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Dr. Wolfgang Baehr, a professor of ophthalmology who has spent his career researching the genetic causes of blindness, says you have to be fearless to make advances in science. He talks about the…
April 25th, 2014
Announcer: Examining the latest research and telling you about the latest breakthroughs, the science and research show is on the Scope.
Interviewer: My guest Dr. Wolfgang Baehr says you have to be fearless to make advances in science. He researches the genetic causes of blindness and has just been given a career award from ARVO, the Association for Research in Vision and Ophthalmology. You've been in the same field for about 30 years..
Dr. Wolfgang Baehr: Almost 40.
Interviewer: Almost 40..
Dr. Wolfgang Baehr: 1976.
Interviewer: Oh, right. 1976, yeah. What has been the most exciting moment of your career?
Dr. Wolfgang Baehr: Well, it's kind of hard, I have published about 200 papers, each one was a major, not each one but most of them were hard work. And, in the last 5 years I discovered it is very difficult to publish, even, a good paper. One of my best papers in Nature Neuroscience about two years ago, we worked five years on this project. And tried eight different [terms], we started with a top major in science, and it was very frustrating. But, eventually, we got it published in Nature Neuroscience. It was a wonderful paper and that was very satisfying. So persistence is something which is really my characteristic. We don't give up.
Interviewer: Do you think that you approach science any differently than some of your colleagues?
Dr. Wolfgang Baehr: Well, I think I do because I'm trained as an organic chemist, with basic science education and when I finished my PhD I basically decided to drop chemistry and learn something else, and I got into biophysics, fast kinetics, Stopped-flow kinetics and eventually into biochemistry. And then I came to the United States as a post doc and got into retinal research, so that's really when our research started back in 1976. During that time we started to work on phototransduction, which is the mechanism that starts to generate an electrical impulse in the retina, which is transmitted through the optic nerve to the brain, which is initially [meant] for vision.
Interviewer: What are some of the most striking ways that your field has changed over the last 30 years?
Dr. Wolfgang Baehr: At that time phototranduction was completely unknown, and at that time biochemistry was the thing to do to identify [inaudible 00:02:23] to identify G-proteins like transducing and eventually the main components we identified and then molecular biology started, DNA sequencing became possible in the 1970s, so I was one of the first starting sequencing trials, in [inaudible 02:46] for example. And then in 1990 the first mutation linked to autosomal dominant retinitis pigmentosa was identified in rhodopsin. And we decided to take this mutation, make the same mutation in mouse, and the mouse would [generate] the molecule internally to transgenic mouse, which was really not easy in those times.
Interviewer: One impression that I have is that you're not afraid to jump in with both feet.
Dr. Wolfgang Baehr: You have to be fearless. And just try and go and see this new gene published and new mutations. So we are very quick to make a knockout because it's relatively easy in mice.
Interviewer: Well, right, and this is something that seems to make you stand out from others..
Dr. Wolfgang Baehr: Yes.
Interviewer: Is that you do make these mouse models for genetic retinal diseases.
Dr. Wolfgang Baehr: We've probably knocked out 20 different genes in the last 10 years, and many of those models were first and unique. Nobody had ever produced any of those mice.
Interviewer: Can you give one example of a mouse model and what defects it had and how you were able to reverse some of those?
Dr. Wolfgang Baehr: Well, the best mouse model would be the dominant disease caused by a mutation in a calcium binding protein, which is called guanylate cyclase activating protein, called GCAP for short.
Interviewer: So, basically, if there's a mutation in this GCAP it causes a dominant disease and the protein is overactive, correct?
Dr. Wolfgang Baehr: Protein is overly active, but using a molecule cGMP, which is damaging photoreceptors. We depend on cone vision for color vision, acuity, reading newspapers is all dependent on cones, and this disease destroys first, cones. So, you basically become photophobic because light intensity is very damaging. And you start having problems with reading newspapers, begin central vision problems and you wear sunglasses. So it's very difficult for patients to very slowly lose cone vision and visual acuity and then slowly becoming blind. And mice being inoculated with AV virus that knocks down the mRNA...
Interviewer: When you're knocking down the mRNA, what happens is that there's less protein being made, right?
Dr. Wolfgang Baehr: It's less damaging protein being made and the [inaudible 05:22] of the retina is not damaged.
Interviewer: Right. So, you're taking away the problem in the first place.
Dr. Wolfgang Baehr: We can slow down the damage and have a very positive effect after one year, in terms of visual acuity and cone photo function is way improved. So in a mouse model it works beautifully, and the additional advantage that we have with this construct is that it is applicable to any mutation in GCAP, there are about 2,000 families worldwide, which have been identified so far, with 100 to 150 patients. All of those patients could use the same [inaudible 06:01] virus with our knock-down construct and could have beneficial health experiences and slow down the disease dramatically. The point where we are right now is, is it worthwhile to do clinical trials, there's a very small patient collection...
Dr. Wolfgang Baehr: In different parts of the country or the world. And, as you know, will there be a company that supports us, and that's the question I don't know.
Interviewer: Another aspect, of course, of your work is that you're understanding the whole process of phototransduction and getting new insights into how that works..
Dr. Wolfgang Baehr: Yes, how that works. In the beginning we know all details, and my interest really, is to understand mechanisms leading to disease, and I think we might essentially, each gene is a new area, [of possibilities]
Interviewer: What keeps you fascinated in this work?
Dr. Wolfgang Baehr: Because there's always something new. We've focused, of course, at genes very specific for photoreceptors, but eventually we got into [Centronics dystrophy] like effecting multiple tissues. You know, cut a gene and some of those genes would cause embryonic lethality, mice would never be born; or would die early. And, of course, that's much more complicated, you cannot do just retinal research, you have to look into kidneys, for example. And that is, of course, not my field, so I need collaborators.
Interviewer: Yeah. Yeah.
Dr. Wolfgang Baehr: But that makes it more interesting because those diseases are very, very devastating. But it's also expanding research and making it more interesting, you know. Getting into new areas, being [fielders] and being persistent I think that's the characteristic in which we can demonstrate.
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