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Faculty Spotlight: William Kirby Gottschalk, PhD

Monday, April 4, 2016

For William “Kirby” Gottschalk, PhD, the road to the Duke Department of Neurology began with a nematode taken from a local Oscar Meyer plant. In our first faculty spotlight of the new year, Gottschalk talks about these beginnings, his research in Alzheimer’s disease, and mentoring neuroscience students.

What are your responsibilities within the Department? What does a typical day look like for you?
I am focused on research. In collaboration with Drs. Allen Roses, Ornit Chiba-Falek and Mike Lutz, Mirta Mihovilovic, and a cast of undergraduate students, I am engaged in deciphering how an intronic poly-T stretch of the TOMM40 gene contributes to risk for Alzheimer’s disease. A typical day involves discussions – lots of discussions with my colleagues and our students – keeping up with the literature, planning and conducting experiments, and obsessing about, and writing, grant applications.

How did you first get interested in neurology?
In graduate school, I was surrounded by developmental neurobiologists, and my first graduate rotation was in a lab focusing on retina development. Tony Stretton, a member of my PhD committee, was a student of Sidney Brenner’s, and while Brenner’s group was busy mapping the nervous system of C elegans, Stretton’s group mapped, and developed a computer model of, the nervous system of the giant nematode Ascaris lumbricoides, which they obtained from the local Oscar Meyer plant.

[Close to one billion people worldwide are infected with Ascaris lumbricoides, which at least has the courtesy to grow neurons useful for research purposes. Image courtesy CDC.]

Close to one billion people worldwide are infected with Ascaris lumbricoides, which at least has the courtesy to grow neurons useful for research purposes. Image courtesy CDC.

The advantage of working with Ascaris was the large sizes of the neurons; the disadvantage is the worm can grow to > 14 inches – a bit too large for a petri dish! In the end, I chose a more basic approach and focused on biochemistry, and until I joined GlaxoSmithKline my research focus had been diabetes and related metabolic disorders. However, the company offered great opportunities to expand one’s vistas, and I soon found myself working on an AD-related team headed by Allen Roses, who was then head of the Genetics Directorate at GlaxoWellcome.

The project focused on developing a treatment that would delay, if not prevent, the onset of AD in carriers of the APOE e4 gene. We demonstrated the compound, a the PPARg agonist similar to rosiglitazone, stimulated glucose metabolism in the brain, and others on the team showed it promoted neuronal mitochondrial biogenesis in mice.

One area that you’re researching is how genetic polymorphisms affect the progression of Alzheimer’s and other diseases. How has our understanding of this area changed over the past decade?
In the early 1990’s, Duke investigators headed by Allen Roses discovered the APOE gene is a risk factor for developing late-onset Alzheimer’s disease (LOAD). There are three APOE alleles, and the Roses group found specifically that APOE e4 increases the risk of developing LOAD and is associated with earlier age of disease onset. By contrast, APOE e2 is protective, and APOE e3 had been thought of as “neutral.”

A number of GWAS studies have confirmed association between LOAD and the linkage disequilibrium (LD) region that encompasses APOE, TOMM40 and APOC1. To learn more about the relationship of this region with LOAD, the Roses team performed deep sequencing of the TOMM40-APOE LD region, and applied phylogenetic analysis to the results. They discovered a length variation of a polymorphic deoxythymidine (polyT) tract in intron 6 of the TOMM40 gene is associated with the age of LOAD onset and may explain much of the effect previously ascribed to APOE. The TOMM40 polyT allele lengths in Caucasians are classified as Short (S: T < 19), Long (L: < 20 T < 29) or Very Long (VL: T > 30), and, notably, the genotypes are informative with respect to LOAD age of onset for all APOE genotypes, not just APOE e4-bearing genotypes.

What implications does this improved knowledge have for treating patients with these conditions? 
AD is the poster child of unmet medical needs: no one recovers from it. We hope by learning the biological underpinning of the TOMM40 polyT effect, to uncover tractable drug targets for delaying, or perhaps even preventing, LOAD. Of more immediate practical benefit, the design of clinical trials for new therapies for treating or delaying the onset of AD will be improved by incorporating knowledge of subjects’ TOMM40-APOE haplotypes.

You’re also a mentor for students in the neurosciences study program. How did you get involved in that? What is that experience like?
Some of the students have come to us through word of mouth, and some through the Bass Connections interdisciplinary research program. It has been a wonderful experience – and a challenge that has kept my colleague and partner in crime Mirta Mihovilovic and me on our toes. The students bring excitement and energy to their projects, and a true sense of wonder. Watching them connect what they’ve been learning in texts and lectures to what is actually happening in the experiments they are doing is like watching children open their holiday presents…and then that spark, that fire gets re-ignited in us, and so it continues full circle.

[Kirby Gottschalk candid photo]

Gottschalk relaxing during a recent vacation.

What passions or hobbies do you have outside of the Department?
Passions? My family. (Following the Packers and the UW Badger Hockey team are distant seconds) Hobbies? Wissenschaft Uber Alles! [Editor’s translation: Science over all!]Photography is a not-so-bad second.