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A Meeting of Minds The idea that autism and psychosis are two ends of a common spectrum is stirring up debate among geneticists and psychiatrists alike. It’s controversial, but thanks to advances in comparative genomics, this hypothesis is now testable. Nicola Jones weighs the evidence. Bernard Crespi is demure when asked how he feels about an article in the New York Times calling the idea he developed with Christopher Badcock psychiatry’s “grandest working theory since Freud.” “It’s very flattering, and it’s nice that someone thinks that,” says Crespi, a geneticist at Simon Fraser University near Vancouver, Canada. But one has to remember that the compliment came from a journalist rather than a leading scientist, he adds modestly. “I think one has to give it another 50 years, or at least ten, before making that judgment.” Crespi’s and Badcock’s theory is that the brain’s balance is fundamentally set by an evolutionary tug-of-war between our genes— not, as Freud might say, by our relationships with our parents. Specifically, their theory proposes that autism and psychotic-affective conditions such as schizophrenia, bipolar disorder and depression are developmental opposites: autism results from the underdevelopment of the ‘social’ brain, whereas psychotic-affective conditions stem from its overdevelopment.
Such simple, sweeping theories don’t come along every day. For some, its simplicity carries power. Thomas Lehner, head of the US National Institute of Mental Health’s Genomics Research Branch in Bethesda, Maryland, calls it a “very beautiful argument.” Having read their work, Lehner is now excited to invite the authors to submit a proposal for a grant. Others, however, emphasize that the simplicity makes the theory unlikely. “If you think about the old original Star Trek series, to make time go backwards you just pull out the plugs and put the positive in the negative and the negative in the positive and it goes backwards,” says Patrick Sullivan, a psychiatric geneticist at the University of North Carolina– Chapel Hill. “If mental illness ends up being that conceptually straightforward, that would be shocking.” The good news is that the theory is testable. Extraordinary claims require extraordinary evidence, and the evidence for this claim is now being gathered.
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Unlucky inheritance The idea that autism and schizophrenia might be two sides of the same coin first struck Badcock in the late 1990s. He realized that people with both diseases show a number of opposite characteristics. For example, individuals with autism often have difficulty understanding when others are looking at them, are insensitive to the intentions or feelings of others and have a deficit in their sense of self. People with paranoid schizophrenia, in contrast, often think they are being watched, are so oversensitive to others that they imagine persecution and conspiracy and have delusions of self grandeur. Badcock, a sociologist at the London School of Economics, was invited to give a talk at Simon Fraser University at around that same time, and Crespi happened to be in the audience. That chance meeting spurred a scientific partnership, with Badcock specializing in grand ideas and thinking from the top down, and Crespi, the detailed scientist, collecting data from the bottom up. Together, they have co-authored
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several papers tallying the evidence for the sweeping idea. Autism and schizophrenia are both known to be up to 80% heritable. Hundreds or even thousands of common genetic variants are thought to convey a tiny increased risk for schizophrenia, along with a few dozen rare variants that might have a more powerful effect. The picture for common variants linked to autism isn’t so clear, but, again, there are thought to be dozens of rare variants that have an impact on the disease. There are hints that some of these genes—including those encoding the languageassociated gene product forkhead box protein P2, the tumor-suppressor protein adenomatous polyposis coli and the neurotransmitter dopamine receptor D1—are involved with both disorders, with certain alleles associated with autism in one case and schizophrenia in the other. That fits neatly with the notion that the conditions might be opposites. Some of these associations, however, are as yet supported only by single, unreplicated studies, cautions Crespi. “I wouldn’t go so far as to call that evidence,” he says. The stronger evidence for their theory lies in two other mechanisms of genetic influence— copy number variation and imprinting—which can both affect the number of functional copies of a gene that a child inherits and thus the dose of gene product that he or she receives during
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two copies of the silenced gene from mom and nothing from dad; the result is a type of dwarfism known as Silver-Russell syndrome. Other times a child gets two copies of the functioning gene from dad, and hence a double dose of the gene product. These children, who suffer from an overgrowth disorder called Beckwith-Wiedemann syndrome, are about 50% bigger than usual. In 2006, Crespi and Badcock suggested that autism and psychotic disorders might similarly result from imprinting gone wrong. The logic behind their argument is largely evolutionary. For body-size traits, for instance, bigger babies are better for the perpetuation of dad’s genes but not so great for mom herself, who has to deliver and nurse the super-sized child. This duality, Badcock and Crespi theorized, should also affect genes for mental cognition and personality (J. Evol. Biol. 19, 1007–1032, 2006). Some genetic evidence seems to support this idea: children with autism have higher expressed levels of IGF2, for example. And 8% of children with Beckwith-Wiedemann syndrome have autism—a ten-fold higher rate of incidence than in the population at large. Children who inherit two imprinted, silenced sets of genes on chromosome 15 from their mother have PraderWilli syndrome, and a remarkable 100% of these children grow up to show psychotic-affective disorders such as serious depression. This implies that the imprinted genes in question might have more sweeping effects—on both Battle of the sexes The other mechanism with data to back the body and mind—than previously recognized. Crespi’s and Badcock’s “notion that imprinting theory is a process called imprinting, by which either the mother’s egg or the father’s sperm can play a role seems an interesting idea,” says Matthew Belmonte, who marks a particular gene studies the neuroscience to be switched off in the “The theory has a of autism at Cornell resulting baby. No one certain elegance University in Ithaca, New knows exactly how such York, although “it needs imprinting works, but it is about it in polarizing further study.” Testing for an example of an ‘epigenetic’ autism and the effects of imprinting effect—a process by which directly, however, is a tricky gene expression is altered by schizophrenia on task. For example, some something other than the different dimensions.” genes are imprinted only in straightforward sequence —Simon Baron-Cohen certain cells of the body or of letters of DNA. only at specific stages of life, So far, imprinting is known to be important in at least 60 of which makes investigating such tissue samples humankind’s 20,000 genes. That might not extremely difficult. Although Crespi and Badcock keep collecting sound like a lot, but these genes often have big, sweeping impacts. Take the gene encoding multiple lines of evidence, there are some who insulin-like growth factor-2 (IGF2), for example, think the fundamental idea that schizophrenia which is a hormone needed for fetal and placental and autism have opposite genetic causes is growth. The mother’s egg normally ‘imprints’ unlikely, and some who call the data behind it the gene, shutting it down, and healthy babies shaky. Nick Craddock, a psychiatrist at the University get only one functional copy of IGF2 from their father. The result is one active copy of the gene, of Cardiff, UK, maintains that it’s more likely that providing enough of the growth hormone to the two conditions result from the same genetic effects, noting that “the simplest explanation, for make for a ‘normal’-sized child. Sometimes, however, children receive me, is when you’re seeing similar symptoms and development. Thus, both systems have the ability to create diametrically opposing effects, which make them obvious candidates for the mechanism behind Crespi’s and Badcock’s theory. In January, Crespi published work in which he meticulously trawled through hundreds of pages of data, looking for stretches of DNA with copy-number variants linked to both autism and schizophrenia. He found five sections associated with both conditions for which he could say with considerable certitude whether the diseases were associated with increases or decreases in copy number. Of these, four acted in diametrically opposite directions—too many copies were associated with autism and too few were associated with schizophrenia, or vice versa (Proc. Natl. Acad. Sci. USA 107, 1736–1741, 2010). “I was just astonished by this,” says Crespi. “I couldn’t have asked for any more exciting data to support these ideas.” Although these findings lend support to Crespi’s and Badcock’s theory that autism and schizophrenia are opposites, Sullivan points out that some of the same genes predispose people to other mental conditions, including epilepsy, mental retardation and abnormal brain size. As such, a more obvious conclusion may be simply that the affected genes “predispose to a general psychological hit,” he says.
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finding similar genes at the root, then maybe there is a similar cause.” That assessment matches the findings of Elaine Walker, a psychologist at Emory University in Atlanta, who found that adolescents with mild schizophrenia possess an unusually high number of autistic traits (Schizo. Res. 104, 265–273, 2008). Tim Crow, honorary director of the Prince of Wales International Centre for SANE Research in Oxford, goes so far as to say that the work does harm to the young field of psychosis genetics by throwing “half-baked evolutionary speculation” into the ring. Corroborating evidence might be on its way. The Psychiatric Genomewide Association Study Consortium—the largest biological experiment ever conducted in psychiatry—is currently analyzing whole-genome data from more than 80,000 subjects, including people with autism, schizophrenia, attention deficit hyperactivity disorder, major depression and bipolar disorder. Emerging results from this data set should help support or refute Crespi’s and Badcock’s theory. Men are from Mars Perhaps most intriguingly, Crespi’s and Badcock’s theory might relate to social differences between the sexes. In our evolutionary past, it is believed that in most cases mainly women and children congregated in small groups, whereas men were often gone for long periods on hunts and battles. This probably created selective pressure for women to be more empathic and better navigators of complex social interactions, Crespi says. So, the argument goes, if women are inclined toward having a more developed social brain in the first place, they will be buffered, to some extent, against genetic changes that tend toward autism and will only be diagnosed when the disorder is quite extreme. This matches the observation that autism is more common among men, but women are more likely to develop severe forms of it; the opposite is true for depression, a psychotic-affective disorder with links to schizophrenia. “Males are more likely to be autistic because they’re partway there already,” says Crespi, “and
females—and this is where you really get into trouble—are partway to psychotic-affective disorders.” This sounds similar, but is different, to Simon Baron-Cohen’s famous theory that autism is a manifestation of the ‘extreme male’ brain. Baron-Cohen has suggested that a boost of testosterone or some other factor in the womb might shift the brain toward autism. The Crespi-Badcock theory says it’s a heavy-handed influence of paternal genes. “The Crespi-Badcock theory has a certain elegance about it in polarizing autism and schizophrenia on different dimensions,” says Baron-Cohen, who directs the Autism Research Centre at the University of Cambridge. He, like others, is intrigued by the idea, but will withhold judgment until more data is in. “Badcock is a philosopher rather than an experimentalist,” he adds, “so I think there is more model-building than evidence.” If all of the theory is true, however, it could alter the way patients with mental illness are treated. Badcock says it could lead to the displacement of ‘talking cures’—therapies that aim to unravel problems by discussing them and their roots. This, he says, involves overanalyzing everything and becoming paranoid about the meaning of insignificant things, which effectively reenforces psychotic ways of thinking in people with psychosis. “I personally think psychoanalysis is very dangerous,” says Badcock, who trained in psychoanalysis with Freud’s youngest daughter until her death in 1982. “I think it should be banned.” Instead, Badcock envisions ranking each patient on a scale of ‘mentalism’ and ‘mechanism’ to see whether people are overly mentalistic (schizophrenic) or overly mechanistic (autistic). Psychiatrists could then implement an appropriate treatment to correct the balance. Just as a person with a weak arm has physiotherapy to build up those muscles, a person with weak social skills might be tasked with matching pictures of facial expressions to emotions, and individuals who are overmentalistic might perform pitch-recognition exercises to build up the mechanistic parts of their brains.
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Pharmaceutical options are possible as well. Crespi notes that if a drug candidate is found to counteract the symptoms of autism or schizophrenia, perhaps a drug with the opposite effect should be investigated for the opposing condition. Some studies seem to match this idea. For example, a drug that antagonizes the mGluR5 receptor for neurotransmission has been investigated for Fragile X syndrome, an autism-like condition (J. Med. Genet. 46, 266– 271, 2009). Independently, other researchers have reported investigating mGlur5 agonists for schizophrenia (Trends Pharmacol. Sci. 30, 25–31, 2008). But such dual-nature drug development is a long way down the road, warns Lehner, especially given that we don’t really understand how most drugs work against mental illnesses in the first place. “It’s a great hypothesis, but will it actually turn into different treatments? I’m not so sure,” he says. “Will we try it? Absolutely.” Until then, Crespi will continue testing the theory. Last year, he landed a three-year, $120,000 grant from Canada’s Natural Sciences and Engineering Research Council to pursue his studies of the genetics of mental illness. His first step will be to test healthy volunteers for their degree of ‘mentalism’ and cross-check these scores against physical traits such as head size (because a large head might go along with other ‘selfish’, paternally influenced developmental traits such as autism) and genetic variants matched to mental illness. With such data in hand, he should be able to test whether the pushes and pulls toward autism or psychosis behave as the theory would predict. In a decade or two, researchers might be better placed to say whether Crespi and Badcock really should stand in the scientific hall of fame next to Freud. “The rhetoric surrounding it has been blown out of proportion,” laughs Belmonte. But, he says, “It’s one of these broad-stroke ideas that I think is very useful for the field, even if the details need to be refined.” Nicola Jones is a commissioning editor for the Opinion section of Nature.
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