Why did you shift from clinical practice to basic research?
In medical school [at the University of Tübingen, Germany], I took advantage of an opportunity to do Ph.D.-level research, to get a taste of it. That led to a fellowship in stem cell research at the National Institutes of Health [NIH], and I was hooked. It was a very interesting time for the field.
New technologies were fundamentally changing basic research, especially the use of induced pluripotent stem cells [iPSCs]. We take a patient’s blood or skin cells, reprogram them into pluripotent stem cells, and then coax the stem cells to differentiate into cells of interest such as a person’s neurons. That allows us to study human neurological disease in cell culture.
Are iPSCs important in your work?
They’ve been central to my research since my postdoctoral studies with Dr. Ron McKay at the NIH and Dr. Rudolf Jaenisch at the Massachusetts Institute of Technology. Together we found new ways to use iPSCs to study the genetic basis of PD [Parkinson’s disease].
Inherited genetic mutations account for just 10% of PD cases. What causes the other 90%?
Dozens of genetic variants have been identified in that large majority of PD patients with no family history of the disease—what we call “sporadic PD.” Those variants are not sufficient to cause PD on their own but are thought to substantially increase the risk for developing it.
Are you studying those variants?
I’m studying how the risk variants interact with other genetic and environmental factors to cause sporadic PD, and how the same variants may interact with inherited mutations to influence the development and progression of familial forms of PD. This involves using iPSCs as well as three-dimensional brain organoids.
In essence, these are minibrains that we grow in tissue culture from the cells of patients. Organoids replicate some of the structural and functional features of actual human brains, so they move us one step closer from iPSCs to modeling the real thing.
What are you studying with your latest NIH grant?
Histone acetylation, a common epigenetic process that influences gene expression. Compelling evidence suggests that histone acetylation is dysregulated in neurodegenerative diseases, but the underlying mechanisms are not known.
Is there a role for artificial intelligence [AI] in your work?
Genetics researchers have been using machine learning, a form of AI, for some time. For example, AI helps us see in large datasets patterns that we cannot detect with conventional tools.
What do you like to do outside the lab?
My wife and I are foodies. We love sampling restaurants in New York. We also love to travel, usually internationally, but since COVID-19 we’ve been exploring national parks around the United States. This country is so diverse, so beautiful.