What is Epilepsy?
Just a few years ago, epilepsy’s mysteries made it appear intractable. But now, thanks to new data and new research methods, there’s real hope for accelerated progress in finding its causes and identifying more effective therapies.
Jackson Laboratory researcher Wayne Frankel, Ph.D. is leading the way. His long-time epilepsy research efforts and promising future directions gained recognition in the fall of 2014, when he received the prestigious Javits Neuroscience Investigator Award from the National Institute of Disorders and Stroke. The Javits Award, made to distinguished investigators with “exceptional talent, imagination, and preeminent scientific achievement,” will support Frankel’s pioneering work to combine the insight of human patient data with the experimental power of precise mouse models.
When Frankel began working on the genetics of epilepsy more than 20 years ago, it was regarded as a particularly puzzling and difficult condition to research— so much so that many scientists steered clear.
“I was a geneticist, not a neuroscientist,” Frankel says, “but I worked with a lab that was investigating epilepsy. I found it very interesting — the disease susceptibility varied between different strains of mice — but so little was being done in the field that I saw opportunity as well as challenge.”
Epilepsy is a complex neurological disorder with a common trait: seizures provoked by spikes of electrochemical activity in the brain. Beyond that, however, the underlying causes and observable symptoms, including seizure type and severity, are highly variable. About one third of cases arise from a known brain trauma, such as an accident or a tumor, but most cases are idiopathic, meaning that they arise without known cause. And while recent progress suggests that most of these cases are genetically based, they are not necessarily heritable in the classic parent-offspring manner, confounding traditional approaches to studying them.
'People thought that was kind of crazy'
When Frankel launched his program at JAX in 1992, he investigated mice with both spontaneous and induced mutations leading to seizures. It was painstaking research, years of identifying the underlying genetics in mice and teasing out the neural mechanisms affected by the mutations, but his progress was steady. Frankel identified mouse mutations that could be matched with ones found in human epilepsy patient populations. And his efforts provided insight into the mechanisms of different kinds of seizures and the roles of the proteins affected by the mutations. The complexity of the disease, however, continued to present obstacles.
“So far, spontaneous seizures have been identified with over 200 different genes after they were knocked out in mice, mostly for other purposes,” says Frankel. “Surely there are hundreds more. When we were doing our early gene mapping studies, I estimated that there might be as many as 1,000 genes with a seizure phenotype. People thought that was kind of crazy, but it looks like the actual number will in fact be closer to 1,000 than 100.”
Excitement ran high in the scientific community after the human genome was sequenced in 2003, but the early genomics research methods were not terribly effective for epilepsy. Despite all the genes identified in mice, association studies in humans yielded only a few genes with strong signals. Clearly, more precise methods were needed.
Sequencing human epilepsy
Over the past several years, genome sequencing has taken phenomenal leaps forward in speed and cost, making it feasible at last to closely investigate changes in patient genomes.
“Several notable groups published a paper a couple of years ago looking at the exomes [the sequences of all protein-coding genes] of children with severe seizures,” says Frankel. “They screened in particular for de novo mutations, meaning mutations that arise in patients spontaneously during early development and aren’t inherited from their parents. They found 329 de novo mutations in different genes, emphasizing their prevalence in pediatric epilepsies.”
Many of these genes are also implicated in autism spectrum and cognitive disorders. And as it turns out, the expanding knowledge of human genetics substantially benefits disease research.
Better disease models
While sequencing technology has improved rapidly, scientists’ ability to actually change the genome has remained limited. Just in the past two years, however, new techniques that use specific RNA sequences to identify locations in the DNA have changed all that. The most promising of these, CRISPR —clustered regularly interspaced short palindromic repeats — is relatively easy, cheap and quick to implement; it allows for exact cuts and DNA alterations. With CRISPR, scientists are readily able to precisely disrupt gene function, so creating mouse models based on human genetics discoveries is now much more straightforward.
“This makes collaborating with human geneticists very powerful,” says Frankel. “Human genetics is finally at the point where it can provide insight into which gene variants are actually causal for the disease, so there’s way less guesswork. And we can take those genes, quickly make mice to model the disease, and then look at the molecular mechanisms behind it.”
With tools that are so much faster, easier and more precisely connected with human patients, Frankel can now focus on disease pathways with unprecedented efficiency and effectiveness.
“We can dissect cells — and even parts of cells — to assess function and learn more detail about how neurons connect with other neurons,” says Frankel. “We can compare gene activity and regulation in mutant cells and healthy cells and ask how are they different and what might be contributing to the disorder?”
The 'virtuous' bench-to-bedside loop
Frankel’s work shows how biomedical research’s traditional bench-to-bedside approach is giving way to a faster, more effective process. Data and insight flow continually from lab to clinic and from clinic to lab, with computational analysis playing a large role on both ends. It makes the disease models more useful and relevant to the patient’s biology, and it provides a closer relationship between experimental discovery and clinical impact.
Genomics methodologies have progressed so quickly, research that was quite simply impossible only a few years ago is becoming routine. The effect of this progress is not lost on Frankel.
“We can do so much more, and every week it changes and improves,” he says. “It’s really exciting stuff.”
The search for better therapies
It is indeed exciting stuff, and it provides reason for optimism that the mysteries surrounding epilepsy — and other complex neurological disorders — can finally start to be unraveled. In the end, of course, there is the ever-present goal: better outcomes for epilepsy patients, who comprise approximately 1% of the population.
“About 30% of epilepsy patients still can’t be effectively treated,” says Frankel. “Moving forward, we can work on novel mechanisms that haven’t been well studied yet and identify new, previously unappreciated targets. Hopefully, some of those targets will yield the better therapies that we need.”
And someday, perhaps, dedicated researchers like Frankel, armed with the tools of genomic technology, will solve all the intricate mysteries of epilepsy.