A deeper understanding of genetics may unlock autism’s mysteries

by Anna Simon

autism - boccuto
Photo of Luigi Boccuto courtesy of Lori Bassett / GGC.\

 

In researching the causes of autism, scientists hope to give a community new options

Clemson University researchers combine science and detective work as they piece together clues, cell by cell, to solve a genetic puzzle behind an increasingly common disorder that alters a child’s social interactions, behavior, emotions, and learning.

Autism Spectrum Disorder (ASD) affects one in every sixty-eight children in the U.S., according to the Centers for Disease Control, yet its cause remains shrouded in myth and mystery. ASD is five times more prevalent in males than females, and is found across all class and ethnic lines. And the numbers are on the rise, the CDC reports.

Public awareness of the autism spectrum is growing. A boy with Asperger’s syndrome, a form of autism, was a main character in NBC’s hit show Parenthood. A recent New York Times article alludes to numerous well-known personalities possibly being “on the spectrum.” At the same time, misunderstandings of the various disorders that fall under the umbrella of ASD abound. The South Carolina Autism Society has a webpage to rebut the myths: Autism is a developmental disorder; it is not a mental illness. These are not unruly kids who choose to misbehave. And autism is not caused by bad parenting.

We don’t know exactly what causes autism. And we don’t know why we’re seeing more of it. It could be solely due to greater awareness and better diagnosis. However, the CDC doesn’t rule out the possibility that there’s something more behind the increasing number of people with ASD.

By discovering the causes, researchers at Clemson University and the Greenwood Genetic Center hope to develop more definitive diagnostic tools and biologically specific treatment, says Kevin Champaigne, a research assistant professor of bioengineering. Champaigne is one of several Clemson researchers working with Greenwood Genetic Center scientists and clinicians to delve into the mystery of ASD.

“We are trying to investigate differences at the cellular level that are part of ASD,” Champaigne says. “If we can discover the differences between cell lines of children with ASD and typically developing children, we might be able to develop a diagnostic test or a treatment and potentially understand the underlying cause.” One difference is in the utilization of tryptophan, an essential amino acid in the human diet found in foods ranging from turkey to chocolate. Researchers exposed cell lines from children with and without ASD to various energy sources. When tryptophan was the only energy source provided, cells from patients with ASD showed a lower metabolic rate, Champaigne says. The researchers want to know why.

Perhaps a molecular defect affects tryptophan utilization, says Chin-Fu Chen, an assistant research scientist at Greenwood Genetic Center who works with Champaigne.

The team also includes Delphine Dean, Clemson’s Gregg-Graniteville Associate Professor of bioengineering; Greenwood Genetic Center faculty member Luigi Boccuto, an assistant research scientist who heads the team; and Charles Schwartz, research director at the center. They make up one of five multidisciplinary research teams, composed of Clemson and Greenwood Genetic Center scientists and clinicians, conducting studies related to autism.

A complicated condition

Unlocking the mystery behind the genetic disorder “is a critical challenge that can improve the lives of patients and their families,” Boccuto says.

Advocates for people with ASD point out that autism is not always a problem in need of a cure. For some, autism endows special gifts of intellect or creativity. Many individuals, and their families, are simply happy with themselves as they are. But for others, ASD impairs basic function. So there is no one-size-fits-all approach to diagnosis and treatment, researchers say. Yet everyone seems to agree that we need more research to understand ASD’s causes and to offer better options for helping people on the spectrum function in their families, their schools, and their society.

Why do the cells from patients with ASD metabolize tryptophan differently? One area of interest is mitochondrial function, which has been associated with ASD in multiple studies, Champaigne says. Mitochondria are the powerhouse of the cell. They provide energy and regulate the cellular metabolism. The researchers want to know if mitochondria play any role.

“If we can understand the mechanism and learn whether it is related to diet and nutrition, environment, genetics, or a combination of those factors, we may be able to reduce the prevalence of ASD,” Champaigne says.

Everyone seems to agree that we need more research to understand ASD’s causes and to offer better options for helping people on the spectrum function in their families, their schools, and their society.

Understanding why patients with ASD use tryptophan less efficiently could lead to new treatments, Schwartz says, and it also could lead to a diagnostic blood test. First researchers must learn whether the difference is specific to patients with ASD or if it shows up in patients with other developmental disorders, such as ADHD. If it’s consistent only in patients with ASD, the difference could be used as a biological marker in the development of a blood test to give doctors a more definitive diagnostic tool and identify at-risk children earlier in life, Schwartz says.

Several of the teams are working toward development of a blood test, and for good reason.

“Most of the time diagnoses now are based on behavior. If we can detect indications based on the metabolic signs, it should have an impact in earlier diagnosis and treatment,” says Anand Srivastava, a senior research scientist and associate director of the Center for Molecular Studies at the Greenwood Genetic Center and an adjunct professor of genetics and biochemistry.

The earlier treatment starts the more effective the intervention can be, and that has a lifelong effect on the patient, says Feng Luo, an associate professor in Clemson’s School of Computing, who is a part of the research team headed by Srivastava.

In order to understand the mechanism that causes ASD, the researchers have examined hundreds of metabolites—small molecules in the cell tissue, such as lipids, nucleotides, carbohydrates, and amino acids—and have identified more than twenty-five metabolites that differ in children with ASD compared with typically developing children, Srivastava says. These metabolic differences also could be used as potential biomarkers in development of a blood test.

Srivastava is after another big piece of the puzzle as well: Are the metabolic differences caused by ASD, or do they cause ASD? Srivastava wants to know, he says, because “If it is causing ASD, then researchers could be on the road to preventing ASD.”

Srivastava and his coinvestigators Luo and Liangjiang Wang, an associate professor of genetics and biochemistry, also are trying to capture disturbances in ASD at the transcription level. The team is elucidating contributions of long noncoding RNA genes and protein-coding genes in ASD to better understand the pathogenesis of ASD and to identify biomarkers for ASD.

Understanding toxic stress

Toxicologist Bill Baldwin, a professor of biological sciences at Clemson, suspects that exposure to chemicals in the environment or a poor diet plays a role in the increased occurrence of ASD. Baldwin and biological sciences professor Charles D. Rice, along with Boccuto and Schwartz, are comparing cells of autistic patients with a control group to see if toxic chemicals figure into the altered metabolism of tryptophan.

Baldwin’s starting point is the work Schwartz has done on differences in metabolizing tryptophan. Tryptophan makes NAD and NADH, which are part of the electron transport chain and carry electrons needed to make the high-energy molecule ATP in our bodies, Baldwin explains. The process occurs in the mitochondria. Baldwin is investigating whether a toxic component is obstructing mitochondrial function.

Toxic chemicals contribute to rising rates of other conditions, including obesity and reproductive disease in males, so perhaps a toxic component is interacting with genetics to fuel the increase in ASD, Baldwin says.

“The person who has autism probably has a genetic defect, but if it wasn’t for exposure to a toxic chemical or a really poor diet, this autism may not show,” Baldwin says.

If successful, this would open the door to new research that could offer a new level of treatment for patients with ASD.

Baldwin wants to find out if mitochondria are more sensitive in patients with autism than in other individuals. The research team has isolated cell lines from seventeen patients. First, they’re comparing the sensitivity of the cells of patients with ASD to those without ASD. Next, they’ll add toxicants to the cells to see whether mitochondria of cells of patients with ASD are more sensitive to the oxidative stress caused by substances ranging from polyunsaturated fats in our diet to toxic chemicals in the environment, Baldwin says.

If oxidative stress is a factor, “maybe changes can be made in the patient’s diet or in pregnant and breastfeeding mothers’ diets,” Baldwin says. “Perhaps certain antioxidants can be added to the diet to provide more protection.” This “may not get rid of autism but certainly can help the patients and the families that are susceptible to autism.”

Modi Wetzler’s work is slightly different. Wetzler, a research assistant professor of chemistry, is interested in brain development, synapses, and a substance called N-modified creatine. He is working with Sue Chapman, an associate professor of biological sciences, and Schwartz on a project aimed at treating an X-linked intellectual disability with autistic features, not autism itself.

About 1 percent of Americans suffer from X-linked intellectual disabilities. The team is studying a specific X-linked problem, called creatine transporter deficiency, that affects an estimated 50,000 Americans, Wetzler says. Creatine, an amino acid that provides the burst of energy needed for the cell to do its job, can’t get from the bloodstream to the brain in individuals with this deficiency. Protein transporters aren’t able to carry it across the blood-brain barrier.

“If you could make a substance that mimics creatine that can cross the blood-brain barrier by itself instead of having to be carried by a transporter, then you could treat the underlying cause of the intellectual disability as opposed to treating just the symptoms with medication such as mood-altering drugs,” Wetzler says.

Although the idea isn’t new, the Clemson and Greenwood Genetic Center researchers are using a different approach that is currently in the patenting process.

“Historically there is basically no treatment of any X-linked intellectual disability. Instead of treating the cause, they treat the symptoms with medications not related to the intellectual disability. It improves the manageability and quality of life for the patient and caretakers, but you aren’t treating the underlying cause of the disability,” Wetzler says.

The various collaborative studies of cellular differences and mitochondrial function could open up enormous possibilities for treating ASD, Schwartz says.

He envisions development of a treatment that can be applied to the patient’s cells to normalize them, just as insulin helps diabetic patients normalize their blood sugar levels or blood pressure medications help regulate patients with high blood pressure.

“If successful, this would open the door to new research that could offer a new level of treatment for patients with ASD,” Schwartz says.

Kevin Champaigne is a research assistant professor of bioengineering at Clemson University; Chin-Fu Chen is an assistant research scientist at the Greenwood Genetic Center; Luigi Boccuto is an assistant research scientist at the Greenwood Genetic Center; Charles Schwartz is the director of research at the Greenwood Genetic Center; Anand Srivastava is a senior research scientist and associate director of the Center for Molecular Studies at the Greenwood Genetic Center and an adjunct professor of genetics and biochemistry; Feng Luo is an associate professor in Clemson’s School of Computing; Bill Baldwin is a professor of biological sciences at Clemson; and Modi Wetzler is a research assistant professor of chemistry at Clemson. Anna Simon is a freelance writer based in Pendleton, South Carolina.
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