Dauer Interview Part 2
This exclusive interview with Dr. William Dauer of University of Michigan is continued from Part 1 in Promise & Progress...
DMRF: An unexpected finding in your models was evidence of neurodegeneration, death of brain cells. Can you put this in context?
WD: One of the things that was a big surprise to us when we developed these models is finding that small groups of cells within the motor system degenerate. Also, this degeneration happened exclusively during the juvenile period when symptoms occur. We are continuing to explore the potential implications of this finding. I would emphasize, we have not identified degeneration in human samples. It may be in humans that these cells just become dysfunctional but don't die. Regardless, we believe that our findings pinpoint those few cells among the billions in the brain that are particularly susceptible to Torsin dysfunction, and going forward these cells will be a focus. One way we will address this is with human brain imaging studies. As part of our Udall Center research we’ve developed special tracers that allow us to visualize cholinergic function in living patients (cholinergic cells are among those cells that die following Torsin dysfunction). We are interested in testing whether patients with DYT1 dystonia and other forms of primary dystonia show abnormalities of cholinergic function. Identifying a specific cell type that is dysfunctioning in the disease would be very important, as it would help to focus a range of efforts on these neurons.
DMRF: You also found that TorsinA and related proteins can rescue impaired cells, correct?
WD: One of the things we found, and are continuing to work on, is that TorsinA has brother and sister proteins that share some of its functions. The most notable is TorsinB. We've shown that the levels of TorsinB are important in determining which cells are vulnerable to TorsinA. In DMRF-funded work, for example, we've shown that when we remove TorsinA from all cells in a mouse, nerve cells get sick but other cells don't get sick--skin cells, for example, don’t get sick. It seems clear that the reason is that skin cells express high levels of TorsinB which can take over the work of the impaired TorsinA, but brain cells don't express as much TorsinA. So that leads to the idea that perhaps increasing the levels of TorsinB in the brain we could actually protect or reverse some of the effects of the TorsinA problem. We showed this works at least in a petri dish, and a very big project in the lab now is looking at that same question in the symptomatic mouse models of dystonia that we've published recently.
DMRF: How do you explain the relevance of DYT1 research for patients who have different types of dystonia, for example adult onset dystonias?
WD: There have been many genes that have been identified just in the last 10 years, including some that appear to be involved in adult onset dystonia, like cervical dystonia. Genetics is increasingly helping us understand many forms of dystonia, including adult onset forms. Having identified these various genes, we and others are looking for links between the different genetic forms. This research is important because to the extent we understand what Torsin does and how it acts, we're going to be in a much better position to try to look at these other genes and understand how they may play a role in a similar pathway or related pathways. What research in other diseases has shown is the more you can use genetic forms of a disease to understand what basic things are going wrong within cells and how that amplifies out to affect brain circuits, that helps you identify the road to be taken when other genes are found, and helps identify problems in forms that are thought to be non-genetic.
DMRF: What do you believe are the most meaningful steps the DMRF is taking to accelerate research progress?
WD: A critical activity has been the DMRF’s sponsorship of research meetings. These are meetings that enable the community can come together, including very early investigators, to present their most current work and debate and argue about it, which is essential to figuring out the best direction forward. I like to say that “no one is smarter than everyone” and these meetings allow everyone to bring their views to bear.
Beyond these meetings, funding projects that are not necessarily in the direct mainstream has been critical. NIH [National Institutes of Health] funding is increasingly uncertain. And even in best of times NIH--while it's of course the critical and dominant funder--tends to fund the safer, more “tried and true” work. Foundations like the DMRF are more like the venture capitalists who can make investments in more innovative and risky science that may lead to unexpected new directions and progress. A research portfolio—like an investment portfolio—should have stable, conservative investments, but also investments that are a little more risky, and some that are really out there, ambitious investments that you believe can pay off. You need all of those, and the DMRF plays a particularly important role in reaching out and trying new things.
Part of that riskiness is supporting young researchers. We're excited by the work we've done and that others are doing, but we always need new, smart, energetic people who want to enter the field. The DMRF were the first to invest in my work, and the were also key early supporters of the work of Rose Goodchild, Pedro Gonzalez-Alegre, and others. That is essential, to help get those people on board, especially early in their career where they might get into Parkinson’s disease or ALS or other diseases that are more prominent in the neurologic community.
Accelerating Research & Inspiring Hope
The Dystonia Medical Research Foundation (DMRF) has served the dystonia community since 1976. Join us in our global effort to find a cure.