Mental disorders as a conflict of genes
Saturday, 29 November 2008
Syed Fattahul Alim
Mind was once thought to be an entity that is separate and independent from the body.
This view of the body-mind duality led to the developments of the philosophies of the past. Who controls whom in this body-mind system of human existence? Those who believed in the supremacy of the mind over the body belonged to the idealist school. On the other hand, those who believed that body was everything and that mind was just an extension of it in certain intangible form belonged to the materialist school. In the beginning, the latter group of thinkers were few in number. However, with the development of science their number also grew. Thus the science of mind grew into another branch of scientific disciplines called psychology.
In the beginning, psychology depended on too many assumptions. Sigmund Freud, who is the father of modern of clinical psychology, started his work with the analysis of dream. According to him, whatever humans desire and cannot achieve in real life is reflected through dream.
But this was just the era of bringing mind, which had so far been enjoying a kind of immunity from the scrutiny of empirical study, if only due to its aura of supremacy, under rigorous scientific study.
Meanwhile, the science of psychology has become part of the study of brain. So, the psychological disorders, generally attributed to some kind of malfunctioning of the brain, have also come under the purview of brain research. Autism and schizophrenia are two kinds of mental disorders that had long been studied by the psychiatrists. Of late, different kinds of physical and mental disorders are being traced to the genes that are said to carry the blueprint of the physical and mental map of the individual. The molecular programme thus embedded in the form of genetic blueprint is also thought to include the tendency of future disorders whether in the brain or in any other parts of the body. Against this backdrop, a biologist and a sociologist have come up with quite an unconventional theory to explain psychological disorders like schizophrenia and autism. The theory tries to explain development of human psyche as well as the tendencies of its disorders as the outcome of a conflict between the genes a child inherits from its parents Though the theory itself may not come up to much in the long run, it has at least opened up a completely new window of research in the arena of mental disorder and its link to other areas of research on body-mind
Benedict Carey of New York Times describes below the new theory on particular kind of mental disorders and its impact on the overall research in the arena of mental research.
Two scientists, drawing on their own powers of observation and a creative reading of recent genetic findings, have published a sweeping theory of brain development that would change the way mental disorders like autism and schizophrenia are understood.
The theory emerged in part from thinking about events other than mutations that can change gene behaviour. And it suggests entirely new avenues of research, which, even if they prove the theory to be flawed, are likely to provide new insights into the biology of mental disease.
At a time when the search for the genetic glitches behind brain disorders has become mired in uncertain and complex findings, the new idea provides psychiatry with perhaps its grandest working theory since Freud, and one that is grounded in work at the forefront of science. The two researchers- Bernard Crespi, a biologist at Simon Fraser University in Canada, and Christopher Badcock, a sociologist at the London School of Economics, who are both outsiders to the field of behaviour genetics - have spelled out their theory in a series of recent journal articles.
"The reality, and I think both of the authors would agree, is that many of the details of their theory are going to be wrong; and it is, at this point, just a theory," said Dr. Matthew Belmonte, a neuroscientist at Cornell University. "But the idea is plausible. And it gives researchers a great opportunity for hypothesis generation, which I think can shake up the field in good ways."
Their idea is, in broad outline, straightforward. Dr. Crespi and Dr. Badcock propose that an evolutionary tug of war between genes from the father's sperm and the mother's egg can, in effect, tip brain development in one of two ways. A strong bias toward the father pushes a developing brain along the autistic spectrum, toward a fascination with objects, patterns, mechanical systems, at the expense of social development. A bias toward the mother moves the growing brain along what the researchers call the psychotic spectrum, toward hypersensitivity to mood, their own and others'. This, according to the theory, increases a child's risk of developing schizophrenia later on, as well as mood problems like bipolar disorder and depression.
In short: autism and schizophrenia represent opposite ends of a spectrum that includes most, if not all, psychiatric and developmental brain disorders. The theory has no use for psychiatry's many separate categories for disorders, and it would give genetic findings an entirely new dimension.
"The empirical implications are absolutely huge," Dr. Crespi said in a phone interview. "If you get a gene linked to autism, for instance, you'd want to look at that same gene for schizophrenia; if it's a social brain gene, then it would be expected to have opposite effects on these disorders, whether gene expression was turned up or turned down."
The theory leans heavily on the work of David Haig of Harvard. It was Dr. Haig who argued in the 1990s that pregnancy was in part a biological struggle for resources between the mother and unborn child. On one side, natural selection should favour mothers who limit the nutritional costs of pregnancy and have more offspring; on the other, it should also favour fathers, whose offspring maximize the nutrients they receive during gestation, setting up a direct conflict.
The evidence that this struggle is being waged at the level of individual genes is accumulating, if mostly circumstantial. For example, the foetus inherits from both parents a gene called IGF2, which promotes growth. But too much growth taxes the mother, and in normal development her IGF2 gene is chemically marked, or "imprinted," and biologically silenced. If her gene is active, it causes a disorder of overgrowth, in which the foetus's birth weight swells, on average, to 50 percent above normal.
Biologists call this gene imprinting an epigenetic, or "on-genetic," effect, meaning that it changes the behaviour of the gene without altering its chemical composition. It is not a matter of turning a gene on or off, which cells do in the course of normal development. Instead it is a matter of muffling a gene, for instance, with a chemical marker that makes it hard for the cell to read the genetic code; or altering the shape of the DNA molecule, or what happens to the proteins it produces. To illustrate how such genetic reshaping can give rise to behavioural opposites - the yin and yang that their theory proposes - Dr. Crespi and Dr. Badcock point to a remarkable group of children who are just that: opposites, as different temperamentally as Snoopy and Charlie Brown, as a lively Gaugin and a brooding Goya.
Those with the genetic disorder called Angelman syndrome typically have a jerky gait, appear unusually happy and have difficulty communicating. Those born with a genetic problem known as Prader-Willi syndrome often are placid, compliant and as youngsters low maintenance.
Yet these two disorders, which turn up in about one of 10,000 newborns, stem from disruptions of the same genetic region on chromosome 15. If the father's genes dominate in this location, the child develops Angelman syndrome; if the mother's do, the result is Prader-Willi syndrome, as Dr. Haig and others have noted. The former is associated with autism, and the latter with mood problems and psychosis later on - just as the new theory predicts.
Emotional problems like depression, anxiety and bipolar disorder, seen through this lens, appear on Mom's side of the teeter-totter, with schizophrenia, while Asperger's syndrome and other social deficits are on Dad's.
It was Dr. Badcock who noticed that some problems associated with autism, like a failure to meet another's gaze, are direct contrasts to those found in people with schizophrenia, who often believe they are being watched. Where children with autism appear blind to others' thinking and intentions, people with schizophrenia see intention and meaning everywhere, in their delusions. The idea expands on the "extreme male brain" theory of autism proposed by Dr. Simon Baron-Cohen of Cambridge.
"Think of the grandiosity in schizophrenia, how some people think that they are Jesus, or Napoleon, or omnipotent," Dr. Crespi said, "and then contrast this with the underdeveloped sense of self in autism. Autistic kids often talk about themselves in the third person."
Such observations and biological evidence are hardly enough to overturn current thinking about disorders as distinct as autism and schizophrenia, experts agree. "I think his work is often brilliant," Dr. Stephen Scherer, of the University of Toronto and the Hospital for Sick Children, said by e-mail message of Dr. Crespi. At the same time, Dr. Scherer added, "For autism there will not be one unifying theory but perhaps for a proportion of families there are underlying common variants" of genes that together cause the disorder.
The theory also does not fit all of the various quirks of autism and schizophrenia on flip sides of the same behavioural coin. The father of biological psychiatry, Emil Kraepelin, in the late 1800s made a distinction between mood problems, like depression and bipolar disorder, and the thought distortions of schizophrenia - a distinction that, to most psychiatrists, still holds up. Many people with schizophrenia, moreover, show little emotion; they would seem to be off the psychosis spectrum altogether, as the new theory describes it.
But experts familiar with their theory say that the two scientists have, at minimum, infused the field with a shot of needed imagination and demonstrated the power of thinking outside the gene. For just as a gene can carry a mark from its parent of origin, so it can be imprinted by that parent's own experience.
The study of such markers should have a "significant impact on our understanding of mental health conditions," said Dr. Bhismadev Chakrabarti, of the Autism Research Centre at the University of Cambridge, "as, in some ways, they represent the first environmental influence on the expression of the genes."
Mind was once thought to be an entity that is separate and independent from the body.
This view of the body-mind duality led to the developments of the philosophies of the past. Who controls whom in this body-mind system of human existence? Those who believed in the supremacy of the mind over the body belonged to the idealist school. On the other hand, those who believed that body was everything and that mind was just an extension of it in certain intangible form belonged to the materialist school. In the beginning, the latter group of thinkers were few in number. However, with the development of science their number also grew. Thus the science of mind grew into another branch of scientific disciplines called psychology.
In the beginning, psychology depended on too many assumptions. Sigmund Freud, who is the father of modern of clinical psychology, started his work with the analysis of dream. According to him, whatever humans desire and cannot achieve in real life is reflected through dream.
But this was just the era of bringing mind, which had so far been enjoying a kind of immunity from the scrutiny of empirical study, if only due to its aura of supremacy, under rigorous scientific study.
Meanwhile, the science of psychology has become part of the study of brain. So, the psychological disorders, generally attributed to some kind of malfunctioning of the brain, have also come under the purview of brain research. Autism and schizophrenia are two kinds of mental disorders that had long been studied by the psychiatrists. Of late, different kinds of physical and mental disorders are being traced to the genes that are said to carry the blueprint of the physical and mental map of the individual. The molecular programme thus embedded in the form of genetic blueprint is also thought to include the tendency of future disorders whether in the brain or in any other parts of the body. Against this backdrop, a biologist and a sociologist have come up with quite an unconventional theory to explain psychological disorders like schizophrenia and autism. The theory tries to explain development of human psyche as well as the tendencies of its disorders as the outcome of a conflict between the genes a child inherits from its parents Though the theory itself may not come up to much in the long run, it has at least opened up a completely new window of research in the arena of mental disorder and its link to other areas of research on body-mind
Benedict Carey of New York Times describes below the new theory on particular kind of mental disorders and its impact on the overall research in the arena of mental research.
Two scientists, drawing on their own powers of observation and a creative reading of recent genetic findings, have published a sweeping theory of brain development that would change the way mental disorders like autism and schizophrenia are understood.
The theory emerged in part from thinking about events other than mutations that can change gene behaviour. And it suggests entirely new avenues of research, which, even if they prove the theory to be flawed, are likely to provide new insights into the biology of mental disease.
At a time when the search for the genetic glitches behind brain disorders has become mired in uncertain and complex findings, the new idea provides psychiatry with perhaps its grandest working theory since Freud, and one that is grounded in work at the forefront of science. The two researchers- Bernard Crespi, a biologist at Simon Fraser University in Canada, and Christopher Badcock, a sociologist at the London School of Economics, who are both outsiders to the field of behaviour genetics - have spelled out their theory in a series of recent journal articles.
"The reality, and I think both of the authors would agree, is that many of the details of their theory are going to be wrong; and it is, at this point, just a theory," said Dr. Matthew Belmonte, a neuroscientist at Cornell University. "But the idea is plausible. And it gives researchers a great opportunity for hypothesis generation, which I think can shake up the field in good ways."
Their idea is, in broad outline, straightforward. Dr. Crespi and Dr. Badcock propose that an evolutionary tug of war between genes from the father's sperm and the mother's egg can, in effect, tip brain development in one of two ways. A strong bias toward the father pushes a developing brain along the autistic spectrum, toward a fascination with objects, patterns, mechanical systems, at the expense of social development. A bias toward the mother moves the growing brain along what the researchers call the psychotic spectrum, toward hypersensitivity to mood, their own and others'. This, according to the theory, increases a child's risk of developing schizophrenia later on, as well as mood problems like bipolar disorder and depression.
In short: autism and schizophrenia represent opposite ends of a spectrum that includes most, if not all, psychiatric and developmental brain disorders. The theory has no use for psychiatry's many separate categories for disorders, and it would give genetic findings an entirely new dimension.
"The empirical implications are absolutely huge," Dr. Crespi said in a phone interview. "If you get a gene linked to autism, for instance, you'd want to look at that same gene for schizophrenia; if it's a social brain gene, then it would be expected to have opposite effects on these disorders, whether gene expression was turned up or turned down."
The theory leans heavily on the work of David Haig of Harvard. It was Dr. Haig who argued in the 1990s that pregnancy was in part a biological struggle for resources between the mother and unborn child. On one side, natural selection should favour mothers who limit the nutritional costs of pregnancy and have more offspring; on the other, it should also favour fathers, whose offspring maximize the nutrients they receive during gestation, setting up a direct conflict.
The evidence that this struggle is being waged at the level of individual genes is accumulating, if mostly circumstantial. For example, the foetus inherits from both parents a gene called IGF2, which promotes growth. But too much growth taxes the mother, and in normal development her IGF2 gene is chemically marked, or "imprinted," and biologically silenced. If her gene is active, it causes a disorder of overgrowth, in which the foetus's birth weight swells, on average, to 50 percent above normal.
Biologists call this gene imprinting an epigenetic, or "on-genetic," effect, meaning that it changes the behaviour of the gene without altering its chemical composition. It is not a matter of turning a gene on or off, which cells do in the course of normal development. Instead it is a matter of muffling a gene, for instance, with a chemical marker that makes it hard for the cell to read the genetic code; or altering the shape of the DNA molecule, or what happens to the proteins it produces. To illustrate how such genetic reshaping can give rise to behavioural opposites - the yin and yang that their theory proposes - Dr. Crespi and Dr. Badcock point to a remarkable group of children who are just that: opposites, as different temperamentally as Snoopy and Charlie Brown, as a lively Gaugin and a brooding Goya.
Those with the genetic disorder called Angelman syndrome typically have a jerky gait, appear unusually happy and have difficulty communicating. Those born with a genetic problem known as Prader-Willi syndrome often are placid, compliant and as youngsters low maintenance.
Yet these two disorders, which turn up in about one of 10,000 newborns, stem from disruptions of the same genetic region on chromosome 15. If the father's genes dominate in this location, the child develops Angelman syndrome; if the mother's do, the result is Prader-Willi syndrome, as Dr. Haig and others have noted. The former is associated with autism, and the latter with mood problems and psychosis later on - just as the new theory predicts.
Emotional problems like depression, anxiety and bipolar disorder, seen through this lens, appear on Mom's side of the teeter-totter, with schizophrenia, while Asperger's syndrome and other social deficits are on Dad's.
It was Dr. Badcock who noticed that some problems associated with autism, like a failure to meet another's gaze, are direct contrasts to those found in people with schizophrenia, who often believe they are being watched. Where children with autism appear blind to others' thinking and intentions, people with schizophrenia see intention and meaning everywhere, in their delusions. The idea expands on the "extreme male brain" theory of autism proposed by Dr. Simon Baron-Cohen of Cambridge.
"Think of the grandiosity in schizophrenia, how some people think that they are Jesus, or Napoleon, or omnipotent," Dr. Crespi said, "and then contrast this with the underdeveloped sense of self in autism. Autistic kids often talk about themselves in the third person."
Such observations and biological evidence are hardly enough to overturn current thinking about disorders as distinct as autism and schizophrenia, experts agree. "I think his work is often brilliant," Dr. Stephen Scherer, of the University of Toronto and the Hospital for Sick Children, said by e-mail message of Dr. Crespi. At the same time, Dr. Scherer added, "For autism there will not be one unifying theory but perhaps for a proportion of families there are underlying common variants" of genes that together cause the disorder.
The theory also does not fit all of the various quirks of autism and schizophrenia on flip sides of the same behavioural coin. The father of biological psychiatry, Emil Kraepelin, in the late 1800s made a distinction between mood problems, like depression and bipolar disorder, and the thought distortions of schizophrenia - a distinction that, to most psychiatrists, still holds up. Many people with schizophrenia, moreover, show little emotion; they would seem to be off the psychosis spectrum altogether, as the new theory describes it.
But experts familiar with their theory say that the two scientists have, at minimum, infused the field with a shot of needed imagination and demonstrated the power of thinking outside the gene. For just as a gene can carry a mark from its parent of origin, so it can be imprinted by that parent's own experience.
The study of such markers should have a "significant impact on our understanding of mental health conditions," said Dr. Bhismadev Chakrabarti, of the Autism Research Centre at the University of Cambridge, "as, in some ways, they represent the first environmental influence on the expression of the genes."