Understanding the Architecture of Autism

June 2010- Here at Hopkins, where autism was described by Kanner and autism twins study author Susan Folstein subsequently established the Division of Psychiatric Genetics, researchers who analyze data from next-generation sequencers are working with those who gather clues from parents-to-be of the next generation, all in an attempt to reveal the architecture of autism.

Real progress in finding its cause depends on the genetics folks collaborating with environmental epidemiologists, says Dani Fallin, director of the Center for Autism and Developmental Disabilities Epidemiology (CADDE) in the Johns Hopkins Bloomberg School of Public Health.

“We need to get past any lingering notion that the cause of autism is either genes or environment,” Fallin says. “I think people are realizing now that sort of silo approach is not going to work, and that we need to be thinking about both things together.”

Genes likely provide the substrate of autism, such as in the context of how quickly an individual can metabolize something or detoxify, Fallin says: “With a partnership of genetic and environmental scientists, you can design studies and collect data and samples in ways that are informative to both sides of that story.”

Second only to the importance of collaboration is the ability to ask relevant questions, which means figuring out the “window of risk.”

Dani Fallin, director of the Center
for Autism and Developmental
Disabilities Epidemiology (CADDE).

“Should we be asking about what happened when the baby was 1, or should we be asking about what was happening when the mom and dad were conceiving, or during the pregnancy,” she wonders. Which window is the relevant one? Or should we be asking about what happened to the dad before the baby was conceived. What is that window?”

Currently, Fallin is collaborating with Rebecca Landa, director of the Center for Autism and Related Disorders at Kennedy Krieger Institute, on a case-control study that recruits children between the ages of 2 and 5, and retrospectively asks the mothers of both autistic and non-autistic children about relevant happenings during pregnancy and birth as well as in the first few years of life. Called SEED, which stands for Study to Explore Early Development, more information about the study is available at the SEED website.
Another major collaborative research project involves recruiting women who already have children with autism and following them throughout subsequent pregnancies to note environmental factors as well as analyze blood samples. This EARLI Study has been designed to examine possible environmental risk factors for autism and study whether there is any interplay between environmental factors and genetic susceptibility.

“There really are no biomarkers yet, but that’s part of our goal,” Fallin says. “If we take blood samples during pregnancy and infancy, we may be able to discover something that distinguishes children who are going to become autistic from those who aren’t.

“The hope is that if we understand what’s causing autism, we’d be able to figure out how to either prevent it or treat it earlier. If you understand the biology, you know what and how to attack, whether with a pharmaceutical or behavioral treatment, or some preventive measure.”

In addition to these projects, other autism-related research is ongoing at Johns Hopkins and Kennedy Krieger, including:

Carlos Pardo, associate professor of neuroimmunology, Johns Hopkins University School of Medicine

Carlos Pardo, associate
professor at Johns Hopkins.

Pardo’s focus is on the immune system and how it may interact with other factors to produce the complex manifestation of autism. Using the brains of individuals who had been diagnosed with autism when they were alive, he investigated immune system responses in the central nervous system and demonstrated for the first time that there was some sort of immune activation. He’s not yet sure if it’s part of the overall complex of pathogenic events, a result of neurological abnormalities these patients had, or part of the disease process. That’s where he’s focusing his research efforts now.

With NIH, Pardo is analyzing blood and spinal fluid of a cohort of children to try to identify proteins that might help us to distinguish a group of normal subjects from subjects affected by autism. He has identified a potential protein biomarker candidate in spinal fluid—macrophage chemoattractant protein I—an immune system protein that is elevated in brain tissues and spinal fluid of autism patients: “We don’t know yet the meaning of that elevation. It could be facilitating an immune response or neuronal protection,” he says. “We need to figure out its role.”

Mary E. Blue, research scientist in the neuroscience laboratory at Kennedy Krieger Institute and associate professor, Department of Neurology and Neuroscience, at Johns Hopkins University School of Medicine

Mary E. Blue, research scientist
at Kennedy Krieger Institute and
associate professor at Johns
Hopkins.

Blue’s hypothesis is that a disruption of serotonin homeostasis may be responsible for some of the symptoms of autism—that serotonin is interacting with and may modulate the immune system. In children with autism, depending on when in brain development researchers look, they see levels of serotonin that are either too low or too high. Blue’s autism research involves using a mouse model to investigate the interface between serotonin level and immune system. She has shown that if serotonin is depleted in the cerebral cortex of neonatal mice, they show altered immune system activation and have permanent behavioral abnormalities—analogous to aspects of behavior in autism. As the mice get older, although serotonin receptors repopulate, the mice still don’t socialize in proper ways, and instead exhibit stereotyped behaviors.

“Perhaps serotonin is at the nexus of a mechanism for autism,” Blue says. “I’m interested in that interplay between the immune system and serotonin in terms of brain development. It makes sense to me that some sort of environmental issue might be affecting the immune system and, indirectly, the nervous system.”

Rebecca Landa, director, Center for Autism and Related Disorders, Kennedy Krieger Institute, and associate professor of psychiatry, Johns Hopkins University School of Medicine

Play works at the Center for Autism
and Related Disorders at the Kennedy
Krieger Institute where early-detection
specialist Rebecca Landa engages a
patient by imitating him: “If I do what
he is doing, he soon learns new ways
to get me to change what I’m doing
and suddenly we’re taking turns,” she
explains.

Landa’s research shows that autism, in most cases, is a progressive disorder. Her studies also show how dramatically the course of autism can be changed by early intervention— early meaning the first, second or third year of life.
“We must be really vigilant in order to detect the behavioral divergences in infant or toddler development as early in life as possible,” Landa says. “We also need to develop the most potent interventions, and then translate those interventions into ways that people—moms, dads and babysitters around the world—can implement. Because I know that early detection and intervention changes outcomes.”
A baby’s or child’s experiences actually influence the way the neural pathways lay themselves down, Landa explains. “That’s why I think of these behavioral interventions as neurobiologically relevant.”

--by Maryalice Yakutchik