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Interviewer: Trying to stay informed about the latest COVID-19 variants can be exhausting. It seems like things change every week, and if you're like me, you're often left wondering, "What do I do with all this information?"

Dr. Stephen Goldstein is an expert in coronavirus. He has a Ph.D. in coronavirus research. And today I'm going to take a step back and try to find out what information is important and what isn't when a new variant is announced, and how you can decide how the new variants might impact your life.

As of right now, Omicron remains the dominant strain of COVID-19. And my first question is do variants of Omicron tend to give people the same symptoms, the same level of sickness, the same chance of developing long COVID, or are they all a little bit different?

Dr. Goldstein: A little different in certain ways and probably about the same in others. So in terms of impacts, like the virulence or the severity, average severity of infection, there's pretty good evidence that, for example, BA.1 was less severe on average than Delta, for example, which was more severe than the original version of the virus.

And there's some evidence from animals that BA.2 was maybe a little bit more severe than BA.1, but all of that is kind of pretty thin and the differences are probably small.

So if I were a person thinking, "Oh, I got a BA.5 infection. This is going to be much worse than a BA.1 infection would've been," the likelihood is that the severity is not going to differ a huge amount between these different versions.

They are different in terms of the way they're recognized by the immune response. And that's where the major differences between different versions of Omicron lie.

Interviewer: And is that in terms of the symptoms how they're recognized, or when you say they're different in terms of the immune system, what does that mean?

Dr. Goldstein: Yeah. So, for example, the original version of the virus, the spike protein had a particular sequence of amino acids, the chain of letters that constitutes the spike protein. And that kind of folds up in a very complicated way into a structure, and our antibodies that are produced as part of the immune response recognize essentially the shape of that structure.

And so Omicron BA.1, the first version, had a pretty different structure or shape on the part of the protein that antibodies are able to access than the original version of the virus. And that meant that if you were infected in, say, 2020 or by Alpha or Delta, then the antibodies you made at that time in reaction to the shape of, say, the Delta spike protein might not be very good at recognizing the shape of the Omicron BA.1 spike protein.

And so you would be at an elevated risk of reinfection. Say your risk of reinfection by the original version was whatever percent chance, then once BA.1 took over, your risk of reinfection went up by some amount.

Interviewer: It's kind of like in the analog world, I recognize a threat by its shape off on the distance, and now if that animal or that critter's shape has changed, I'm like, "Is that . . .? I don't know."

Dr. Goldstein: Yeah, that's a really nice metaphor, I think. And the vaccines until now, until very recently, consisted of only the original version of the spike protein, which has a pretty different shape than the Omicron version. So if you got your vaccines before this fall, your immune system was trained to recognize just the original version, the original structure of that spike protein of the original virus.

This all gets really complicated because there were people who were vaccinated with the original version, but then infected with BA.1, or BA.2, or BA.5. And so all of these different combinations interplay with each other in really complex ways that are difficult even for scientists to really pull apart.

And so individuals should not worry themselves about the details of all of this. They should just know that the vaccines have been updated now to a version of the BA.5 Omicron spike. That is a significant update for your immune system if it was previously trained by the original version of the spike protein or the BA.1 version of the Omicron spike.

Interviewer: And this vaccine that is better at BA.5 is the one that's just recently come out within the past month or two?

Dr. Goldstein: Yeah. Exactly. Just within the past month or two, and I just got mine.

Interviewer: All right. Great. So now you're hearing some subvariants of. . . Are these subvariants of BA.5 or are these variants of their own, this BQ.1 and BQ.1.1?

Dr. Goldstein: So these are sub variants of BA.5.

Interviewer: Okay. So COVID BA.5, and then underneath BA.5 . . .

Dr. Goldstein: And then underneath BA.5 we've got all these diversifying subvariants now. And look, viruses are picking up mutations all the time. So any lineage we have, especially a lineage that's dominant, means there's going to be a lot of those viruses out there in the world. They're picking up additional mutations and splitting off into different sub-lineages all the time, every day. The question is whether any of those sub-lineages are better at replicating and transmitting in people than the lineage they kind of spawned off from.

Most of them are not, so they might occur in a few people and transmit one or two times but not go anywhere. BQ.1 and BQ.1.1 seem like maybe they are better at doing those things than the original BA.5, and that's why they're increasing and why we're talking about them.

Interviewer: And as just a regular person, what should I do with that information? Because part of me is like, "Well, maybe I should pay attention to it," but then the other part of me is, "Although they might just go away."

Dr. Goldstein: You should get the BA.5 booster.

Interviewer: Okay. That's easy, right?

Dr. Goldstein: Yep.

Interviewer: We've taken this very complicated subject and once again it seems to come down to this very easy action that we all take, which is just get the most recent booster.

Dr. Goldstein: Get the most recent booster. There's a really cool immunology that explains why you should get the recent booster even if it's matched to the original BA.5, not to BQ.1 and BQ.1.1.

As your immune system gets exposed to different versions of the spike, it expands what we call its breadth. When you were vaccinated with the original version of the spike, you made antibodies targeting primarily the original version of the spike.

Then if you got infected with BA.1, you made some new antibodies and some new antibody-producing cells that will recognize BA.1. You also boosted your original antibody producing cells to the original version of the spike.

But what you also do is actually make different kinds of antibodies as well that actually end up being able to recognize variants your body hasn't even seen yet that may not exist. And so that's when we talk about kind of expanding the breadth or the scope of the immune response.

So if you've been vaccinated with the original version two times or three times, and maybe you had BA.1, and now you're getting the BA.5 spike, you're actually going to have an antibody response that is able to do all kinds of different things, not just the specific things that it's been trained to do.

And so the BA.5 booster, even if it's not a perfect match for BQ.1, is actually probably going to produce some antibodies that recognize BQ.1 anyway.

Interviewer: Back to the metaphor, you're just gaining experience at recognizing, "Well, the shape's not quite the same, but the way it moves is kind of the same, so that could be the same threat."

Dr. Goldstein: Yeah, I love that.

Interviewer: So what about symptoms? Somebody who had the original COVID-19 virus versus maybe a BA.5 virus, are they going to have different symptoms? I remember loss of smell and taste was big in the beginning. Is that still a thing?

Dr. Goldstein: I think those things are still happening. The difficulty in kind of picking that all apart is very few of us . . . If you got infected with the original version of the virus, it's the first time in your life your body and your immune response have seen that virus.

If you get it again, even with a slightly different variant . . . The immune system has a lot of different components to it, and just because the virus is maybe a little bit better at slipping past your antibodies doesn't mean it's not recognized by other parts of your immune response that can still serve to dampen the amount of symptoms you see.

So reinfections on average, on a population level, are going to be less severe than primary infections. It doesn't mean an individual person can't have it worse the second time, because we're talking about averages, or the third time. It can happen. But probably, the chances that you're going to have some particular symptoms on average become less likely as you go through more infections in your life.

So even if, say, BA.5 is just as likely to cause a loss of taste and smell the first time someone gets infected by it, it doesn't mean that if it's your fourth exposure to this virus through some combination of infection and vaccination that you're just as likely to lose your sense of taste and smell.

So a lot of that, as the immune landscape becomes more complex, the symptomology becomes more difficult to kind of tease apart.

Interviewer: And that's why you hear people that have had it a few times say, "Oh, it's just a cold this time."

Dr. Goldstein: Yeah. Sure.

Interviewer: It's not quite as bad because the immune system is getting smarter, and your body has seen it.

Dr. Goldstein: Yeah, absolutely. And I want to emphasize that that's the average scenario. For most people, that will be true, but everybody is different. There are people who are going to say, "I had it the second time and it was way worse."

Interviewer: Got it. Because we're all different.

Dr. Goldstein: When there are seven billion people in the world, you're going to have people who are worse than the . . . I mean, the average is the average for a reason. Because there are people who are worse than that, and there are people who are less. There are people who are going to have no symptoms their first time even, or their second and third time. Then there are a lot of people who are going to have mild or moderate, and then some people are going to have it worse the second time for whatever reason. In most cases, we don't understand why.

Interviewer: What about post-COVID? So long COVID, I guess, is what I'm trying to say, right? Do different variants cause different extremes of the long COVID, or is it much like what you just described with the immune response and the symptoms?

Dr. Goldstein: This is an area that is still pretty murky. I think we don't even have a really good understanding of exactly what causes long COVID yet. And long COVID is . . . if we define it very broadly as kind of any symptoms that are persisting past three months or six months, whatever date you want to pick . . .

Interviewer: And some examples of that would be shortness of breath. What are some other examples?

Dr. Goldstein: Sure. Brain fog, extreme fatigue, things like that. But we don't know if those are caused by the same thing in all people. Some people maybe are having some persistent replication of the virus in their bodies. Other people, maybe the virus is gone, but their immune response has gone haywire after their infection. So we still need to kind of pick all of that apart, in my opinion. Our knowledge is still kind of thin in that area.

And then also, again, we don't really have a great understanding of . . . My expectation would be that if you didn't get long COVID the first time, the chance of getting long COVID on the second time is probably less than the first time. But it's also complex because the more times you get COVID, the more likely you may be to . . .

Interviewer: Your odds.

Dr. Goldstein: Yeah, your odds. It's really complicated, is what I think the best answer I can give you is.

Interviewer: And I think I realized maybe a flaw in my thinking as we're having this discussion, which is I'm putting the symptoms and, "Is this going to give me long COVID?" on the disease. But it's really the individual and how they're reacting to the disease that's a big part of that equation too.

Dr. Goldstein: Yeah, I think the kind of inflammatory part of the immune response probably has a lot to do with long COVID in a lot of cases. But there's still so much that we need to learn about this.

I mean, unfortunately, this has been an area I think that largely there's been underinvestment in on the research front. Hopefully that changes.

But I think the best way to put it is probably your risk of long COVID goes down . . . For each infection, the risk of getting long COVID after that infection goes down, but every time you get COVID there's probably an additional chance. So the average risk goes down, but there is some additive effect.

Interviewer: As far as I'm aware, I have not had COVID, right?

Dr. Goldstein: Good.

Interviewer: And so then I hear about these variants, and they're like, "Oh, this variant is less severe and whatever," and I'm like, "Well, I'm not so afraid of getting that variant now because I've been vaccinated. I feel pretty healthy. I know I'm probably not going to get severely ill." But that long COVID thing scares me a little bit.

Dr. Goldstein: Yeah. I mean, my expectation is that vaccination, especially keeping up with the boosters, probably reduces your risk of getting long COVID ultimately. It's just an area we don't have a lot of hard data yet. But from an immunological standpoint, that's my expectation.

Interviewer: Now, when COVID first came out, we had one line of defense and that was social. It was wearing masks, it was keeping our distance, those sorts of things. And then we got a vaccine, and then . . . And maybe this isn't the exact chronological order, but then now we also have treatments as well, right?

Dr. Goldstein: Yep.

Interviewer: I hear these words like treatments, therapies, interventions. Are those all essentially the same thing? Give me the hierarchy of that.

Dr. Goldstein: Yeah. So treatments and therapies kind of come in two flavors. So one is antiviral drugs like Paxlovid, and that works to disrupt the actual replication of the virus. So it doesn't stop the virus from getting into your cells, but it stops it from replicating.

Then you've got these antibody therapies, and they basically work like your immune response, but they're giving it to you from kind of outside, what we would call passive immunization in a sense. But you can also do it therapeutically. It gives these antibodies . . . the virus that's in your body, it stops them from infecting new cells.

The problem with these is that a lot of these antibodies are designed against an older version of the virus and are becoming much less effective against Omicron. So we need new antibody therapies.

One way is ones that are developed specifically against different Omicron variants, but actually the better goal is to make antibody therapies that are based on what we call broadly neutralizing antibodies that show the ability to target many different versions of the spike protein. And those do exist, they've been identified, but we need to get them across the finish line as far as developing therapies based on them.

Interviewer: And in those instances, that is after somebody contracts COVID. These are tools that are used to help reduce the severity?

Dr. Goldstein: For the most part, yes. There is one antibody drug called Evusheld that's used to actually protect people. That's given every few months and it's primarily given for people who are immunocompromised to protect them preemptively or preventatively. Looks like it's not going to be working very well against the latest Omicron variant, so we do badly need an update there.

Interviewer: But that is something that, much like the vaccines, can be updated.

Dr. Goldstein: Yes.

Interviewer: It just is going to take some time.

Dr. Goldstein: Takes some time. We ideally want to develop them based on those broadly neutralizing antibodies, because then we're not chasing variants and we're cutting down the chance that we're going to get a variant that escapes that antibody therapy. We can just have ones that are based on broadly neutralizing antibodies and roll with those hopefully for a very long time.

Interviewer: And then what about home test accuracy when we're talking about the variants? I know people that said, "Oh, I'm sure I had COVID, but I kept getting negative on my tests." Are the variants not as detectable by some of those home tests? How does that work?

Dr. Goldstein: So far, we have not seen any variants that seem to have dented the accuracy of the home test, especially, I think, the most popular ones that people are using, especially in the U.S.

So these home tests, they're not designed to detect the spike protein, which is the part of the virus that changes the most. And so they're not super sensitive to the variants escaping them.

I think more of the variable performance of the home tests is people vary in the amount of virus they have in different parts of their body. So some people have a lot of virus in the lungs and maybe those are the people who get really sick, and some of them will also have a lot of virus in the nose. Some people have very little virus in the nose.

So you may have heard a story where someone got infected and their partner or wife or husband didn't get it. Why? I mean, they live together. People are often transmissible before they get symptoms. So maybe they slept in the same bed. How is that possible? It's crazy.

Interviewer: Yeah, why? I'm asking.

Dr. Goldstein: So one big reason is probably that some people just don't shed a lot of virus out of their nose or their upper airway, their trachea. And if you don't have a lot of virus coming out of your nose, the home test is not going to work as well.

Sometimes people will say, "Oh, I didn't test positive until Day 3." Well, some people, maybe the amount of virus in their nose spikes up really fast, and those are the people who are going to test positive the first day they have symptoms, like me when I had COVID.

Other people, maybe the amount of virus in their nose kind of increases much more gradually. And so maybe it's two or three days into their sickness before they have enough for the test to detect.

The final point of your question, "I'm sure I had COVID. Why did I keep testing negative?" So one possibility is you did have COVID, but you never had a lot in your nose.

The other possibility is you were infected with one of literally hundreds of other viruses that can cause a very similar respiratory disease. Maybe they're less likely, even much less likely in some cases, to cause severe pneumonia, but distinguishing between different viruses . . . If you just had essentially an upper respiratory tract infection, maybe you had a mild fever. Distinguishing between those from a clinical standpoint is impossible.

Interviewer: Give me some advice on how I should move forward. When COVID first came out, I paid very close attention to what was going on, as I would imagine a lot of people, and then it gets very fatiguing. And then I hear a news story about, "Oh, there's a new variant." But then I'm like, "Oh, I don't know if I have the wherewithal to dive into learning all about that. Where should I be in my life as far as when I hear news stories about new variants or whatnot?

Dr. Goldstein: So aside from making sure your vaccine is updated, getting the booster . . . We covered that. Definitely do that. Beyond that, I personally, even myself, and so certainly for someone who's not a coronavirus researcher, don't worry day-to-day about which variant is dominant. So I would look more at the curve, the number of cases than which variant it is. For most people, the specifics of which variant are dominant at any given time, this is not important information to me, frankly.

And I wish there was less coverage in the media of, "This variant, this variant, this variant," because the things that people can do in their day-to-day lives are the same. Get boosted, and if your risk mitigation practices are prone to change, if you're interested in changing them based on what's going on, just look at the number of cases. It doesn't matter which variant they're being caused by. Just pay attention to how much virus is transmitting in your community and react to that.

Interviewer: And that's for the average person. What about for somebody who might be immunocompromised or something like that? Same advice?

Dr. Goldstein: Well, I think someone who's immunocompromised should be taking more precautions all the time. And that still scales, I think, with the amount of virus that is going around in the community.

And another thing people who are immunocompromised should do is . . . We talked about that drug Evusheld that can be given preventively. If that continues to be recommended by the FDA, meaning that it still works against what they expect to be the variants that are circulating, get that if you're immunocompromised.

Actually, a huge problem is this drug has not been promoted well enough, and many fewer people than the number who would benefit from it are getting it. Hopefully, there'll be an update to this kind of preventative antibody therapy soon to better match the variants that are circulating. Definitely, as soon as that happens, if you're immunocompromised, if you qualify for this drug, get it. It's very effective.

Interviewer: Let's wrap it up with what should the average person take away from this conversation when it comes to COVID-19 variants?

Dr. Goldstein: Most people can just tune out the noise about what particular variant, the news stories that you're seeing every day about the newest variant and the immune escape properties of the latest variant, etc. I think it's not important for most people. I think it's drowning people in complexity that frankly is irrelevant to them.

I mean, give people the best advice. Like I said, get boosted, match your risk mitigation to the number of cases in your community, and that is literally all you need to know. You do not need to know what amino acid changes there are in the BQ.1.1 spike relative to the original BA.5 spike. There's not a separate vaccine for the two of them, so who cares? Go get the booster, for sure.

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.

Interviewer: A different way of thinking about how cancer starts. 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. Charlie Murtaugh. Professor of Human Genetics at the University of Utah and with Nathan Krah. They've just published a paper in the journal "E-Life."

Dr. Murtaugh, as far as I understand it, your results really kind of put the initiation of cancer in a different light.

Dr. Murtaugh: The standard model for how cancer starts is that you have a cell that accumulates a bunch of different mutations until that cell becomes sufficiently abnormal that it turns into a cancer cell and stops behaving like a normal cell. And we were interested in how that applied in pancreatic cancer. And we and others have found that the genetic mutations that occur in pancreatic cancer in the model that we use are not enough to actually trigger the beginning of the disease. So we knew there's something else had to be going on. And what we think is going on now is that the differentiation state of the cell.

So how the cell knows what it normally is supposed to do. In this, case the cells are cells that make digestive enzymes to break down food. And they are normally focused 100% on that task. They're not really dividing. But then, a change happens and those cells forget what they're supposed to do and then in that context then those mutations that can cause cancer can become hyperactive and the cells start to become transformed and move toward cancer.

Interviewer: Nathan, maybe you can tell me why you're focusing on pancreatic cancer in the first place.

Nathan: Yeah definitely. So pancreatic cancer is one of the deadliest solid tumors that patients can have. It has one of the poor survival rates of just about any cancer with a five-year survival of only about 5%. So really, any clues that we can get that push toward earlier detection or better treatment options would be good.

Interviewer: You're implying principles of development to understand cancer. What does that mean exactly?

Dr. Murtaugh: Right. I have a long-standing interest in the process of differentiation. This maybe does go back 20 years. So it just how cells learn to adopt the mature fates that they're supposed to achieve, starting in the embryo and the differentiation continues in the adults. So, of course, we are continually shedding skin so we have to differentiate new skin all the time, new hair, etcetera. And it was through studies of differentiation in the pancreas and trying to understand how the different cell types, the endocrine and exocrine cells, how they get to differentiate that we began to be interested in how that might apply in cancer.

Because it seemed, based on classical work, that it was possible. That in fact cancer might start from not only genetic mutations that we know are important, but changes that are non-genetic like loss of differentiation.

Interviewer: So kind of the ideas that when a cell is differentiated, it's mature and is thought to be just sort of fixed that way, kind of stable that way. And so if you disrupt that, things go wrong?

Dr. Murtaugh: Yeah, exactly. Exactly.

Interviewer: And how did you move that into the cancer paradigm? I think you've been researching a gene, PTF1, for a while?

Dr. Murtaugh: Right. So PTF1 is a gene that's called a transcription factor. And transcription factors are proteins that regulate other genes. So a lot of what differentiation involves is turning on expression of genes that are important for the carrying out the function of the cells. So, for example, the exocrine cells that we study, they make hundreds of digestive enzymes. Like huge concentrations.

And so what PTF1A does normally, in a mature cell, is it activates those genes. So without PTF1A during development, you can never make the cells that normally digest food. And what we found is that once you are a mature cell you still require PTF1A in order to continue making those enzymes and in order to repress alternative choices.

So cells tend to not like to do nothing. If you take away a factor like PTF1A that forces them into a specific identity, if you take that away they will kind of cast around and look for an alternative identity. And in a healthy cell, that might not be a big deal. And in fact, we find that just taking PTF1A away is not enough to cause cancer.

But in a cell that has an underlying cancer-causing mutation, when the cell starts trying to change its mind about what it's supposed to do, those mutations can kind of express themselves and then the cell very, very quickly becomes abnormal.

Interviewer: You've done these experiments in an environment where there's already something wrong? And so this is like one more step that breaks the camel's back?

Dr. Murtaugh: Yeah, exactly.

Interviewer: Nathan, what do you see when you do that?

Nathan: When we take away PTF1A in the context of cancer-causing genes or oncogenes, we see that these cells are rapidly transformed into pre-cancerous lesions. And what's really interesting is that if we just express these oncogenes or cancer-causing genes alone, that's really not sufficient to do too much. They occasionally form these pre-cancerous lesions, but in the context that PTF1A loss, almost every cell that loses PTF1A will give rise to cancer.

Interviewer: And is there any indication that this happens in human pancreatic cancer?

Dr. Murtaugh: Right. So that's a really good question. So one of the things that we were able to show is that in fact in the lesions of humans, these early stage precancerous lesions, the PTF1A is also being shut down. And in fact, there are some other studies out there that didn't focus on PTF1A, but have all sort of implied the same thing that this must be happening at a very early stage in cancer. And so it does look like it probably does happen to humans and one of the things we're really interested in going forward is sort of doing the reverse, which is if we could turn it back on in human cells, would we be able to stop the cancerous cells from growing.

Interviewer: Right. I mean, will that point to a different kind of therapy?

Dr. Murtaugh: I think so. I mean, most cancer therapies in pancreatic and other cancers are targeted to cell division. And, of course, that's what conventional chemotherapy does and it has limitations because it can kill the normal dividing cells. And there are other therapies that are targeted at the mutated signals that occur in the cancer and in some cases like lung cancer, those have been really effective therapies. But in pancreatic cancer, it's been very challenging to do that. So the oncogene, the cancer-causing mutation that is so central to pancreatic cancer is one that is in a protein that is very hard to make drugs against.

And so this has been a long-standing problem in the field. But we do feel that differentiation is something that there's almost no disadvantage. In theory, at least, there are no side effects from having too much differentiation in the pancreas because it's an organ that is normally very differentiated. So if there were a way to reactivate the normal differentiation of these cells, that by itself shouldn't have any major side effects. And the question is whether it would be effective as a therapy.

Interviewer: Yeah, fascinating. I mean, is there any indication that this happens in other cancers as well?

Nathan: Yeah, that's a really good question. So one thing I think that's exciting to us is if we really look throughout the GI tract, there are a lot of cancers that undergo this process called metaplasia or a change in cell fate, which almost always precedes cancer and is usually associated with chronic inflammation.

And so one good example is in the esophagus, a lot of people have the acid reflex and that can lead to changes in the cell populations in the lower esophagus. And it's thought that those changes are actually necessary for cancer formation. And so we show a very similar story in the pancreas. We think that this actually a broadly applicable principle where you need a loss of differentiation in order to actually initiate cancer.

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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.