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Li-Huei Tsai's studies of protein interactions and Christopher Walsh's gene-seeking strategy are beginning to provide clues to autism's origins.
Like many children with autism spectrum disorders, Nicole's connection to the world is an extremely narrow one. Her single overwhelming interest is animals—her dog Lulu (she will read out loud only to Lulu), zoo animals, animals in photos, stuffed or plastic ones that she used to arrange in particular, ritualistic ways. “She has her own agenda,” says her mother, Maureen. “She can't take other people's perspective and doesn't understand why they don't go along with what she wants to do.”
Sixty-five years after child psychiatrist Leo Kanner described the puzzling cluster of cognitive, emotional, and social disturbances of 11 children with what he dubbed “infantile autism,” much about autism remains an enigma. An ever-widening array of disturbed behaviors and developmental obstacles—from mild to devastating—now fits under the umbrella term “autism spectrum disorders” (see sidebar).
Research into this mysterious disease, however, has gotten a recent “kick in the pants,” says Gerald Fischbach, former director of the National Institute of Neurological Diseases and Stroke who has served on the HHMI scientific review board. A convergence of funding, a handful of key discoveries about the autistic brain, and technology advances that enable fine-grained DNA searches have attracted major scientific players who've narrowed the search for causes, according to Fischbach, now scientific director of the autism-focused Simons Foundation, a private philanthropy launched by billionaire hedge fund manager James H. Simons, whose daughter has mild autism.
Discoveries of gene mutations in some autistic individuals support the growing suspicion that the key problem in autism may lie within the synapse—the tiny, chemical-filled gap between the tip of a transmitting neuron's long, spindly arm and the receiving end of the next.
An estimated 100 billion neurons make up the human brain, connecting at synapses to create powerful information-processing networks that enable humans to think and remember, interpret sensory information from the outside world, and navigate the challenges of social relationships.
Sir Charles Sherrington, the neurologist and Nobel laureate who coined the term “synapse,” famously likened the brain to “an enchanted loom where millions of flashing shuttles weave a dissolving pattern, always a meaningful pattern though never an abiding one.” Perhaps the autistic brain is a loom that creates flawed patterns or can't easily be programmed to weave new designs.
Though Kanner believed autism was inborn, many psychiatrists blamed it on cold, unloving mothers whose inadequate parenting marred their autistic children's developing psyches. But studies in the 1970s showed that among twins with autistic disorders, identical twins are very likely to both be affected, whereas fraternal twins—like Nicole and Carly Branconnier—are rarely both affected. These studies provide strong evidence that faulty genes are largely responsible, most likely combined with unknown and unmeasurable inputs from environmental factors.
“Genetic” doesn't always mean “inherited.” Although the less-disabling forms of autism can often be traced in families, scientists believe severe cases most often arise from spontaneous, or de novo, mutations. These are DNA mutations—present in the child but not in the parents—that occurred during the formation of the eggs or sperm before conception.
“This is not surprising, as autistic children rarely marry and have children,” says Christopher Walsh, an HHMI investigator at Children's Hospital Boston and Beth Israel Deaconess Medical Center, who is searching for relevant genes.
Photos: Li-Huei Tsai: Matt Kalinowski; Christopher Walsh: Joshua Dalsimer