Search for tag: "mutations"

Interviewer: Antibiotic resistant bacteria are a big public health concern. These superbugs are resistant to life-saving drugs that we take for granted. We'll talk about how changing doctors' attitudes about antibiotics could help overcome the problem, up next on The Scope.

Announcer: Examining the latest research and telling you about the latest breakthroughs, the Science and Research Show is on The Scope.

Interviewer: I'm talking with Dr. Barbara Jones with University of Utah Health and the VA IDEAS Center for Innovation. First of all, what is a superbug, and why are they such a threat?

Dr. Jones: Well, superbugs are a bacteria that are resistant to standard antibiotic therapies. Bacteria can mutate with every generation, and some of these mutations can give bacteria resistance. When you're constantly exposing these bacteria to standard antibiotics, what emerges is a selection pressure for those bacteria that are resistant to those antibiotics.

Interviewer: Something that you helped to find in your research is that doctors are actually part of this problem of emergence of antibiotic resistant bacteria.

Dr. Jones: In many cases, we use antibiotics unnecessarily. And one of the biggest diseases that we do this in is in acute respiratory infections or kind of the common cold. Most of those diseases are caused by viral infections that really don't respond to antibiotics at all, and what we found across the VA system was that doctors just tend to get into habits. So some doctors prescribe antibiotics for colds almost every time that they have a patient with one. And other doctors, though, have figured out ways to prescribe a lot more judiciously.

Interviewer: And is this something that you experience? I mean, do you sometimes feel pressure to prescribe antibiotics when it might not be the best thing to do?

Dr. Jones: Well one of the things that I think is also a misperception for a lot of providers is we tend to assume that patients have an expectation that they'll receive the antibiotics, and when there's that assumption, when you only have 15 minutes to see a patient, you don't necessarily have the time that is taken to really get to know what your patient's expectations are.

And so if we then have a cultural assumption that our patients are expecting this, we have a busy clinic, we don't have a whole lot of time to educate our patients about the dangers of the antibiotics and why we would not prescribing, it's a lot of times easier to give the prescription than to have that conversation about the risks of antibiotics and what other things that you should do to take care of yourself during a viral infection.

Interviewer: Why is it important to understand these pressures that doctors face?

Dr. Jones: I think that the more we understand the perspectives of the providers and the physicians taking care of the patients, the more we can design interventions that support them to more rationally weigh the risks and benefits of antibiotics appropriately, and that will help replace some of the bad habits with better ones.

Interviewer: It sounds like what that means is changing behaviors, attitudes, habits, and that is not easy.

Dr. Jones: What we've found so far is giving providers data about their practicing of patterns is a really powerful tool to change behavior. So we call it audit and feedback, and what we've been doing across the VA settings that we've been implementing some of the stewardship efforts has been to show providers their prescribing patterns over a month or a six-month period and to show them kind of what their proportion of prescribing is and then start a conversation from there about what interventions they might be able to do to change their habits.

A couple other things have been clinical decision support systems that are often tied to an electronic health record. In a busy clinic, a lot of times you don't have a chance to have those important patient education conversations. If you have an electronic health record that supports prescribing symptomatic therapies that substitute that antibiotic or help print out a patient education handout, spend some of that time educating the patient for you, that can really help physicians feel like they're listening to their patients.

They're giving them the empathy that they need when they're feeling poorly, but also reserving the antibiotics for times that are more appropriate.

Interviewer: This is all a little different from the usual doom-and-gloom scenario that you hear about when it comes to superbugs. Are you optimistic?

Dr. Jones: Just like any shift, I feel like this is a cultural thing that can get to a tipping point. The more doctors start prescribing differently, the more their colleagues can see this and feel like they can change as well. I'm really optimistic that we can change our habits and our attitudes toward antibiotics, and so I think that some of these interventions for humans is really important. I think that if we do this, we can really impact that selection pressure and help reduce the emergence of superbugs.

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

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.

Announcer: Examining the latest research and telling you about the latest breakthroughs, the Science and Research Show is on The Scope.

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.

Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on the Scope.

Interviewer: Tibetans thrive in the high mountains of the Tibetan Plateau, conditions that most others just can't survive in. My guest, Dr. Josef Prchal, a professor in internal medicine at the University of Utah, led a study; identifying an 8000-year-old variation in the DNA sequence of Tibetans that help explain their amazing adaptation.
Today, I'm also joined by first author of the study, Dr. Felipe Lorenzo, and Dr. Tsewang Tashi, who is also an author on the paper and a native Tibetan. Dr. Prchal, Tibetans and lowlanders like us adapt very differently to high altitude conditions, what are the differences that you're interested in?

Dr. Prchal: The obvious difference is that if lowlanders go to very high altitude, they may die, but if you stay there for a long time, there are some chronic consequences which are not suitable for reproduction and for thriving in this high altitude. There are many and some of them we will not fully understand, but one of them is, what we call, pulmonary hypertension; that the pressure on the lungs is so high that it interferes with the circulation and you get, eventually, heart failure.
The other well-known adaptation is the level of oxygen tightly controls how many red cells we make. It means if we don't have enough oxygen, we make more red cells. So if you go to high altitude where the oxygen pressure is lower we make too many red cells. That's called polycythemia. That means the blood gets too thick and it's not very suitable for them, but it has been known that most of the Tibetans have a normal level of hemoglobin in very high altitude and this is something which gave us tools to study this.
And we selected then the Tibetans who had high hemoglobin and low hemoglobin, and that allows us to look at the genetic differences in these two populations. And with a graduate student here from department of genetics, Tatum Simonson, we selected these two population, did, at that time, the state of our genetic studies and we were able to look at the fingerprint of the genes of interest. We selected about 300 genes and 10 of them had clearly selected, that means they achieve much higher frequence in Tibetans, in those who were adapted well to high altitude.
And these adaptation mutations then must have some beneficial effect and so that was the first lead. And at two of the genes, which are selected, had something to do with how the body responds to oxygen, so one of them, a gene called PHD2 is a negative regulator of master regulators of response to hypoxia which is called HIF.

Interviewer: And what does the gene do?

Dr. Prchal: It decreases the over-response to very low oxygen. So sometimes our physiological responses may be detrimental. And so by modulating the intensity of the response, I think that was one of the benefits.

Interviewer: Dr. Lorenzo, you've been on the trail of this gene for a long time. It must have been satisfying to find it at last.

Dr. Lorenzo: It's really a challenge actually. Sequencing that region of a gene we just recently reach took me like six to nine months of trial and error. Finally, when we get it, it was just like you win a lottery and it's something to move on.

Interviewer: So when you saw it, you knew that was the one.

Dr. Lorenzo: Yes, because it's reproducible, it's there, it's common in our sample, and not common in the controls, so there's a story to tell.

Interviewer: So if the variation was selected for it, it must be important.

Dr. Prchal: If a gene happens to be beneficial in a given environment, with each generation the prevalence of these genes will increase. And so, again, if the Dr. Lorenzo's mutation of variant is find of 85% of Tibetans, it must be beneficial.

Interviewer: Dr. Tashi, you're a native Tibetan, it sounds like you guys went through great lengths to gain acceptance by the Tibetan community.

Dr. Tashi: So I join here in 2012 in University of Utah and one day Dr. Prchal approached me while I was in clinic and he was very excited that I was a Tibetan and I was kind of surprised.

Interviewer: Who's this guy?

Dr. Tashi: Initially, it seemed to me that he just wanted some blood and I said, "Well, that's easy. I can get some friends and get some blood."

Interviewer: Were you one of the ones sequenced in this study?

Dr. Tashi: Oh, of course, yes.

Dr. Prchal: He is.

Dr. Lorenzo: One of the first ones.

Dr. Tashi: And later on as the study progressed, I realized the significance of the whole study and this is a new potential, a very groundbreaking discovery, in a sense, and the importance that it would have, not only for the science as a whole. But being a Tibetan and also something uniquely Tibetan that's potentially the result of this, then we decided, okay, we should go and get involved more Tibetan. Actually, we went there twice and they don't really like to give blood because when you hear blood, it's kind of "Wow."

Interviewer: Yeah. But once you were able to explain it to them, and probably the fact that you are a Tibetan yourself and you're willing to undergo this, that helped them to accept it?

Dr. Tashi: Yeah, that was one of the major helping point.

Dr. Lorenzo: This is why Tsewang is a key for the success of this study because Dr. Prchal and I went actually to the community. It took us six to nine months talking to them and we got two samples.

Dr. Tashi: It's really difficult.

Dr. Prchal: We were well received.

Dr. Tashi: When it came to collecting blood, they just backed out. So it's really a key to get them into the study, and it really did go well.

Interviewer: And in the end, how many took part, the Tibetans?

Dr. Tashi: For here, locally, we have 26 or 28 and then I brought it 60 plus.

Interviewer: Wow.

Dr. Prchal: Well, began probably more than 200 samples.

Dr. Lorenzo: More than 200 in China.

Dr. Prchal: Yeah, more than 200 samples.

Interviewer: It's important for you to get letters of support from high leaders in the Tibetan community, including the Dalai Lama.

Dr. Prchal: The Dalai Lama was contacted by a principle physician called Dr. Dorjee, who easily organized all these Tibetan health care in exile community and that only happen through Dr. Tashi. And Dr. Dorjee has contacted Dalai Lama, explained to him what we try to do, and Dalai Lama felt a better of the Tibetan adaptation would be helpful to Tibetan community, but also to humanity at large. And I think that Dalai Lama is very ethical man and when it comes to ethic issues, I think it's very important to him.

Interviewer: What are the implications of this work?

Dr. Prchal: There are many human disorders which are regulated by oxygen; not only the pulmonary or lung diseases, brain edema, but also cancer. So we think that delineation of this Tibetan adaptation and deeper understanding of this can eventually lead to better understanding of common human diseases.

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

Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on the Scope.

Host: Only 15% of patients with squamous cell lung cancer survive to five years past their diagnosis. It is a difficult cancer to treat. My guest, Dr. Trudy Oliver has developed a new tool for understanding the disease and developing targeted therapies.

Dr. Oliver, you've developed a mouse model for lung squamous cell carcinoma. Why is this important?