Washington - The metal detectors for the Dalai Lama's upcoming lecture already were installed, but luckily not yet in operation when Jeffrey Noebels gave his plenary lecture on "Profiling Ion Channel Disorders In The Brain" on Nov. 12, making obtaining a seat far less complicated than it would be a few hours later.

Noebels spoke about the history of research into the genetics of epilepsy, as well as some of his own discoveries in the area, and gave an overview of the newest attempt to shed light on those genetics, called the human channelopathy project.

The findings of the project could bear fruit for the treatment of many brain disorders, as well as diseases of the kidney, heart and muscles, all of which depend on ion channels to function. Noebels, who is a professor of neurology, neuroscience and genetics at Baylor College of Medicine in Houston, is most interested in epilepsy, which is "one of our most prevalent primary neurological disorders," yet often cannot be treated adequately.

"About half of these people continue to seize despite our best efforts," he told the audience.

A genetic contribution to epilepsy has been recognized for more than half a century, and as molecular techniques became available, a "constant drumroll" of about 75 such genes was identified through an approach Noebels termed "the two-stroke engine of epilepsy gene identification" - positional cloning of genes in patients with familial epilepsy and mutagenesis studies in animals.

"First, we were so excited about our gene discoveries that we thought most or all cases [of epilepsy] could be explained by single-gene mutations," Noebels said. Not so - most clinical cases could not be traced to a single genetic culprit, and he now believes that "the reality is probably a lot different."

The current theory is that single-gene epilepsies are rare; instead, most cases might be due to several genetic mutations that have additive effects on neural functioning. Similar to the concept of total mutational load in cancer patients, "total channelopathy load" exceeding a certain threshold might be the cause of epilepsy. According to that theory, the reason most epilepsy occurs in patients without a family history of it is that epileptics might inherit mutations from each parent that are insufficient to produce outright disease by themselves, but combined add up to produce clinical symptoms.

The human channelopathy project was conceived to test that idea. The project will sequence all 250 known ion channel genes, investigate them for SNPs and look for associations between the number of mutations and clinical epilepsy.

Mindful of the saying that association studies are "easy to do, but hard to do well," the scientists will be sequencing 1,000 people, half of whom suffer from some form of epilepsy, for their SNP discovery project. About a fifth of the way into the project now, the group has identified almost 1,100 SNPs in ion channel genes, including 44 novel SNPs in 11 known genes.

Noebels stressed that to date, the project has not sequenced enough people to know whether their findings are real or statistical flukes. But he also said that the patients do seem to have more mutations overall in their ion channel genes than the controls. If true, that finding would support the hypothesis that clinical epilepsy can arise when total mutational load crosses a threshold level.

Noebels - while being shooed out of the lecture room by security personnel waiting for the State Department to examine it - discussed the implications of the total channelopathy load theory for drug treatment with BioWorld Today. Given that the channelopathy project already has seen one patient with eight mutations in ion channel genes, it appears that multidrug therapy might be needed to actually control the clinical symptoms of epilepsy. On the other hand, he said, "The first generation of [anti-epileptics] were generally dirty drugs - they were nonspecific, they had a lot of different effects, and patients were still not responding.

"But there are certainly new targets in there," Noebels added.

Durham, N.C.-based Icagen Inc. presented several posters on targeting ion channels for epilepsy at the meeting. The good news is that its compound ICA-27243 is a selective agonist of the KCNQ2/Q3 subtype of potassium channel, it hyperpolarizes neurons, has good specificity and showed effectiveness blocking epileptic fits in brain slice preparations as well as in vivo. The bad news is that it generates toxic metabolites and is not going into clinical development, though Icagen senior scientist Jeffrey Krajewski said that there is "a shortlist" of compounds for clinical development that includes relatives of ICA-27243.

Asked why the company would go through the effort of presenting data on a compound that is, clinically speaking, a dud, vice president of new product development Gregory Rigdon told BioWorld Today that regardless of whether they report on a clinical candidate or not, posters establish the company's presence in the space and generate interest from potential collaborators.

"And," he added, "as a scientist, you always want to publish."