The
Secrets of Autism
The number of children diagnosed with
autism and Asperger's in the U.S. is exploding. Why?
By
J.
Madeleine Nash
Tommy Barrett is a dreamy-eyed
fifth-grader who lives with his parents, twin brothers, two cats and
a turtle in San Jose, Calif., the heart of Silicon Valley. He's an
honor-roll student who likes math and science and video games. He's
also a world-class expert on Animorph and Transformer toys. "They're
like cars and trains and animals that transform into robots or
humans I love them!" he shouts exuberantly.
And that is sometimes a problem. For
a time, in fact, Tommy's fascination with his toys was so strong
that when they weren't around he would pretend to be the toys,
transforming from a truck into a robot or morphing into a kitten. He
would do this in the mall, in the school playground and even in the
classroom. His teachers found this repetitive pantomime delightful
but disturbing, as did his mother Pam. By that point, there were
other worrisome signs. Pam Barrett recalls that as a 3-year-old,
Tommy was a fluent, even voluble talker, yet he could not seem to
grasp that conversation had reciprocal rules, and, curiously, he
avoided looking into other people's eyes. And although Tommy was
obviously smart he had learned to read by the time he was 4 he
was so fidgety and unfocused that he was unable to participate in
his kindergarten reading group.
When Tommy turned 8, his parents
finally learned what was wrong. Their bright little boy, a
psychiatrist informed them, had a mild form of autism known as
Asperger syndrome. Despite the fact that children with Asperger's
often respond well to therapy, the Barretts, at that moment, found
the news almost unbearable.
That's because just two years earlier
Pam and her husband Chris, operations manager of a software-design
company, had learned that Tommy's twin brothers Jason and Danny were
profoundly autistic. Seemingly normal at birth, the twins learned to
say a few words before they spiraled into their secret world,
quickly losing the abilities they had just started to gain. Instead
of playing with toys, they broke them; instead of speaking, they
emitted an eerie, high-pitched keening.
First Jason and Danny, now Tommy. Pam
and Chris started to wonder about their children's possible exposure
to toxic substances. They started scanning a lengthening roster of
relatives, wondering how long autism had shadowed their family.
The anguish endured by Pam and Chris
Barrett is all too familiar to tens of thousands of families across
North America and other parts of the world. With a seeming
suddenness, cases of autism and closely related disorders like
Asperger's are exploding in number, and no one has a good
explanation for it. While many experts believe the increase is a
by-product of a recent broadening of diagnostic criteria, others are
convinced that the surge is at least in part real and thereby cause
for grave concern.
In the Barretts' home state of
California, for instance, the number of autistic children seeking
social services has more than quadrupled in the past 15 years, from
fewer than 4,000 in 1987 to nearly 18,000 today. So common are cases
of Asperger's in Silicon Valley, in fact, that Wired magazine coined
a cyber-age term for the disorder, referring to its striking
combination of intellectual ability and social cluelessness as the
"geek syndrome." Wired went on to make a provocative if anecdotal
case that autism and Asperger's were rising in Silicon Valley at a
particularly alarming rate and asked
whether "math-and-tech genes" might be to blame.
Yet the rise in autism and Asperger's
is hardly confined to high-tech enclaves or to the children of
computer programmers and software engineers. It occurs in every job
category and socioeconomic class and in every state. "We're getting
calls from school systems in rural Georgia," observes Sheila Wagner,
director of the Autism Resource Center at Atlanta's Emory
University. "People are saying, 'We never had any kids with autism
before, and now we have 10! What's going on?'"
It's a good question. Not long ago,
autism was assumed to be comparatively rare, affecting as few as 1
in 10,000 people. The latest studies, however, suggest that as many
as 1 in 150 kids age 10 and younger may be affected by autism or a
related disorder a total of nearly 300,000 children in the U.S.
alone. If you include adults, according to the Autism Society of
America, more than a million people in the U.S. suffer from one of
the autistic disorders (also known as pervasive developmental
disorders or pdds). The problem is five times as common as Down
syndrome and three times as common as juvenile diabetes.
No wonder parents are besieging the
offices of psychologists and psychiatrists in their search for
remedies. No wonder school systems are adding special aides to help
teachers cope. And no wonder public and private research
institutions have launched collaborative initiatives aimed at
deciphering the complex biology that produces such a dazzling range
of disability.
In their urgent quest for answers,
parents like the Barretts are provoking what promises to be a
scientific revolution. In response to the concerns they are raising,
money is finally flowing into autism research, a field that five
years ago appeared to be stuck in the stagnant backwaters of
neuroscience. Today dozens of scientists are racing to identify the
genes linked to autism. Just last month, in a series of articles
published by Molecular Psychiatry, scientists from the U.S.,
Britain, Italy and France reported that they are beginning to make
significant progress.
Meanwhile, research teams are
scrambling to create animal models for autism in the form of mutant
mice. They are beginning to examine environmental factors that might
contribute to the development of autism and using advanced
brain-imaging technology to probe the deep interior of autistic
minds. In the process, scientists are gaining rich new insights into
this baffling spectrum of disorders and are beginning to float
intriguing new hypotheses about why people affected by it develop
minds that are strangely different from our own and yet, in some
important respects, hauntingly similar.
AUTISM'S GENETIC ROOTS
Autism was first described in 1943 by Johns Hopkins psychiatrist Leo
Kanner, and again in 1944 by Austrian pediatrician Hans Asperger.
Kanner applied the term to children who were socially withdrawn and
preoccupied with routine, who struggled to acquire spoken language
yet often possessed intellectual gifts that ruled out a diagnosis of
mental retardation. Asperger applied the term to children who were
socially maladroit, developed bizarre obsessions and yet were highly
verbal and seemingly quite bright. There was a striking tendency,
Asperger noted, for the disorder to run in families, sometimes
passing directly from father to son. Clues that genes might be
central to autism appeared in Kanner's work as well.
But then autism research took a badly
wrong turn. Asperger's keen insights languished in Europe's postwar
turmoil, and Kanner's were overrun by the Freudian juggernaut.
Children were not born autistic, experts insisted, but became that
way because their parents, especially mothers, were cold and
unnurturing.
In 1981, however, British
psychiatrist Dr. Lorna Wing published an influential paper that
revived interest in Asperger's work. The disorder Asperger
identified, Wing observed, appeared in many ways to be a variant of
Kanner's autism, so that the commonalities seemed as important as
the differences. As a result, researchers now believe that Asperger
and Kanner were describing two faces of a highly complicated and
variable disorder, one that has its source in the kaleidoscope of
traits encoded in the human genome. Researchers also recognize that
severe autism is not always accompanied by compensatory intellectual
gifts and is, in fact, far likelier to be characterized by
heartbreaking deficits and mental retardation.
Perhaps the most provocative finding
scientists have made to date is that the components of autism, far
more than autism itself, tend to run in families. Thus even though
profoundly autistic people rarely have children, researchers often
find that a close relative is affected by some aspect of the
disorder. A sister may engage in odd repetitive behavior or be
excessively shy; a brother may have difficulties with language or be
socially inept to a noticeable degree. In similar fashion, if one
identical twin has autism, there is a 60% chance that the other will
too and a better than 75% chance that the twin without autism will
exhibit one or more autistic traits.
How many genes contribute to
susceptibility to autism? Present estimates run from as few as three
to more than 20. Coming under intensifying scrutiny, as the papers
published by Molecular Psychiatry indicate, are genes that regulate
the action of three powerful neurotransmitters: glutamate, which is
intimately involved in learning and memory, and serotonin and gamma-aminobutiric
acid (gaba), which have been implicated in obsessive-compulsive
behavior, anxiety and depression.
Those genes hardly exhaust the list
of possibilities. Among the suspects are virtually all the genes
that control brain development and perhaps cholesterol and
immune-system function as well. Christopher Stodgell, a
developmental toxicologist at New York's University of Rochester,
observes that the process that sets up the brain resembles an
amazingly intricate musical score, and there are tens of thousands
of genes in the orchestra. If these genes do what they're supposed
to do, says Stodgell, "then you have a Mozart's Concerto for
Clarinet. If not, you have cacophony."
A DIFFERENCE OF MIND
Autistic people often suffer from a bewildering array of problems
sensory disturbances, food allergies, gastrointestinal problems,
depression, obsessive compulsiveness, subclinical epilepsy,
attention-deficit hyperactivity disorder. But there is, researchers
believe, a central defect, and that is the difficulty people across
the autistic spectrum have in developing a theory of mind. That's
psychologese for the realization, which most children come to by the
age of 4, that other people have thoughts, wishes and desires that
are not mirror images of their own. As University of Washington
child psychologist Andrew Meltzoff sees it, the developmental stage
known as the terrible twos occurs because children normal
children, anyway make the hypothesis that their parents have
independent minds and then, like proper scientists, set out to test
it.
Children on the autistic spectrum,
however, are "mind blind"; they appear to think that what is in
their mind is identical to what is in everyone else's mind and that
how they feel is how everyone else feels. The notion that other
people parents, playmates, teachers may take a different view of
things, that they may harbor concealed motives or duplicitous
thoughts, does not readily occur. "It took the longest time for
Tommy to tell a lie," recalls Pam Barrett, and when he finally did,
she inwardly cheered.
Meltzoff believes that this lack can
be traced to the problem that autistic children have in imitating
the adults in their lives. If an adult sits down with a normal
18-month-old and engages in some interesting behavior pounding a
pair of blocks on the floor, perhaps, or making faces the child
usually responds by doing the same. Young children with autism,
however, do not, as Meltzoff and his colleague Geraldine Dawson have
shown in a series of playroom experiments.
The consequences of this failure can
be serious. In the early years of life, imitation is one of a
child's most powerful tools for learning. It is through imitation
that children learn to mouth their first words and master the rich
nonverbal language of body posture and facial expression. In this
way, Meltzoff says, children learn that drooping shoulders equal
sadness or physical exhaustion and that twinkling eyes mean
happiness or perhaps mischievousness.
For autistic people even
high-functioning autistic people the ability to read the internal
state of another person comes only after long struggle, and even
then most of them fail to detect the subtle signals that normal
individuals unconsciously broadcast.
"I had no idea that other people communicated through subtle eye
movements," says autistic engineer Temple Grandin, "until I read
it in a magazine five years ago."
At the same time, it is incorrect to
say autistic people are cold and indifferent to those around them
or, as conventional wisdom once had it, lack the high-level trait
known as empathy. Last December, when Pam Barrett felt overwhelmed
and dissolved into tears, it was Danny, the most deeply autistic of
her children, who rushed to her side and rocked her back and forth
in his arms.
Another misperception about people
with autism, says Karen Pierce, a neuroscientist at the University
of California at San Diego, is the notion that they do not register
faces of loved ones as special that, in the words of a prominent
brain expert, they view their own mother's face as the equivalent of
a paper cup. Quite the contrary, says Pierce, who has results from a
neuroimaging study to back up her contention. Moreover, the center
of activity in the autistic mind, she reported at a conference held
in San Diego last November, turns out to be the fusiform gyrus, an
area of the brain that in normal people specializes in the
recognition of human faces.
In a neuroimaging study, Pierce
observed, the fusiform gyrus in autistic people did not react when
they were presented with photographs of strangers, but when
photographs of parents were substituted, the area lit up like an
explosion of Roman candles. Furthermore, this burst of activity was
not confined to the fusiform gyrus but, as in normal subjects,
extended into areas of the brain that respond to emotionally loaded
events. To Pierce, this suggests that as babies, autistic people are
able to form strong emotional attachments, so their social aloofness
later on appears to be the consequence of a brain disorganization
that worsens as development continues.
In so many ways, study after study
has found, autistic people do not parse information as others do.
University of Illinois psychologist John Sweeney, for example, has
found that activity in the prefrontal and parietal cortex is far
below normal in autistic adults asked to perform a simple task
involving spatial memory. These areas of the brain, he notes, are
essential to planning and problem solving, and among their jobs is
keeping a dynamically changing spatial map in a cache of working
memory. As Sweeney sees it, the poor performance of his autistic
subjects of the task he set for them keeping tabs on the location
of a blinking light suggests that they may have trouble updating
that cache or accessing it in real time.
To Sweeney's collaborator, University
of Pittsburgh neurologist Dr. Nancy Minshew, the images Sweeney has
produced of autistic minds in action are endlessly evocative. They
suggest that essential connections between key areas of the brain
either were never made or do not function at an optimal level. "When
you look at these images, you can see what's not there," she says,
conjuring up an experience eerily akin to looking at side-by-side
photographs of Manhattan with and without the Twin Towers.
A MATTER OF MISCONNECTIONS
Does autism start as a glitch in one area of the brain the
brainstem, perhaps and then radiate out to affect others? Or is it
a widespread problem that becomes more pronounced as the brain is
called upon to set up and utilize increasingly complex circuitry?
Either scenario is plausible, and experts disagree as to which is
more probable. But one thing is clear: very early on, children with
autism have brains that are anatomically different on both
microscopic and macroscopic scales.
For example, Dr. Margaret Bauman, a
pediatric neurologist at Harvard Medical School, has examined
postmortem tissue from the brains of nearly 30 autistic individuals
who died between the ages of 5 and 74. Among other things, she has
found striking abnormalities in the limbic system, an area that
includes the amygdala (the brain's primitive emotional center) and
the hippocampus (a seahorse-shaped structure critical to memory).
The cells in the limbic system of autistic individuals, Bauman's
work shows, are atypically small and tightly packed together,
compared with the cells in the limbic system of their normal
counterparts. They look unusually immature, comments University of
Chicago psychiatrist Dr. Edwin Cook, "as if waiting for a signal to
grow up."
An intriguing abnormality has also
been found in the cerebellum of both autistic children and adults.
An important class of cells known as Purkinje cells (after the Czech
physiologist who discovered them) is far smaller in number. And
this, believes neuroscientist Eric Courchesne, of the University of
California at San Diego, offers a critical clue to what goes so
badly awry in autism. The cerebellum, he notes, is one of the
brain's busiest computational centers, and the Purkinje cells are
critical elements in its data-integration system. Without these
cells, the cerebellum is unable to do its job, which is to receive
torrents of information about the outside world, compute their
meaning and prepare other areas of the brain to respond
appropriately.
Several months ago, Courchesne
unveiled results from a brain-imaging study that led him to propose
a provocative new hypothesis. At birth, he notes, the brain of an
autistic child is normal in size. But by the time these children
reach 2 to 3 years of age, their brains are much larger than normal.
This abnormal growth is not uniformly distributed. Using mri-imaging
technology, Courchesne and his colleagues were able to identify two
types of tissue where this mushrooming in size is most pronounced.
These are the neuron-packed gray
matter of the cerebral cortex and white matter, which contains the
fibrous connections projecting to and from the cerebral cortex and
other areas of the brain, including the cerebellum. Perhaps,
Courchesne speculates, it is the signal overload caused by this
proliferation of connections that injures the Purkinje cells and
ultimately kills them. "So now," says Courchesne, "a very
interesting question is, What's driving this abnormal brain growth?
If we could understand that, then we might be able to slow or stop
it."
A proliferation of connections
between billions of neurons occurs in all children, of course. A
child's brain, unlike a computer, does not come into the world with
its circuitry hard-wired. It must set up its circuits in response to
a sequence of experiences and then solder them together through
repeated neurological activity. So if Courchesne is right, what
leads to autism may be an otherwise normal process that switches on
too early or too strongly and shuts off too late and that process
would be controlled by genes.
Currently Courchesne and his
colleagues are looking very closely at specific genes that might be
involved. Of particular interest are the genes encoding four
brain-growth regulators that have been found in newborns who go on
to develop mental retardation or autism. Among these compounds, as
National Institutes of Health researcher Dr. Karin Nelson and her
colleagues reported last year, is a potent molecule known as
vasoactive intestinal peptide. vip plays a role not only in brain
development but in the immune system and gastrointestinal tract as
well, a hint that other disorders that so frequently accompany
autism may not be coincidental.
The idea that there might be early
biomarkers for autism has intrigued many researchers, and the reason
is simple. If one could identify infants at high risk, then it might
become possible to monitor the neurological changes that presage the
onset of behavioral symptoms, and someday perhaps even intervene in
the process. "Right now," notes Michael Merzenich, a neuroscientist
at the University of California, San Francisco, "we study autism
after the catastrophe occurs, and then we see this bewildering array
of things that these kids can't do. What we need to know is how it
all happened."
The genes that set the stage for
autistic disorders could derail developing brains in a number of
ways. They could encode harmful mutations like those responsible for
single-gene disorders cystic fibrosis, for instance, or
Huntington's disease. They could equally well be garden-variety
variants of normal genes that cause problems only when they combine
with certain other genes. Or they could be genes that set up
vulnerabilities to any number of stresses encountered by a child.
A popular but still unsubstantiated
theory
blames autism on the MMR (measles, mumps and rubella) vaccine, which
is typically given to children at around 15 months. But there
are many other conceivable culprits. Researchers at the University
of California at Davis have just launched a major epidemiological
study that will test the tissues of both autistic and nonautistic
children for residues of not only mercury but also pcbs, benzene and
other heavy metals. The premise is that some children may be
genetically more susceptible than others to damage by these agents,
and so the study will also measure a number of other genetic
variables, like how well these children metabolize cholesterol and
other lipids.
Drugs taken by some pregnant women
are also coming under scrutiny. At the University of Rochester,
embryologist Patricia Rodier and her colleagues are exploring how
certain teratogens (substances that cause birth defects) could lead
to autism. They are focusing on the teratogens' impact on a gene
called hoxa1, which is supposed to flick on very briefly in the
first trimester of pregnancy and remain silent ever after. Embryonic
mice in which the rodent equivalent of this gene has been knocked
out go on to develop brainstems that are missing an entire layer of
cells.
In the end, it is not merely possible
but likely that scientists will discover multiple routes some
rare, some common; some purely genetic, some not that lead to
similar end points. And when they do, new ideas for how to prevent
or correct autism may quickly materialize. A decade from now, there
will almost certainly be more effective forms of therapeutic
intervention, perhaps even antiautism drugs. "Genes," as the
University of Chicago's Cook observes, "give you targets, and we're
pretty good at designing drugs if we know the targets."
Paradoxically, the very thing that is
so terrible about autistic disorders that they affect the very
young also suggests reason for hope. Since the neural connections
of a child's brain are established through experience, well-targeted
mental exercises have the potential to make a difference. One of the
big unanswered questions, in fact, is why 25% of children with
seemingly full-blown autism benefit enormously from intensive
speech- and social-skills therapy and why the other 75% do not. Is
it because the brains of the latter are irreversibly damaged,
wonders Geraldine Dawson, director of the University of Washington's
autism center, or is it because the fundamental problem is not being
adequately addressed?
The more scientists ponder such
questions, the more it seems they are holding pieces of a puzzle
that resemble the interlocking segments of Tommy Barrett's
Transformer toys. Put the pieces together one way, and you end up
with a normal child. Put them together another way, and you end up
with a child with autism. And as one watches Tommy's fingers
rhythmically turning a train into a robot, a robot into a train, an
unbidden thought occurs. Could it be that some dexterous sleight of
hand could coax even profoundly autistic brains back on track? Could
it be that some kid who's mesmerized by the process of
transformation will mature into a scientist who figures out the
trick?
With reporting by Amy Bonesteel/Atlanta
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