Clement Chow, Ph.D., assistant professor of human genetics at the University of Utah, explains why science has been slow to acknowledge genetic variation, and describes his research on how an individual’s overall genetic makeup influences manifestation of retinitis pigmentosa, a genetic disease that causes blindness. Learn more in his review “Bringing genetic background into focus” and read about his retinitis pigmentosa research in Human Molecular Genetics.">

Dec 22, 2015 — At the heart of precision medicine is taking into consideration that each person is unique. Two people with the same disease can have very different outcomes depending on their specific genetic milieu, a complication that is largely overlooked in research and therapeutics. Clement Chow, Ph.D., assistant professor of human genetics at the University of Utah, explains why science has been slow to acknowledge genetic variation, and describes his research on how an individual’s overall genetic makeup influences manifestation of retinitis pigmentosa, a genetic disease that causes blindness. Learn more in his review “Bringing genetic background into focus” and read about his retinitis pigmentosa research in Human Molecular Genetics.

Interview

Interviewer: Precision medicine is all about acknowledging that each of us is different, even our genetics. We'll talk about that more next on The Scope.

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Interviewer: I'm talking to Dr. Clement Chow, assistant professor of human genetics at the University of Utah. Give me an example of a particular disease that looks different in different people.

Dr. Chow: Cystic fibrosis is kind of the classic textbook example, and when you take these patients that have the same mutation in the CF gene, what you often see is that there's a lot of clinical differences in the way they manifest their disease, whether they get certain kinds of infections or whether different organs are affected. It can be quite variable between individuals that have the same disease causing mutation.

Interviewer: Why is that important to know and to acknowledge?

Dr. Chow: Right now, a lot of drug development is based on this idea that a certain disease, say, cancer or type II diabetes for example is the same in every individual. It targets a specific pathway, a response and it treats that pathway and response in every individual as if it's the same.

The problem is that that's not the case almost ever in any disease in any group of patients. So in order to think about more personalized therapies and personalized drugs, we need to understand how the genetic makeup of each individual affects how that disease is going to show up in those individuals and how that differs from this other group that has a different set of background genetic variance.

Interviewer: So when it comes to laboratory research, which is how we understand what causes disease and how to treat them, this kind of genetic diversity has largely been ignored, I would say. Why is that?

Dr. Chow: The typical genetic study or model of a genetic study in the lab is done on what's known as an inbred strain and the different fields, the Drosophila fly genetics field have adopted one or two standard genetic backgrounds.

Interviewer: So are they basically genetic clones of each other?

Dr. Chow: Yeah, so basically they are genetic clones, and that's one way of ensuring that the experiments are standardized and that we can make conclusions. They teach us a lot about physiology and the genetic disease but they don't really reflect the variation that's in a population.

Interviewer: So you're investigating how these differences can influence a particular disease called retinitis pigmentosa.

Dr. Chow: So retinitis pigmentosa is a retinal degeneration. It's a hereditary form of blindness. The cells in the retina begin to degenerate for different reasons depending on what type of retina pigmentosa you have.

Interviewer: And what did you find out about this disease in your lab?

Dr. Chow: We know when you look in the literature especially at the papers of studies looking at patients with retinitis pigmentosa, you see that there's a large amount of heterogeneity in the way that retinitis pigmentosa presents in those patients.

And so we thought we could take advantage of genetic variation in Drosophila, the fruit fly, to identify some of the modifier genes that might be driving these differences in the human population. So what we did was we took a model on retinitis pigmentosa in the fly and crossed it on to 200 genetic backgrounds and what that does is it captures variation that's existent in a population, variation that we know is present in living organisms.

Once we cross this mutation on to the 200 backgrounds, we basically found that retinal variation was incredibly variable between these 200 strains, basically ranging from almost completely degenerated retina to almost no degeneration. And so this is quite striking because it's the same mutation on 200 different backgrounds, 200 different individuals and you get basically 200 different versions of the disease.

So then we used that variability to identify the modifier genes using a genetic mapping strategy, and we identified a really nice lists of modifier genes that haven't really been implicated in the retinitis pigmentosa before.

Interviewer: So what kinds of modifier genes? It's hard to imagine what it could be that's making that the disease look so different in different strains.

Dr. Chow: Right, at the heart of retinitis pigmentosa is the death of the retina cells, and we do find a large number of genes that are involved in cell depth which is what's driving these retina cells to die ultimately. What's interesting is that these are genes involved in cell death or apoptosis that aren't typically thought of as the main players in the pathway. And so probably because variation can't really change the main players of any particular pathway too much without hurting the organism, so it can tolerate variation in these peripheral members but maybe not in the main members. And that's what we are finding with natural variation is that oftentimes variation comes from these less important players.

Interviewer: Yeah, that's interesting.

Dr. Chow: Rather than the main drivers of that response in the organism.

Interviewer: Do you have any idea at this point whether any of the modifiers you found in your screens are also seen in people?

Dr. Chow: We don't know yet whether they're modifying disease in humans, but we are collaborating with the group to look at sequences from patients that have mutation in retinitis pigmentosa genes to see if any of these . . . if there are mutations in any of these modifier genes in the background that might be modifying their disease, so that work is undergoing now.

Interviewer: So why is it important to do this type of work?

Dr. Chow: Personalized therapies are dependent on this idea that people are different, that everyone's genetics is a little different and this drives disease differences. So we hope that by studying genetic variation in model organisms we have this nice controlled way to start breaking down some of these effects, which are much more difficult to do in a human population. And so we think that we can make some progress using model organisms this way.

Interviewer: NIH has a push now to make sure that labs do research on female as well as male cells or animals or whatever it is. Do you think this type of work is kind of the next wave?

Dr. Chow: I think that people are becoming more and more attuned to these kinds of differences, though I think that there's also a lot of resistance to it because it complicates the laboratory setting. It makes it harder to make firm conclusions, which is what science is so used to, but there really aren't any firm conclusions in science.

Announcer: Interesting, informative and all in the name of better health. This is The Scope Health Sciences Radio.