Columbia University Medical Center

Epilepsy Expert Joins Columbia’s Institute for Genomic Medicine

Advances in epilepsy genetics may put seizure disorders at the front line in precision medicine

Wayne Frankel (right). Photo by Marie Chao, courtesy of the Jackson Laboratory.

Wayne Frankel (right). Photo by Marie Chao, courtesy of the Jackson Laboratory.

In the early 1990s, a prominent geneticist quipped that “whoever described diabetes as a geneticist’s nightmare had evidently not given due consideration to any claims the epilepsies have on this title.”

Fast forward to 2016, and epilepsy genetics has rapidly progressed. New techniques in genomic sequencing have uncovered a host of new genes linked to epilepsy, bringing the number of strong candidates known today to about 300.

But the identification of genes is not enough to find new therapies for epilepsy, says Wayne Frankel, PhD, the newest member of Columbia’s Institute for Genomic Medicine. “We have to determine how they cause disease and identify the parts of the process that we can target with drugs.”

Dr. Frankel says these types of studies can now progress at a much faster rate than ever before by using the newest techniques in gene editing, like CRISPR, to develop mouse models that more precisely reproduce human disease. The National Institute of Neurological Disorders and Stroke agreed, and in 2014 gave him a Javits Neuroscience Investigator Award, which will provide funding for the project for up to seven years.

Dr. Frankel arrived at Columbia in November after 24 years as a professor at the Jackson Laboratory in Bar Harbor, Maine. Below he discusses the state of his field and his own research goals.

 

Q: How did the field of epilepsy genetics go from a field that some feared to tread, to one that that some say may turn seizure disorders into the next front line in precision medicine, after cancer?

A: Until recently, efficiently finding genes linked to epilepsy in patients was difficult. When I started in this field 25 years ago, I looked for genes in mice with seizure disorders and then examined what those genes did. It was slow work but we steadily made progress and many of these genes were later found in epilepsy patients. That’s what I did up until a few years ago.

But now with advances in genomic sequencing, folks like David Goldstein [director of Columbia’s Institute for Genomic Medicine] and others have shown it’s much more efficient to find the genes in people with the diseases.

At the same time, gene editing in mouse models has become so much easier and faster, to the point where things are now really exciting. We can learn what these genes are doing much more rapidly than in the past.

 

Q: How will that lead to new treatments?

A: In many cases, these mouse models actually do mimic children with these types of severe epilepsy disorders, and that means you can do preclinical testing of drugs that we predict may help the patients either by targeting the genetic change or the pathways around the genetic change.

We can even do more large-scale screening of drugs. The IGM is now developing a screening assay based on primary neurons from these models. Cell activity is often abnormal in neurons from models carrying a disease gene, so we can use those assays to quickly screen compounds in a dish to see if any can normalize neuronal activity.

The thing that’s exciting is that if you find something that works in a dish, you can go back to the mouse and ask—even before going to the clinic—do these compounds work? Not only can we look at the drugs’ effects on seizure behaviors, we can also look at other behaviors that accompany the seizures, which are often more serious than the seizures themselves.

 

Q: About 300 genes have now been identified that are likely to cause epilepsy, and you’ve said there will probably be around 1,000. Does that mean we need 1,000 therapies?

A: That’s another part of our research. Most people including me think that those 1,000 genes, or whatever the actual number is, will actually converge onto a small number of mechanisms–maybe as few as a dozen–that cause the exact same clinical syndrome.

Our research is not just asking, what’s the gene, what’s the molecule that can target it, but what’s the cellular manifestation of that mutation? Do all these different genes lead to the same defect in the cell, and is that why the disease looks the same at the end?

We don’t think we’ll have to target all those hundreds of molecules; instead we’ll be able to target common points of convergence. I think that’s where the real excitement is going to be when the smoke begins to clear.

 

Q: The focus in epilepsy genetics is still on severe, but rare, childhood epilepsies. What about the more common forms?

A: That’s where the next push at the genetic level will be.

I think some of the more common epilepsies are not necessarily going to be more genetically complex with lots of different genes combining to cause a disease. That’s the way people have classically thought about complex traits, and it’s going to be true for some cases of epilepsy.

But I think more of these common epilepsies will be caused by more subtle mutations of the same genes that cause the severe epilepsies. We’ll have to look more closely at these genes and see if other changes are causing other forms of the disease. I think that’s how we’re going to make headway with the more common forms of epilepsy.

 

Q: What attracted you to Columbia?

A: Columbia is a hotbed of cutting edge translational research. With all the graduate students, postdocs, and medical fellows available here, there are all sorts of creative, bright, aggressive young people to help push the research along. And with the recent progress in human genetics, I feel like I need to be closer to clinical genetics.

I’m also going to be the director of preclinical models for the IGM, so I will be the primary consultant for others in the institute who want to develop models for other diseases.

My own research is important to me and I get excited about it, but I really like working with other people’s data, advising them, and seeing them succeed. I do hope to make our own significant contributions here, but if I can also contribute to others’ successes, that will make my day.