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FEATURES
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GETTING CLOSER TO FINDING THE CULPRITS

 "" PHOTO — Neuroimmunologist Judy Van de Water is investigating how the immune system may play a role in the onset of autism.
 
Neuroimmunologist Judy Van de Water is investigating how the immune system may play a role in the onset of autism.
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For many years, autism research was focused on improving behavioral approaches to treating the disease and medical treatment of some associated symptoms, including sleep disruptions and aggression.

That began to change five years ago when the UC Davis M.I.N.D. Institute launched an unprecedented effort to discover the underlying mechanisms of the disease that affects one out of every 150 children born today and for which there is no cure. The institute's translational, multidisciplinary approach has resulted in benefits to improve both bench science and clinical trials. This has facilitated the search for cures and clarified for researchers there are likely several different types of autism all labeled with a single diagnosis.

"When we started, we didn't even have good theories as to what causes autism spectrum disorders," explains Robert Hendren, executive director of the M.I.N.D. Institute. "Now, we have started to find evidence supporting specific theories, and we are able to start testing those theories."

Immune system dysfunction

One of the most promising theories to emerge implicates the immune system – in either the mother or the child – as causing at least certain types of autism. Malfunctioning of the immune system has been found to play a role in other neurological disorders, says neuroimmunology researcher Judy Van de Water.

"The immune system and nervous system are more closely integrated than people originally thought," explains Van de Water, who is part of the M.I.N.D. Institute's multidisciplinary research team.

She and fellow researcher Paul Ashwood have spent the past five years surveying markers of immune system function in children with autism and comparing them to those in children who do not have the diagnosis.

"One of our first findings was that immunoglobulin G was much lower in children with autism," Van de Water says. IgG, as it is more commonly called, is an antibody sub-type responsible for the majority of the immune response to invading pathogens.

"This tells us there is likely something wrong in a very basic cell-signaling pathway."

Van de Water and her collaborators also have found that antibody responses to vaccines against bacteria are lower than expected in people with autism, while antiviral responses are fairly normal. This, she explains, was their first clue that the problem lies in the innate immune response – the short-term, non-specific host response to pathogens. Her goal now is to study whether children with autism have autoantibodies to brain proteins and if mothers of children with autism show exaggerated immune responses to proteins in fetal brains.

"We want to know the function of these antibodies during gestation."

Toxic stress

A second promising line of research is based on the theory that some forms of autism are caused by the body's inability to handle environmental stress.

In the past year, Hendren and his colleagues began treating patients with methyl B12 (MB12). MB12 helps the body handle toxins and oxidative stress from the environment. Oxidative stress results in the production of peroxides and free radicals that are toxic to cells, damaging DNA and other cellular components.

A preliminary study at Arkansas Children's Hospital showed that MB12 supplementation reduced markers of oxidative stress in the blood of children with autism. Hendren's study goes further by gathering both biologic and behavioral data. Children are given either MB12 or a placebo at six-week intervals then switched over to the other supplement (MB12 or placebo). Parents, who keep detailed logs of the children's behavior, do not known when the children are receiving the placebo.

PHOTO — Sacramento pediatrician Tracey Dinh, who has one child with autism and is pregnant, is participating in the M.I.N.D. Institute's newest study, Markers of Autism Risk in Babies - Learning Early Signs, which will search for causes and early markers of the disorder during pregnancy.  ""

Sacramento pediatrician Tracey Dinh, who has one child with autism and is pregnant, is participating in the M.I.N.D. Institute's newest study, Markers of Autism Risk in Babies – Learning Early Signs, which will search for causes and early markers of the disorder during pregnancy.
 
   

"We have seen about 21 children so far, and when we reveal the treatment schedule, over half of the parents say they want to continue with the MB12 feeling it helped the children more than the placebo even though they did not know which supplement the children were taking," Hendren says.

Five children have done remarkably well, he adds. "One four-year-old boy who spoke no words at the beginning of the study was speaking in sentences six months later."

A few children, however, exhibited increased hyperactivity as a side effect.

"We need to do a larger study and look for biomarkers that predict which children will respond to the treatment," Hendren says. This information could lead researchers to discover causes of autism, at least in the children that respond favorably to MB12.

"We do find that it seems to work well for some kids, but we need to know why."

Studies behind the studies

Hendren and Van de Water point out that their work would be impossible without the long-term epidemiological studies being conducted at the M.I.N.D. Institute. These studies provide the participants and biological samples used in their research.

"Every piece of data that we have we can relate back to medical and behavioral data," Van de Water says. "It's what makes our studies so valuable."

M.I.N.D. Institute researchers are involved in three large-scale studies which recruit patients needed to conduct laboratory-based research like Van de Water's, as well as clinical trials studies such as Hendren's.

  • The Autism Phenome Project is a longitudinal study of 1,800 children with autism, with mental retardation or with typical development. Researchers want to identify the biological and behavioral patterns that define autism subtypes. "The tremendous variation in autism leads us to believe that it is a group of disorders rather than a single one," says David Amaral, research director of the M.I.N.D. Institute and co-director of the project.
  • The CHARGE Study, Childhood Autism Risks from Genetics and the Environment, is part of a grant made to UC Davis as one of 11 national Centers for Children's Environmental Health and Disease Prevention supported by the National Institute of Environmental Health Sciences and the U.S. Environmental Protection Agency. The study is enrolling up to 2,000 children with autism, developmental delay or typical development to discover the particular genes and/or environmental exposures that might result in different patterns of development. "We pull together all of this information and try to figure out what's different for children with and without autism," says M.I.N.D. Institute researcher Irva Hertz-Picciotto, an epidemiologist and professor of public health.
  • The MARBLES Study, or Markers of Autism Risk in Babies – Learning Early Signs study, is the newest UC Davis autism study. Research staff will eventually enroll 1,000 pregnant women who already have at least one child with autism and follow their new babies for three years. These women are at least 10 times as likely to have another child with autism or some other neurological disorder. "Right now, we don't know if the differences we see in children with autism existed before the disease developed or because of it," says Hertz-Picciotto, principal investigator for the study. "The really exciting part is that we'll know what was there before and after the diagnosis."

These larger studies are what allow M.I.N.D. Institute researchers to push the field of autism research into significant new discoveries, Hendren says.

"Discovering the biological mechanisms behind autism requires that scientists think about the disorder in a translational way, moving from basic science research to the clinical symptoms and from the clinical symptoms to basic science research."

Van de Water agrees. "I have never worked with so many people from such diverse disciplines, nor have I seen it done so well. It's a great way to do science."

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  "We have started to find evidence supporting specific theories [related to the cause of autism] and we are able
to start testing those theories. " — UC Davis M.I.N.D. Institute, Executive Director Robert Hendren  
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