cases, the child will develop normally up to a certain age, and then will\r\noften regress and sometimes will die. \r\nSo, the idea that you can’t have sudden onset of an illness when the\r\nchild is two or three is just wrong. 

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If there were a clear environmental signal, for example,\r\nsonograms, or too much television, or vaccinations, that would be something\r\nthat one could study, but in the absence of evidence for that, you have to ask\r\nyourself, well what should we be looking for?  Should it be the plastic in bottles?  And I don’t think we can do that in our\r\nculture.  I don’t think we can look\r\nfor these possible environmental insults. \r\nThere are just far too many. \r\nBut if you go to a place like Nepal, or Mongolia, or someplace whose\r\nenvironment is completely different, they don’t have television, they still\r\nhave grandmothers raising the children, they don’t get sonograms.  You could begin to tease out and do\r\nwhat epidemiologists do.  They go\r\nand do cultural comparisons.  So,\r\nfor example, cultural comparisons have told us the incidences of breast cancer\r\nin Japan is one-third the rate of the incidences of breast cancer in America,\r\nand when Japanese women grow up in America, their rate of breast cancer is the\r\nsame is American women.  Okay.  You can say, the environment possibly\r\nincluding culture in some way, because the rate, or the age on which you\r\nundergo puberty is relevant to breast cancer.  Has a study like that been done for autism?  No.  That’s where you would start.  And none of that’s been done as far as I know.

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Question: What will be the impact of your research on autism\r\ntreatment?

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Michael Wigler: Yes, well there are two ways in which our\r\nwork could inform clinical treatment. \r\nIn the area of early diagnosis. \r\nIf there’s a child and it’s developing—it’s giving off developmental\r\nclues there might be something wrong, if we had a list of the kind of genetic\r\nlesions we could screen for, we might be able to determine early on that this\r\nchild is going to develop a form of autism.  And if it’s correct—most disorders are correctable to the\r\nextent that they are correctable, are more correctable early than late, when we\r\nknow how to correct or treat, we’ll be able to start that sooner.  So, early diagnosis is going to be\r\nimportant for any disorder.  That’s\r\none way. 

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Another way is children with a particular genetic abnormality,\r\nthat is, those children who share genetic abnormality, may have one particular\r\nway of treating them that’s different than children who have a different\r\nabnormality.  We will only learn\r\nabout that once we can separate these children according to their genetic\r\nabnormalities.  That’s going to\r\ntake many, many years. 

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The third way is that in some cases, we will be identifying\r\ngenes, who by their very nature, tell us this is a correctable, treatable,\r\nsyndrome.  For example, we find a\r\ngene that’s involved in metabolism. \r\nThis child is perhaps got really a storage disorder of some type, but\r\naltering the diet in those cases might be able to treat the child.  But unfortunately, we don’t yet know\r\nthe identities of the autism genes. \r\nWe have regions and there’s a huge effort underway.  I would say, in particular by doing\r\nvery exhaustive sequence comparisons of children to their parents, we will\r\nidentify the actual culprit genes. \r\nAnd that will take us two to four years.  And there may be, unfortunately, I’m estimating around 400\r\nsuch genes that each one of which can cause autism.  But when we have those genes, we see what they do; we can\r\nsee what pathways they are interacting with, some of those will suggest\r\nimmediately treatments that can be tested.  We will be able to make animal models and test drugs in\r\nanimals to correct these things. 

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So, in general, the way to understand a disorder is to\r\nunderstand its causes and then address those causes.  In the case of autism, most people would agree, I think most\r\nscientists would agree the causes are genetic, and we have a pathway to\r\ndiscover the genes.  So it will be\r\neasier to diagnose, classify by diagnosis into behavioral and even drug\r\ntreatments, and discover new drug treatments. 

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Question: What made you choose science as a career?

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Michael Wigler: Well, the first thing I remember wanting to\r\nbe was a middleweight boxer.  And\r\nthat was because I used to punch my older brother and he said, some day you’ll\r\nbe middleweight champion.  That was\r\nmy first ambition.  After that, I\r\ndrifted to science.  I think\r\nbecause my father was a chemist and my mother had a great deal of respect for\r\nthe social utility of the mind.  In\r\nthat period, which was the late ‘40s, following World War II, early ‘50s,\r\npeople were very optimistic about the impact of technology on quality of\r\nlife. 

\r\n\r\n

The life of an artist was generally considered to be one of\r\nsuffering, and so my parents certainly didn’t wish that on me.  And those were my two choices.  It was either science or the arts.  We didn’t have any—my grandfather was a\r\ntailor, so anything involving the hands was out of the question.  One had to live the life of the mind,\r\nand there were really these two paths. \r\nI choose science, but toyed with writing when I was in high school and\r\ncollege, ultimately settling on mathematics, which I really enormously\r\nenjoyed.  And actually began to\r\ndevelop a disdain for science because science depended on the empirical world\r\nas a source for the imagination, whereas in mathematics, you didn’t have to\r\ndepend on the empirical world.  So,\r\nto me, I thought that mathematics was the highest enterprise of the mind. 

\r\n\r\n

But I wasn’t good enough at it and it was taking me out of\r\ncontact with humans, so I decided I had to do something socially useful, so I\r\nwent into medicine.  And that was a\r\ndisaster.  I really couldn’t deal\r\nwith the uncertainty of medicine, so I started doing research instead.  And that’s how I ended up being a\r\nbiologist and molecular biologist. \r\nSo, I didn’t finish medical school, I went into microbial research\r\ninstead and came back much later in my life to utilize mathematics. 

\r\n\r\n

But in my case, it was entirely the influence of my\r\nparents.  They had admiration for\r\nthe life of the mind and they didn’t have admiration really for anything\r\nelse.  I mean, I guess there might\r\nhave been some athletes that they admired.  They admired people who had broken down cultural\r\nbarriers.  So, they had some\r\nadmiration for people that struck down political archetypes, social\r\narchetypes.  But mainly they felt\r\nthat their kids should be active with their minds and do things that they\r\nenjoyed based on their own imaginations, their own training.  So, I never questioned that. 

\r\n\r\n

Unfortunately, I didn’t realize what they had done.  So, when I had children—in case Ben and Josh find this—it\r\ndidn’t occur to me that you actually had to imbue this.  I thought it would just be natural for\r\na child to want to be either a scientist or an artist.  And neither of my children had an\r\ninterest in science.  And I\r\nrealized that when it was too late. \r\nSo, I missed out with my kids. 

\r\n\r\n

I think to get, if one has as a goal to have a society with\r\nmore scientists and engineers in it, then the culture has to respect people who\r\ndo that.  And the way these people\r\nare depicted in the cultural media is not generally positive.  There were in the ‘30s a number of\r\nbooks that were written.  I don’t\r\nremember their names, in which scientists of one type, Marie Curie, Louie\r\nPasteur, were depicted in dramas as heroes.  But you don’t see that at all anymore.  Instead, scientists are villains,\r\nthey’re socially awkward, they’re not the kind of people you can cuddle up to. And I think that if popular culture does not reflect the value of science,\r\npeople are not going to go into it. \r\nAnd America will be dependent on people coming in from the outside to\r\nfulfill the positions of engineers and scientists.

\r\n\r\n

Question: Have you ever been completely surprised by the\r\noutcome of your research?

\r\n\r\n

Michael Wigler: Well, science is a very—it’s actually a very\r\ndifficult field because you need probably above everything else, extraordinary\r\npatience.  And what keeps you going\r\nis discovery.  And sometimes in a\r\nlifetime, you may have one outstanding discovery.  Einstein used to say that he was unusual in that he had had\r\ntwo.  But any one would have been\r\nenough to have kept him going. \r\nMost scientists are not in that league, but we’ve all had at some scale\r\nthings that we’re really very proud of if discover them.  Often, we are looking for them.  The idea that a lot of discovery is\r\nserendipitous and accidental is tremendously, tremendously overplayed.  I think it’s much more likely that one\r\nsees something, almost in everyday life that puzzles you and you carry it\r\naround with you for some period of time, and then you see some way of\r\nconnecting to it.  You could say\r\nour discoveries in autism as an example of that.  At a very early age, I was impressed by this child and later\r\nsaw an opportunity and I struck when the opportunity was there to satisfy my\r\ncuriosity.  So, most discovery is\r\nof that type. 

\r\n\r\n

Sometimes you see things that you can’t explain.  And I shouldn’t say sometimes, a lot of\r\ntimes you see things that you can’t explain.  And sometimes you come up with explanations that are really\r\nexciting.  And 99% of the time,\r\nthose are wrong and there’s really some trivial explanation of the thing that’s\r\ngotten you excited. 

\r\n\r\n

Early in my career I used to hate those things and I used to\r\nsay, only a manic depressive would love living like this.  You see something that’s weird, you\r\ncome up with some great encompassing idea that will explain it, it’s going to\r\nchange how people think, and then the next day you realize that you were really\r\na dumbass.  Nowadays when those\r\nthings happen, I actually really enjoy them because there are so few real "Eureka!" moments\r\nin one’s life that you have to almost have to enjoy the fake ones.  I mean, after all, the feeling is\r\njust as good.  So, I’ve actually\r\ngotten to enjoy those weird results that we can’t explain, come up with\r\nfanciful ideas, and then try to batter them.  And then you get double satisfaction because you end up\r\ndestroying the idea and it’s satisfying to destroy the idea.  Almost as much fun to destroy an idea\r\nas to create one.

Recorded April 12, 2010

\r\n\r\n\r\n\r\n\r\n

A conversation with the genetics professor at Cold Spring Harbor Laboratory.

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