DAVIS, Calif. -- What causes autism? The question has spurred about a billion dollars' worth of genetics research that has found no clear answer.
But University of California, Davis, epidemiologist Irva Hertz-Picciotto has been pursuing another angle: Does the environment around a pregnant woman play a role in determining whether her child develops autism?
Over the last 10 years, her work with more than 1,000 autistic children has changed how science looks at autism, refocusing the debate on the crossroads of environment and genetics.
Hertz-Picciotto's group has published hundreds of papers, including one that suggests, among other things, that a mother's proximity to congested roads and, thus, dirty air increases her risk of giving birth to an autistic child. Her group more recently suggested that obese women may be 67 percent more likely to have autistic children.
Those findings have raised the profile of Hertz-Picciotto and UC Davis' autism institute as parents have seen autism rates soar and look for anything they can do to prevent their children from developing the disorder. The Centers for Disease Control and Prevention said last year that 1 in 88 U.S. children has an autism disorder, a 23 percent jump since 2009 (Greenwire, March 29, 2012).
Alycia Halladay, a senior director at the advocacy group Autism Speaks, called Hertz-Picciotto a "pioneer." Without Hertz-Picciotto's work, she said, it would have taken years for environmental factors to emerge as a focus of research.
"Not only is she a pioneer," Halladay said, "but she really continues to be one of the major leaders in this area. If you think about the scope of her research, she is involved in all things involving environmental epidemiology of autism."
Hertz-Picciotto, who knew little about autism when she began her research more than a decade ago, said her objective is ostensibly simple.
"My goal is to reduce the incidence of autism," she said. "We've seen it going up and up and up. I want to see it start plateauing, and I want to see it start going down."
And while Hertz-Picciotto's research so far has been retrospective -- relying on mothers' accounts of what they may have been exposed to -- her latest study is following women from pregnancy to a potential autism diagnosis when their children turn 3 years old. Along with many other scientists, she believes that those results, though still years away, could fundamentally alter the prevalence of autism in the United States.
Outside her cluttered office at UC Davis, Hertz-Picciotto said in an interview that she has always been attracted to environmental factors because they are much easier to control than one's genes.
"With the environment, it presents its own challenges," she said, "but at least we can know that this is a factor and we can reduce it to have an impact."
'Wide open field'
Hertz-Picciotto, 64, is tiny but filled up the conference room next to her office with enthusiasm. She had just hopped off her bicycle, which she rides to work, and was rocking back and forth in a chair as she recalled growing up the daughter of a software designer father and homemaker mother in Whittier, a suburb of Los Angeles.
She recalled two formative experiences, the health of her mother and her experience with the family's red wagon.
When she was young, she and her brother played with a red metal wagon. The other families on their street eventually upgraded to a new, plastic version, though Hertz-Picciotto's family couldn't afford one.
A year later, she recalled, the plastic wagons were all broken, but the metal one rolled on. The observation led Hertz-Picciotto to view all new technologies with skepticism.
"I've always looked upon new technologies as what does it bring and what does it take away?" she said.
Her mother contracted tuberculosis when Hertz-Picciotto was very young.
"Health was always an issue for me," she said. "I grew up always wondering [whether] I was going to follow in my mother's path and have an extended illness."
Hertz-Picciotto, who eschews makeup and enjoys yoga, studied biology and mathematics at the University of California, Berkeley. She went on to teach high school math as she raised her two children.
It wasn't until the late 1970s and early 1980s that she started becoming interested in how prenatal exposures to environmental toxins may affect the health of children. The concept led her back to Berkeley for a degree in biostatistics and eventually a Ph.D. dissertation on how drinking tap water could be linked to pregnancy problems like low birth weight.
From Berkeley, she headed for about a decade to the University of North Carolina, Chapel Hill, where she focused on similar issues, like lead exposure and the effects of arsenic in Chile's drinking water.
Those studies caught the eye of David Amaral, who was setting up the Medical Investigation of Neurodevelopmental Disorders, or MIND, Institute in Sacramento in the early 2000s. One requirement for funding was hiring an epidemiologist, so he approached Hertz-Picciotto even though she knew nothing about autism.
Amaral sent Hertz-Picciotto some background materials, and within three days, she was hooked, because no one had looked at common environmental contaminants like polychlorinated biphenyls, or PCBs. Moreover, she was convinced the environment played a role, since studies on twins showed that even though they are identical genetically, in some cases one twin had autism while the other didn't have it.
"To see nothing at all, nothing on PCBs, which were pretty hot then, nothing on metals, which we know are neurotoxins," she said. "It was a wide open field."
Results grab headlines
By January 2001, Hertz-Picciotto was writing the grant for what would eventually become the Childhood Autism Risks from Genetics and Environment, or CHARGE, study.
Backed by federal cash two years later, she partnered with California to identify autistic children, eventually enrolling about 800 families with autistic children (they are now up to 1,700). Her team collects information about the pregnancy, the health of the mother, residential history and possible exposure to heavy metals, among other things. They ask the mother to recall beginning three months before the pregnancy, and every month since.
More recently, they have started collecting data on the use of household pesticides such as Raid and pet products, as well as chemicals like the controversial plasticizer bisphenol A (BPA), cosmetics, flame retardants, anti-microbial products, food packaging and nutrition.
They compare that information to what they collect from similar families whose children don't have autism to deduce, and calculate, differences.
For example, Hertz-Picciotto's team can take residential history and cross-check it against California's pesticide use registry, as well as air monitors and auto traffic. That led to her group's December 2010 paper suggesting that a pregnant mother's proximity to a freeway may be associated with an increased risk of autism in the child.
Another paper from her group looked at nutrition and found that women who consume the recommended daily dosage of folic acid during pregnancy may reduce their risk of having an autistic child.
In sum, the findings have cemented the idea that the mother's health and immune system are factors, and they have grabbed countless headlines as parents have grown increasingly curious about what, if anything, they can do to prevent autism.
Given that she now has a spotlight that most researchers would dream of, observers have been impressed by how carefully Hertz-Picciotto presents her work.
"What she publishes is very carefully done, and her claims are conservative," said Susan Hyman, who until recently chaired the American Academy of Pediatrics' autism subcommittee. "She doesn't go beyond her data. Other people do, but she doesn't."
'Genetics is a loaded gun, and environment pulls the trigger'
A problem with Hertz-Picciotto's research is its methodology. Because it's epidemiological, and therefore relies on a subject's recollection, the research can't determine causation, only possible associations.
The CHARGE Study, for example, doesn't actively test its air pollution hypothesis by exposing one pregnant woman to soot and then comparing that woman's child to the child of another woman who is known to have breathed only pristine air while pregnant.
Moreover, Hertz-Picciotto's findings often make the "what causes autism" question even more complex. In the case of maternal obesity, researchers now need to study what, exactly, made the women obese. What were they eating? Where they exposed to "obesogens," chemicals associated with weight gain? Did they smoke? Is there a socioeconomic aspect?
Rebecca Schmidt, a former graduate student of Hertz-Picciotto's who is now a professor at UC Davis, said that while that may be frustrating to a public that wants answers now, the findings provide somewhere to begin prospective research.
"At least these studies show us a direction to pursue," she said. "You have a starting point."
Those starting points have become the basis of Hertz-Picciotto's more recent research, the Markers of Autism Risk in Babies -- Learning Early Signs, or MARBLES, study. The 5-year-old study is prospective, making it much more difficult to set up than CHARGE was, Hertz-Picciotto said, because her team must recruit mothers who may be predisposed to having autistic children, possibly because they already have an autistic child.
Her team then monitors the women during pregnancy, collecting blood and urine samples and information about their environment. They obtain the placenta after birth and follow the child through his or her first three years. This will allow them to see whether there are chemicals or other pollutants in the mother during pregnancy and what the baby was exposed to after birth.
Project funding comes from the National Institutes of Health and California, and she has yet to publish any papers.
What the study will help answer, Hertz-Picciotto said, is what she calls "lines" or "upstream" causes of the disorder. Her next grant, for example, will look at what whether those obesogens are, in fact, causing metabolic conditions that lead to maternal obesity -- which, in turn, can lead to autistic children.
"So," she said, "it might be that there [are] exogenous chemicals in the environment that are contributing to the inflammatory process, that could then end up being neuro-inflammatory."
That work, along with her previous studies, has also helped geneticists, who were initially skeptical of environmental factors playing a role in autism.
Simon Gregory, a geneticist at Duke University, said Hertz-Picciotto's work has been "groundbreaking" and has become part of the latest autism research on how external factors affect gene expression, or epigenetics.
One example is DNA methylation, in which a chemical is literally next to or on top of a gene and determines whether it is activated. That process, Gregory said, is highly vulnerable to outside influences.
And, as Hertz-Picciotto will attest, genetics is still part of the cause. Some scientists estimate that roughly 20 percent of autism cases can be traced to specific genetic abnormalities.
"It's not going to be one thing; it's going to be a combination of risks," Gregory said. "My favorite analogy is: Genetics is a loaded gun, and environment pulls the trigger."
Hertz-Picciotto also benefits from the robust team she has surrounded herself with at Davis, most notably the MIND Institute.
Located next to UC Davis' hospital in Sacramento, the center was founded in the late 1990s by five local families who had autistic children. The families wanted a multifaceted center that could diagnose, treat and, most importantly, study the causes of the disorder.
After state funding was secured, the result was a building and research facility designed to inspire hope in autistic children and their families. The entrance, for example, is a rotunda with high arches, reminiscent of a cathedral, and the walls are decorated with art by autistic children.
Every detail was accounted for, said Amaral, the institute's research director. The architect, for example, hired an interior decorator who has three autistic children. She used only muted and natural colors to avoid overstimulation -- the opposite of most pediatricians' bright offices. Lighting is also carefully planned throughout the sprawling, two-story building; fluorescent fixtures generally aren't used, and most lighting is indirect.
"The idea is the MIND Institute looks like a family room instead of a hospital," Amaral said.
Amaral's team accommodates 2,500 patient visits every year at the institute, many of which are part of Hertz-Picciotto's research, which he said is the crux of the center's mission.
The program, he said, represents the "founding parents' vision."
The institute, which is now funded primarily through grants and philanthropy, has also brought together scientists focused on autism from nearly every field, from neurologists to epidemiologists to immunologists. The result has been a breeding ground for theories and cutting-edge research.
"A lot of it is having the epidemiology and the science feed back and forth," Hertz-Picciotto said. "Ultimately, causation comes from working together with these pieces."
An example is UC Davis professor Judy Van de Water's experiments on rhesus monkeys. Van de Water, an immunologist, looked at research suggesting that a subset of mothers with autistic children produce antibodies to fetal brain tissue, meaning their immune systems erroneously attack the fetus's brain as it develops.
Van de Water took some of those human antibodies, put them in a serum and injected it into pregnant rhesus monkeys. The offspring clearly displayed autistic behaviors. Van de Water has found that about 12 percent of women with autistic children produce these antibodies, but it remains unclear why so far.
And while there are still complex questions remaining and more work to be done, Hertz-Picciotto looks back on her work with a sense of accomplishment.
"I think we have changed the landscape to the extent that 10 years ago, environment was absolutely not on the map," she said. "Now it is."