The devastating derangements of autism also
show up in the gut and in the immune system. That unexpected discovery is
sparking new treatments that target the body in addition to the brain.
“There were days I considered shutting the
garage door and letting the car run until I was dead,” says Colorado mom Erin
Griffin, of the time nine years ago when she learned that both her boys—not
just her firstborn—suffered from autism.
Brendan, her angular, dark-haired older child, was diagnosed in 1996 at age 4.
Kyle, her round-faced, hazel-eyed younger son, was diagnosed in 1998 at age
2½. But Kyle and Brendan’s story does
not have a tragic ending. After
interventions that included occupational and speech therapy, as well as dietary
change and nutritional supplements, both boys improved significantly. Their
tale of slow, steady recovery reflects the changing landscape of autism today.
The condition, traditionally seen as genetic and originating in the brain, is
starting to be viewed in a broader and very different light, as a possible
immune and neuroinflammatory disorder.
As a result, autism is beginning to look like a condition that can, in
some and perhaps many cases, be successfully treated.
That is
astonishing news about a disorder that usually makes headlines because it seems
to be growing rapidly more widespread.
In the United States, the diagnosis of autism spectrum disorders has increased about tenfold
over the past two decades, and a 2003 report by the Centers for Disease Control
suggests that as many as one in every
166 children is now on the autism spectrum, while another one in six
suffers from a neurodevelopmental delay. This explosion of cases has raised
countless questions: Is the increase real, is it the result of increased
awareness and expanding diagnostic categories, is it due to environmental
changes, or all of the above? There may
be no single answer. But the public
concern about autism has caught the ear of federal lawmakers. The Combating
Autism Act, approved last December, authorized nearly $1 billion over the
next four years for autism-related research and intervention.
Meanwhile,
on the sidelines of that confusing discussion, a disparate group—immunologists,
naturopaths, neuroscientists, and toxicologists—is turning up clues that are
yielding novel strategies to help autistic patients. New studies are examining
contributing factors ranging from vaccine reactions to atypical growth in the
placenta, abnormal tissue in the gut, inflamed tissue in the brain, food
allergies, and disturbed brain wave synchrony. Some clinicians are using
genetic test results to recommend unconventional nutritional therapies, and
others employ drugs to fight viruses and quell inflammation.
Above all,
there is a new emphasis on the interaction between vulnerable genes and
environmental triggers, along with a growing sense that low-dose, multiple
toxic and infectious exposures may be a major contributing factor to autism and
its related disorders. A vivid analogy is that genes load the gun, but
environment pulls the trigger. “Like cancer, autism is a very complex disease,”
says Craig
Newschaffer, chairman of Epidemiology and Biostatistics at the Drexel
University School of Public Health, “and it’s exciting to start asking
questions about the interaction between genes and environment. There’s really a
very rich array of potential exposure variables.”
In one
way, the field seems like a free-for-all, staggeringly disordered because it is
littered with so many possibilities. But one can distill a few revolutionary
insights. First, autism may not be rigidly determined but instead may be
related to common gene variants, called polymorphisms, that may be derailed by
environmental triggers. Second, affected genes may disturb fundamental pathways
in the body and lead to chronic inflammation across the brain, immune system,
and digestive system. Third, inflammation is treatable.
“I can’t think of it as a
coincidence anymore that so many autistic kids have a history of allergies,
eczema, or chronic diarrhea.”
“In spite
of so many years of assumptions that a brain disorder like this is not
treatable, we’re helping kids get better. So it can’t just be genetic,
prenatal, hardwired, and hopeless,” says Harvard pediatric neurologist Martha Herbert, author of a 14,000-word
paper in the journal Clinical Neuropsychiatry that reconceptualizes the
universe of autism, pulling the brain down from its privileged perch as an
organ isolated from the rest of the body. Herbert is well suited to this task,
a synthetic thinker who wrote her dissertation on the developmental
psychologist Jean Piaget and who then went to medical school late, in her early
thirties. “I no longer see autism as a
disorder of the brain but as a disorder that affects the brain,” Herbert says.
“It also affects the immune system and the gut. One very striking piece of
evidence many of us have noticed is that when autistic children go in for
certain diagnostic tests and are told not to eat or drink anything ahead of
time, parents often report their child’s symptoms improve—until they start
eating again after the procedure. If symptoms can improve in such a short time
frame simply by avoiding exposure to foods, then we’re looking at some kind of
chemically driven ‘software’—perhaps immune system signals—that can change fast.
This means that at least some of autism probably comes from a kind of metabolic
encephalopathy—a systemwide process that affects the brain, just like cirrhosis
of the liver affects the brain.”
In 1943 Johns Hopkins University psychiatrist Leo Kanner first described
autism as a now-famous collection of symptoms: poor social engagement, limited
verbal and nonverbal communication, and repetitive behaviors. Back then, autism
was considered rare; Kanner first reported on just 11 patients, and Johns
Hopkins still has records of about 150 patients he examined in total. Even within this small group of patients,
other, less visible symptoms were evident. In his 1943 paper, “Autistic
Disturbances of Affective Contact,” Kanner noted immune and digestive problems
but did not include them in the diagnosis.
One reads with a shiver sentences lifted out of various case histories:
“large and ragged tonsils . . . she was tube-fed five times daily . . . he
vomited all food from birth through the third month . . . he suffered from
repeated colds and otitis media. . . .”
Herbert believes that the clues linking the obvious behavioral symptoms to more basic, but less obvious, biological dysfunction were missed early on. “What I believe is happening is that genes and environment interact, either in a fetus or young child, changing cellular function all over the body, which then affects tissue and metabolism in many vulnerable organs. And it’s the interaction of this collection of troubles that leads to altered sensory processing and impaired coordination in the brain. A brain with these kinds of problems Herbert’s full-body perspective helps make sense of the confusion surrounding the diagnosis of autism and helps justify the increasingly common use of the plural “autisms” to describe the wide variations in this disorder. As Newschaffer points out, “Children with Asperger’s syndrome certainly share a lot of the behaviors of those with more severe autism. But is it the same disease, and is it caused by the same thing? A number of significant features of autism are not part of the diagnostic schema right now, but eventually, those features may end up distinguishing one causal pathway from another. How is a child sleeping? Does he or she have gastrointestinal symptoms? By looking at those things we may see risk-factor associations pop out that we’ve never seen before.”
Herbert likens autism to a hologram: “Everything that
fascinates me is in it. It’s got epidemiology, toxicology, philosophy of
science, biochemistry, genetics, systems theory, the collapse of the medical
system, and the failure of managed care. Each child that walks through my door
is a challenge to everything I ever knew, and each child forces me to think
outside the box and between categories.”
Each child’s path to autism may be distinct, she says, but they may
share common inflammatory abnormalities. She has shown through morphometric
brain imaging that white matter—which carries impulses between neurons—is
larger in children with autism. “It was
the most absolutely outstanding piece of information in all the brain data I
looked at,” Herbert recalls of the years 2001 and 2002, when she was analyzing
this brain imaging data. “People were saying, don’t look at the white matter,
look at the cerebral cortex, but I knew we had an important finding.”
Could white matter become chronically inflamed? It may well
be, according to new research from Carlos Pardo, a
neurologist at Johns Hopkins. In a 2005 study in the Annals of Neurology, he
found inflammation in immune-responsive brain cells of autistic patients.
“Patients with autism report lots of immunological problems. We looked for the
fingerprints of those problems in the brain,” says Pardo. “We had brain tissue
from autistic individuals as young as 5 and as old as 45 and we found
neuroglial inflammation in all of them. Neuroglia are a group of brain cells
that are important in the brain’s immune response. This inflammatory reaction
appears to happen both early and late in the course of the disorder. If it
happens early, it could dramatically influence brain development. We’re very
excited about this research because one potential treatment approach, then, is
to downregulate the brain’s immune response.”
To study that approach, Pardo is collaborating on a pilot study funded
by the NIH to test minocycline, an anti-inflammatory antibiotic drug, on
autistic children. “Minocycline is a
very selective downregulator of microglial inflammation,” he says.
“Neurologists already use it in multiple sclerosis and Parkinson’s.”
“What we’ve got here is a far more comprehensive set of
characteristics for autism,” says Herbert, “one that can include behavior,
cognition, sensorimotor, gut, immune, brain, and endocrine abnormalities. These
are ongoing problems, and they’re not confined just to the brain. I can’t think
of it as a coincidence anymore that so many autistic kids have a history of
food and airborne allergies, or 20 or 30 ear infections, or eczema, or chronic
diarrhea.”
All this marks a Copernican-scale shift in our approach to
the disorder. I myself was irresistibly drawn to the subject when viewing an
online video of a heavily affected 11-year-old who, after a series of chelation
treatments to remove mercury, announced to his mother, “Mom, I’m back from the
living dead.” The statement was heartbreaking in its simple eloquence. Mercury
chelation, in this particular child’s case, was a near panacea.
Lisa Beck, of Oviedo, Florida, tells a similar story. Her
son Joshua was diagnosed with autism in 2004 at about age 2. After 18 intensive
months of treatment that involved chelation—a treatment that draws heavy metals
out of the body—and dietary changes, among other therapies, Josh appears
neurotypical. “We took him to Dr. Leslie Gavin, a specialist at Nemours
Children’s Clinic, who administers the ADOS test, a diagnostic test to see
where on the spectrum a child falls,” she says. “After the two-hour evaluation,
Gavin said he did not meet the criteria for autism. In her words, he was
‘responsive, curious, and active, able to engage in the test without a problem,
able to express himself clearly.’ ”
But, fascinating anecdotes aside, does hard evidence exist
of specific vulnerability genes or how they might impair the immune system,
brain, and gut—and most important, do we have any rational, reliable approaches
to help repair the damage? The answer
is a provisional yes.
“We’re beginning to understand that genetics is
really about vulnerability,” says neuroscientist Pat
Levitt, director of the Vanderbilt Kennedy Center for Research on Human
Development. Levitt and his colleagues recently discovered that a common
variant of a gene called MET doubles the risk of autism. The finding was widely
regarded as a breakthrough because MET modulates the nervous system, gut, and
immune system—just the kind of finding that matches up with the emerging new
view of autism.
“Everyone was focusing on genes expressed in the brain,”
says Levitt, “but this gene is important for repair of the intestine and immune
function. And that’s really intriguing because a subset of autistic children
have digestive and immune problems.” Equally interesting is that the gene
variant occurs in 47 percent of the population—in other words, it is just one
contributing factor, and it probably works in concert with other vulnerability
genes. And finally, in a twist that intrigues other researchers, the activity
of the gene is affected by what is known as oxidative stress—the kind of damage
one sees with excessive exposure to toxins. “As we identify other vulnerability
genes like this,” says Levitt, who hopes to engineer a mouse model of this gene
variant for study, “we may be able to develop effective interventions for
children.”
In other provocative research, Jill James,
director of the Autism Metabolic Genomics Laboratory at the Arkansas Children’s
Hospital Research Institute (and professor of pediatrics at the University of
Arkansas for Medical Sciences) has found that many children with autism do not
make as much of a compound called glutathione as neurotypical children do.
Glutathione is the cell’s most abundant antioxidant, and it is crucial for
removing toxins. If cells lack sufficient antioxidants, they experience
oxidative stress, which is often found with chronic inflammation.
In her most recent
study, published in the American Journal of Medical Genetics in 2006, James
found that common gene variants that support the glutathione pathway may be
associated with autism risk. Intriguingly, this pathway is linked metabolically
to the methylation pathway. Methylation is a fundamental biochemical process
that helps regulate which genes are expressed; abnormal methylation can cause
disease. Because the pathway provides the precursors to glutathione,
impairments in methylation can also lead to oxidative stress. “It’s very
provocative,” James says. “It suggests that some autistic behaviors are a
neurologic manifestation of a genetically based systemic, metabolic
derangement.” Some of the abnormalities James saw in this study have already
been associated with gastrointestinal and immunologic dysfunction.
The good news is that oxidative stress in some autistic
children may be treatable with targeted nutritional intervention. James and her
colleagues have tracked eight autistic children who were taking supplements of
key nutrients in the methylation pathway—folinic acid, trimethylglycine, and
methyl-B12—and found a significant increase in important markers of methylation
and glutathione synthesis. The next step is to see if the symptoms improve as
well.
James and her colleagues just received a $2.4 million grant
from the NIH, part of which will be devoted to sorting out the relationship
between metabolism, genes, and behavior. ”What would be incredible is if we
could correlate individual differences in behavior with specific abnormal
metabolites,” James says. They will then look at children between 18 to 24
months old, which is usually before autism is diagnosed. That could help
identify the causes of the disease, as well as permit earlier intervention.
“We also plan to look at mitochondrial dysfunction,” she
says. “Since mitochondria are the energy powerhouses of the cell, they’re also
the place where the most free radicals (which play a role in oxidative stress)
are produced. If the electron transport chain in the mitochondria is faulty and
you’re not efficiently making ATP, you’ll produce more free radicals and
deplete your glutathione. If this hypothesis turns out to be correct, we can
give nutrients like coenzyme Q10, magnesium, and acetyl-L-carnitine to help
stabilize the mitochondria. Now, this is just a hypothesis, but that’s the risk
you take with science. You make your best guess and you carry out your study
and you see.”
“It’s interesting to see metabolic abnormalities addressed
this way,” says Isaac
Pessah, chairman of Molecular Biosciences and director of the Center for
Children’s Environmental Health and Disease Prevention at the University of
California at Davis. “I think glutathione balance in the kids is potentially
very important in terms of toxic environmental exposures.”
There is a growing sense, Pessah adds, that our heavily
industrialized, chemical-soaked environment—and the way it acts on vulnerable
genes in some individuals—may be a major culprit. In December 2006, Harvard
researchers boldly announced
in The Lancet that industrial chemicals may be impairing the brain development
of children around the entire world. And at a November 2006 conference at the
University of California at Davis’s M.I.N.D. Institute, Pessah gathered experts
to discuss the clinical implications of environmental toxicology in autism.
Says Herbert, “We discussed the enormous number of chemicals in our environment
and how little we know about chronic, low-dose, multiple exposures and their
effect on diseases like autism. Maybe the many autism cases we are now seeing
are a new illness of the current generation.”
Several large-scale, federally funded epidemiological
studies are under way to pinpoint possible environmental triggers, as well as
early biomarkers of autism. “We have to build a large enough study to be able
to look at both genes and environment together,” says Newschaffer, who is a
principal investigator on a study by the Centers for Disease Control that will
look at 2,700 children over the next five years.
“As far as the impact of chemicals on neurodevelopment, only
about 20 to 30 of the 85,000 chemicals have been studied.”
In another ambitious study, called the Autism
Birth Cohort, Columbia University and the Norwegian Institute of Public
Health will follow 100,000 pregnant women for 72 months, studying their health
and genetics and testing everything from blood to urine samples. The hope is to
discover environmental factors that contribute to autism risk, from diet or
infection to toxins like heavy metals, pesticides, and the countless synthetic
molecules in products today.
Other large NIH- and EPA-funded studies are teasing out
immune abnormalities that may contribute to autism. In research on more than
700 families with an autistic as well as a neurotypical child, Pessah and his
colleagues have found in the autistic child a significant reduction in
immunoglobulins and an abnormal profile of cytokines, which are critical to
immune response. “The immune system is involved in important aspects of
neurodevelopment,” says Pessah. “We’ve found the presence of immune antibodies
that we think may influence brain proteins. In the next five years, as the
study continues, we hope to reach about 1,600 families total. We need that many
to get real statistical power. We hope to find out what type of skewed immune
response the typical autistic child has and to isolate toxic exposures, such as
proximity to highways or toxic waste dumps.”
Herbert argues that “we can address the disturbed pathways
now, before the gene hunters have definitive information. Genes, after all,
don’t specify behaviors. They make regulatory factors that interact in highly
complex ways. And as far as the impact of chemicals on neurodevelopment, only
about 20 to 30 of the 85,000 chemicals made have been studied. We can, at the
very least, try to modulate autism by treating the tissue inflammation.”
In other words, treat now, before the gavel of
science strikes a final judgment, which might be decades away. That’s what Erin
and her husband, Michael, did for Brendan and Kyle: They blended mainstream
treatments like speech and occupational therapy with the best biomedical
approaches available. “I was told to
take my boys home and love them,” recalls Erin. “The neurologist said don’t
waste your time on alternative treatments, nothing about them is proven. My boys could have ended up
institutionalized, or my husband and I would have had to take care of them
their whole adult lives. When your
child gets a diagnosis of autism, you lose the child you were dreaming about,
the one who will go to college, get married, become a parent. That just wasn’t
an option.”
The boys first saw an alternative Colorado practitioner who
had been trained by a group called Defeat Autism Now!
(DAN!). DAN! was cofounded in 1995 by the psychologist Bernard Rimland, whose
own son was autistic. DAN! treatments focus on intestinal issues,
detoxification, nutrition, and neuroinflammation. Recommendations include
dietary restriction, usually eliminating gluten (present in wheat and other
grains) and dairy. “For weeks after
Kyle stopped drinking milk, he had welts all over his body,” Erin recalls, “as
if he were going through a detoxification reaction. At the same time, he had
his first formed, regular bowel movements. His sleep improved.”
Other DAN!-recommended treatments include detoxification to
remove heavy metals and other suspected pollutants, nutritional
supplementation, and sometimes off-label use of anti-inflammatories, antivirals,
and allergy medications. These so-called biomedical treatments range from
relatively inexpensive dietary changes costing a few hundred dollars a month to
doses of antifungal drugs that can cost several hundreds of dollars. Many DAN!
supplements play critical roles in the pathways studied by scientists like Jill
James. DAN! practitioners are, of course, leaping into the deep end of the pool
before science has truly proved these treatments effective, but there are many
anecdotal cases of improvement.
Not surprisingly, there has been criticism of the biomedical
approach, especially when doctors promise too much or parents hope too
desperately for recovery. As James
notes, one mother killed herself after seeking every possible treatment for her
autistic daughter to no avail, causing a furor among parents with autistic
children. Some children just do not get
better, no matter what the intervention. Elizabeth Mumper is CEO of a group
called Advocates for Children and former director of pediatric education at the
Lynchburg Family Practice Program affiliated with the University of Virginia.
Of the 2,000 children in her practice, about 400 have autism spectrum
disorders. She describes one boy whom “I have not helped despite my best
efforts. He is 17 and still nonverbal and has horrible, erosive esophagitis in
spite of the fact that he works very closely with a gastroenterologist. He has
to sleep standing up and leaning over his dresser because of the pain, and he
has very idiosyncratic reactions to medications. And even though he is
nonverbal, he can type anything to me. He’s alpha-smart. The horror is that
he’s trapped in a body that doesn’t work.”
“I hate the term ‘full recovery,’ ” James adds,
“because of this false hope. Some children do lose the diagnosis, but that’s
rare. I don’t think that should be out there as a goal. We need to accept [the
kids] and love them for who they are—because they are lovable. They’re quirky.”
Erin’s boys benefited from their DAN! doctor,
she says, but it was in 2003, when she switched to a highly unconventional
molecular biologist and naturopath based in Maine, Amy Yasko, that she began
to see more striking changes. Yasko blends the new findings on methylation with
a scientist’s background in the finer steps of fundamental detoxification
pathways in the body. However, she largely favors herbs, dietary change, and
nutritional supplements over prescription medications. She monitors biomarkers
of detoxification in the urine as often as every week or two and tweaks
supplements accordingly. Her program is intensive and steeped in molecular
biology; her twice-yearly conferences are extremely dense, scientific, and
intended to help parents become at least semiproficient in the biology and
chemistry themselves. It is a far cry from the old doctor-patient model—Yasko
works primarily on the Internet now, with phone consultations, to interpret
test results. She decided to do this when her waiting list for individuals
stretched to five years, and, she says, she felt she was not helping enough
children. Erin e-mailed me about 40 charts of metal “dumps” for both of her
boys—urinalyses Yasko had ordered and charted on a graph to show the excretion
of everything from arsenic to aluminum, mercury, and lead over time. “All these
little things started clicking after we started with her,” says Erin.
“I call this approach biomolecular nutrigenomics, after
Bruce Ames, a professor of biochemistry and molecular biology at the University
of California at Berkeley,” says Yasko. “He said that someday it would become
routine to screen individuals for polymorphisms and that nutritional
interventions to improve health were likely be a major benefit of the genomics
area.” Yasko tests for common polymorphisms in the methylation pathway, even
though these findings are still preliminary. This has made her controversial
among her peers. Yet several doctors and scientists with autistic children
admitted privately to using Yasko’s services while being unwilling to go on the
record to support her.
Yasko, who says she moved her husband and three daughters
from Connecticut to a rural area of Maine to “hear the snowflakes fall on the
snow and get to that quiet place inside where I can think,” seems immune to the
controversy. “I was in a research environment for a long time, where you had to
publish. Then I was in biotech for a long time, where you had to keep
everything quiet. When I began to focus on autistic children, I made a decision
that instead of publishing in peer review journals, I was going to go directly
to the moms and help them. I knew in making that decision I was going to get
flak. That’s OK. It was like I was on those cliffs you see in the movies, and
you’re going to jump. You don’t know if there’s water below, or enough momentum
to get to the other side, but you just jump.”
Can we cajole a mysteriously shuttered brain and body back
toward normal? And if so, will autism give us new insight into other disorders?
Today Erin’s boys participate in individualized programs at
school and are being monitored in two national studies of families with more
than one autistic child—one at the Duke Center for Human Genetics, another at
the University of Washington. Kyle has, in addition, been tested three times at
the University of Colorado Health Sciences Center’s toddler development
program. Both are still on the autism spectrum—but the incessant tantrums,
digestive problems, and infections have vanished. Brendan no longer chews on
his shirt, flaps his arms, and grinds his teeth. In fact, he made honor roll in
his classes last year. Kelly Swift, the boys’ schoolteacher since the autumn of
1996, describes them as “sociable and on the whole very happy, with a great
sense of humor. Kyle is probably the most changed of any autistic child I’ve
ever worked with.”
Kyle, who stopped speaking entirely at age 2, is now a font
of creative language. I know this because Erin and the boys spent a weekend at
my house. At lunch, Kyle poured a Vesuvius of ketchup onto his plate and began
transforming his french fries into boats that sailed across the ketchup before
they were disposed of in his mouth; he then began to entertain us by pretending
he was an announcer at a regatta, where he, of course, was winning the race.
What had once been autism had erupted into a geyser of quirky creativity.
The boys’ blossoming, according to their mom, is one not
easily measured on tests. “It’s the length of their sentences, their empathy
and sense of humor. Last night we went by a house that was all lit up for the
holidays and Kyle joked, ‘Does that guy want to be seen from space?’ When we
used to take Kyle to the dentist, he would scream bloody murder and we’d try to
papoose him—put him on a board and wrap him in sheets, but even that didn’t
work, so they put him to sleep just to clean his teeth. Last year we went to
the dentist, and he heard a little boy crying, walked over to him, rubbed his
back, told him it wouldn’t hurt, and not to worry. My heart was melting.”
Can we cajole a mysteriously shuttered brain and body back
toward normal? And if so, will autism give us new insight into other disorders?
Martha Herbert thinks so: “A lot of these metabolic pathways are pretty fundamental
to life. If we can crack the puzzle of autism and be clear about how we did it,
that may have huge implications for other chronic environmentally triggered
systemic illnesses. Autism could be a much-needed wake-up call to us all.”