Timothy Greenamyre, MD, PhD, is the Love Family Professor and vice-chair of neurology, chief of movement disorders and director of the Pittsburgh Institute for Neurodegenerative Diseases (PIND) and the American Parkinson Disease Association Advanced Center for Parkinson’s Disease Research at the University of Pittsburgh. He is also a member of the scientific advisory board of The Michael J. Fox Foundation and a member of the scientific advisory boards of the Parkinson’s Foundation and the American Parkinson Disease Association. He has been listed as one of the Best Doctors in America since the mid-1990s. He is editor-in-chief of Neurobiology of Disease, a scientific journal, and a faculty member of F1000Prime, a medical information service. His laboratory studies mechanisms of neurodegeneration in Parkinson’s disease with a focus on gene-environment interactions. He conducts translational studies using drug and gene therapy approaches.
The following has been paraphrased from an interview with Prof. Timothy J. Greenamyre on July 3rd, 2018.
(Click above to listen to the full audio version or click here for a downloadable version)
Over the course of your career, which discovery took you most by surprise?
When I was in med school, I was taught that genetics had nothing to do with Parkinson’s disease. Since then, the discoveries in the genetics of PD have been really illuminating. As more genes came, more pathways involved in this disease process opened up giving us more therapeutic targets.
Are there any widely held beliefs that you believe are holding the field back?
In terms of treatment, one common belief is that when you start levodopa you only have 5 or 10 years for it to work, which has made people reluctant to start treatment. This is a clear misunderstanding, there is no downside to starting treatment.
What knowledge do you think you would gain if you had access to the subjective experience of having the disease?
I see patients regularly, and as an ‘outsider’ just observing, I think I have a pretty good feel for how the disease impacts them in ways that they can tell me or that I can observe. But, I’m sure the actual experience of having it is very different. I’ve often wondered what bradykinesia (slowness of movement) feels like, and how aware people are of it when they have it. Often I hear more about it from their spouses than themselves.
Given the vast array of cellular dysfunction in PD, do you think it is possible that one biological domino piece can set everything off?
Parkinson’s is clearly caused by multiple different environmental and genetic factors. In my lab we try to focus on common points of intersection and we are coming to the conclusion that there are central choke points that, regardless of the cause, might be targetable pharmacologically or by other means. One example is LRRK2, many who don’t have the mutation still have dysfunction in the associated pathway. If we can prevent or stop that dysfunction it should be beneficial even for people that don’t have the mutation.
It seems that these factors get isolated and studied one at a time, yet in reality, the disease is a result of the interplay between a number of different factors. Are we able to study multiple interrelated factors and if so, what is the limit to the amount of complexity that we can study?
That is something that we try to do in my lab, we take a model and see how it impacts a variety of implicated mechanisms to understand how they are related to each other. There are interrelated factors, and to find each you have to look at them in detail separately. But, we also have more complex systems that allow us to see how they interrelate and change in response to a particular mutation or toxin implicated in the cause of the disease. With some of the new high throughput systems (the use of automation equipment with classical cell biology techniques) and big data, you can examine these things in a very complex way.
Though if you are asking if we will ever be able to determine the signature cause of PD in an individual, that becomes very difficult because that involves an almost infinitely complex interplay of genetic factors superimposed on a lifetime of environmental exposures. I don’t think we’ll ever be able to tell what causes an individual’s PD, but if we can get at the common mechanisms that lead to cellular death, and figure out how to target them, then we are in good shape to develop therapies that change the course of the disease.
Do you think the big transformative breakthroughs are more likely to come from large consortium or singular geniuses?
I think the breakthroughs are likely to come from both sources. Science is a creative endeavor, in part, and relies on individual creativity to think about how to attack a problem, or what the nature of the problem even is. But science also requires a team approach, and as we move towards therapeutics, many different kinds of expertise are needed to achieve our goals. I think there is room for both the singular creative lab and the team approach.
What do you think are some of the biggest gaps in our knowledge base?
There is so much we don’t know, I would say one of the biggest gaps in helping us advance is a model of PD that is predictive for disease modifying therapies. We don’t have a model that has proved to be useful for screening compounds. People still often use the MPTP mouse model (toxin which quickly kills dopamine cells and induces Parkinson-like symptoms), which has been cured hundreds of times and none of that has translated to disease modifying therapies for people. I don’t quite know how to get around that, we go on our best guesses, based on our understanding of the disease, and take leaps of faith that they will work.
What excites you most about the future of this field and where would you place your bets on where progress will come from?
I have been seeing patients for more than 25 years, I don’t think there is a cure around the corner, but I do think we will have something that is going to change the course of this disease within the next 5-7 years. There’s no good time to be diagnosed with PD, but this is the best time in history. We will know the results of the isradipine trial soon, there are synuclein lowering strategies coming down the pipe, there are several LRRK2 kinase inhibitors, and more. It is very likely that one or more will hit the mark in terms of slowing the disease. I think these will turn this from a devastating degenerative illness into a chronic annoying ailment that allows for good quality of life for the duration of one’s lifespan.
If our current approaches fail, would that mean that our basic assumptions of this disease are wrong, or would we just have to find new ways of testing our assumptions?
I think the latter. I learned from a great neurologist named Ira Shoulson that clinical trials are a terrible way to test a scientific hypothesis. There are so many reasons why a clinical trial can fail that have nothing to do with the basic science behind the trial. The dose could be wrong, the drug might not be hitting the target effectively, etc. Unfortunately when a trial fails it could lead to the death of that target because investors will be more hesitant to put money into similar drugs for the same target.
Click here to learn more about the work of Prof. Tim Greenamyre