Gene ‘Flavor’ Differences Likely to Provide Valuable Data

by Margaret Wahl on Sat, 2006-04-01 15:53

Alana Lysholm-Bernacchi is working at the gene chip fluidics  station.

(above) Alana Lysholm-Bernacchi is working at the gene chip fluidics station.

(below) Sarah Brautigam works at TGen's gene chip hybridization ovens. Photos by David Pantoja

Sarah Brautigam works at TGen's gene chip hybridization ovens.

At 36, Dietrich Stephan has already completed three years of postdoctoral study at the National Human Genome Research Institute at the National Institutes of Health (NIH), and been an assistant professor of pediatrics, genetics, biochemistry and biology, and an associate professor of neurology. Most recently, he’s become director of the Neurogenomics Division of the nonprofit Translational Genomics Research Institute (TGen) in Phoenix.

TGen has received a $652,000 grant from MDA to use state-of-the-art technology to find the most minute differences in the genes of people with ALS compared to people who don’t have ALS. (The grant is funded through MDA’s ALS Translational Research Program and Augie’s Quest.)

These differences in gene "flavors," as Stephan describes them, could unlock the secrets to early diagnosis of ALS and provide new targets for drug development.

So far, scientists have identified five genes that can, when mutated, directly cause ALS. But they suspect there are at least five more that can, when they contain certain variations, predispose a person to the disease.

Small variations in a gene’s “sequence” — its chemical composition — account for genetic differences among people. So, for instance, even though everyone has a gene for APOE, it’s possible to have variations in the APOE sequence known as APOE2, 3 and 4.

He expects to find similar leads in ALS by studying blood cell DNA from 1,000 people with and 1,000 people without the disease and comparing their gene sequences.

Stephan’s TGen group will use silicon chips to look for “single nucleotide polymorphisms,” or SNPs, a new technology that’s been developed in association with NIH’s Human Genome Project.

“A lot of common disorders are going to topple to this technology, which has only become available in the last six to nine months,” Stephan says.

Dietrich Stephan

Dietrich Stephan

“We’ll understand which positions in the genome predispose an individual to ALS and then we can test them and see what their risk would be before they develop ALS. For the future, for people who don’t have ALS yet, we can envision developing a diagnostic test that would allow us to monitor individuals early, diagnose them early, and put them on a to-be-developed therapy that would intervene before the pathology gets too devastating.”

Also, he says, therapeutic targets are likely to reveal themselves. “Therapeutic targets are what you get once you have a gene name. What I anticipate emerging is a list of maybe five new genes, each of which becomes a new therapeutic target that drug companies can aim their bullets at.”

Stephan expects to have identified his five targets by the end of this year, assuming he can soon add 1,000 ALS-affected blood samples to the 1,000 unaffected samples he already has. “The core of the issue is collecting those 1,000 ALS patients. As soon as we get that done, we can rip through the rest of it in the lab.”

Anyone with a confirmed ALS diagnosis who doesn’t have any other motor neuron disorders can donate a blood sample to the TGen gene search by contacting any of these sites:

Stacey Champion, Study Coordinator
Forbes Norris MDA/ALS Center
California Pacific Medical Center
San Francisco
(415) 600-3967;

Danielle Rowlands, Study Coordinator
University of Pittsburgh
(412) 393-9181;

Mary-Louise Spears, Study Coordinator
Methodist Neurological Institute
(731) 441-3765;

Margaret Wahl
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