The Scientific Journals

by : Uta Frith

Structural abnormalities in the brains of autistic individuals have turned up in anatomic studies and brain-imaging procedures. Both epidemiological and neuropsychological studies have demonstrated that autism is strongly correlated with mental retardation, which is itself clearly linked to physiological abnormality. This fact fits well with the idea that autism results from a distinct brain abnormality that is often part of more extensive damage. If the abnormality is pervasive, the mental retardation will be more severe, and the likelihood of damage to the critical brain system will increase. Conversely, it is possible for the critical system alone to be damaged. In such cases, autism is not accompanied by mental retardation.

CLOSE LINK between autism and mental retardation is reflected in this chart. The percentage of children showing the social impairments typical of autism is highest at low levels of intelligence as measured by tests in which an intelligence quotient (IQ) below 70 is subnormal. For example, 86 percent of 44 children in the lowest IQ range showed the social impairments of autism. The data are drawn from a population of about 35,000 children aged under 15 years.

Neuropsychological testing has also contributed evidence for the existence of a fairly circumscribed brain  abnormality. Autistic individuals who are otherwise able show specific and extensive deficits on certain tests that involve planning, initiative and spontaneous generation of new ideas. The same deficits appear in patients who have frontal lobe lesions. Therefore, it seems plausible that whatever the defective brain structure or system is, the frontal lobes are implicated.

Population studies carried out by Lorna Wing and her colleagues at the Medical Research Council’s Social Psychiatry Unit in London reveal that the different symptoms of autism do not occur together simply by coincidence. Three core features in particular—impairments in communication, imagination and socialization—form a distinct triad. The impairment in communication includes such diverse phenomena as muteness and delay in learning to talk, as well as problems in comprehending or using nonverbal body  language. Other autistic individuals speak fluently but are overliteral in their understanding of language. The impairment in imagination appears in young autistic children as repetitive play with objects and in some autistic adults as an obsessive interest in facts. The impairment in socialization includes ineptness and inappropriate behavior in a wide range of reciprocal interactions, such as the ability to make and keep friends. Nevertheless, many autistic individuals prefer to have company and are eager to please.

The question is why these  pairments, and only these, occur together. The challenge to psychological theorists
was clear: to search for a single cognitive component that would explain the deficits yet still allow for the abilities that autistic people display in certain aspects of interpersonal interactions. My colleagues at the Medical Research Council’s Cognitive Development Unit in London and I think we have identified just such a component. It is a cognitive mechanism of a highly complex and abstract nature that could be described in  computational terms. As a shorthand, one can refer to this component by one of its main functions, namely, the ability to think about thoughts or to imagine another individual’s state of mind. We propose that this  component is damaged in autism. Furthermore, we suggest that this mental component is innate and has a unique brain substrate. If it were possible to pinpoint that substrate—whether it is in fact an anatomical structure, a physiological system or a chemical pathway—one might be able to identify the biological origin of autism.

The power of this component in normal development becomes obvious very early. From the end of the first year onward, infants begin to participate in what has been called shared attention. For example, a normal child will point to something for no reason other than to share his interest in it with someone else. Autistic children  do not show shared attention. Indeed, the absence of this behavior may well be one of the earliest signs of  autism. When an autistic child points at an object, it is only because he wants it.

Next : Defect in Frontal Lobes (2)
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by : Uta Frith

Autism is rare. According to the strict criteria applied by Kanner, it appears in four of every 10,000 births. With the somewhat wider criteria used in current diagnostic practice, the incidence is much higher: one or two in 1,000 births, about the same as Down’s syndrome. Two to four times as many boys as girls are affected.


For many years, autism was thought to be a purely psychological disorder without an organic basis. At first, no obvious neurological problems were found. The autistic children did not necessarily have low intellectual ability, and they often looked physically normal. For these reasons, psychogenic theories were proposed and  taken seriously for many years. They focused on the idea that a child could become autistic because of some  existentially threatening experience. A lack of maternal bonding or a disastrous experience of rejection, so the theory went, might drive an infant to withdraw into an inner world of fantasy that the outside world never penetrates.


These theories are unsupported by any empirical evidence. They are unlikely to be supported because there are many instances of extreme rejection and deprivation in childhood, none of which have resulted in autism. Unfortunately, therapies vaguely based on such notions are still putting pressure on parents to accept a burden of guilt for the supposedly avoidable and reversible breakdown of interpersonal interactions. In contrast, well-structured behavior modification programs have often helped families in the management of autistic children, especially children with severe behavior problems. Such programs do not claim to reinstate normal development in the children.

The insupportability of the psychogenic explanation of autism led a number of workers to search for a biological cause. Their efforts implicate a defective structure in the brain, but that structure has not yet been identified. The defect is believed to affect the thinking of autistic people, making them unable to evaluate their  own thoughts or to perceive clearly what might be going on in someone else’s mind.

Autism appears to be closely associated with several other clinical and medical conditions. They include maternal rubella and chromosomal abnormality, as well as early injury to the brain and infantile seizures. Most impressive, perhaps, are studies showing that autism can have a genetic basis. Both identical twins are much more likely to be autistic than are both fraternal twins. Moreover, the likelihood that autism will occur twice in the same family is 50 to 100 times greater than would be expected by chance alone.

Next : Defect in Frontal Lobes (1)
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by : Uta Frith


Autistic people suffer from a biological defect. Although they cannot be cured, much can be done to improve their lives.

The image often invoked to describe autism is that of a beautiful child imprisoned in a glass shell. For decades, many parents have clung to this view, hoping that one day a means might be found to break the invisible barrier. Cures have been proclaimed, but not one of them has been backed by evidence. The shell remains intact. Perhaps the time has come for the whole image to be shattered. Then at last we might be able to catch a glimpse of what the minds of autistic individuals are truly like.

Psychological and physiological research has shown that autistic people are not living in rich inner worlds but instead are victims of a biological defect that makes their minds very different from those of normal individuals. Happily, however, autistic people are not beyond the reach of emotional contact and attachment to others.

Thus, we can make the world more hospitable for autistic individuals just as we can, say, for the blind. To do  so, we need to understand what autism is like—a most challenging task. We can imagine being blind, but  autism seems unfathomable. For centuries, we have known that blindness is often a peripheral defect at the sensory-motor level of the nervous system, but only recently has autism been appreciated as a central defect at the highest level of cognitive processing.  Autism, like blindness, persists throughout life, and it responds to special efforts in compensatory education. It can give rise to triumphant feats of coping but can also lead to disastrous secondary consequences— anxiety, panic and depression. Much can be done to prevent problems. Understanding the nature of the handicap must be the first step in any such effort.

Autism existed long before it was described and named by Leo Kanner of the Johns Hopkins Children’s Psychiatric Clinic. Kanner published his landmark paper in 1943 after he had observed 11 children who seemed to him to form a recognizable group. All had in common four traits: a preference for aloneness, an insistence on sameness, a liking for elaborate routines and some abilities that seemed remarkable compared with the deficits.

Concurrently, though quite independently, Hans Asperger of the University Pediatric Clinic in Vienna prepared his doctoral thesis on the same type of child. He also used the term “autism” to refer to the core features of the disorder. Both men borrowed the label from adult psychiatry, where it had been used to refer to the progressive loss of contact with the outside world experienced by schizophrenics. Autistic children seemed to suffer such a lack of contact with the world around them from a very early age.

Kanner’s first case, Donald, has long served as a prototype for diagnosis. It had been evident early in life that the boy was different from other children. At two years of age, he could hum and sing tunes accurately from memory. Soon he learned to count to 100 and to recite both the alphabet and the 25 questions and answers of the Presbyterian catechism. Yet he had a mania for making toys and other objects spin. Instead of playing like other toddlers, he arranged beads and other things in groups of different colors or threw them on the floor, delighting in the sounds they made. Words for him had a literal, inflexible meaning.

Donald was first seen by Kanner at age five. Kanner observed that the boy paid no attention to people around him. When someone interfered with his solitary activities, he was never angry with the interfering person but impatiently removed the hand that was in his way. His mother was the only person with whom he had any significant contact, and that seemed attributable mainly to the great effort she made to share activities with him. By the time Donald was about eight years old, his conversation consisted largely of repetitive questions. His relation to people remained limited to his immediate wants and needs, and his attempts at contact stopped as soon as he was told or given what he had asked for.

Some of the other children Kanner described were mute, and he found that even those who spoke did not really communicate but used language in a very odd way. For example, Paul, who was five, would parrot speech verbatim. He would say “You want candy” when he meant “I want candy.” He was in the habit of  repeating, almost every day, “Don’t throw the dog off the balcony,” an utterance his mother traced to an earlier incident with a toy dog.

Twenty years after he had first seen them, Kanner reassessed the members of his original group of children. Some of them seemed to have adapted socially much better than others, although their failure to communicate and to form relationships remained, as did their pedantry and single-mindedness. Two prerequisites for better adjustment, though no guarantees of it, were the presence of speech before age five and relatively high intellectual ability. The brightest autistic individuals had, in their teens, become uneasily aware of their peculiarities and had made conscious efforts to conform. Nevertheless, even the best adapted were rarely able to be self-reliant or to form friendships. The one circumstance that seemed to be helpful in all the cases was an extremely structured environment.

As soon as the work of the pioneers became known, every major clinic began to identify autistic children. It was found that such children, in addition to their social impairments, have substantial intellectual handicaps. Although many of them perform relatively well on certain tests, such as copying mosaic patterns with blocks, even the most able tend to do badly on test questions that can be answered only by the application of  common sense.

Next : Part 2
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by : Simon LeVay and Dean H. Hamer

At each marker, a pair of gay brothers was scored as concordant if they inherited identical markers from their mother or as discordant if they inherited different ones. Fifty percent of the markers were expected to be identical by chance. Corrections were also made for the possibility of the mother's having two copies of the same marker.

GENE SHARING in the Xq28 region is significantly greater in gay brothers than in the general population. Of 40 pairs of gay brothers studied, 33 pairs shared the Xq28 region. In a control group of 314 randomly selected pairs of brothers, Xq28 markers were found to be almost equally distributed.

The results of this study were striking. Over most of the X chromosome the markers were randomly distributed between the gay brothers. But at the tip of the long arm of the X chromosome, in a region known as Xq28, there was a considerable excess of concordant brothers: 33 pairs shared the same marker, whereas only seven pairs did not. Although the sample size was not large, the result was statistically significant: the probability of such a skewed ratio occurring by chance alone is less than one in 200. In a control group of 314 randomly selected pairs of brothers, most of whom can be presumed to be heterosexual, Xq28 markers were randomly distributed.

The most straightforward interpretation of the finding is that chromosomal region Xq28 contains a gene that influences male sexual orientation. The study provides the strongest evidence to date that human sexuality is influenced by heredity because it directly examines the genetic information, the DNA. But as with all initial studies, there are some caveats.

First, the result needs to be replicated: several other claims of finding genes related to personality traits have proved controversial. Second, the gene itself has not yet been isolated. The study locates it within a region of  the X chromosome that is about four million base pairs in length. This region represents less than 0.2 percent  of the total human genome, but it is still large enough to contain several hundred genes. Finding the needle in this haystack will require either large numbers of families or more complete information about the DNA sequence to identify all possible coding regions. As it happens, Xq28 is extraordinarily rich in genetic loci and will probably be one of the first regions of the human genome to be sequenced in its entirety.

A third caveat is that researchers do not know quantitatively how important a role Xq28 plays in male sexual orientation. Within the population of gay brothers studied, seven of 40 brothers did not share markers. Assuming that 20  siblings should inherit identical markers by chance alone, 36 percent of the gay brothers show no link between homosexuality and Xq28. Perhaps these men inherited diÝerent genes or were influenced by nongenetic physiological factors or by the environment. Among all gay men -most of whom do not have gay brothers- the influence of Xq28 is even less clear. Also unknown is the role of Xq28, and other genetic loci, in female sexual orientation.

How might a genetic locus at Xq28 affect sexuality? One idea is that the hypothetical gene affects hormone synthesis or metabolism. A candidate for such a gene was the androgen receptor locus, which encodes a protein essential for masculinization of the human brain and is, moreover, located on the X chromosome. To test this idea, Jeremy Nathans, Jennifer P. Macke, Van L. King and Terry R. Brown of Johns Hopkins
University teamed up with Bailey of Northwestern and Hamer, Hu and Hu of the NIH. They compared the molecular structure of the androgen receptor gene in 197 homosexual men and 213 predominantly heterosexual men. But no signiÞcant variations in the protein coding sequences were found. Also, linkage studies showed no correlation between homosexuality in brothers and inheritance of the androgen receptor locus. Most significant of all, the locus turned out to be at Xq11, far from the Xq28 region. This study  excludes the androgen receptor from playing a significant role in male sexual orientation.

A second idea is that the hypothetical gene acts indirectly, through personality or temperament, rather than directly on sexual-object choice. For example, people who are genetically selfreliant might be more likely to acknowledge and act on same-sex feelings than are people who are dependent on the approval of others.

Finally, the intriguing possibility arises that the Xq28 gene product bears directly on the development of sexually dimorphic brain regions such as INAH3. At the simplest level, such an agent could act autonomously, perhaps in the womb, by stimulating the survival of specific neurons in preheterosexual males or by promoting their death in females and prehomosexual men. In a more complex model, the gene product could change the sensitivity of a neuronal circuit in the hypothalamus to stimulation by environmental cues, perhaps in the first few years of life. Here the genes serve to predispose rather than to predetermine. Whether this fanciful notion  contains a grain of truth remains to be seen. It is in fact experimentally testable, using current tools of molecular genetics and neurobiology.

Our research has attracted an extraordinary degree of public attention, not so much because of any conceptual breakthrough -the idea that genes and the brain are involved in human behavior is hardly new- but  because it touches on a deep conflict in contemporary American society. We believe scientific research can help dispel some of the myths about homosexuality that in the past have clouded the image of lesbians and gay men. We also recognize, however, that increasing knowledge of biology may eventually bring with it the power to infringe on the natural rights of individuals and to impoverish the world of its human diversity. It is important that our society expand discussions of how new scientific information should be used to benefit the human race in its entirety.

by : Simon LeVay and Dean H. Hamer

PINPOINTING GENES shared by gay brothers (darker brown) first involved taking DNA from subjects. Several billion copies of speciÞc regions of the X chromosome were then made using the polymerase chain reaction, and the different fragments were separated by gel electrophoresis. Gay brothers shared a marker, in this hypothetical example CA11, in the Xq28 region at rates far greater than predicted by chance.

Why are most gay male relatives of gay men on the mother's side of the family? One possibility -that the subjects somehow knew more about their maternal relatives- seems unlikely because opposite-sex
gay relatives of gay males and lesbians were equally distributed between both sides of the family. Another explanation is that homosexuality, while being transmitted by both parents, is expressed only in one sex in this case, males. When expressed, the trait reduces the reproductive rate and must therefore be disproportionately passed on by the mother. Such an effect may partially account for the concentration of gay men's gay relatives on the maternal side of the family. But proof of this hypothesis will require Þnding an appropriate gene on an autosomal chromosome, which is inherited from either parent.

A third possibility is X chromosome linkage. A man has two sex chromosomes: a Y, inherited from his father, and an X, cut and pasted from the two X chromosomes carried by his mother. Therefore, any trait that is influenced by a gene on the X chromosome will tend to be inherited through the mother's side and will be preferentially observed in brothers, maternal uncles and maternal cousins, which is exactly the observed pattern.

To test this hypothesis, Hamer and his colleagues embarked on a linkage study of the X chromosome in gay men. Linkage analysis is based on two principles of genetics. If a trait is genetically influenced, then relatives who share the trait will share the gene more often than is expected by chance, this is true even if the gene plays only a small part.  Also, genes that are close together on a chromosome are almost always inherited together. Therefore, if there is a gene that influences sexual orientation, it should be 'linked' to a nearby DNA marker that tends to travel along with it in families. For traits affected by only one gene, linkage can precisely locate the gene on a chromosome. But for complex traits such as sexual orientation, linkage also helps to determine whether a genetic component really exists.

To initiate a linkage analysis of male sexual orientation, the first requirement was to find informative markers, segments of DNA that flag locations on a chromosome. Fortunately, the Human Genome Project has already generated a large catalogue of markers spanning all of the X chromosomes. The most useful ones are short, repeated DNA sequences that have slightly different lengths in different persons. To detect the markers, the researchers used the polymerase chain reaction to make several billion copies of specific regions of the chromosome and then separated the different fragments by the method of gel electrophoresis.

The second step in the linkage analysis was to locate suitable families. When scientists study simple traits such as color blindness or sickle cell anemia -which involve a single gene- they tend  to analyze large, multigenerational families in which each member clearly either has or does not have the trait. Such an approach was unsuited for studying sexual orientation. First, identifying someone as not homosexual is tricky; the person may be concealing his or her true orientation or may not be aware of it. Because homosexuality was even more stigmatized in the past, multigenerational families are especially problematic in this regard. Moreover, genetic modeling shows that for traits that involve several different genes expressed at varying levels, studying large families can actually decrease the chances of finding a linked gene: too many exceptions are included.

For these reasons, Hamer and his coworkers decided to focus on nuclear families with two gay sons. One advantage of this approach is that individuals who say they are homosexual are unlikely to be mistaken.  Furthermore, the approach can detect a single linked gene even if other genes or noninherited factors are required for its expression. For instance, suppose that being gay requires an X chromosome gene together with another gene on an autosome, plus some set of environmental circumstances. Studying gay brothers would give a clear-cut result because both would have the X chromosome gene. In contrast, heterosexual brothers of gay men would sometimes share the X chromosome gene and sometimes not, leading to confusing results.

Genetic analysts now believe that studying siblings is the key to traits that are aÝected by many elements. Because Hamer and his colleagues were most interested in Þnding a gene that expresses itself only in men but is transmitted through women, they restricted their search to families with gay men but no gay father-gay son  pairs.

Forty such families were recruited. DNA samples were prepared from the gay brothers and, where possible, from their mothers or sisters. The samples were typed for 22 markers that span the X chromosome from the tip of the short arm to the end of the long arm.

Next : Part 6

by : Simon LeVay and Dean H. Hamer




Twin and family tree studies are based on the principle that genetically influenced traits run in families. The first modern study on the patterns of homosexuality within families was published in 1985 by Richard C. Pillard and James D. Weinrich of Boston University. Since then, Þve other systematic studies on the twins and siblings of gay men and lesbians have been reported.

The pooled data for men show that about 57 percent of identical twins, 24 percent of fraternal twins and 13 percent of brothers of gay men are also gay. For women, approximately 50 percent of identical twins, 16 percent of fraternal twins and 13 percent of sisters of lesbians are also lesbian. When these data are compared with baseline rates of homosexuality, a good amount of family clustering of sexual orientation becomes evident for both sexes. In fact, J. Michael Bailey of Northwestern University and his co-workers estimate that the overall heritability of sexual orientation -that proportion of the variance in a trait that comes from genes- is about 53 percent for men and 52 percent for women. (The family clustering is most obvious for relatives of the same sex, less so for male-female pairs.)

To evaluate the genetic component of sexual orientation and to clarify its mode of inheritance, we need a systematic survey of the extended families of gay men and lesbians. One of us (Hamer), Stella Hu, Victoria L. Magnuson, Nan Hu and Angela M. L. Pattatucci of the National Institutes of Health have initiated such a study. It is part of a larger one by the National Cancer Institute to investigate risk factors for certain cancers that are more frequent in some segments of the gay population.

Hamer and his colleagues initial survey of males confirmed the sibling results of Pillard and Weinrich. A brother of a gay man had a 14 percent  likelihood of being gay as compared with 2 percent for the men without gay brothers. (The study used an unusually stringent deÞnition of homosexuality, leading to the low average rate.) Among more distant relatives, an unexpected pattern showed up: maternal uncles had a 7 percent chance of being gay, whereas sons of maternal aunts had an 8 percent chance. Fathers, paternal uncles and the three other types of cousins showed no correlation at all.

Although this study pointed to a genetic component, homosexuality occurred much less frequently than a single gene inherited in simple Mendelian fashion would suggest. One interpretation, that genes are more important in some families than in others, is borne out by looking at families having two gay brothers. Compared with randomly chosen families, rates of homosexuality in maternal uncles increased from 7 to 10 percent and in maternal cousins from 8 to 13 percent. This familial clustering, even in relatives outside the nuclear family, presents an additional argument for a genetic root to sexual orientation.

Next : Part 5

by : Simon LeVay and Dean H. Hamer

What might lie behind these apparent correlations between sexual orientation and brain structure? Logically, three possibilities exist. One is that the structural differences were present early in life -perhaps even before birth- and helped to establish the men's sexual orientation. The second is that the differences arose in adult life as a result of the men's sexual feelings or behavior. The third possibility is that there is no causal connection, but both sexual orientation and the brain structures in question are linked to some third variable, such as a developmental event during uterine or early postnatal life.

Family trees of male sexual orientation show the rates of homosexuality (darker brown) in maternally related males. Rates in paternal relatives were not significantly above the average population rate of 2 percent. This finding raised the possibility of involvement of the X chromosome (shown below). Males have two sex chromosomes—a Y inherited from the father and an X from the mother. Thus, a trait inherited through the mother’s side might logically be influenced by a gene on one of her X chromosomes (indicated here in red ). In fact, further experiments showed that one small area at the tip of the X chromosome— Xq28—was shared by a large percentage of gay brothers.

We cannot decide among these possibilities with any certainty. On the basis of animal research, however, we and the second scenario, that the structural differences came about in adulthood, unlikely. In rats, for example, the sexually dimorphic cell group in the medial preoptic area appears plastic in its response to androgens during early brain development but later is largely resistant to change. We favor the Þrst possibility, that the structural differences arose during the period of brain development and consequently contributed to sexual behavior. Because the medial preoptic region of the hypothalamus is implicated in sexual behavior in monkeys, the size of INAH3 in men may indeed influence sexual orientation. But such a causal connection is speculative at this point.

Assuming that some of the structural differences related to sexual orientation were present at birth in certain individuals, how did they arise? One candidate is the interaction between gonadal steroids and the developing brain; this interaction is responsible for differences in the structure of male and female brains. A number of  scientists have speculated that atypical levels of circulating androgens in some fetuses cause them to grow into homosexual adults. Specifically, they suggest that androgen levels are unusually low in male fetuses that become gay and unusually high in female fetuses that become lesbian.

A more likely possibility is that there are intrinsic differences in the way individual brains respond to androgens during development, even when the hormone levels are themselves no different. This response requires a complex molecular machinery, starting with the androgen receptors but presumably including a variety of  proteins and genes whose identity and roles are still unknown.

At first glance, the very notion of gay genes might seem absurd. How could genes that draw men or women to members of the same sex survive the Darwinian screening for reproductive fitness? Surely the parents of most gay men and lesbians are heterosexual? In view of such apparent incongruities, research focuses on genes that sway rather than determine sexual orientation. The two main approaches to seeking such genes are twin and family studies and DNA linkage analysis.

Next : Part 3