Jennifer and Sarah Ross are 6-year-old twins, but they couldn't be more different. Jennifer is quiet, reserved and calm. She likes to dance, do gymnastics and jump on trampolines. She has plenty of friends. Sarah, on the other hand, is all energy. She has trouble sitting still. She has a gift for math and puzzles, and she likes to play video games. While Sarah has only a few friends and is usually content to be on her own in the playground, she does love a captive audience.
"Everyone know I can sing opera?" she asks. "Whaaaaaaa! "
Jennifer and her mother, Alycia Halladay Ross, giggle. On a recent morning, the three sat in the playroom at the Seaver Autism Center for Research and Treatment at the Icahn School of Medicine at Mount Sinai in New York City. Halladay Ross, the chief science officer at the Autism Science Foundation, planned to spend the better part of the day at the center with her two daughters. The girls would undergo a series of exercises and activities to test their cognitive and intellectual abilities. Jennifer and Sarah were to be observed while playing with blocks, then they'd participate in word-association games. The girls, along with their mother, were also there to provide the center with saliva samples—the most critical part of their visit.
"In our spit, there's lots of scientific information," Paige Siper, chief psychologist of the Seaver Autism Center and an assistant professor of psychiatry, tells the girls. "It tells us lots of different things about us—about kids, about adults. So we're getting spit from lots of different kids and families so we can learn lots of things about inside our bodies."
Siper was explaining the methodology of an ambitious effort currently under way at the center in collaboration with the Autism Science Foundation. Sarah was diagnosed with autism several years ago, but her sister wasn't. The Rosses are one of 3,000 families enrolled in the Autism Sisters Project, a long-term study of families with at least one child who has autism and at least one female sibling who does not.
As genetics research has advanced, scientists have discovered some 50 genes linked to autism risk; there are likely many more. As this research has exploded, geneticists in the field have observed a curious pattern, leading to a compelling theory that begs for closer investigation. Studies appear to show that being female provides some protection from developing autism.
When comparing the genome of a girl with autism to the genome of a boy with autism, females tend to have twice as many genetic mutations as boys. What this means is girls have a higher genetic threshold before developing the disorder. Girls need more mutations "to actually pass that boundary to autism traits," says Joseph Buxbaum, director of the Seaver Center. "Autism is highly genetic, and a big part of the genetic risk is inherited."
That's not to say heritable genetic traits are the only determinants for autism risk. Other things, such as the ages of parents at birth and environmental and biological factors, play into risk; they may be involved in a spontaneous mutation that results in having one child who develops autism.
The biological differences of males and females appear to have a strong influence. For example, studies have found that cells involved in the brain's process of synaptic pruning, known as microglia, are thought to be involved in the development of autism. Some recent research from University of California, San Francisco, looked at the impact of sex differences on brain development. The study finds that microglia differ in number and behavior in boys versus girls, and the genes that cause microglia to develop are more active in males, especially in the months before birth.
Buxbaum, who is helping lead the Autism Sister Project, says it will be one of the first that not only pinpoints risks for autism but also identifies protective factors. This approach to research, says Siper, "represents an important shift in our thinking about how to develop the most promising treatments." Siper, Buxbaum and their colleagues worldwide want to know what leads to an autism diagnosis in kids like Sarah. They also want to figure out what exactly confers resilience in (and protects) girls like Jennifer.
Those findings, says Buxbaum, will be useful in research for treatments. "We can actually think about drug development," he says. "If we have a pathway in the brain that is actually protecting against autism, we can stimulate that pathway through medicine. Then, we think, we can actually reduce the risk and ameliorate the manifestations of autism." The research could also help develop sex-specific interventions for autism.
The Extreme Male Brain of Autism
While still mostly a theory that requires supportive evidence from studies like the Autism Sisters Project, the female protective effect has already influenced some clinical practices. In 2013, health officials in Western Australia changed regulations to allow fertility clinics to select embryos for implantation based on sex if a family was considered at "high risk" for having a child with autism. They defined "high risk" as families with two or more boys with severe autism. Couples with an autistic child are as much as 25 percent more likely that their next child will also develop autism, and boys are at least four times more likely to develop autism than girls. While questionable to some bioethicists, the thinking was that for some families, sex selection may result in better outcomes for both child and parents.
Boys are more likely to develop autism than girls, and they may also have more severe symptoms. As a result, they are often diagnosed far earlier and may receive better supportive services. Research shows that earlier intervention for autism brings the most promise in long-term outcomes.
Some experts argue that basic gender differences, and even cultural norms, are at play in this disparity and puts girls with autism at a disadvantage. In 2002, Simon Baron-Cohen, now a director of the Autism Research Centre in Cambridge, U.K., and a professor of developmental psychopathology at the University of Cambridge, published a paper outlining what he called the "extreme male brain theory of autism," a concept first proposed by Dr. Hans Asperger in 1944. Asperger, an Austrian pediatrician, suggested that the autistic personality is simply an "extreme variation of male intelligence." He went on to define a less severe form of autism in which a person is high-functioning but still exhibits traits of the autistic personality, such as lack of empathy or difficulty forming friendships. For decades, this subtype of autism was referred to by doctors as Asperger's syndrome, until it was folded into single diagnosis autism spectrum disorder in the DSM-5 diagnostic manual in 2013.
Baron-Cohen brought further insight to the theory. He pointed out that scientists had long defined the sex differences of the male and female brain by studying verbal and spatial abilities, leading to some significant understandings of how people of both genders communicate differently. But Baron-Cohen proposed that researchers were neglecting two other important behavioral dimensions for understanding sex differences of the human brain: empathizing and systemizing. The latter is defined as the need or drive to analyze or construct systems that involve input and output and that follow rules within a person's control. This is a common trait in people with autism, who are stifled by the need to engage in repetitive behavior, become fixated on certain hobbies or interests and obsessed with order.
"The male brain is a defined psychometrically as those individuals in whom systemizing is significantly better than empathizing, and the female brain is defined as the opposite cognitive profile," Baron-Cohen wrote in the paper. "Using these definitions, autism can be considered as an extreme of the normal male profile."
Those gender differences also mean that autism symptoms are often less pronounced in girls. "There is a theory that some girls don't get diagnosed with autism until later because they're able to camouflage their symptoms," says Halladay Ross. "It's very possible, 20 years ago, Sarah wouldn't have received an autism diagnosis."
While Halladay Ross has spent the better part of her career in the field of autism research, it took a while to arrive at the diagnosis for her daughter Sarah. When her daughters were 3, she received a call from their preschool, informing her that Sarah was having meltdowns that were more than the teachers could manage. They also suggested that Sarah was having sensory issues. At first, Halladay Ross thought her daughter had obsessive-compulsive disorder. Her pediatrician sent them to a neurodevelopmental specialist, and days and hours of exams and tests led to her daughter's diagnosis of autism spectrum disorder.
Sarah's autism was challenging to diagnose because many of her traits are less pronounced. Sarah is smart and funny and generally high-functioning. She attends a regular school, and is enrolled in an integrated first-grade classroom. But some of the classic signs are there—just not necessarily all the time.
"The whole thing really erupted three years ago during the polar vortex, when she would sit in the car and insist that she tap her car-seat straps together three times," says Halladay Ross. "If that didn't happen, all hell would break loose—which would have been OK during the summer, but my other daughter was freezing and so was I."
Halladay Ross says the only way to avert Sarah's meltdowns is to give in to her requests for sameness and routine, such as driving a set route home from school every day and always visiting McDonald's after her Monday therapy appointment.
Sarah's toys need to be in a certain place at all times and lined up in a particular way. And then there's her extensive collection of My Little Ponies. "She knows the backstory on every single My Little Pony and what their cutie mark is," says Halladay Ross. "She rarely leaves the house without a My Little Pony."
When things don't go as planned, Sarah may have epic meltdowns and become aggressive. Halladay Ross has learned to handle her volatility, but it's much more difficult for Jennifer. Sarah has been known to lash out at her sister when she is struggling to regulate her emotions. Sarah once bit Jennifer's nose so badly it caused a bruise that almost prompted the school administration to call Child Protective Services on the family.
But Halladay Ross says Jennifer is one of the few people who knows exactly how to help Sarah when she's exhibiting some of the more challenging behaviors that come with autism.
Though her family is actively involved in several studies for autism, Halladay Ross says this project is particularly valuable because it involves her other daughter as well. "Jennifer feels it's a way she can help people understand Sarah," she says. "And I think Sarah really wants to be understood."
