Studying genetic variants in “the worm”

Andy Golden, Ph.D., Section Chief: Genetics of Early Development, Laboratory of Biochemistry and Genetics, The National Institute of Diabetes and Digestive and Kidney Diseases Health Information Center

---

I have been working with Caenorhabditis elegans, a microscopic roundworm that lives on rotting fruit and insects, for most of my scientific career. This organism is affectionately referred to as “the worm” and many thousands of researchers worldwide study it.

I’ve worked at the National Institutes of Health for the past 20 years, and I have seen many researchers studying rare diseases in humans. Interestingly, the worm shares many of its genes with humans, and thus I became interested in modeling rare diseases in the worm. 

How I came to learn about Timothy syndrome (TS) is quite fortuitous. About 10-12 years ago, I attended a Genetic Alliance meeting and met many interesting advocates of many different rare diseases.

I happened to sit next to Adrienne Butterwick from the Sudden Arrhythmia Death Syndromes (SADS) Foundation. I asked what SADS was and quickly realised I had a SADS condition (another story for another time). I have been attending their annual meetings for at least the past 8 years. 

A few years ago, at the meeting, they announced a breakout session for those families with Timothy syndrome, and I asked if I could attend this small group meeting to learn more about this disease. I was welcomed with open arms by the group and their leader Katherine Timothy, after whom the syndrome is named. Katherine was the first to recognise the combination of unusual symptoms in this group of kids. 

After learning about this disease and the genetic variants, I returned to lab and realised we could try to model this disease in the worm because the worm had a very similar gene.

Even though the worm does not have a heart or many of the organs found in humans, we believe that at the cellular level, this CACNA1C gene is doing the same thing in both organisms – shuttling calcium into cells.

We were able to edit the genome of the worm and make single amino acid changes to mimic the changes found in TS individuals. And so began my interest in Timothy syndrome, and a great friendship and collaboration with Katherine Timothy and the TS families.