For the past six months, I have been recording and transcribing interviews with a wide variety of Parkinson’s specialists and biomedical researchers. It has been an incredibly enlightening experience that has given me insights into my own journey with Parkinson’s disease, as well as the future of biomedical science. Below are my biggest takeaways so far.
Author: Benjamin Stecher
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Biology is complicated.
I know that is not the most profound statement, but it cannot be overstated just how complex problems in modern biology are. Talking to so many biologists and Parkinson’s disease experts, I have constantly been struck by just how multifaceted the study of this one disease is. Not long ago, the basic biologists studying Parkinson’s disease (PD) would have almost only included those who study the death of dopamine producing cells in the substantia nigra. Today their ranks have swelled to include gut microbiologists, olfactory specialists, glial cell experts, epigeneticists, computational biologists, and on and on it goes. While this has greatly improved our understanding of the underlying biology, it has made any attempt to synthesize all the information out there on this one disease incredibly difficult.
The history of our attempts to make sense of neurodegenerative diseases shows that they consistently defy Occam’s razor, almost always proving to be more complicated than we thought. As several senior researchers pointed out to me, when they were starting their careers the prevailing wisdom was that Parkinson’s would be solved rather quickly because the problem seemed pretty simple, loss of dopamine in one part of the brain. Yet, time and time again neurodegenerative diseases flout such a simple explanation. It now seems that any attempt to understand PD will have to blend together the various disciplines studying it into a coherent whole if we are ever going to make sense of this disease. Thankfully…
The pieces of the puzzle are starting to come together.
Under seemingly every rock we look in relation to this disease, from gut endothelial cells, to synaptic vesicle transmission, to the various mechanisms governing proteostasis, we see signs of dysfunction. For too long, many of them were studied in isolation, leading to scores of papers linking a wide variety of different factors and aberrant cellular processes to PD. What we were left with was a mess of independent variables, but little understanding of how each fit into the larger picture that is this disease.
Thankfully, we are starting to see more attempts to converge all of that seemingly disparate information into an organized understanding of the pathogenic process. There is now widespread acceptance that no single cause, or deleterious cellular phenomenon, could possibly account for all the variety we see in PD. Almost everyone I spoke to acknowledged that real progress in our ability to treat this disease will only come from further efforts to bring together the various fields of knowledge into a concerted effort to determine the causal chain of events that lead to the various disease states we call Parkinson’s.
Also, the more people I spoke to, the more it became clear that the question driving research today is no longer what causes PD, but what combination of factors, in which subset of people, leads to conditions that give rise to PD. While there is still much to be done, this approach is starting to bear fruit, with the first targeted therapies for genetic subsets making their way through clinical trials. They will likely be the first in a procession of trials for select cohorts of people with PD that allow us to ask, which therapy for what person and at which stage of disease process.
Science is a very human endeavor.
We are living through an explosion in our understanding of the brain and its associated biology. Entire fields of research have popped up in the last few decades that would have been solely the domain of science fiction a mere generation ago. Optogenetics, neuromodulation, iPS cell therapy, neuroimmunology, gene therapy, brain organoids, etc., etc. Each has brought with it some profound new insights into how we work and what goes wrong as we age. They have also given us reason to believe that one day we will be able to properly treat this and other diseases.
However, it is important to remember that progress does not happen in a vacuum, it is driven forward by women and men asking questions, probing our biology, and pushing forward our understanding of this disease. I have been fortunate enough to speak to some of those individuals, and am sincerely grateful for the time they have given answering my questions. They have certainly helped me, and I hope many others, better understand the science behind this disease, the barriers holding us back, where the research is taking us, and what future treatments for this disease might look like.
Below is a collection of quotes from those interviews that I have found most meaningful.
QUOTES:
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“Try to understand the principles, you don’t need to become an expert, but you should understand what separates the good trials from the bad.” – Prof. Lorenz Studer
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“The brain is so complicated, I seriously doubt that it comes down to one protein. If it really was that simple, then we would probably be too simple to understand it.” – Dr. Simon Stott
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“I didn’t start this, it was started by and driven by the patients who we educated through lab tours. It does add some challenges in keeping them up to date with everything going on, also seeing them so often we do see some of them getting worse which makes us feel bad that this is taking so much time. But for me the benefits have outweighed the negatives.” – Prof. Jeanne Loring (discussing her patient-led research from the Summit for Stem Cells)
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“It is highly unlikely that in the present risk-averse climate L-DOPA would get a license as a medicine if it were discovered today.” – Prof. Andrew Lees
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“…patients go to their neurologist and ask ‘should I be drinking more green tea or stop drinking milk?’ The neurologist rightly so says ‘that data only tells us who is likely to get PD or not, you already have PD and we have no data on what happens from the point of diagnosis forward.’” – Dr. Laurie Mischley
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“Once you’ve got two or more variables it becomes incredibly hard to work out what is important. Everything we do is dependent upon solving one variable at a time, which is very inefficient.” – Prof. John Hardy
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“We developed effective smallpox prevention back when we had close to zero understanding of virology and immunology.” – Prof. George Church
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“What I see from scientists is that they are very interested in the science, but once their paper has been published they fly off like a butterfly to the next flower well before the previous flower has bloomed.” – Prof. Bastiaan Bloem
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“I travel the world and I see that every country has a slightly different healthcare system. My favorite is Denmark. They have one medical records system, no barriers to patient-doctor data exchange, as well as an understanding that sharing medical data records benefits society.” – Dr. John Halamka
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“…in medicine quite often we use things that work even though we don’t know how. The biggest misconception about DBS is that it is a stimulator, the reality is that it actually inhibits circuits.” – Dr. Alfonso Fasano
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“We need to move this beyond phenomenology and into understanding by identifying biological subgroups of the disease and then develop very specific biological targets against that subgroup.” – Dr. Todd Sherer
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“If we are going to develop a therapy for this disease, we’ll need to look at the triggers, facilitators and promoters and recognize that they might be distinct processes that each require specific therapeutic strategies.” – Prof. Patrik Brundin
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“I understand why people with Parkinson’s are frustrated with clinical trials and the companies that support them. They want your brain to do research on it but if they don’t hold you in high regard and value your contribution then what is the point?” – Eli Pollard
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“It is critical to be able to list these different types of neurons, the genes expressed, and who they talk to. We should have that complete within the next 5 years for the mouse brain. It’ll probably take around a decade to do the same for humans.” – Prof. Christof Koch
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“…we should spend more time supporting research networks, where we identify people at diagnosis to receive care in an expert setting and will be part of an outcomes registry project…then we can take those people and more accurately match them up with trials that would be appropriate for them, taking a better account of how fast their disease has progressed and their trajectory.” – Dr. Peter Schmidt
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“…what people do is they look at a mutation and its effects in a test tube, with a hypothesis in mind about what the protein it produces should be doing. Though you can’t love your hypothesis too much, at the end of the day you do have to make decisions” – Dr. Peter Lansbury
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“Only by using very advanced computation and adding that (biologic) data to all that we know about the effects of people’s diet, lifestyles, their environment, and their psychology, are we ever going to get to true precision medicine. “ – Dr. Joseph Geraci
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“…we mostly focus on the risk factors that lead to the disease. We haven’t really started to look seriously at those factors that lead to faster or slower decline, which is what patients care most about.” – Prof. Beate Ritz
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“The cause for the initial misfolding is still a black box because we still know very little about the correct shape that alpha-synuclein should be in for it to function properly.” – Prof. Kelvin Luk
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“…in the future people will print whole organs for replacement. I believe we will see this with organs like livers, kidneys and maybe hearts within the next 10 years.” – Prof. Tal Dvir
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“…there are certain epigenetic markers that are so closely correlated with age that just by looking at them you can predict a person’s chronological age within four years.” – Dr. Viviane Labrie
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“I think we have a tendency to view age-related diseases in silos, but many of these disorders have a lot in common. I think we are on the brink of solutions to these problems, not in the next decades, but within years.” – Dr. Julie K. Andersen
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“Genes and genetic variants group together into communities, and those communities tend to be associated with specific functions within cells. This moves us from an old model in which a single genetic variation might influence a single gene and takes us to a model in which a group of genetic variants could not just shift a particular gene, but could actually change how a cell functions. This has allowed us to move from just looking at one variant one trait, to examining families of variants that increase the likelihood of a person being tall or developing a disease like Parkinson’s.” – Prof. John Quackenbush
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“Let’s say you’ve got an agent that you want to test to see if it will slow the course of the disease. First you’ve got to find a group of people that have early stage Parkinson’s disease, hope that they are reasonably similar, and then track their progress over 3–5 years using a test like the Unified Parkinson’s Disease Rating Scale (UPDRS). This scale itself is pretty crude and varies quite a lot, and we use changes of two or three points in this scale as evidence that your treatment works. Even if you did have the cure, it’s very difficult to prove it works.” – Dr. Jon Palfreman
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“The number is roughly two million mitochondria in each neuron. That’s two million mitochondria frantically consuming oxygen and making ATP, all to keep that one cell alive.” – Prof. Thomas Schwarz
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“I think we are at a point where we have enough strong data that it is worth the investment from biotech and pharma to test certain hypotheses and to do the clinical trials. The most promising puzzle pieces are: Parkin activators, LRRK2 inhibitors, alpha-synuclein antibodies and vaccines, c-Abl inhibitors, PARIS inhibitors, and things that manipulate the GBA system.” – Prof. Ted M. Dawson
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“How do you screen people for one drug or the other when you have a limited number of people that fit the criteria for entry into these trials? This is an ethical concern that our field needs to consider.” – Prof Anthony E. Lang
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“…you have to be very skeptical, headlines are often misleading, you have to really delve into the subject to know what to believe, unfortunately, very few people and media outlets are willing to go that far.” – Prof. Randy Schekman
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“The second biggest challenge is the research silos even within the domain of mitochondria. There are people studying just bioenergetics or protein import or calcium, that don’t really know much about the other aspects of mitochondria. That is a big challenge, we spend decades becoming specialists, but now we need to back up and work together so we can put the whole puzzle together.” – Prof. Heidi McBride
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“If you look at Parkinson’s disease, there is not enough money going to basic research. This stems from not matching other disease markets for size, growth and value. The answer must be making the market more attractive. Give higher prices, longer patent protection and make Parkinson’s a disease worth treating.” – David Ashford Jones
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“…looking at how trials are conducted today it is unlikely that we are going to get to the point any time soon where people are subtyped well enough to be able to say if they should be expected to respond to a certain treatment or not.” – Sara Riggare
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“Knowing the genes is important in understanding the biological pathways linked to disease, but it is not enough, it usually takes years of research trying to understand the molecular and atomic level interactions before we can get a really useful drug.” – Dr. Miratul Muqit
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“We stuck them into the basal ganglia, and it was one of those experiments that worked the first time we tried it. We turned on the direct pathway and the mice immediately started running around, we then turned on the indirect pathway and the mice completely froze. It was really remarkable to see that we could change the motor behavior of the animal in an instant.” – Prof. Anatol Kreitzer
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“…why, evolutionary, would we have kept a toxic cell capable of driving neurodegeneration? We hypothesize that these neurons are only targeting damaged or dysfunctional neurons and that by doing so they might be protecting the overall function of the brain” – Prof. Shane Liddelow
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“…people gravitate towards genetics because it is easier to measure than life exposure and the environment, but it doesn’t tell you everything you need to know about a disease process. You have to look at all facets and how they integrate and lead to a symptom or diagnosis.” – Prof. Sarkis Mazmanian
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“…it is not about how excited the media gets over a particular study, it is about reproducibility, can someone else build on it, and can we use it in our collective goal to impact disease progression.” – Dr. Mark Cookson
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“Cells are parts of a bigger organism, but when we look at them in our experiments we can think of them as little individuals. We try to track where they come from, where they’re going, and how they get there. In many ways it does resemble what happens to people as they go through life” – Prof. Arnold Kriegstein
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"I personally believe this (precision medicine in neurology) is going to happen much sooner than people think, the days when we had one treatment for all kinds of brain disorders are over.” – Dr. Ricardo Dolmetsch
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“…there are probably genetic and environmental factors involved. But even so, the changes in the brain remain similar, for the most part. We get loss of dopamine in the cells, loss of dopamine in the striatum, and alpha-synuclein positive cells and fibers throughout the brain.” – Prof. Jeffrey H. Kordower
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“I hope that in time we will be able to create a 'mini-you', where we will take your cells and grow your own organ-chips to test drugs on before giving them to you.” – Dr. Ben Maoz
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“When Fred Sanger worked out how to sequence DNA in 1977, he wasn’t thinking about how this was going to be helpful for people with genetic disorders, he just wanted to find out how to do it. You do then need other people to build off that kind of work and see how it can be translated, but that should not be the explicit goal of everything we do.” – Prof. Roger Barker
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And a final quote from somebody I wish I had the chance to interview but who passed away just before my interest in all this piqued.
“Our patients are our teachers” – Dr. Oliver Sacks
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