Searching for Autism's Treatable Roots

One researcher's quest to reveal the underpinnings of autism has far more at stake than scientific inquiry.

April 30, 2010

Valerie Hu in lab smiling

Valerie Hu, Ph.D. Professor Department of Biochemistry and Molecular Biology The George Washington University Medical Center

By Danny Freedman

Down a side hallway and in a cluttered office tucked away inside a lab, Valerie Hu is attempting to crack one of biology’s most vexing riddles: her son.

Matthew, 22, has an autism spectrum disorder. And nothing quite brings determination to the case like a mother.

Dr. Hu’s lab seeks to understand autism through the fast emerging field of epigenetics—studying inheritable marks on DNA that determine levels of gene activity—rather than hunting for genetic mutations.

Each provides important pieces of the puzzle, as does work to identify environmental triggers. But exploration of the epigenome, which is the middle-man between DNA and the environment, is particularly intriguing because it’s leading scientists to the more immediate causes of autism’s symptoms and tantalizingly close to ideas about how they might be improved or even reversed.

Though a relative newcomer to the field, Dr. Hu, a professor in GW’s Department of Biochemistry and Molecular Biology, is helping to chip away at some of the mysteries of ASD, which on average afflicts one-in-110 children in the U.S. and boys four times as often as girls.

Through the prism of epigenetics, autism looks like a disorder of a thousand cuts; a cascade of malfunctioning genes throughout the body that results in a curious slate of symptoms—impaired social and communication skills, repetitive behaviors, the risk of epilepsy and other disorders—that register along the autism spectrum.

For example, a previous study by Dr. Hu found that more than 4,000 genes appear to behave differently in a group of severely autistic people as compared with non-autistic controls—a startling number, considering the human genome comprises 20,000 to 25,000 genes. “That alone suggests there’s got to be master switches that are turning the genes on and off,” she says.

In a pair of small-scale studies published this month, Dr. Hu and colleagues took a closer look at the presence of two of these switches: chemical tags on DNA called methylation, and tiny but powerful snippets of regulatory RNA called microRNAs.

In broad examinations of cell lines derived from autistic individuals, the researchers found dozens of instances of abnormal methylation and altered levels of microRNAs. When they compared that data against a map of abnormally expressed genes from the same individuals, they found the extra methylation and microRNAs may have accounted for hundreds of those misbehaving genes.

And many of those genes, the researchers predicted, control health problems associated with autism.

In one of the studies, the researchers further examined a gene that had been muted, called RORA. A loss of RORA can be linked to a host of autistic issues—like the death of certain tell-tale cells in the brain, called Purkinje cells—and the researchers were able to add it to the list of genes that may be implicated in autism.

And findings from both studies raise the possibility that blood tests could be developed to provide a window into the dysfunctions occurring in an autistic brain.

(The articles appeared online, ahead of print, in the journal of the Federation of American Societies for Experimental Biology and the online journal Genome Medicine.)

Unraveling the mysteries of epigenetics is nice and all, but Dr. Hu finds herself driven by a reason beyond scientific inquiry: the roles of methylation and microRNAs in contributing to autism may be reversible.

With the ability to correct genetic mutations still a distant possibility, says Dr. Hu, epigenetics may lead scientists to better near-future treatments to ease or erase symptoms—a thousand Band-Aids for the thousand cuts of autism.

With epigenetics “it’s not like you have to change the sequence of the DNA to correct the problem,” she says. “You just have to alter the way the gene is used. So that's a big difference."

Drugs to reverse methylation already are used in cancer patients, she says, and levels of microRNA also can be controlled. But in order to parlay that to autism much work remains in targeting treatments to precisely the right genes.

“We’re not there yet, for sure,” she says. “But there’s a possibility.”

Dr. Hu’s office in Ross Hall is a stereotypical scholar’s workshop: Mounds of paper crowd her desk and are beginning to form into foothills on the floor. A second desk is entirely overrun by paper. Books on chemistry and biology and the interactions between them climb the walls.

Nearby, a magnet reminds any visitors with raised eyebrows that, apparently, Einstein’s desk also was a mess.

On the chalkboard in front of Dr. Hu’s desk hangs a poster print of a lush landscape, fed by cascading water. Her inspiration, however, comes from the stuff all around it: photos of family, of smiling golden retrievers, and most importantly of Matthew—as a child and through the years leading up to him in cap and gown for high school graduation in 2006.

Her pride is evident—on her face and everywhere around her office—but “it was such a struggle,” she recalls.

Dr. Hu and her husband took their son to the doctor in 1989 when he was 2 years old, concerned that he wasn’t yet speaking. After six months of testing he was diagnosed with Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), one of the several types of autism.

The diagnosis offered little relief; uncharted territory for her as a parent and a researcher. Dr. Hu had joined the GW faculty the year before as a chemist working with cell membranes; she was more than a decade away from launching a career in autism research.

Looking for answers at the time she found “virtually nothing” about PDD-NOS in the medical literature, and the more she read about autism “the more depressing it was because the prognosis for anyone with autism was pretty bleak.”

“From the time he got a diagnosis your life changes, honestly. Because all you’re thinking about is: What can I do to help my kid?”

For years, those efforts would be outside the lab. Matthew made quick advances in a specialized preschool program but labored the rest of the way through the public school system, too intelligent and high-functioning to be grouped with the learning disabled, too socially impaired to fit in with mainstream classes. Along the way Dr. Hu helped establish a support group for parents of kids with Asperger syndrome and high-functioning autism that did bring about changes at school, though not fast enough to impact Matthew.

At the end of 2004 she took a sabbatical and decided to shift her research energies into a new realm. “Because I’m a parent,” she says, “the answer was autism.”

“I jumped in feet first,” she says. “I didn’t have any [funding], I hadn’t done any work on autism prior to this, I didn’t have a track record.”

But she had worked before on analyzing levels of gene activity, and found that to be an opening into a realm of autism research that appeared all but vacant.

Since then she’s come to see autism as a problem for personalized medicine. Suspected genetic mutations, she says, are so varied they are almost unique to each family. And even as her lab is working to define specific gene expression profiles among people with different types of autism, the fact remains that one person’s tangle of disrupted genes and symptoms are different from the next.

“The key,” she says of treatment, “would be to identify the individual’s deficits.” It’s something she longs to do for her son. All of the drugs he’s been prescribed have missed the mark.

“I would like to test him and see what’s wrong, what pathways are faulty—then maybe there could be something pretty simple.” But her hands are tied here, for now, without funding or approval for such a study.

She remains hopeful, though, that some day her grant proposal to pattern these disrupted gene pathways in human subjects will go through … and perhaps involve studying just the right age group. “As he gets older,” she says with a laugh, “I have to move it up.”

In the meantime, she’s learned to leverage her experience as a mother. “It’s nothing but an advantage for me because I think it helps me see autism in a different light,” she says. “I think it also makes me better able to talk about our research with parents because I know what their concerns are; I know where they’re coming from, and they know where I’m coming from.”