Behind the Children of Autism

 


FOR SCIENTISTS AT UC SAN DIEGO, THE EFFORT TO CONQUER AUTISM IS PERSONAL

 

By Scott LaFee

Heart disease and cancer kill. Chronic conditions like diabetes and arthritis plague millions. Alzheimer’s disease robs the elderly of their memories. But none are more terrifying than autism, which afflicts children and whose symptoms, seeming to appear without warning between the ages of two and three, can dramatically erase a child’s previous development and personality.

The scientists and doctors who study and treat autism spectrum disorders work in a field fraught with public emotion, angst and heated discourse, unlike any other. Years after former British surgeon Andrew Wakefield published his controversial research study linking autism to childhood vaccines, untold numbers of parents still choose not to vaccinate their children, fearing the idea of autism more than the known peril of measles, mumps and rubella.  

“Autism has a different kind of history,” says Laura Schreibman, Ph.D., distinguished professor emeritus of psychology who founded the groundbreaking Autism Intervention Research Program at UC San Diego in 1984. “For example, cancer never started off with parents being blamed. People got defensive. We know a lot about cancer, but relatively little about autism, which can result in some very strange or wrong-headed ideas. It’s sad, confusing and unfortunate . . . But I’ve never felt there was a better career for me.”

Nor a better place to pursue it. UC San Diego has become a focal point for innovative autism research. It regularly garners headlines for discoveries that illuminate the complex origins and causes of autism and offer hope where once there was none.

Such achievements do not come easy, of course. They demand curiosity, determination and persistence, all traits of any good scientist. Yet the study of autism demands even more: the desire and will to grapple with scientific questions inextricably linked to wrenching real life. Such questions can lead down diverse paths, as the work of several UC San Diego researchers illustrates.

KAREN PIERCE AND ERIC COURCHESNE


“You can’t help but feel a tugging of the heartstrings,” says Karen Pierce, M.A. ’93, Ph.D. ’96, associate professor in the Department of Neurosciences and assistant director of the Autism Center of Excellence in the UC San Diego School of Medicine. “These children face a lifetime of difficulties and challenges. You want so much to give a voice to those without any voice.”

 

Karen Pierce

Eric Courchesne

Part of that voice involves Eric Courchesne, Ph.D. ’75, professor of neurosciences, director of the UC San Diego Autism Center of Excellence, who attracted international attention with the publication of a 10-page paper in the prestigious New England Journal of Medicine.

The study reported clear and direct new evidence that autism begins during pregnancy. Based upon genetic analyses of post-mortem brain tissue in children with and without autism, they found that some layers of the prenatal brain did not develop uniformly, resulting in patches of neuronal disconnectedness and dysfunction.

The findings generated more than 1,000 media stories around the world.

Courchesne’s connection to autism is quite personal. He was among the last wave of children in the 1950s to contract polio. “I have memories of not walking, of being in the hospital for a very long time, of my mother carrying me around, so there was a strong motivation from very early on to contribute to helping children with a major disability, one that makes life difficult and separates them from other people.”

Early in his career, Courchesne was interested in how young children learned through novelty. He studied neural activity patterns, in particular something called the “novelty brain wave.” A colleague mentioned that there was a group of autistic children for whom novelty held no allure. In fact, the colleague said, these children shunned it. When Courchesne looked at the brain activity patterns of autistic children, he could find no novelty brain wave. He was astounded. How could this be?

“I was hooked,” he says.

Pierce, who co-directs the Autism Center of Excellence and is married to Courchesne, recalls a different sort of cerebral introduction to autism. In college, she worked with autistic children, some of whom “had aggressive impulses.”

“One day, I took a young boy out for ice cream to celebrate a week in which he had shown no violent behaviors. We were just sitting there eating our ice cream when he suddenly punched me in the face. There was no reason, but I wanted to know why. That’s when I became hooked.”

After initially working on therapeutic interventions for autism, Pierce redirected her attention to the underlying neuroscience. She thought it gave her a chance to help more children, more effectively.

Pierce’s particular interest is in hastening diagnoses of autism. It’s believed the earlier the condition is identified, the more likely subsequent treatment will be effective and lasting.  

A few years ago, Pierce and colleagues decided that the best way to detect autism as early as possible was to mobilize pediatricians to screen for autism at the first-year check-up. They created a network of 170 pediatricians throughout San Diego and trained them to hand out a simple checklist to parents during well-baby visits. Today, more than 50,000 babies have been screened and those found to exhibit delayed development enter treatment.  Given that the mean age of diagnosis for autism in the United States is age four, Pierce’s program is a substantial improvement in early detection. Her pilot program has since expanded to other cities.

“When I started in the field 25 years ago, an autism diagnosis was devastating,” says Pierce. “Nobody thought it was treatable, let alone curable. Now, there is a significant chance of improvement, especially with early diagnosis and treatment.”


ALYSSON MUOTRI


Alysson Muotri, Ph.D., professor in the Department of Pediatrics, has always been interested in the human brain, at least in terms of how it differs from chimpanzees, among our closest relatives on the evolutionary tree.

One difference is in the prefrontal cortex, an outer layer of neurons in the front portion of the brain associated with complex cognitive skills, decision-making and social behavior. Humans have sizeable prefrontal cortices, chimps not so much.


Alysson Muotri

“People have the capacity to maintain active social contacts with 150 different persons,” says Muotri. “Chimps can manage maybe 50.”

Muotri became curious about diseases that impacted the sociability of the human brain, most notably autism, which is commonly characterized by an inability to establish social contacts or display appropriate behaviors.

As a postdoctoral fellow in 2002, he joined the lab of Fred Gage, Ph.D., a highly regarded professor of genetics at the Salk Institute for Biological Studies and an adjunct professor of biology at UC San Diego. Gage was exploring the idea that, contrary to accepted belief, the human brain was surprisingly plastic and adaptable, capable of growing new nerve cells throughout life. In theory, such ability might be exploited to repair damage from neurodegenerative diseases, brain trauma, and perhaps even improve cognitive functions in patients with autism.

Since conducting experiments on living patients was obviously impossible, the scientists needed to create a cellular model of an autistic neuron, a so-called “disease in a dish” that they could probe, parse and subject to myriad tests and concepts.  They did so in 2010, by which time Muotri was at UC San Diego with a lab of his own.

Muotri’s autism research is fundamental. He works at the level of cells and cellular mechanisms. But like others, there is a personal consideration. He has a seven-year-old stepson with autism. It would be fantastic to discover a cure, but Muotri says he would be happy to simply advance the science, to make smaller but significant contributions.

“You have to think about the real world and the fact that we are talking about very complex conditions. There is no possibility of a single, quick cure for autism,” Muotri says. “But I think that if we can find a therapy that can modify the brain even just 10 percent, maybe help stop an autistic child’s seizures or help him talk or walk, become a little more independent, then that is success. We aim high, but even small advances mean a lot.”

LAURA SCHREIBMAN


As an undergraduate at UCLA in the 1960s, Laura Schreibman initially imagined she might become a TV writer. Then she took a class by the late Ivar Lovaas, a pioneering psychologist who developed one of the most widely used therapies for children with autism.


Laura Schreibman

“One day he brought in some of the children he was working with,” recalls Schreibman. “It was like being struck by lightning. I looked at these kids, how they behaved, and I just knew I had to learn more about them.”

Schreibman became a psychologist, with an emphasis on behavior analysis and treatment of autistic children. She joined UC San Diego faculty in 1984 and launched the Autism Intervention Research Program the next year. The program develops tests and refines behavioral autism treatment programs, but focuses primarily on Pivotal Response Training, a child-directed intervention that uses naturally occurring teaching opportunities, coupled with appropriate consequences and rewards, to introduce, modify or reinforce desired social skills and other behaviors.

“The work requires persistence and patience,” says Schreibman. “Small improvements are celebrated. A lot of people get burned out in the field. They don’t get enough positive reinforcement. But I’ve always thrived on it. These children fascinate me. Just when I think I’ve seen everything, I see something new.”   

JONATHAN SEBAT AND LILIA IAKOUCHEVA


In 2004, Jonathan Sebat was a postdoctoral fellow in the lab of noted molecular biologist Michael Wigler at Cold Spring Harbor Laboratory in New York. “We had just published the first study of copy number variations (CNV) in the human genome. The autism epidemic was in full swing. The autism community was clamoring for answers,” says Sebat. “We knew that the vaccine health scare was not based on credible science. We knew that autism had a genetic basis. I’m not sure whether I chose to study autism, or autism chose me. Looking back, I’d say it was pretty much a collision course.”




Jonathan Sebat

Lilia Iakoucheva

Sebat is now an associate professor in the Department of Psychiatry and chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases at UC San Diego. His research has shown that genes play an elemental role in autism.

“We now have a very general understanding of how genetic factors contribute to autism, and about a dozen genes or CNVs have been strongly linked. There are hundreds more genes that we have not yet been identified, but now we have the tools to find them.

“The major challenges over the next decade will be to understand how genes influence development of the brain and to develop new treatments based on this knowledge,” says Sebat. “I think it’s likely that some promising new treatments will be in development within the next 10 years. I’m an optimist.”

So is his wife, Lilia Iakoucheva, Ph.D., an assistant professor in the Department of Psychiatry. In the mid-2000s, Iakoucheva studied protein structures and interactions at Rockefeller University.

Genes get headlines, she thought, but proteins do the real chores of life. What role did they play in autism, Iakoucheva wondered. Since 2009, she has been trying to find answers in the lab.

“But I read the stories and see what’s happening outside,” she says. “I’m a mom with two kids. I can’t imagine anything worse than having a sick kid. I think about these things all of the time, every day. How can we do things faster? How can we speed up the basic research, translate it more quickly into treatments?”

Still, she’s a believer in the progress being made.

“Think about it, in just a few decades we’ve gone from having no understanding, to having identified genes and plausible drug targets.”

ROBERT NAVIAUX


Robert Naviaux, M.D. ’86, Ph.D., is a relative newcomer to autism research.

A professor in the departments of Medicine, Pediatrics and Pathology, Naviaux is a highly regarded authority on mitochondria—the tiny power plants in all cells, whose dysfunction can result in an alarming array of metabolic diseases.  

For decades, Naviaux and colleagues have pioneered genetic research in mitochondrial conditions. Some are well-known afflictions, such as diabetes, but others are not. Leigh’s disease, for example, is a rare inherited disorder that typically strikes without warning in a child’s first year of life, triggering seizures and rapid development regression. Patients rarely survive to adolescence.


Robert Naviaux

Naviaux got seriously involved in autism research after being invited to a meeting of autism scientists. He listened, pondered and soon had the glimmerings of a new hypothesis. Different from classical forms of mitochondrial diseases, which are solely genetic, Naviaux concluded that autism was the result of multiple converging causes: genetic, environmental and a phenomenon dubbed the “cell danger response” (CDR).

The CDR hypothesis posits that when genes and environmental factors interact adversely, cells that feel threatened or become damaged react defensively. Their protective membranes stiffen. Internal metabolic processes change, most notably those involving mitochondria. Communications with other cells are dramatically reduced.

“Cells behave like countries at war,” Naviaux said. “When a threat begins, they harden their borders. They don’t trust their neighbors. But without constant communication with the outside, cells begin to function differently. In the case of neurons, it might be by making fewer or too many connections. One way to look at this related to autism is this: When cells stop talking to each other, children stop talking.”

Naviaux’s work pushes the limits of the prevailing autism paradigm, but he insists it is actually complementary. Autism results from genetics, environmental factors and dysfunctional metabolic processes.  

In the last two years, he has published papers showing that when CDR is tamped down, allowing cells to restore normal communications and functions, autism-like symptoms in a mouse model are reversed.

The particular remedy uses a century-old drug for treating sleeping sickness. While its beneficial effects are temporary and adverse side effects make it unsuitable for long-term use, Naviaux thinks it could lead to new insights and therapies not yet imagined.

“We can only be observers and ask questions of nature. We can use the tools of the scientific method to test new ideas. We must have the courage to follow where the data leads us without bias.”


Scott LaFee is a public information officer at UC San Diego Health Sciences.