Last week I went to Boston for what turned out to be one of the best advocacy trips I have yet taken. Not only did I get to meet some incredibly inspiring scientists and companies working at the bleeding edge of Parkinson’s research, but I also got a vivid reminder of why I do this work, all while enjoying the sights of Boston as it basked in the last few days of summer. It was an idyllic trip.
Except for one thing: my PD symptoms were worse than they have been in quite some time. I began the trip battling a two-week bout of medication-induced sleep deprivation which was triggered by some scary episodes of dysautonomia. Also on the short flight over in those cramped Porter Airlines seats my tremor, bradykinesia and dystonia started to act up which in turn threw my balance off.
It didn’t help that Boston is a mess of a city. As my Uncle who has lived there for 30+ years joked, “When they were planning Boston they brought together all the best city planners from Harvard and MIT and told them, ‘we need you to design this city so that no one knows how to get anywhere.’” The curving hilly streets of Boston combined with the rush of cars traveling in seemingly every direction at once did not help to make me feel at ease.
Still, I managed to gut through, wobbling my way around the city and walked away feeling inspired by all the great minds I had met.
Lighting The Way Forward
My trip began with a visit to the Fanning Lab at Harvard doing research at the forefront of lipidomics. Lipidomics is the study of cellular lipids (fats) and their networks within a biological system, integral to how every cell in your body functions. Lipidomics doesn’t exist in a vacuum; it sits at the intersection of proteomics, genomics, transcriptomics…just about any ‘omics you can think of.
It was a real delight getting to sit down with Dr. Saranna Fanning and her incredible team, explaining as best I could the journey I have been on, and hearing about their work and how it might translate to patients like me. They were each brimming with enthusiasm for their subject and for what I could tell them about the patient journey. I want to once again thank the entire lab for being so hospitable with your time and allowing me to play scientist while taking me on a guided tour of these microscopic blobs of fat that are so essential to both health and disease.
I spent much of the next afternoon with Dr. Yotam Eldar (pictured above) in his office above downtown Boston as he guided me through all that the company he co-founded, Modulight Biotherapeutics, is trying to do. From the beginning of my journey through PD research I’ve been looking for what’s next for Parkinson’s therapies? I hope this doesn’t come across as too hyperbolic, but I think I have found it.
Modulight Bio is working to translate the precision of optogenetics into the clinic for Parkinson’s disease. By delivering light-sensitive proteins to specific neuronal populations, the company intends to selectively modulate only the dysfunctional networks driving motor symptoms. The objective is to achieve a level of cellular and circuit specificity that surpasses traditional electrical stimulation, maximizing symptomatic relief while minimizing off-target effects associated with broader neuromodulation.
In a nutshell, they are inventing a less invasive yet more precise and more targeted version of DBS.
Why this is so important is something that was made abundantly clear to me on this trip. As I have previously written about, DBS is a blunt instrument used to treat very fine symptoms. In the majority of cases it is unable to specifically target just the symptoms. It also has a tendency to worsen some existing symptoms or even create new ones. Hence, there is a dire need for what the team at Modulight Bio is trying to build, a system that can selectively turn on only those pathways that help patients.
For example, one of the more distressing symptoms for me that seems to be getting worse lately is the inability to vocalize myself as effectively as I used to. Not too long ago I could speak to rooms full of scientists and physicians for hours on end; now, I have trouble at times making myself understood at the kitchen table. This is a common side-effect of DBS, known as dysarthria.
A rough illustration of why DBS is itself such a rough tool.
The next day, I sat down with Dr. Todd Herrington in his office at Massachusetts General Hospital, where he gave me a guided tour of the brain that scaled seamlessly from individual neurons up to complex motor networks. Listening to him parse the functional architecture of the basal ganglia reminded me of the day I spent with Dr. Hagai Bergman at Hadassah Medical Center (Dr. Bergman also happens to be a scientific advisor to Modulight Biotherapeutics). Just as Dr. Bergman had previously laid the foundation for my understanding of adaptive deep brain stimulation, Dr. Herrington provided a vivid framework for how targeted circuit manipulation can directly influence the clinical manifestations of movement disorders.
Finally, I spent an afternoon with Dr. Peter Lansbury, someone for whom my respect has only grown with each visit I have had with him. On this visit he broke down some of the hard-won lessons learned from the recent failure of Bial’s Phase 2b ACTIVATE trial. Dr. Lansbury brilliantly dissected why he believes the activator originally developed by his former company, Lysosomal Therapeutics— failed to slow disease progression in the trial participants. He was genuinely surprised by this outcome and is examining several possible explanations, one of which is that the widely-held hypothesis that increasing the activity of GCase will slow progression may be incorrect. This served as a sobering warning that I hope all scientists take to heart, never fall too far in love with your hypothesis.
One final point on the limitations of DBS. It remains a fundamentally blunt instrument burdened by systemic flaws. It is highly invasive and requires a team of dedicated experts; these barriers too often deter patients— roughly 5-10% of those who could benefit from DBS actually undergo the procedure. In addition, because the electrical stimulation lacks cellular specificity, it requires exhausting clinical adjustments just to maintain efficacy as the disease progresses. This creates an enormous logistical burden on both patients and care teams, compounded by ongoing software management and battery replacements. I can only hope that we are finally approaching a threshold where cruder interventions give way to the targeted precision therapies being developed.
That said, make no mistake: I would still choose to undergo DBS again. It is still the best therapy we have; however, I do not believe that it is the best we could have. The disruption to my daily routine and the escalating physical toll are becoming an impediment to future planning. As much as I want to visit every lab pushing the boundaries of this disease, I have to be pragmatic and accept my own limitations.
The streets of Boston may be chaotic to navigate, but the science being forged there is the kind of focused, precise force that has the potential to outpace this disease.
Dedicated to V & F for their warm hospitality and the constant reminder throughout my youth that we are here to do some good in the world.
Illustrations above were created using Gemini.