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Greenwood Researchers Report Positive Results Using Biolog Phenotype Arrays to Develop Autism Dx

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Researchers from the Greenwood Genetic Center have reported positive results that confirm their earlier findings in an effort to develop a test for autism spectrum disorders using Biolog's phenotype array technology.

Last week, the group — led by Charles Schwartz, the center's director of research — published data in Molecular Autism from a study of 87 patients with ASD and 78 controls that showed that the reduction of nicotinamide adenine dinucleotide production in the presence of tryptophan in lymphoblastoid cells can distinguish patients with ASD from normal subjects and from those with other neurological disorders.

In the study, the researchers found that this aberrant tryptophan metabolism was present in all of the ASD subjects in several separate cohorts, but in none of the normal controls, or in cell lines from non-ASD patients with other intellectual disability disorders or conditions exhibiting other similarities to autism syndromes apart from behavioral traits.

Ultimately, the researchers hope that the project will lead to the development of an array-based test for ASD.

The study, funded by a $275,000 grant from the National Institutes of Health that began last year (BAN 5/22/2012), utilized Biolog's array platform, which can measure up to 1,400 metabolic and chemical sensitivity phenotypes of mammalian cells.

According to the firm, arrays are provided in 96-well plates. Cells of interest are scanned for phenotypes by adding cell suspension to each well followed by the addition of Biolog's redox dye. In some wells, the cells are stimulated and in other wells inhibited. The generation of energy-rich NADH by the cells reduces the redox dye and brings about a color change.

Biolog CEO Barry Bochner, who worked with the Greenwood team on the study, told BioArray News that the published results confirm observations the researchers had made previously in smaller cohorts — that ASD cells appear to be less capable of using tryptophan as an energy source than do cells from control populations.

"The correlation was really amazing. All 87 samples from autistic children tested positive — so it looks like they may have here [the beginning of] a blood test that can distinguish autism from not-autism," he said.

In the recent Molecular Autism report, Schwartz and his colleagues at the Greenwood center described results from three independent experiments comparing a total of 87 individuals with ASD to 78 controls using the Biolog phenotype array technology and analyzing the array results in a blinded fashion.

In the first investigation, the Greenwood used arrays spanning a large number of metabolic sensitivity phenotypes. For the team's more recent studies, Bochner said that the company created more specific arrays narrowing down first to a number of tryptophan dipeptides along with tyrosine — an amino acid that shares some common pathways with tryptophan — and then to just the five most promising tryptophan dipeptides, positive and negative controls, and L-tryptophan.

"[For the latest validation] we made a special plate for them focused on the best tests out of the 367 starting tests we had, really focusing on the tests that looked like the interesting ones," he said.

Overall, the three different experiments all yielded a statistically significant signal — lower levels of NADH generation in the presence of tryptophan — that clearly distinguished cells from individuals with ASD from both normal controls and samples from patients with other neurological disorders.

The group also studied gene expression microarray data in a small subset of 10 ASD samples and 10 controls, using Agilent's Whole Human Genome Oligo Microarray, and found that levels of some genes involved in pathways that link tryptophan and serotonin were reduced in ASD cell lines compared to controls. But no two patients exhibited the same expression profile.

According to Bochner, this finding offers important biological confirmation of the cellular phenotype array results, and is particularly important because tryptophan is converted to many important neurochemicals that affect brain development.

In the study, the researchers discuss a number of potential biological mechanisms influenced by reduced tryptophan metabolism that could affect brain development and function.

According to Bochner, autism may be a good example of a disease where high genetic heterogeneity has foiled efforts based on genomics, transcriptomics, and even proteomics and metabolomics, to identify a unifying criterion for diagnosis.

The fact that poor tryptophan metabolism was present across ASD individuals' cells in the Greenwood study demonstrates the value in zooming out, he said.

Biolog hopes the results of the study may broadcast the utility of the phenotype array approach to other human disease researchers.

Bochner said that the Greenwood researchers have also identified a few other intellectual disability disorders where a metabolic defect might be present using the Biolog arrays. But "other than the [Greenwood team], this has not been picked up by other disease researchers, though we are hoping for that," he said.

"[Autism] is an example where genomics has not really succeeded, but it's not the only disease where that is the case. We believe that there are a lot of other disorders where this could be a really valuable approach," he said.

According to the Greenwood study authors, the team believes that its findings represent a "preliminary step in the development of a ... quick reliable screening test for ASDs."

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