When my brother was diagnosed with autism in the 1960s, my mother was told that she was a “refrigerator mother,” too cold to bond with my brother, and that his autism was her fault. The doctor said she should try harder with her next child. Thank goodness those days are behind us. We know that autism is a genetic disorder, and we are learning more and more every day about the genes that cause autism. Important research is being done now to understand the causes of autism and to develop better treatments for people with autism.10
Once it became clear that autism has a biological basis, scientists could begin to refine our understanding of the disorder. They have found, for example, that the social interactions of people with less severe autism are guided by actual behavior, not by the intentions hidden in behavior. This makes it hard for those autistic people to spot ulterior motives and manipulation, a bit like the naïve young man playing cards in the painting in figure 2.4. Severely impaired autistic people are inherently straightforward and honest: they feel no pressure to conform to other people’s ideas and beliefs. Autistic people who function at a high level in social situations do feel pressure to conform, but they have no innate sense of how to do it. This lack of an internal social compass contributes to the depression and anxiety that children who are on the mild end of the autism spectrum often experience.
Learning about mental states such as believing, desiring, and intending does not eliminate problems with social communication; it just alleviates them. Even the most able, highly adapted people on the autism spectrum have some difficulty deciphering and interpreting mental states. They need time to do it. Written communications, such as e-mail, are easier than face-to-face interactions. Nevertheless, it would be a mistake to underestimate the stress and anxiety that most individuals on the autism spectrum experience in trying to fit into a world of neurotypical people.
Erin McKinney, who has autism, describes how she experiences the stresses caused by the disorder:
Autism makes my life loud. That’s the best adjective I have found. Everything is amplified. I don’t mean this only in terms of my sense of hearing, although that is one part of it. I feel loudly. A light touch feels not so light. A bright light feels brighter. A soft buzzing from a light feels thunderous. Instead of happy, I feel overwhelmed. Instead of sad, I feel overwhelmed. The general perception is that autistic people don’t feel empathy. I, along with most individuals on the spectrum, find the reverse is true.… Autism makes my life stressful. When everything is louder, situations tend to be a little more stressful.11
When she was first diagnosed with autism, McKinney says, she felt “very conflicted.” But soon, she felt thankful for having received the diagnosis and began the difficult, continuing work of coming to terms with it:
I live my life constantly on edge. And sometimes, I fall off the edge and a meltdown occurs. And that’s OK. Well, maybe it isn’t OK. But it has to be. I don’t have a choice.… I have to keep going. I work hard to notice when I see myself trending toward a meltdown, so I can change course. It has taken a lot of work for me to get to this point of self-awareness, but it still doesn’t work all the time.
… I do the same thing the same way every time. I count lots of things, notice things that most think are unimportant, and stress over tiny imperfections. I get thoughts stuck in my head, over and over and over again. Phrases, images, memories, patterns. These can all become overwhelming. I use them to my advantage as much as I can. I think this is part of why I am good at my job. And I am very good at my job. I notice the little things, the nuances that others tend to overlook. I find the pattern and I find it quickly.12
In reflecting on her life, McKinney concludes:
There is no doubt that autism makes my life difficult, but it also makes my life beautiful. When everything is more intense, then the everyday, the mundane, the typical, the normal—those things become outstanding. I can’t speak for you or anyone else, on the spectrum or not. Our experiences are all unique. Regardless, I do believe that it is important to find the beautiful. Recognize that there is bad, there is ugly, there is disrespect, there is ignorance, and there are meltdowns. Those things are inevitable. But there is also good.13
About 10 percent of people with autism have low IQ scores, but many have special talents for writing poetry, learning foreign languages, performing music, drawing and painting, calculating, or knowing the day of the week for any date in the calendar. In Bright Splinters of the Mind, a book about her research with autistic people, the experimental psychologist Beate Hermelin noted that autism researchers are continually fascinated with the remarkable talents displayed by these autistic savants.14 One of the best-known autistic savants is Nadia. When she was a young girl, between the ages of four and seven, Nadia made a number of drawings that were generally admired, even by professionals, and that compared in beauty to the cave paintings from thirty thousand years ago. We will discuss the creative capabilities of people with autism more fully in chapter 6.
THE ROLE OF GENES IN AUTISM
Scientists have known for years that genes play an extremely important role in autism. Studies of identical twins, who have the same genetic makeup, show that if one twin has autism, the chances are up to 90 percent that the other twin will be autistic. No other developmental disorder has as high a concordance between identical twins.
This startling finding has convinced many scientists that the quickest route to understanding the brain mechanisms involved in autism is to focus on the genetics of the disorder. Once scientists have scoped out the genetic landscape and understand what the risk factors are, they will be in a much better position to figure out where in the brain these genes are working. However, autism is not a simple one-gene, one-disease disorder. Many genes are likely to contribute to the risk of autism.
At the same time, we cannot rule out environmental factors, because all behavior is shaped by the interplay between genes and the environment. Even a mutation in a single gene that invariably causes a disease can be influenced strongly by the environment. Take phenylketonuria (PKU), a simple metabolic disease that babies are routinely tested for at birth. This rare genetic disorder affects one person in fifteen thousand and can result in severe impairment of cognitive functioning. People with the disease have two abnormal copies of the gene that is ultimately responsible for breaking down the amino acid phenylalanine, a component of protein in the foods we eat. (People with just one defective copy of the gene don’t develop PKU.) If the body can’t break down phenylalanine, it builds up in the blood, leading to the production of a toxic substance that interferes with normal brain development. Fortunately, mental retardation can be completely prevented by a simple, amazingly effective environmental intervention—restricting the amount of protein that people at risk of PKU eat.
Dramatic advances in our ability to study DNA at high resolution and in many people have begun to give scientists a clearer view of the genetic landscape. Those technological advances have transformed our understanding of how DNA varies among people and how some variations lead to disorders like those on the autism spectrum. Specifically, they have revealed two previously unknown types of genetic aberrations: copy number variations and de novo mutations. Both contribute to autism as well as to schizophrenia and other complex disorders produced by mutations in more than one gene.
COPY NUMBER VARIATIONS
We all have slight differences in the nucleotide sequences of our genes. (Nucleotides, as we learned in chapter 1, are the molecules that make up DNA.) These slight differences are called single-nucleotide variations (fig. 2.7). About a decade ago, scientists discovered that we may also have major differences in the structure of our chromosomes. These rare structural differences are known as copy number variations (fig. 2.8). We may be missing a small bit of DNA from a chromosome (a copy number deletion), or we may have an extra bit of DNA in a chromosome (a copy number duplication). Copy number variations may decrease or increase the number of genes on a chromosome by twenty to thirty genes, but in
either case they heighten the risk of autism spectrum disorders.
Copy number variations have given us a better understanding of the specific genes involved in autism, which in turn has afforded us a much better view of the molecular basis of social behavior. A case in point is copy number variations on chromosome 7. Matthew State, now at the University of California, San Francisco, has found that having an extra copy of one segment of chromosome 7 puts people at much greater risk of developing a disorder on the autism spectrum. When that same brain region is lost, however, the result is Williams syndrome.15
Williams syndrome is virtually the reverse of autism. Children with this genetic disorder are extremely social (fig. 2.9). They have a strong, almost irrepressible desire to speak and communicate. They are very friendly and trusting, even of strangers. Moreover, whereas some children with autism have strong drawing skills, children with Williams syndrome tend to be musical. In fact, children with Williams syndrome have difficulty constructing visuospatial relationships, which may account for their inability to draw well. Unlike children with autism, children with Williams syndrome have good language skills and do well with face recognition; they have no difficulty reading the emotions of others and gauging their intentions.
Figure 2.7. Single-nucleotide variation
Figure 2.8. Copy number variations: DNA deletion and duplication
Thomas Insel, formerly the director of the National Institute of Mental Health, argues that the contrast between autism and Williams syndrome suggests that our brain uses specific networks for specific types of functions, such as social interaction. Deficits in the functioning of the social network may lead the brain to compensate by developing expertise in a non-social network, resulting in the kinds of unusual abilities we see in autistic savants.16
Figure 2.9. Copy number variations: deletion of a particular segment on chromosome 7 causes Williams syndrome, whereas duplication of that segment increases the likelihood of developing an autism spectrum disorder.
The fact that this single segment, containing about twenty-five of the twenty-one thousand or so genes in our genome, could have such a profound influence on complex social behavior is astonishing. This kind of discovery gives scientists something very specific to pursue and should open important new avenues in developing treatments.
DE NOVO MUTATIONS
The second genetic aberration revealed by advances in technology is the recent discovery that not all mutations are present in the genomes of our parents. Some mutations arise spontaneously in the sperm of adult men. These rare spontaneous mutations are called de novo, or new, mutations, and a father can transmit them to his children. Four nearly simultaneous studies by scientists at Yale, the University of Washington, the Broad Institute at the Massachusetts Institute of Technology, and Cold Spring Harbor Laboratory have found that de novo mutations markedly increase the risk of autism.17
Moreover, the number of de novo mutations increases with paternal age. A recent study led by deCODE Genetics, a biotechnology company in Iceland, confirmed this finding using a genome-wide technique in which all of the DNA in a person’s genome, not just the portion coding for proteins, is studied.18 This is important because scientists have recently discovered that the noncoding DNA in our genome, formerly considered “junk,” may play a major role in complex diseases by switching genes on and off.
The reason de novo mutations increase with age is that sperm precursor cells divide every fifteen days. This continued division and copying of DNA leads to errors, and the rate of error increases significantly with age. Thus, a father who is twenty years old will have, on average, twenty-five de novo mutations in his sperm, whereas a father who is forty years old will have sixty-five mutations (fig. 2.10). Most of these mutations are harmless, but some are not: de novo mutations are now thought to contribute to at least 10 percent of autism cases. Mothers do not appear to contribute to autism by means of de novo mutations because egg cells, unlike sperm, do not divide and multiply throughout life; they are all generated before a woman is born.
De novo mutations are particularly interesting because the incidence of autism has increased substantially in recent years. A large part of this upswing is probably attributable to the fact that we are now much more aware of the disorder and are better at identifying it than we were fifty years ago. But another part of the explanation is that people are having children at a later age. We now know that older fathers are more prone to de novo mutations in their sperm and are therefore more likely to pass on these mutations—and thus a greater risk of autism—to their children.
We also have evidence that de novo mutations in an older father’s sperm contribute to schizophrenia (fig. 2.10) and to bipolar disorder. (As Bleuler observed a century ago, some of the same social difficulties that characterize autism are shared by people with schizophrenia.) Moreover, we know that schizophrenia and bipolar disorder are not caused by single genes. Thus the assortment of possible genetic culprits responsible for autism seems to be common to these psychiatric disorders as well. We don’t know exactly how many genes are capable of contributing to autism, but there are very likely at least fifty, and more likely hundreds, of such genes.
Figure 2.10. Paternal influence: researchers analyzed genetic material from seventy-eight Icelandic children and their parents, including forty-four children with autism. Children of older fathers tended to have a higher number of de novo mutations, which are not present in the genomes of either parent.
Finally, de novo mutations might account for another interesting feature of autism: the disorder is not dying out. Autistic adults are less likely to have children than neurotypical people, yet the number of children diagnosed with autism spectrum disorders each year has not dropped. De novo mutations in the sperm of fathers who do not have autism could be one reason for the persistence of autism in the population at large.
NEURAL CIRCUITS AS TARGETS FOR MUTATIONS
A recent study revealed that the brains of adolescents with autism have too many synapses.19 Ordinarily, the excess synapses in our brain—the synapses we don’t use—are removed in a process known as synaptic pruning, which begins quite early in childhood and peaks in adolescence and early adulthood. The finding of too many synapses indicates that not enough of them were pruned out, resulting in a thicket of neural connections rather than streamlined, efficient neural circuits. Interestingly, while autism involves insufficient synaptic pruning, schizophrenia involves excessive synaptic pruning, as we shall see in chapter 4.
The process of wiring the developing brain is extraordinarily complex and presents a wide-open opportunity for mistakes. Moreover, roughly half of our genes are active in the brain, and the formation of synapses between neurons requires a huge number of proteins to function normally. Proteins, you will recall, are synthesized according to instructions sent out by genes. If mutations in these genes disrupt the composition or operation of normal proteins at the synapse, a cascade of events results: synapses do not function properly, neurons cannot communicate with one another, and the neural circuits they form are disrupted.
The genetic mutations that contribute to autism spectrum disorders may be distributed anywhere on our twenty-three pairs of chromosomes. Regardless of where they are located, these mutations disturb neural circuits in the social brain, and those disturbances end up compromising theory of mind.
Some of the mutations play key roles in the working of synapses. In fact, de novo mutations occur more frequently in genes that code for synaptic proteins. This fact raises the exciting possibility that autism and other developmental disorders may be amenable to treatment. In other words, we may be able to treat a genetic disorder by fixing faulty synapses (fig. 2.11).
Figure 2.11. Hundreds of genes throughout the genome contribute to synaptic function. A mutation in any one or in a combination of those genes could result in a disorder such as autism. By developing drugs that target the synapse rather than particular genes, we may be able to treat these genetically complex
disorders.
This is a fundamental change in thinking. Rather than being conditions that are set in stone from birth, developmental disorders may prove to be reversible, or at least treatable throughout life.
GENETICS AND SOCIAL BEHAVIOR IN ANIMAL MODELS
Most animals spend at least part of their lives in association with others of their own kind. We acknowledge that reality in the way we talk about them—as schools of fish, flocks of geese, or hives of bees. Clearly, animals recognize one another, communicate with one another, and generate coherent behavior. The naturalist E. O. Wilson noticed that many of the social behaviors of animals are similar, even in animals that are very different. When anyone makes an observation like that in biology, it usually means that the underlying genetics are very ancient and that they are contributing to the same output in many different animals. In fact, almost all of our own genes are present in other animals.
Because both social behavior and genes are conserved through evolution, scientists studying the genetic underpinnings of behavior often turn to simple animals such as the tiny worm Caenorhabditis elegans and the fruit fly Drosophila. Cori Bargmann, a geneticist at The Rockefeller University, who now heads the Chan Zuckerberg Initiative, studies C. elegans, which lives in the soil and eats bacteria. Most members of this species want to spend their time with their fellow worms. Although they sometimes wander off by themselves, they always come back and join the group. This behavior is not about food—food is available everywhere—and it’s not about mating. The animals are social; they simply like to associate with one another.
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