Prof. Patrik Brundin leads the Center for Neurodegenerative Science at Van Andel Research Institute where his research team is focused on experimental models and novel therapies in Parkinson’s disease. Dr. Brundin is one of the most cited scientists in neurodegenerative diseases, with a focus on Parkinson’s, and has received numerous awards for his work. He is the co-editor-in-chief of the Journal of Parkinson’s Disease and is a consultant for several biotech and pharmaceutical companies. Research in Patrik Brundin’s laboratory focuses on pathogenetic mechanisms and pharmacological treatment in cell and animal models of Parkinson’s disease. The group’s mission is to understand neurodegenerative diseases and develop new therapies that are of benefit to patients and their caregivers.
The following has been paraphrased from an interview with Prof. Patrik Brundin on January 10th, 2018.
(Click here for the full audio version)
A wide range of factors have been associated with neurodegeneration: heavy metals, air and water pollution, gut dysbiosis, chronic infection, lack of certain micro-nutrients, etc. These are believed to lead to some of the factors that are more widely studied: neuroinflammation, misfolded proteins, oxidative stress, cellular dysfunction etc. If it were up to you, how much attention should we give to studying each group?
The field of Parkinson’s has recently focused on a series of single genes as causes of the disease, largely because of some incredible advances in genetics that have allowed us to identify these as causes of rare inherited forms of the disease. But the remaining 90 to 95% of cases have a mixture between genetic predisposition and environmental causes that makes them much harder to study. Over the last 20 years, since the discovery of the first mutation in the alpha-synuclein gene, the advances of genetics has given us a wealth of important information, but for that reason we have probably overlooked some exciting and compelling environmental influences. This includes things like diet, which changes risk of PD, or smoking, which was previously actively studied as a “protective” agent. There is a whole host of other environmental influences that I wish we would study more. The problem is that there is unlikely to be just one environmental agent in play in each patient, and you have to superimpose the genetic data on top of the different environmental factors that each patient is exposed to. Another problem is that these environmental modifiers of Parkinson’s risk may have been present 10, 20 or even 30 years prior to diagnosis, which makes it tremendously difficult to properly study.
One of my current favorites is anything that affects the gut microbiome. We know that both coffee drinking and smoking have very significant effects on the gut microbiome and that might be why they protect against Parkinson’s disease. There is also emerging evidence that alpha-synuclein is involved as part of the normal response to certain infections. Furthermore, the epidemiology of people who had their Vagus nerve cut (as a treatment for peptic ulcer), suggests that the surgery lowers risks for PD, which might mean that nerve is a highway that transports aggregated alpha-synuclein from the gut to the brain.
I have a new idea of how to view the disease process in Parkinson’s. I have not fully developed the idea yet, but I think the process can be divided into three aspects. First, I think there are distinct “triggers”, then there probably exists “facilitators” that help the triggers cause the disease, and then, once the disease process has started there are “promoters” that underlie its progression. The trigger is the simple part, it might be a virus or an environmental toxin that triggers, for example, mitochondrial defects or misfolding of alpha-synuclein. The facilitator may be one of many things that are essential for the trigger to work. For example, it could be something that allows the virus to gain access to the gut wall or olfactory system, i.e. one could imagine it requires a specific genetic makeup in the patient or exposure to an environmental toxin that breaks down the protective barriers in the gut and nose. The promoters then come into play once the disease is already ongoing and makes the disease worse. These are things like neuroinflammation or factors that increase cell to cell transfer of small alpha-synuclein aggregates. So, 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.
Do you agree that there seems to be an unhealthy obsession from funding bodies for a need for everything to be translational given, it seems, we don’t understand the underlying disease process well enough?
Not all funding bodies are obsessed with translational research—some are—but not all of them. Also, one has to remember that there are times when translational work leads to incredible mechanistic insights. We started doing neural transplants in Sweden 30 years ago, which was very direct translational work. To our surprise, 15 to 20 years after the transplants and after the patients passed away we opened their brains and found Lewy bodies in the transplants, which opened up a new avenue in basic fundamental research, that is the notion that a misfolded protein could jump from cell to cell.
Another example is the recent Exenatide trial which suggests that this repurposed anti-diabetic drug can slow down Parkinson’s disease progression. We don’t really know how it works—we know it binds to the GLP1 receptor but the connection to PD is unclear. However, it is going to spur a tremendous amount of basic science that probably will help us understand underlying disease mechanisms.
Also look at all the genetic studies, which by definition are “clinical”. Without all the clinical genetic studies of the last 20 years, we would lack a great deal of the understanding of basic disease mechanisms that we have today. So often translational work leads to better insights into disease mechanisms.
Can you talk about the new ASAP initiative that you are a part of? What do you hope will come from it?
Aligning Science Across Parkinson’s disease (parkinsonsroadmap.org), which was started by the Sergey Brin Family Foundation, will focus on some basic science that might, down the road, lead to translational discoveries. Sergey Brin is a co-founder of Google and he has inherited a mutant copy of the LRRK2 gene which dramatically increases his risk for developing PD. With this initiative, we are looking at new ways to accelerate PD research by improving our basic understanding of Parkinson’s. The initiative is holding brainstorming workshops to identify research priorities. We are hoping to look at things a little more outside of the box, and might end up highlighting things like the role of viral infections or poor sleep, and what role they might play in triggering or facilitating the disease process. We might also focus on aging because, for example, we don’t really know what the effects of cellular senescence are in the context of neurodegeneration.
At one of our meetings, Sergey Brin sent a quote to us that said, “if I had to write a check for a billion dollars, knowing it would lead to a cure for Parkinson’s disease, it would be the easiest check I’ve ever written.” We are very excited that this kind of private philanthropy is coming forward because the pharmaceutical industry seems to now be taking a step back from neurodegenerative diseases, which I think is very short sighted. I heard that about $23 billion have been spent on Parkinson’s disease drugs that have failed. Surely, there is a fundamental flaw in the way the industry is currently working. Perhaps it is that they often apply a model of “one disease and one target” while Parkinson’s is a series of diseases that we have given one name, but where a variety of mechanisms probably play important roles in different people. If you think about it in terms of there being “triggers”, “facilitators” and “promoters”, hoping to stop the disease by only addressing one target may be naive.
You are also part of a new project funded by DARPA to study environmental exposure, looking at the link between airborne particulates and late-onset PD. What other aspects of environmental exposure do you wish we could study more thoroughly?
The role of infections as triggers should be studied a great deal more. I would also love for somebody to study what is really going on with coffee and smoking; they both lower the risk for PD but we don’t know how. And as we eventually run out of genetic factors to study, we need to start studying interactions between genes and environment. This does add a tremendous layer of complexity to how we design our studies, but it is going to be extremely important.
There seems to be a growing frustration in the medical and research community over the ‘publish or perish’ model that drives researchers’ careers as well as the lack of open source publishing. As one of the editors of the Journal of Parkinson’s Disease, how big of a problem do you think these are and can you talk about the difficulties involved in reforming this model?
This has been recognized as a problem for 15 to 20 years. At some point in our scientific culture, we became obsessed with publishing in high impact journals. Everybody started looking at the impact factor of each journal, which is a measure of how many times an average paper in the journal is cited. Impact factor plays an important role when people are looking for jobs or promotions, so everyone tries to publish their research in the high impact journals, where only 5 to 10% of all the things submitted to them actually get published. It delays publication and it can promote a culture of selective viewing of data where relevant data gets ignored by the authors because it makes the paper less likely to be published. This is a terrible disease in the biomedical research culture and I’m not quite sure what the cure is. It may require that we all start using bioRxiv (now sponosored by Chan Zuckerberg Initiative) to try to make more data openly accessible to a wider audience before it has undergone peer review.
The soaring cost of publishing research is also a major concern. Journals need to be paid because the people that work for them need salaries, but the huge profits made by some of the large scientific publishing houses is absurd. They publish work that is submitted by scientists who do not work there, it gets quality checked by other scientists who don’t work there, and then those same scientists have to pay to gain access to see that work. That’s a crazy culture. In a utopia, scientific publishing should be centrally funded, but then we would still have the problem of assessing the quality of work. There is so much research published these days, there is no way any one individual can read all of it, so we congregate around high-impact journals to read what might be the most exciting work.
What do you think are the best arguments, both for and against, the spread of alpha-synuclein from cell to cell being the key target in PD?
I’d like to change that question from “the key target” to “one of the key targets”. Alpha-synuclein is important in the progression of the disease once its misfolding and aggregation has been triggered. I think the process is facilitated and promoted by mitochondrial deficiencies and inflammation. In the last nine years or so, there has been a body of literature clearly showing that synuclein can move from one cell to another and induce misfolding in neighboring cells, in a prion-like fashion. Also, we can take aggregates from patients, put them in animals and the animal develops Parkinson-like pathology. Furthermore, we now understand that not all alpha-synuclein aggregates are identical. Each type of alpha-synuclein fibril seems to generate a specific type of pathology when it moves from one cell to another and the Lewy body pathology spreads between inter-connected brain regions.
As to what speaks against it, first, we have no evidence that Parkinson’s disease is a communicable disorder outside an artificial laboratory setting. We also have trouble explaining why it prefers to spread along certain pathways in the brain more than others. Finally, not all patients show the same pattern of pathology in the brain, and the rate of progression differs significantly. So some patients live for decades and do relatively well while others deteriorate rapidly. We have to presume that alpha-synuclein aggregates spread between cells in all patients, but we can’t adequately explain why the rates are so different between patients.
(You must add this to your transcript. Let me take the opportunity to thank you for being a very good communicator and blogger. When I first saw your work I thought, who is this? This is so insightful and knowledgeable. I’m really impressed.) ☺