Transcript of the Interview with Dr. Cynthia McMurray on Huntington's Disease
May 2, 2008
Introduction: This Findings podcast is brought to you by the National Institute of General Medical Sciences, part of the National Institutes of Health. The Findings podcast series features the NIGMS-funded scientists profiled in each issue of the Findings magazine.
Carlson: Hi, I'm Emily Carlson. Right now in the United States, about 1 in every 10,000 adults is living with Huntington's disease, an incurable and devastating disorder passed from parent to child. Cynthia McMurray, a scientist at the Mayo Clinic in Minnesota, is trying to understand the basic biology of the disease. Her research focuses on DNA and how it repairs itself. Dr. McMurray, what part of DNA repair do you study?
McMurray: One of my basic interests is actually genome stability and instability, and I became interested in kind of the idea of gene amplification events. You'll maybe have a gene but you might have three copies of the gene. So part of this region of DNA has multiple copies. And this is a really fascinating process to me because somehow your genome has decided to take on a whole big chunk of DNA that's extra. And I always wondered why would ... you know, what could give rise to this extra DNA, basically? And so my segue into this was to really start looking at the CAG expansion disorders. And they are small amplification events, but for example, one of the diseases that I study is called Huntington's disease ... and it's one of a number of severe hereditary progressive neurodegenerative diseases, and the underlying defect is an amplification of these small DNA elements that are three nucleotides long. It's CAG, a cytosine adenine guanine. So there are three of these and they are copied multiple times. So a normal person may have six and a diseased individual may have 40. So this is an amplification event where these small nucleotides actually get amplified to be too many. And what we discovered in that process was, interestingly enough, that the amplification events actually were caused in the process of repairing DNA.
Carlson: How would you describe progress in this area?
McMurray: From a patient's perspective, nothing is fast enough, and I would feel the same way and do feel the same way. Every day I wish it were different. But in terms of movement forward, I think there's been a tremendous progress. You know, it's very difficult to really find the genesis of a disease. But I would say that the number of really good laboratories working on these disorders has been tremendous and I think that while I agree that we do not have a therapeutic that will fix this disease, and I would say that probably it's not even around the corner, meaning we're not going to have one in 5 years, I think we really know a lot more about how the disease is progressing and some of the contributing factors.
Carlson: With so many things unclear about DNA repair and DNA instability, where do you even decide to begin with your questions and your attempts to answer them?
McMurray: Well, I think there is more or less a standard process. I should say right now that personally I have two interests. One is that I believe that this disease really has two components: the defects that are mediated by the toxic gene product. The protein itself is bad and we have to figure out what the protein is doing. But I also have ... feel strongly that the second component is the DNA-mediated process. So we're as interested in that process as we are the protein. That is a viewpoint not shared by many.
At the cellular level, then, you usually take a gene and you actually have it expressed in the cell type where you have a much more ability to actually watch what is going on in the cell. You can manipulate the cell. You can put colored tags on the protein. You can see where it goes. You can look and you can measure individual cellular events that occur. For example, we have found that the mutant Huntington's protein interacts with a very specific kind of vesicle that carries lipids around. And we find that the protein inhibits the trafficking of the lipids so it ends up accumulating in cells. So rather than traffic go in and out on the highway smoothly, it jams up. It's a traffic jam. So the idea is we look at a global event like lipid trafficking, go deeper, find out what molecules might be associated with lipid trafficking. Now we can make changes in those proteins and see if we can alter the phenotype, say in this case, cholesterol accumulation. So if you find that, then you can start tearing apart the molecule. We could start cutting up different regions of the proteins, finding out do certain regions interact, and then you can actually put these back in cells and try to watch cellular processes. So you hone in smaller and smaller on the molecular events that might underlie the problem. So I think this is the progression. You go from big observations down to molecules ... man to molecules.
Carlson: Growing up, did you always want to be a scientist?
McMurray: You know, it's funny. People ask me that question and I'm usually like, in a way I thought, no, how can you know that when you're young, but then when I really started thinking about it, it was kind of remarkable that the answer might actually be yes. I went to a private Catholic school, and science was not big on the list. But when we actually had it, I loved it. There were so many processes that I all of a sudden thought, "Now, this explains life." And I can't tell you how fascinated I was by that. So when I went to college, I didn't know at all what I wanted to do. I had too many things I was interested in. I thought I would go to literature. I thought I would go to language or chemistry. And I decided, you know, I can always read literature and critique it and talk about it with people. I can always go and learn Spanish or French. But what I'll never be able to do is understand science unless I study it now. It's not something you go and pick up later on. Usually you have to learn, you have to devote yourself to it. So that made me decide that that's what I should be doing. And I never will regret that.
Carlson: Do you ever visit local support groups?
McMurray: Yes, I have. I've given talks at the local support groups, and I have to say the first time I did it I really had no concept of what that kind of meeting would be like. But I have to say it moves me every time. It's enormously enriching. To see the amount of courage and hope and the love that exists in these families that are really trying to find ways to live with these disorders is just unbelievably courageous groups and people. It's very humbling.
Carlson: How has your research experience changed you, personally?
McMurray: Well, research is a way of thinking, so research is really a way to visualize and integrate observations and then set up hypotheses and it helps you to use your mind. You're doing logic; it's an exercise in logic and creativity because you have to see and connect facts, meaning sometimes there will be a process that you never really would think about. So every day, the ability to put things together and to set up something and really visualize and crystallize the question you want to ask, is something that permeates your whole life.
Carlson: What would you say is the overall goal of your research?
McMurray: I'm very much interested in how DNA is fluctuating, changing, causing mutations, and then the mutations of course giving rise to disease. But I always see it integrated at this DNA level, and that if we can understand that, we could even prevent the disease, meaning in my viewpoint, and this would not be shared by all, but the expansion process in Huntington's is fascinating to me. And it seems clear to me now that if we could stop the expansion at the DNA level, we could delay onset of the disease.
Carlson: Thank you, Dr. McMurray. I hope your next questions bring you even closer to understanding Huntington's disease.