Interview with Dystonia Researcher William Dauer, MD
Movement, Models, Momentum
As one example of how investing in junior scientists leads to exponential research progress, Dr. William Dauer is a movement disorder specialist and basic scientist at University of Michigan who received his first DMRF grant in 1998. His work in dystonia since that time represents some of the most groundbreaking discoveries in the field. The first half of this interview appears in the 2017 Promise & Progress science report published in April. Part 2 of the interview is available exclusively here on the DMRF website.
DMRF: How did you get involved in dystonia research?
WD: I became aware and interested in dystonia research as a resident at Columbia where I had contact with Stan Fahn and Susan Bressman primarily, and Paul Greene, all of who were actively involved in pursuing research on dystonia, supported by the DMRF. I had a background in basic research, and I was contemplating what project I would pursue during a combined clinical and research movement disorders fellowship. It was during that time that the DYT1 gene was discovered. That was extremely exciting and led me to want to devote my studies at that time to developing a model of that disease and understanding the pathogenesis of DYT1 dystonia, hopefully with the outcome down the road of leading to better treatments.
A moment that was and remains very exciting was getting that first DMRF grant. When you're a young researcher and a little unsure of how people will take to your work, getting that first grant is big. Having the trust of the Foundation to go forward with a project was the start of a really wonderful relationship. Without repeated funding and support and symposia provided by the DMRF, there is a very good chance I wouldn't be doing the work I am doing. That also means that the people who have come through my lab wouldn't have necessarily worked on DYT1—most notably Rose Goodchild who joined my lab early on and who is now an independent researcher. None of that might have happened were it not for that first DMRF grant.
DMRF: What progress in either basic or clinical research, contributed by you or others, stands out for you?
WD: In clinical treatment, the most exciting research advancement since I began has been deep brain stimulation [DBS]. This has without question transformed the lives of many patients. But there remain patients who continue to have symptoms and just don't get that much benefit from deep brain stimulation. There's a lot of work in the DBS field generally, and in dystonia brain imaging and circuit work more specifically, that is trying to understand how we can do better because obviously we want to treat all patients with dystonia effectively. So that includes understanding what circuit changes are happening in the brain, looking for new targets, and there's technical work being done on the DBS machines themselves.
That clinical work on circuits is synergistic with basic research that's going on to understand what groups of brain cells are doing abnormally to cause dystonia movements and how different groups of brain cells might be communicating with each other in an abnormal way, which may be really important to understanding the disease. In relation to our work, what we've been particularly excited about in recent years has been the first development of mouse models of the disease that actually show the overt abnormal movements that people with dystonia have. This allows us, for the first time, to begin to ask some of those questions about brain circuits—different brain regions—and try to figure out which of them might be critical for the movements and how we might manipulate them in new ways. Our hope would ultimately be finding drugs that would be able to accomplish this.
Some other exciting things we have been a part of include asking why does this group of cells, or that group of cells, function abnormally when someone has a dystonia mutation. In DYT1, there's been a lot of exciting things that have happened since the discovery of the gene in terms of how that protein works inside a neuron—a nerve cell. Just to highlight work we've been focused on, we initially discovered that the Torsin protein works on the membrane that surrounds the cell nucleus, the nuclear envelope. Increasingly, we and others are identifying the different things that happen at the nuclear envelope. If you think of the nucleus as the control center of the cell, there is something called the nuclear pore which is the gateway that allows information into and out of that control center. It looks like Torsin may have a role in how those control centers are formed and the kind of information they allow back and forth. That's ongoing work and what's exciting about that, as well as in the circuit fields, is that people who are not "dystonia researchers" but who are interested in these basic processes like brain circuits or nuclear trafficking are becoming interested in the disease.
The more that we learn and map out basic areas that are involved in primary dystonia, and let the research world know about it, we'll then be able to draw in other researchers who right now don't have dystonia on their radar because they don't know they are involved. That in itself is speeding progress because it brings new, smart people into the field who can challenge existing ideas. That is what makes great science. It's an exciting time where many things are coming together. We feel like the coming years are going to produce faster discoveries and hopefully ones that will make a difference to patients.
DMRF: Can you tell us more about your most recent mouse models, and what these models are teaching us?
WD: We've published a couple of papers recently describing a variety of mouse models, all of which show abnormal twisting movements that look like human dystonia. For many years we had great difficulty in making models that had what I would call "overt" twisting movements, which we thought were very important. If you have those symptoms then you can try to figure out what would make them better. What's significant, at least for DYT1 and to a certain extent other primary dystonias, is that they are neurodevelopmental diseases. For people who have the DYT1 mutation, if they are going to get the illness, they do so early in life, typically between the pre-teen years and 19 years. If you don't develop the symptoms during that time, almost overwhelmingly you're not ever going to have a problem, even though you have the mutation. So that really pointed to the fact that something important is happening during development. What we did that was unique was to create new models where the Torsin function was impaired sufficiently during that period of development and the animals lived long enough for the abnormal movements to occur. Previous models either didn't have severe enough Torsin problems or they died prematurely.
Another thing we focused on is asking what is it about the developing nervous system that makes it vulnerable to the failure of Torsin, and we identified that there is a unique vulnerability of certain cells in the movement areas of the brain. We've identified these vulnerable cells in the basal ganglia, called cholinergic interneurons, from millions or billions of other cells. Now we’re asking why are these cells vulnerable, what makes them special? If we knew that hopefully we can figure out a way to block it from happening… or, if it does happen, to reverse or suppress it. Now we feel like we have the tools in hand in order to do that.
We're currently putting a grant into the NIH [National Institutes of Health], and based on the power of these models we've been able to attract world-class electrophysiologists…. Just to give you a little preview, there are all kinds of different technologies now that allow you to, in a genetically modified animal, either turn on or turn off certain types of brain cells out of the billions that are there. So in one of our models we are planning to turn on or off these cholinergic interneurons to see if that by itself will suppress symptoms or exacerbate symptoms—and that has never been done before. So that is very exciting because it has the opportunity to really point the finger at a certain group of cells that are important to focus on. We have some evidence for those cells now, but they've never been looked at in a symptomatic model. Very exciting for us, and we are really looking forward to that.
Continue to Part 2 of interview.
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