Prof. Alice Chen-Plotkin is the Parker Family Associate Professor of Neurology at the University of Pennsylvania School of Medicine.
“Our general approach is to use unbiased genomic- or proteomic-scale screens in human-derived materials to generate leads, which are then followed mechanistically in relevant systems including neuronal culture and in vivo animal models. The pace of technology development is allowing us to acquire more data, faster, than ever before, but this does not always translate into biological understanding. We believe that to unlock the true potential of leads generated in this way, computational methods must work hand-in-hand with bench-based manipulative experiments.” (From the ChenPlotkin Lab website)
The following is a summary of my interview with Prof. Alice Chen-Plotkin, scroll to the bottom to listen to the full audio version.
I met Alice at the Chan Zuckerberg Intitiative’s Neurodegeneration Challenge Network Meeting, where we shared the stage to give an overview of Parkinson’s to the scientists in attendance.
Alice is a physician who also runs her own research lab that looks into the molecular mechanisms of neurodegeneration. Unfortunately she represents a dying breed of physician-scientists in neurology as their numbers are declining precipitously.
Most of what we know in medicine stems from clinical observation. Someone developed a hypothesis based on something they observed in patients, and then devised experiments to test that hypothesis. However in modern neurology there are very few people capable of themselves drawing a hypothesis from an observation and then testing it with sufficient experimental rigor. This is important because our past failures indicate that we don’t as of yet have a good enough understanding of biology and the brain to go from a mechanistic understanding of disease to a successful clinical outcome.
As Alice states, this is part of the reason why being a physician-scientist can be very empowering. One example she gives is the distinction that has been drawn in Parkinson’s disease between individuals that are tremor dominant and those with more postural instability and gait problems. These two classifications were first described by physicians and came to be associated with differential rates of progression. Recently attempts have been made to genotype those two groups to look for genetic markers that could allow us to better predict progression. Evidence now suggests that there are genetic variations that correlate more with one clinical type over the other, which may enable us to more accurately predict disease progression.
She also says that her work as a scientist has helped inform her general understanding of medicine. She talks about how in medical school doctors learn facts with certainty, but her work as a scientist helped her to see that those facts just represent what we know at the time, in reality medical knowledge is constantly evolving. She gives the example that in medical school she learned that signs of cognitive decline exclude individuals from being diagnosed with ALS. This understanding was recently overturned when Prof. Virginia Lee discovered aggregates of TDP-43, a protein associated with frontotemporal dementia in the brains of people that passed away with ALS.
Additionally I asked her about an interesting new biomarker discovery program that she is a part of sponsored by the Chan Zuckerberg Initiative. In it she works with prof. George Church and prof. David Walt looking at neuron derived extracellular vesicles as a potential source of biomarkers. These naturally occurring vesicles (aka exosomes), come off of cell types and sample contents from within the cell, they then circulate in the blood and in the cerebral spinal fluid. They are hoping that we might be able to use them to measure what is going on in the brain, though there is a lot of work that needs to be done to enable us to determine what organ and what cell type these vesicles come from.
We covered a number of other topics as well, including the importance of being agnostic in identifying biomarkers, the viral theory of PD, and more. Here is the full audio from my interview with Dr. Alice Chen-Plotkin recorded on May 15th, 2019.