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

Interviewer: Millions of Americans with diabetes inject themselves with insulin every day or multiple times a day to manage their disease. While that's hard enough, the soaring price of the drug has made things that much harder. I'm talking with nurse practitioner and researcher Dr. Michelle Litchman, about living with diabetes and the lengths people are having to go to just to stay healthy. Hi, Dr. Litchman, thanks for joining us.

Dr. Litchman: Hi, thanks for having me.

Interviewer: Many people with diabetes can't live without insulin. Tell me about how people with diabetes rely on this drug for their health.

Dr. Litchman: Everybody with type 1 diabetes, and about a third of individuals with type 2 diabetes require insulin to stay healthy and well.

Interviewer: Why is that? What does the drug do for them?

Dr. Litchman: Insulin is required to lower blood sugar. It allows glucose to get into the cell and to be used for energy.

Interviewer: And so if they don't have those shots of insulin, what can happen?

Dr. Litchman: If glucose gets down dangerously high, it can result in complications. It can result in diabetic ketoacidosis, otherwise known as diabetic coma. And it can also lead to death.

Interviewer: This drug is necessary for these people to stay healthy, and yet it's getting harder and harder for them to get. The cost of insulin has risen a lot in the last few years. By how much? What are we talking about?

Dr. Litchman: In the last decade, it has at least doubled.

Interviewer: Which is quite a shift for patients who rely on this drug every day.

Dr. Litchman: Absolutely. Access to diabetes medications and actually also supplies is really challenging for people with diabetes. People are faced with a dilemma. Do I pay for the health-related expenses that I need – my medications, my supplies – to survive? Or they're having to make the choice of do I ration my medications and supplies so that my family can have the things that they need like the food, shelter, making my house payment, making my car payment, having gas to get from point A to point B. And so rationing happens on one end or the other. It's either on the side of health and diabetes medications and supplies, or it happens with the family basic needs.

Interviewer: And how crazy is that? Just to stay alive you can't live a normal life.

Dr. Litchman: Absolutely. People are under immense stress and guilt related to the cost of medications. A lot of people in our study felt remorse that they had to put their family in such situations. And it's not fair.

Interviewer: I mean, some people are even questioning whether they deserve to live.

Dr. Litchman: Absolutely. We found that people were feeling guilty about the cost and questioned whether or not their life was worth the cost of insulin to even continue living.

Interviewer: It's quite a thing that we've come to this point, don't you think?

Dr. Litchman: Absolutely. I mean, it should never be the cost of medications and supplies is worth somebody's life.

Interviewer: How are you going about even finding out this information? Is this through conversations at the clinic or something else?

Dr. Litchman:So as a clinician, I'm seeing this all of the time where patients are coming to me with concerns related to their ability to afford medication and supplies. It's actually consuming a lot of the visits not only for me, but also my colleagues. And so this is really affecting our visits.

From a research standpoint, we conducted a cross-sectional survey of adults living with diabetes or caring for somebody with diabetes like a child. And we found that many people are financially struggling. In fact, financial distress is higher among those with diabetes than those without diabetes. And we're also finding that financial distress is related to interpersonal issues because of the cost of insulin. So people are having disagreements or guilt-related issues with their family members because of the cost of diabetes.

Interviewer: So it's not only affecting their ability to get the care that they need, but it's affecting their family life in a lot of different ways.

Dr. Litchman: Absolutely. And when they go to a healthcare provider to seek help or discuss these issues, healthcare providers are somewhat limited in the solutions that they can offer. So clinicians can offer patient assistance programs that currently exists. Not everybody qualifies for certain patient assistance programs, but they're also very time consuming. So it's not just an easy one piece of paper to fill out, it's a lot of papers that needs to be collected and a lot of signatures that are required in order to make the paperwork process move.

Also people who have Medicare fall into the donut hole about halfway through the year depending on the person's circumstances, and not all patient assistance programs are for people with Medicare, and so that's a barrier as well. And we're also finding that some clinicians aren't aware of all of the services that are available, nor do they have all of the support necessary to make sure that patients get what they need.

Interviewer: And so a lot of patients aren't getting assistance. And what are they doing instead?

Dr. Litchman: Patients are having to go through unique channels to access what they need. So in our study for those patients who really want to stay well, some of them are engaging in trading behavior. So I'll trade you this if you can give me these supplies or that insulin. People are engaging in the purchase of medications and supplies from sources that are not approved to be selling those. So, for example, people are leaving the country or they're buying them on the internet.

One of the things that we found that was interesting is the altruism that people are having with regards to donation. So if people had extra supplies or extra medications they were willing to donate. We saw this not only in this survey, but we also saw this on crowdfunding sites where people would list in the comments, you know, if I live near you, I'm happy to send you some insulin if you really are in need.

Interviewer: Then, of course, that's not a long-term solution.

Dr. Litchman: Absolutely, not a long term solution. And people also would only spare the extra that they had, so they needed to make sure that they themselves had the insulin they needed to take care of themselves, and they could only spare the extra.

Interviewer: It seems like it's underground behavior, right? I don't know if it's quite criminal, but it's certainly not what healthcare providers would recommend. You know, it strikes me as being pretty dramatic if people have to resort to that.

Dr. Litchman: Well, again, people have to make a decision, do they stay well? And if so, what are the things that they need to do in order to stay well, and in some cases, people have had to go to extreme measures. One of the concerns that some people have had in these trading communities is that some of them are being shut down, and so that's causing even more access barriers to people. And so there's this ethical dilemma that we're facing, should people be able to access what they need through this underground trading? And if not, what are the solutions that exist so that people can actually get what they need without having to engage in this activity?

Interviewer: I'm wondering if you know, over the course of time that you've been performing these surveys, I mean, if you've seen some changes in attitude. I mean, I imagine people are getting pretty jaded, you know, jaded with the healthcare system, jaded with pharmaceutical companies. Do you observe any of that too?

Dr. Litchman: Absolutely. I see that in the research and I see that clinically. People are getting frustrated, and they want solutions. And they are almost feeling like there's no way out. And it's really sad to see.

Interviewer: Do you think there are downstream implications for that? Do you think it might erode the trust that some of these patients have? I don't know with who, with their providers, I don't know. If this alternative means of getting healthcare becomes a new norm for them, is that going to carry over for maybe for other conditions that they may be having too? Maybe they think, oh, if this works from treating my diabetes, maybe I can do some on the side trading to treat my migraine, to get drugs for treating my migraines or something like that.

Dr. Litchman: There is research showing that there are people who are trading for other conditions such as asthma, and so I think that it's absolutely true. If you can't access a medication and you need it for some reason, then people will go to extreme measures in order to make sure they have what they need, because they want to be healthy. I think that some downstream consequences is, you know, if we don't have a trading system, then we have people in the ER, every time they need a dose of insulin. And what does that do to this system? How much will that cost? We need to have solutions in place that don't just make sense financially, but for actual people that are on the receiving end.

Interviewer: In collecting this information, I mean, what do you hope to accomplish with that? What do you hope to do with that information?

Dr. Litchman: I think the first step is awareness and making sure that people understand what is happening not just on the patient and provider level, but on the health policy level as well. We need people who are willing to step forward to make sure that diabetes management is accessible and if we don't make insulin and other medications and supplies accessible now, we're going to have major consequences later, we're going to have a higher rate of complications and costly hospital stays, and even death. And we need to stop it.

Interviewer: I'm wondering, are there any specific stories that you've kind of picked up in your work that might illustrate this that you feel like you're able to tell?

Dr. Litchman: I've taken care of people who had Medicaid as a child, and who, once they became an adult no longer qualified for childhood Medicaid, and didn't have parents who had health insurance. And they are really struggling to afford what they need because they don't have insurance at all. They can't get adult insurance. And I've sat down with people to try and help them get Medicaid on my off hours because the application process isn't simple. You know, people oftentimes need help with this. And it's a struggle and that person struggles today.

Interviewer: And so have you seen people's health deteriorate as a consequence of what's happening?

Dr. Litchman: Absolutely. And it's not just the physical deterioration, it's the mental. I think that people feel like there's a system in place that doesn't care about them as a person. And despite our efforts, and in trying to find ways to access insulin that's affordable, it's still hard. And you know, people will argue that there is generic insulin that can be purchased without a prescription. But it's not the same as the medication, the insulin that has become the gold standard that's more physiologically matched to people who with food and the way that our liver puts up glucose. And so I think that we need to help people get access to the best medication possible for the diabetes that they have.

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

Announcer: Health information from experts supported by research. From University of Utah Health, this is thescoperadio.com.

Interviewer: We're at the Utah Cardiac Recovery Symposium with Dr. Gary Gibbons, Director of the National Heart, Lung, and Blood Institute, and Dr. Stavros Drakos, a cardiologist and a professor in internal medicine at University of Utah Health. Dr. Gibbons, in your keynote address you talked about the strategic direction of NHLBI and your talk title is "Advancing Discovery Science for Public Health Impact." What does that mean?

Dr. Gibbons: Well, that relates in part to our mission. Our mission is to turn discovery science into the health of the nation. And to do so, we do that in partnership and collaboration with researchers from all over the country and around the world. And an element of that is to have a strategic plan or strategic vision that helps organize and prioritize those research investments we're going to make. And that's a process that has been very inclusive. It's included over 4,500 individuals around the country and around the world that have given us ideas, the most compelling questions and critical challenges we could take on in the next 5 to 10 years that will help us fulfill that mission to turn discovery into the health of the nation.

Dr. Drakos: What is your major goals or major goal with this vision?

Dr. Gibbons: So the strategic vision, we've designed it to really capture four basic goals. Goal one is around understanding how normal human bodily systems function to maintain health and wellness. It's important to understand how these incredible body systems are able to sustain us in wellness. And that we think that's important in understanding any transition to ill health.

And the second goal relates to understanding the pathobiology of disease, the pathways mediators and mechanisms by which people develop, for example, heart disease and therefore getting insights into how we might intervene and change the natural history, maybe even preempt chronic diseases. And so goal three relates to accelerating the translation of discovery science, say, at the bench, the laboratory and making sure that they have an impact eventually on patient care, patient care even in the real world. And so that translational research is important part of our portfolio. And finally, the fourth goal relates to the biomedical workforce overall, the training and enabling resource mission that we have as stewards to ensure that we're creating a diverse next generation of scientific leaders who will drive the breakthroughs of tomorrow.

Interviewer: So what are some of the research areas you think could make the biggest impact?

Dr. Gibbons: Well, a key part of the NHLBI portfolio is the fact that we have within it the major killers of men and women in this country, particularly heart disease and as well as chronic lung disease which is a major cause of death and morbidity in this country. Asthma is a major cause of morbidity among children. So, within our portfolio, we have a number of disorders that affect literally millions of Americans and has an impact on their death and life course. And so discovery sciences that can improve their health can have a dramatic effect on outcomes for our country.

Dr. Drakos: Can you please give us examples of specific translation on research programs that are taking new and exciting approaches to breach this gap between discovery science and public health?

Dr. Gibbons: I think one of the things that's particularly exciting is an appreciation for some of the pathways that are governing the transition between health and disease. I'm excited to be here at the Utah meeting here. We're talking about cardiac recovery, and it highlights what we are learning about heart failure. Very common condition, one of the most common causes of hospitalization. One of the drivers of healthcare expenses, and the more we can understand about what maintains a normal heart and what happens when it declines in function. And more importantly, how we can develop new therapeutic strategies to help it remain more resilient to not just stimuli and injury as well as recover its function is critically important.

We're excited about some of the presentations that have been made here that highlight, for me, one of the paradigmatic examples of a heart recovery that relates to a peripartum cardiomyopathy. That's a situation clinically that many physicians are familiar with in which an otherwise vibrant and healthy woman of reproductive age develops heart failure for unclear reasons as the result of pregnancy. And what's particular remarkable is that we can get her through the pregnancy. Often after giving birth to the child, much of that heart function recovers. And that's an extraordinary clinical observation, but we often didn't really understand what was going on and why.

And the recent research that the institute has funded indicate that a number of these individuals have variants in their genetic code that predisposes them to developing heart failure and cardiomyopathy. And by recognizing that, that gives us an opportunity to diagnose those individuals much earlier in the course and perhaps do interventions that might change the natural history of the disease. And so we're very excited about that.

Indeed, we're doing studies in our top at our Precision Medicine Program where we've now achieved almost 150,000 whole genome sequences of individuals who were carefully characterized in our cohort studies, and we think this is the beginning of being able to identify a lot of the predisposing factors to heart disease and, more importantly, the pathways that promote disease so we can have a whole new generation of novel therapeutic strategies to preempt chronic disease or perhaps, again, facilitate that recovery. So that's the exciting thing.

Interviewer: Yeah. That's fascinating. I mean, you know, it's interesting to think about these differences between individuals. But we know that there's differences regionally as well. And so for example, here in Utah, we actually have pretty good heart health compared to other parts of the country. Is NHLBI thinking of ways to address those variations too?

Dr. Gibbons: Yeah. No. It's a great point that you make. And, you know, part of it is understanding what is it about Utah that keeps you so healthy up here. And I must admit in this day that the clean, dry air and the mountains to walk and stay healthy, I'm sure are a part of that. But we also recognize there are communities in this country where that exposure to a healthy lifestyle is not there. And we can appreciate with congested areas and air pollution that these are things that have a deleterious effect on cardiovascular health. And so understanding these geographic variances and disparities can give us insight into what are the drivers that, again, maintain health and wellness relative to those that might predispose disease.

And hopefully some of those things can be modified and so certainly we're appreciating that the adaption of a healthy diet, indeed access to healthy diet, fresh fruits and vegetables for example, can play an important role in your cardiovascular health and prognosis. And so understanding those variations can help us appreciate it for a complex disorder like heart disease. It's not only your genetic predisposition, but it's your environmental factors and behavioral habits all working together that can, again, promote wellness and prevent disease. And some of those things are the things that are most . . . have the greatest impact in preventing and preempting disease and so things that we need to do more effectively.

Interviewer: Yeah. I mean that's interesting. When I think of the National Institutes of Health and the different institutes within it, I think of them as being drivers of science research, clinical trials. But are you saying that you'll be involve in kind of these more social aspects as well?

Dr. Gibbons: We think it's still within our mission that there's a whole spectrum of taking a discovery and making sure that it's not only something that's seen in a dish or in a mouse, but also translates to humans and communities and appreciating that some of the best interventions may not always be at the level of a cell or individual, but actually may be a community. And so it may be a research question to ask what would be the impact of creating more walkways in certain communities or bringing supermarkets that have fresh fruit and vegetables. Can we change the trajectory of health of individuals in that community just as easily as we might by giving them more pills that might influence their health? Both are probably important.

Dr. Drakos: So how do you hope, Dr. Gibbons, that NHLBI's vision will change our public health landscape during the next five years and beyond?

Dr. Gibbons: Well, I'm actually very excited about that landscape. We think that we have the tools in hand to make a big difference in which the . . . as I mentioned before, we have initiated the Top Med Program at Precision Medicine, where we think we can take some of those unknowns, like the woman who has peripartum cardiomyopathy, and start to be able to diagnose what's really going on with new diagnostic capabilities that are emerging. We also think that that may help us target treatment so that we're not taking a guess as to whether someone's going to respond to a therapy or not. But we have increased the probability that we're giving the right drug to the right person at the right time that can actually prevent or preempt their disease. And I think we have an armamentarium now that's going to give us that capability better than ever and we think that's very exciting and in hand.

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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.

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 Hilda Bastian, the Chief Editor of PubMed Commons. Hilda, in recent years, it's come to light that really the majority, it turns out, of scientific research cannot be replicated. This calls into question the validity of thousands of research studies, maybe tens of thousands, and I think it was you who said that this term, "research reproducibility," is really a euphemism for all of science's problems. What do you mean by that?

Hilda: Well, when you look at the way that people try to define it, they struggle with putting it into different little boxes and breaking it down into parts. But when they start to talk about what needs to change to solve those problems that they're identifying, they basically start to tackle every problem to do with science from how it's done to how it's reported and how people deal with it afterwards and so on. In effect, it's a euphemism, I think, for just anything that can go wrong in science because they are just so many things that can lead to science not being reliable.

Interviewer: Yeah. So there has been a lot of talk about kind of steps people can take, scientists can take before they start the research, maybe planning it very carefully and very well, steps they can take during the research, you know, recording things properly and being very careful and thorough. Something that I thought was interesting is what people can do after publishing their research. I think most people think that once they publish their work, that's the end of the line. It's said and done. But you're looking at it a little bit differently. Can you talk about that a little bit?

Hilda: Yes. Getting published is a really quite important milestone in any kind of research project, but it isn't the end of it. Once something is published, that's really the point at which other people can try to engage with it. They can start to see whether they've got questions about it, whether there is enough information in the publication. They can start to see errors that nobody spotted or have questions about the validity of certain things that nobody could have spotted beforehand.

And as well, people do other research. I mean, things move on, and they could have consequences for things that were published before. Now, sometimes, that can be your own work that you need to do the next project and the next project, and then you realize, gee, we were wrong back then or we found this mistake in it or we'd rather people didn't read that. We'd rather they paid attention to this other paper as well.

So there are all sorts of things that happen after a paper is published, and in fact, there is a lot more that of that kind of engagement with other people often after than there is before. Quite often, the only people who've had anything to do with it, a project beforehand, could be a very small number of people that were actually writing it and then perhaps a couple of peer reviewers, maybe an editor at the publication. The peer reviewers may have spent a half an hour reading the article or whatever, the draft article. So for an awful lot of projects, if they're going to be of value, publication is really just the start, not the end.

Interviewer: So yeah, I could definitely see how, you know, once you open it, publication, published research, up to a lot of people with maybe a lot of different backgrounds or expertise, that they can add their different perspective to what you're looking at. Are there formalized ways for collecting those comments for kind of starting that second wave of discussion?

Hilda: It's kind of patchy because some journals have very, very well-established systems for that, very lively online communities around their journal and established ways of getting letters to the editor to publish and reacting to what people say, whereas other journals don't accept any feedback at all once something is published, or they accept it for only a very short period of time. Now, we've got PubMed Commons, which is the project that I'm involved with, which enables people who are authors of scientific papers to comment on other scientific papers that are in PubMed, which is this enormous biomedical database. And there are other websites that do that sort of thing.

It is largely fragmented around the place, and people are kind of engaging with research in lots of different ways. They're talking about it at conferences. They're talking about it at journal clubs which is sort of gatherings where people get together regularly to talk about research, kind of like a book club. They talk about it at conferences, they're writing blog posts, they're talking on Twitter. They're emailing authors. There is this vast amount of activity that can be going on.

Interviewer: But I think you would argue that this kind of post publication reflection phase is really important and as you said, this could mean sort of changing the culture of science. I mean, how do you begin doing something like that?

Hilda: Well, I think that there is a lot of different ways that it has to happen and it is really quite a big cultural challenge. Part of the first solution for that is for more of this to be done in the open. A real lot of peer review, but before publication and then afterwards, can happen behind curtains if you like and nobody sees it. Sometimes, people are doing it by email or people have made a public comment or criticism of a piece of work, but then the way that the authors and the journals deal with it is completely untransparent. They don't respond, you hear nothing, and you've got no idea what happened behind the scenes.

And so some of the process, I think, that's going to be quite important is for more of this stuff to come out in the open. I think that's both important for people learning how to do it because they can see and see by other people's responses what actually is a useful constructive way to go about these things and find out what works. But it's also important for there starting to be some kind of consequences for this. It's just too easy at the moment for people to just ignore even really quite serious profound criticisms of their work, which is really problematic for that piece of work but also for any other work that they're going to do if they're going to continue making the same mistake and not with their confidence not dented even the slightest bit by the fact that they're probably completely wrong in what they're doing.

So I think there is a range of things that has to happen, but that very thing of asking people to be open and asking for more consequences are really quite profound. People quite find all those things around openness quite challenging partly because they kind of hang onto ideas and thoughts to use later perhaps in the background of a paper of their own. There is level where people actually have to actually take the time to go and contribute their thoughts about somebody else's work in a timely fashion in someone.

Then you have those whole issues of editors and journals and different people or even funding agencies. They all kind of finish something and they move on to the next thing. They're not necessarily continuing to invest effort into the great big pile of things that they're gathering up behind themselves. So they're looking at the new articles coming out, not going back and revisiting all those thousands, if not millions of ones that are lying behind them.

Interviewer: You know, if scientists start taking these steps that we talked about, incorporating constructive criticism, having this time of reflection, how do you think that could improve science?

Hilda: It very clearly, for the person who we're talking about who's doing work, there's a clear benefit for whatever it is that they do next. There is an important benefit if this process of criticism also involves people actually correcting errors when they see an error, retracting a paper without as much fuss and bother as happens now. People are actually more willing to actually correct the mistakes. Then there is also a really big benefit to everybody else who might be using it. You've got people, of course, when somebody publishes something, they might go and start off and spend the next two years of their life trying to extend the work or the idea that they got from somebody else's publication.

Now, if the people who did that publication, the people of that journal now no longer believes that publication is right and they kind of don't let the broader community know, then there is going to be people who are just wasting a colossal amount of time trying to do something that's never ever going to work, and that has enormous consequences for them and it can have enormous consequences obviously for something that gets used if it's clinical research or so on. You can have patients and doctors making decisions based on information that's fundamentally flawed, and so that becomes absolutely essential that people know, look, don't touch this.

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

Interviewer: You never know where basic science will take you. Today, I'm talking to biochemist Wes Sundquist about a nature inspired system that can deliver molecules to human cells. We'll talk about that 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: Tell me what it is you've done here. You've made kind of a delivery system that can bring small molecules to other human cells. What is that?

Wes: Right. So what we've been able to do is to design new proteins that normally wouldn't have these activities to act like viruses in the sense that they can assemble into spherical particles. They can drive their own release from cells. And if we have the appropriate signals, they can enter new cells. Those are properties that we normally associate with viruses, but these are proteins that are designed in ovo and so we would envision that they can be more flexible in terms of what we can do with them than the nature viral systems.

Interviewer: Why is that interesting to maybe some of our listeners?

Wes: Right. So a couple of things, one is we've been for a long time interested in how viruses do this. So this is something that viruses are able to do, leave an infected cell and enter a new cell. That's how they spread infection, and we and others have been studying that those processes.

We wanted to know if we really understood them, and designing new proteins that normally don't have those properties but now acquire them is a good test of whether we understand the rules for how proteins assemble, how they bind to membranes, how they, what we call envelope themselves, that is wrap themselves in the membrane and how they bud, pinch the membrane off behind themselves. So this was a good test of whether we understood what's required for that process.

Interviewer: You know, viruses have a reason for wanting to spread themselves to other cells but why would you want to do that intentionally? Why would you want to deliver things to other cells intentionally?

Wes: So molecular genetics has over the last, perhaps five years, made great strides in terms of having the ability to do things like alter genomes with especially what's called the CRISPR/Cas9 system that can edit DNA so that it can correct, for example, genetic mistakes. The bottleneck now has become how do you deliver those very potent activities to new cells? So you could envision gene therapy situations in which you want to deliver potent enzymes that edit the genome and now you have to get them into cells. So that's really, as I said, a bottleneck and something that we and many other groups are working on trying to do efficiently.

Interviewer: And so, how did that feel when you actually saw that what you learned actually works, that you could tell a cell to do what you had thought it does?

Wes: I actually get excited all the time about research and when Jorg Votteler, who's the person who did the work and he deserves credit for that, came in and said, you know, it looks like it's working, and that was really the first time we tried it, which is an unusual situation in our lab. Usually, it doesn't work and then we sit there and try and figure out why not, but this was a case where the first design worked and that's partly a testament to Jorg, but it's also partly a testament to the fact that it just takes a lot of work to understand how things work, but once you do, you have opportunities to do things that you didn't before you understood how they worked.

Interviewer: That's right. I bet you never expected that your research on viruses would take you here.

Wes: Yes, that's right. There's a big field called nanoparticles and also a big field in terms of development of delivery systems, and we don't pretend to know all of it, but I'd follow it, but only from a distance and not envisioned that our lab was part of it, but I think that's the importance of research is that if you do it well, you don't know where you're going to end up, but I think you can be sure that as a field, things will move forward.

Interviewer: What else do you think viruses have to tell you? Or do you even know?

Wes: Yeah. So viruses have quite a history of teaching us really important things. So DNA replication was first reconstituted in mammalian DNA replication using viral systems. Of course, the discovery of the ACCA gene, so, cancer biologists don't often tell you this, but it wasn't cancer biologists, it was virologists who discovered that there were genes that when misregulated would cause cancer. And I think that there's just no doubt that they have more to teach us maybe particularly in the mechanistic area.

So we don't understand still how many of the machines work. They're exquisitely good at replicating things and moving around the cell, but also exquisitely good at reprogramming cellular pathways. So the great example is the ACCA gene but there are many other viruses modulate their environment. And then I think they're also teaching us a huge amount now about the immune system. So, I would say those are the three areas in which viruses continue to make a major conceptual contribution, not to mention, of course, the fact that they're important pathogens.

Announcer: Interesting. Informative. And all in the name of better health. This is The Scope Health Sciences Radio.

Interviewer: There are a lot of uncertainties in science and that's okay. We'll talk about why it's important to acknowledge that, 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 Christie Aschwanden, lead science writer for FiveThirtyEight. Christie, there seems to be this insatiable appetite for science news, at least on the internet, which you think would be a good thing for science and scientists, but it turns out it's kind of a problem. What's going on here?

Christie: Yeah, I don't know that I would say that it's a problem that there's so much news. I mean, the problem is that we sort of have too much and so it's hard to sort through. But I think, you know, just the fact that there's science reporting isn't a problem in and of itself. You know, that's great. I like science. I'm glad that people are covering it. But I think the problem here is that the way that science is portrayed too often is in sort of a way where it's oversimplified and giving the public sort of a false notion about how it works.

Interviewer: So give me an example of that. How do headlines kind of flip-flop from week to week or month to month?

Christie: Sure. I think that, yeah, the sort of famous ones about coffee, "This week, coffee is good for you." Next week, it's bad for you. Those sorts of headlines are probably sort of the worst offenders here. But it's kind of this idea that gets put up there that science is this magic wand and that a study provides the final word. And here's the Truth, with a capital "T." And so this magic wand of science is eliminating the truth.

And then if another study comes along and overturns it, then it means the first one was terrible. And so it's kind of this dichotomous view where science is both this magic wand that yields truth, you know, everything that it touches. But then, on the other hand, the idea that, well, it's all sort of crap and anything that you're told now might be wrong. And therefore, the whole enterprise is sort of flawed.

Interviewer: So what exactly is the problem with that? I mean, as a savvy consumer of news, I might just assume that it's a little far-reaching to say that coffee prevents cancer, for example.

Christie: Right. I think you bring up a really good point and that is, I think that the public sort of intuitively knows that you can't do one study and then decide for a fact that cancer is healthy or not, that it's oftentimes more complicated than that. And I think the really important and fundamental thing to understand here is that science is sort of a process of uncertainty reduction. So no single study provides the final word. You can never be absolutely certain. But what you can do is take all of the evidence that you have in its totality and that will often yield a very good answer.

And so it's not that you know for sure that the answer is coffee is healthy or coffee is bad, but you're sort of looking at all of the studies. And so, for something like that where it's flip-flopping, the answer may be that, well, there's not a very strong effect. Or if it's there, it's not strong enough to be consistent so it's probably not something to worry about. And yeah, that could give you assurance, right?

Interviewer: So whose responsibility is it to do that? I mean, if I'm looking at the news every day, I'm certainly not going to get that long-term view. Who's going to put that out there? Or how should we be changing how we talk about science?

Christie: Yeah, I think some of it rests with journalists. It also rests with scientists as well, sort of anyone who's communicating about science. And that is the sort of, when we're talking about science, to really talk about it in the context of, "Okay, so here's this new study that we're going to write about, we're going to talk about right now." But instead of just ending there, then saying, "Okay, how does this fit with the other evidence? What does this, add? How is it different? Where does it rest in sort of all of the evidence put together? And what does it tell us? Given all that, what is sort of our over-reaching answer given all of that context?"

Some of it really goes to educating the public and trying to shape and change the way that they look at science so that they're not seeing it as the sort of black and white thing where something's either one way or another, but understanding that it's a process and that there are a lot of uncertainties along the way. But even in the face of those uncertainties, you can make decisions and you can look at the evidence that we have, but not expecting that any single study or any single piece of news will be the "be all and end all."

Interviewer: I think part of what you're saying is that science is very uncertain and that if you have a particular answer this week, that it may change in six months, depending on other factors that you include in your new study or kind of the base of knowledge, how that's changed over time. I mean, I think that's something that we all need to understand, right, that science changes and that's okay.

Christie: Yeah, that's right. And I think, yeah, this is particularly important right now. We're sort of in this age of denialism, or in a time where there are a lot of vested interests who really are seeking to exploit that uncertainty as a tool to sort of fan false doubts. And a good scientist is always skeptical. You always want to doubt things and be sure that you're thinking things through.

But what can happen is if the public thinks that science is very, very certain, and that any study sort of provides the last word and that's it and if it gets overturned, it's because science is a horribly flawed enterprise and researchers are terrible people who are just trying to make money, and all of these things, then they're really susceptible to these doubt-makers and these people who are exploiting legitimate uncertainties in many cases to really tarnish whole fields of science.

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Interviewer: A new understanding of glaucoma could lead to new treatments, 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 am talking with Dr. David Krizaj, an investigator at the Moran Eye Center and Professor of Ophthalmology at the University of Utah. Dr. Krizaj, you've found a way to possibly block glaucoma. That sounds pretty significant.

Dr. Krizaj: Glaucoma is the primary cause of irreversible blindness in the world. So it affects more than three million of Americans. At least 50% of the people who have the disease have no idea that they do have it. And by the time they start experiencing loss of vision it's already too late.

Interviewer: And so what happens? What causes glaucoma?

Dr. Krizaj: The causes are still, to a large extent, unknown but there are major risk factors such as ethnicity, age, and especially increased intraocular pressure which is actually the only factor that we can treat at this point. The main problem here is that we don't actually know how pressure is elevated. So the major impetus has been to look at the molecular mechanisms behind this disease.

Interviewer: So does that mean that the pressure in your eye changes often or normally?

Dr. Krizaj: It changes almost hundredfold when we get out of bed. But that's just for . . . or when we do yoga, for example. But that's just for short periods of time. The problem is if the change is chronic and over a long period of time. Basically, what pressure in the eye is, is a difference between the production and drainage of ocular fluids.

Interviewer: What are some of the properties that you've discovered that people didn't really know about before?

Dr. Krizaj: One major challenge has been to identify the mechanosensors that allow the cells to regulate pressure under normal circumstances. The second major challenge has been to identify the mechanisms through which increasing pressure kills the cells that sends signals to the brain because it's the death of these cells that causes blindness.

Interviewer: And that's what you've done, is that right?

Dr. Krizaj: Exactly. We believe that we have identified the mechanosensor both . . . and which turns out amazingly to be the same in the front of the eye regulating pressure and in the back of the eye in cells that communicate with the brain.

Interviewer: And so why is that important? Why is that significant that it's in both of those places?

Dr. Krizaj: So if we could target this pressure sensor mechanism we would have the first time ever therapeutical approach to regulate pressure while we are neuroprotecting cells. This has been a Holy Grail of glaucoma research, I would say, over the past 30 to 40 years. And we have in fact, collaborated with medicinal chemists here at the University of Utah who have designed antagonists that are specifically optimized for eye drop delivery or ocular delivery and were able to block the disease in mice so far.

Interviewer: Yeah. And that's really amazing. When you add this drug or these eye drops to the mice, what are some of the changes you see?

Dr. Krizaj: So we have a mouse model where we can elevate intraocular pressure by artificially suppressing drainage. So pressure goes up and we found that when we add these antagonists developed by our collaborator, Glenn Prestwich and Ryan Looper at the University of Utah, pressure drops back down like a rock within minutes. And if we do this, and my graduate students have done heroic experiments where they applied these drops three times a day or two times a day for four months. We find that if we do this consistently we can completely prevent the generation of these neurons which is synonymous with glaucoma.

Interviewer: So how does that work?

Dr. Krizaj: Every cell has its own internal bone structure. And it's just like in humans. If these bones are too stiff and non-pliable, the cells become brittle and very sensitive to damage. And we believe this internal cytoskeleton, as we call it, is really a problem in increased drainage. So we found that when we block the mechanosensor there is an increasing calcium ions in these cells which dissolve this cytoskeleton and as you say makes cells more pliable.

Interviewer: Interesting. I was thinking about this. A few weeks ago, I was pumping up a basketball. And I put too much pressure in the ball and it basically burst. But if that were made of a more pliable material, maybe a more rubbery material, then it should be able to withstand more of the pressure and not see as much damage. Is it similar in that way?

Dr. Krizaj: As in everything in life, flexibility is really the rule of the game. We should always strive to be flexible.

Interviewer: That's right.

Dr. Krizaj: And I think ourselves have figured that one out as well.

Interviewer: In terms of this treatment, what are some of the next steps?

Dr. Krizaj: We want to do the final optimization of these drugs that we're developing and then immediately go into Phase 1 clinical trials. So we formed a company which holds the intellectual property for these compounds. And we really think that there is very strong potential of actually helping people who were resistant to the current drugs.

I don't think this project would have taken off the ground if my Chair, Dr. Olson, has not discerned the potential from the very start and then basically supported it from the get go at every single step of the way. So I and my colleagues in the department are very lucky to basically be able to work in such a collaborative and nurturing environment.

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 the latest breakthroughs, the Science and Research Show is on The Scope.

Lynn: My name is Lynn Jorde. I'm the Chairman of the Department of Human Genetics at the University of Utah School of Medicine. I'm here today with Dr. Eric Green, who is the director of the National Human Genome Research Institute.

So, we've heard a lot about the ever decreasing cost of genome sequencing, about a million fold in the last decade. Does this mean that everyone should be sequenced? Or if not, who should be sequenced?

Dr. Green: So from a research perspective, I think there's great power in getting tremendous amounts of data from as many people as possible and using this in very robust ways to try to understand many aspects of health and disease. I think your question though, is aimed more at, "Should everybody get their genome sequenced as part of their medical care?" I'm not sure we're quite there yet. That might be where we are eventually, but just because we have the technical capabilities of doing that, I think we're far away from knowing what to do with that information in a clinical context to say that this should be sort of used for everybody. Rather, I think it's most useful now in very discreet areas where there's clear evidence that having genomic information will be helpful to that patient.

Lynn: Some critics have said that the Human Genome Project, of which you and many of us have been a part, hasn't really delivered on one of the original promises to revolutionize medicine. How would you respond to that?

Dr. Green: When the Genome Project ended 13 years ago, there was incredible celebration. In fact, many of use were euphoric about having achieved the goals that were set out for the Genome Project. I think in our exuberance lots of promises were made and lots of claims were made to have this was going to revolutionize this, that and the other and lead to great medical advances. I think much of that exuberance might have been over interpreted as meaning those advances were going to take place quickly.

There was no reason to believe it was going to happen that quickly. Actually, if you look back in the history of bio-medical research, there is usually periods measured in decades between very basic discoveries, such as the discovery of antibiotics, the discovery of the basic biochemistry of cholesterol metabolism and the actual changes in medical practice that led to advances in medicine. Decades. Here we are only 13 years in to having information about our genome available to us. So we've not seen the revolution, that I think will eventually come. I think for that we've been criticized.

I think we just have to take a step back, recognize that we're 13 years in. There's some vivid examples where genomics has had a profound effect on medicine, but they're the earliest examples. Even in aggregate those don't represent a revolution, but they're highly illustrative of what is coming.

So I think, when we look back at the history of genomics, say 10, 20, 30 years from now, I think that will be the fair time to assess whether or not our claims that were made when the Genome Project ended, were accurate or not. It's just too soon to do it now.

Lynn: So we're seeing investigations now, of all sorts of traits. The genetics of IQ, people claim to have found genes that influence things like aggressive behavior, anxiety. This gets pretty controversial. Are there areas that should be off limits, at least off limits to NIH funding?

Dr. Green: Absolutely. People get very uncomfortable with some of these ideas of doing genomic studies to better understand the basis for IQ, for aggression, various other attributes. It's also controversial scientifically, so before we even think about whether or not we want to limit this, I do want to put some reality on this. I think most scientists would agree that getting an accurate assessment of intelligence is not simple. Getting an accurate assessment of behavior is not simple. I think it is scientifically controversial whether we can even make major gains in this by doing these studies. So I think that really has to temper our enthusiasm for it. But then, of course, there's the ethical and societal implications of this. Are people going to be comfortable with it?

I think we need to be very cautious. When we are going to use these new tools of genomics, especially at this early stage, to prioritize things that are going to have great societal benefit. There's so many major medical challenges, disease areas, that will benefit from using these tools first and foremost, those are the areas that should be prioritized and I think that's where we should be putting our energies. At the same time, we should be very careful looking at what some of these other studies that might be envisioned, how they'll be perceived and how practical they are. I think they're going to end up being a low priority. In some cases, one might imagine doing some studies, along those lines. I just don't think they're going to be at a very high priority.

There's a lot of controversy of whether they'll be successful. It just doesn't seem to be the thing to be emphasizing right now. So, my enthusiasm level is low. I think in general people are making decisions about where money is going are going to deprioritize them. I'm not sure I want to say there should be a ban, but there should be careful scrutiny put on these. Research dollars are precious and we need to go to things that are more practical, and things that will have a higher impact on human health and disease.

Lynn: Over the past two years there's been quite a lot of controversy about patenting human genes. So, how does patenting, or not, affect scientists and consumers? Could it affect interests on the part of the private sector in investing and genetic and genomic research?

Dr. Green: There's not simple answers. The whole intellectual property construct and the ability to get patents and protecting people's advances are very important for the private sector and their ability to invest in things and feel comfortable that they will get a return on investment and so forth.

On the other hand, there's something a little special about the human genome. It is very basic, fundamental to humankind. It is our blueprint and the potential to have fundamental information about our blueprint be used. And a fast note, any day we be restricted makes many people uncomfortable. I think one of the things genomics has done, and its sort of cultural values associated with data sharing, is making as many things available to everybody, freely, widely. I think has served us very well. I think the fundamentals of understanding how the genome works in human genes and so forth, having no restrictions on their use, I think is very, very important.

There's a vision associated with using information about one's genome to tailor their medical care. I think many of us get very uncomfortable if in the process of doing so, if too many patents were laid down they would look like tollbooths across the double helix. Every single time we would go to one to analyze one part of someone's genome, we would have to pay a toll, and that would greatly hinder advances.

So, I think many of us have taken a position that it's so basic, that information, that just raw information, which is easy to get about the human genome and about genes, should sort of be off limits for patenting. Now, if you use that information you come up with a great intellectual advance and you design things around it and you come up with something that is more than just the basic fundamental information, yes, that should probably be fair game for patenting, for getting intellectual property and so forth. I think it's that raw information about genes that has made many people uncomfortable and have said that should be off limits for patenting.

Lynn: A big part of this then is the public understanding of traits, of what it means when we say a gene is associated with a trait. This gets us to the question of genomic literacy. What can we do to increase genomic literacy among the public so that they will better understand these kinds of issues?

Dr. Green: Genomics is a relatively young discipline. It's only been around a little over a quarter century. We are fortunate that it's been wildly successful. I think we're all very proud of that, but that's actually created a bit of a challenge for us. The challenge is that this field of science is finding it's way into medicine faster than any of us could have anticipated.

As a result of that, we have some complicated concepts, but also some basic language of genomics that it's finding its way into medical care. Yet, most people don't necessarily know the basics of this. They haven't been given the opportunity to learn it. Many of the healthcare professionals weren't taught this when they were in school. So this is happening so fast and furious that our ability to educate the public, educate healthcare professionals, is lagging behind.

As a result of that, this becomes very important when patients go to see their healthcare professionals and now will start hearing, in some context, about genomics. They don't really understand those words, they don't understand that language. If the patients don't understand it, they're going to go home and talk to their family. They may not understand it. They talk to their friends, they may not understand it.

So we have a societal responsibility to increase literacy about basic language of genomics, because that is a language that will increasingly be used by healthcare professionals, as part of patient care. It's not anybody's fault that we find ourselves in this situation. We're victims of our own success. We've been successful scientifically and now we need to sort of redouble our efforts to think about how to raise genomic literacy more broadly across society.

Lynn: Looking forward to the next decade, the next two decades, what excites you the most about genomic medicine?

Dr. Green: I think what excites me more than anything is the optimism that I have that what is going to transpire over the next decade is going to be significantly greater than what has transpired over the even last decade or the last two decades. I think we're so much more poised to accelerate progress than we ever have been in the last 25 years of genomics.

So, what I anticipate, what I'm excited about, is on multiple, multiple fronts, multiple areas, whether it's cancer, whether it's rare disease, whether it's infectious disease, whether it's in thinking about how to prescribe medications in a more precise and rational way, it just seems in so many areas, the progress I anticipate over the next ten years, I actually believe will be even more remarkable than what I've seen. Yet, I've been shocked by how much we have seen medical applications of genomics begin to be realized on a timeframe that I simply would not have predicted when I got involved in this field initially. I'm even more excited about the next generation of biodmedical researchers and healthcare professionals who I think are going to be the ones that are going to truly realize genomic medicine.

Announcer: Discover how the research of today will affect you tomorrow. The Science and Research Show is on The Scope.

Interviewer: Killing malaria with light? We'll talk about that 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. Paul Sigala, Assistant Professor of biochemistry and the University of Utah. So Dr. Sagala, malaria isn't something that we think of a lot in the U.S. but it's actually quite a problem in other parts of the world. Can you talk about that a little?

Dr. Sigala: Malaria is really one of the most urgent health problems facing the world. It has been for many decades. Even now with all of our great public health advances, hundreds of millions of people every year around the globe get infected by the malaria parasite, leading to nearly a million deaths. Tragically, most of those deaths are among children under the age of five in Africa.

Interviewer: There are treatments for malaria. How effective are those?

Dr. Sigala: We currently have good treatments. So artemisinin in combination therapy is the frontline therapy and has really been an amazing drug that's saved millions of lives so the importance of was recognized. The discoverer in China was awarded, or shared the Nobel Prize last year. But like most of the drugs that have come before it, eventually parasites come up with ways to develop resistance. And so much attention right now is trying to devise either new drugs that can be combined with artemisinin to overcome that resistance or other ways to combat or reverse multi-drug resistant.

Interviewer: Part of what you're trying to do is understand how malaria works so that you can come up with ways to block it. One of the ways you're doing that is looking at how it interacts with heme, which is part of our red blood cells.

Dr. Sigala: Right, so parasites infect red blood cells, which are the most heme rich cell in the human body. And parasites also utilize heme as a cofactor in its own heme proteins. So it needs a way of getting heme and so we've been looking at how the parasite is able to either make its own heme or scavenge our heme within the red blood cell.

Our red blood cells, during their early development stages, had their own heme biosynthesis enzymes that were massively productive in generating lots and lots of heme. And those stick around in the mature red blood cell. They're not ordinarily active. But what we found with the parasites living inside, that we came up with a way to hyperstimulate the activities these enzymes in a way that allows us to kill the parasite.

Interviewer: Help me understand this. So you can take advantage of some of the heme synthesis tools that happen to be floating around in our blood that we make.

Dr. Sigala: That's right. So these are enzymes that are inside the red blood cell but are no longer active because our red cell heme synthesis petered out at the end of development of those cells. But the enzymes are still there, so when the parasite is inside it now has the enhanced ability to take up nutrients and other compounds from the serum. And so one of the compounds that we found that we could put in actually stimulates the activity of these remnant human enzymes that are there. And some of the intermediates that accumulate as a consequence of that activity actually sensitize the parasite such that when we hit the parasite with light it kills it.

Interviewer: What is the light doing?

Dr. Sigala: So there are classes of compounds that are phototoxic. Meaning that when they absorb light they lead to generation of what are called reactive oxygen species, or really reactive molecules that kind of rapidly react with all sorts of biomolecules and just kill the cell in which they're generated. This is utilized for a form of cancer therapy, which is called photodynamic therapy and we think there are possibilities for adapting this approach for potentially treating malaria.

Interviewer: So how can you do that? I mean, first of all, how are you even getting light in there? This is inside your body.

Dr. Sigala: That's right. So that was part of the creative challenge here. It's not very practical to imagine inserting a fiber optic cable in someone's blood stream and trying to illuminate every infected cell. It's additionally challenging because falciparum malaria sticks to the walls of our blood vessels, so called sequesters, which means a lot of the really mature forms are not in active circulation which makes it difficult to target them.

So we wanted to devise a strategy that overcame the reliance on an external light source and what we figured out is that we could use a compound called luminal, that's a very well characterized chemi-luminescent compound. Meaning it's a small molecule that gives off light. And when we combined luminal with other compounds to simulate heme biosynthesis that those would converge within the parasite infected red blood cell and would generate light within that cell and selectively kill the parasite.

Interviewer: I think you had told me once before that the luminal is actually what's in glow sticks. Right?

Dr. Sigala: That's right. So it's commonly used in glow sticks and also in police departments for forensic reasons for trying to identify blood at blood scenes because one of the curiosities of luminal is that it needs to be activated. And it gets activated by interactions with iron so heme has iron in it. So blood that's a blood spot at a crime scene is exposed to the air and so when you spray luminal in it, it activates it.

But chemistry is also what contributes to the specificity of luminal targeting the malaria parasite. Because it requires this iron activation mechanism, most human cells tightly sequester iron and it's not readily available. But the parasite during its normal 48-hour cycle degrades up to 80% of all hemoglobin within a human red blood cell, breaks the protein part up into amino acids. The heme though, it basically sequesters into a vacuole so all of the iron within that heme is now much more exposed than it would be in a healthy red blood cell. Which then provides ready access to then activate luminal when it is delivered.

Interviewer: That's very convenient.

Dr. Sigala: It is.

Interviewer: So how are you investigating this in the lab? Kind of what stages are you at?

Dr. Sigala: Right, so what we have so far have done is explored in principle whether in an x-vivo culture system can actually potently kill the parasite with this type of combinatorial treatment. And the answer is yes, we certainly can. What we discovered along the way is that not only is the ALA, amino linoleic acid, plus luminal effective, but it synergizes very well with the current antimalarial compound, artemisinin in what is really a new twist. And so the combination of all three of those compounds is extremely potent in vitro at killing the malaria parasite.

So the next challenge is really to ask whether this will be effective in vivo. That's challenging to do directly in humans but one can turn to studies with plasmodium species that infect rodents. There are mouse malaria and those provide a ready means to ask, can we cure a mouse from malaria using a combinatorial treatment with these compounds?

Interviewer: Something else I wanted to bring up is that the parasite that produces malaria is actually somewhat mysterious. There's actually a lot we don't know about it.

Dr. Sigala: That's right. For a bug that we've been battling for thousands of years and especially in the current age of understanding so much about genes and genomes, it's unusual. It's an opportunity to deepen our understanding about how a highly effective parasite carries out its mission and devises clever new strategies to survive within our cells. So it teaches us something about general mechanisms in biology, but more importantly it means there are opportunities because those genes and potentially the proteins themselves are so different from our own proteins that we can selectively target them if we're able to understand their functions in a way that really avoids toxicity to our bodies.

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

Interviewer: With the power of computers behind them, scientists are solving the mysteries of undiagnosed diseases, 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. Aaron Quinlan, associate director of the USTAR Center for Genetic Discovery at the University of Utah. Dr. Quinlan, you recently had some really exciting results using technologies that your group developed. They may have helped solve a health mystery. This is about infants with a particular condition. What was going on?

Dr. Quinlan: We were studying infants with seizure disorders, and the genetic basis of those seizure disorders was unsolved.

Interviewer: So, the idea is that . . . I mean, obviously they had seizures, presumably pretty severe ones, but doctors didn't know what was causing it. So, there were about a dozen or cases, and you were able to possibly find the cause for most of them?

Dr. Quinlan: Yeah, for the majority, I guess 90% of the cases we have a pretty clear candidate that we feel strongly about, and in 9 or 10 of those cases, it's a mutation in a gene that is known to cause this phenotype but was not picked up via standard clinical diagnostic tests, and in a handful of other cases, we think we have discovered new genes that underlie this phenotype.

From a clinical perspective, there's a transition, certainly removing very rapidly from gene panel tests, where we only look at a very, very small subset of the genome to interrogate genes that we know cause a given disease phenotype to, I think, in the coming years, it will be a standard course of care to use exome or genome sequencing to do this diagnosis because it's so effective, and I think the clinicians that we were working with were very excited about the accuracy and the rapidity with which we could make these predictions.

Interviewer: The role of you and your group in this is that you've developed a computational tool called Gemini, and that's what led to these results. What is Gemini?

Dr. Quinlan: So, we used genome sequencing of both the infant and their parents to try and identify genetic mutations, essentially, that cause the disease phenotype in question, and this process requires a broad spectrum of computational methods, everything from rapidly and accurately processing the sequencing data to identifying genetic variants that exist in these families, and then finally to essentially get back to a needle in the haystack problem of what is the single genetic mutation that causes the phenotype and isolate that from the potentially millions of genetic variants that are benign but exist in these infant genomes.

So, the idea is that Gemini takes all the genetic variation that's observed in the genomes or exomes of all the individuals that you're studying, and it integrates all that genetic variation information with the extreme wealth of genome annotations and reference databases that we have. For instance, some people might be familiar with OMIM. It's a list of all the known mutations or genetic variants and genes that are associated with diseases.

Interviewer: Right, so keeping up with the pace of research, the pace of knowledge.

Dr. Quinlan: Right. It's an incredibly demanding problem because there's probably 50 to 60 reference databases that we try to use, and they're all evolving. They all have mistakes. Those mistakes are fixed, and you've gotta propagate those fixes to the mistakes as quickly as possible so that . . . what we're trying to do here is empower discovery for human genetics, and so, having the latest and greatest information, obviously, empowers that process.

Interviewer: So, is there somebody who's monitoring each of those databases and saying, "Oh, gotta update, gotta update, gotta update"?

Dr. Quinlan: Yeah, we have people in the lab who monitor that, but, believe me, the research community that uses this software, they monitor it as well.

Interviewer: And so, the real tricky part is that a lot of us have scads, you can give me the numbers, you know, scads of variations in our genome, and so that the problem is finding the one or ones that increase risk for a certain disease.

Dr. Quinlan: That's right. I mean, any two individuals differ by about 3,000,000 to 4,000,000 genetic variants. So, when you look at a family, do a whole genome sequencing of an entire family, you're going to find on the order of 3,000,000 to 10,000,000 genetic variants that you have to sift through. Now, many of those, admittedly, are very simple to ignore, especially for rare disease phenotypes. We typically focus on genetic variants that affect protein coating genes. But even when you do that, you're talking about on the order of 18,000 to 20,000 genetic variants that need to be considered, and so, we need to be able to do that in a quick and reproducible way, and we want to minimize false predictions, but I think even more concerning are real genetic variants that may be associated with the phenotype that you miss. So, we want to essentially find everything but don't over-predict.

Interviewer: I imagine you spend a good part of your day in front of a computer screen. I'm wondering do you think about how this sequence of letters you have in front of you is actually a real person.

Dr. Quinlan: Yeah. Admittedly, I am fairly disconnected. I'm a genetic researcher that spends 12 to 15 hours a day in front of a computer, and I'm not a clinician, so, I don't interact with patients on a day-to-day basis. However, I mean, that is our motivation here, is, you know, that was the main reason I moved my lab from the University of Virginia to the University of Utah was to have that connection.

We have a very nice interaction between researchers and clinicians here at the U, and I think it really helps to bring home the reality of these cases. We meet with the doctors who actually work with these patients, and when you understand their plight both in terms of the diagnostic odyssey and also the impact on these families, both in the short and long term, it makes it very real.

I would like to be able to provide a resource to try and solve rare disorders in Utah, nationally, and not only retrospectively for families that are sort of pursuing this diagnostic odyssey, but also to have a system where this can be done in real time in collaboration with clinicians in our hospital and other hospitals so that when there's an infant that comes through the NICU or there's some pediatric genetic disorder that is perplexing, we have a system in place where we can sequence the genomes and actually bring our tools to bear on solving that problem quickly and as accurately as possible.

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

Interviewer: It's estimated that half of scientific studies are irreproducible. They can't be replicated and this is a problem. Today, we're talking about a case study in irreproducibility, up next on The Scope.

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Interviewer: I'm talking with Dr. Heidi Hanson from the Huntsman Cancer Institute in the Department of Family and Preventive Medicine at the University of Utah. It's been estimated that up to half of scientific studies are irreproducible. They can't be replicated and this is a big problem. Dr. Hanson, you've actually published a study that feeds right into this conversation. The study calls into question a correlation that has gotten a lot of attention in the past few years.

Dr. Hanson: It's previously been reported that cancer and Alzheimer's disease have an inverse association. So basically, what's been said up to this point is that if you have cancer, you're protected from getting Alzheimer's disease later in life. If you have Alzheimer's disease, it protects you from having cancer.

Interviewer: And this got a fair bit of attention. There was a report in USA Today, there were reviews and nature of reviews, neural science and several other publications. How did the authors of those studies come to that conclusion in the first place?

Dr. Hanson: There have been a couple of studies where they've looked at individuals that have had cancer, and followed them for a period of time, and look at their Alzheimer's disease risk. And then, they also look at patients with Alzheimer's disease and look at their cancer risk later on in life. It's been published using a couple of bigger studies. They did the normal statistical methods that you might be doing just to come to that conclusion.

Interviewer: So basically, for those people who have cancer, fewer of them are found to develop Alzheimer's disease?

Dr. Hanson: Yeah, that's correct.

Interviewer: And what about that result set alarm bells off for you?

Dr. Hanson: I'm trained to think a lot about selection, and in particular, mortality selection. So what that means is I think about how processes that lead to different rates of death can affect the results that we see. And part of my demographic training is to think through some of those things. So I'm constantly looking at a result and asking if I really think that that's what's going on or if there is something underlying the result that we're seeing. So yes, it may be what the data is telling you, but is what the data is telling you actually what's going on? Are we missing something bigger?

Interviewer: Keeping that in mind, what was it that you found in your study?

Dr. Hanson: Our study replicated some of the previously reported results. And then, we showed, once you start to think about these things, and think about how mortality is affecting the rates of Alzheimer's diagnosis in these patients, you actually see a different story. It's not that there is not that inverse association that exists, but it's that mortality is driving that inverse association. It's not because there is some underlying cellular genetic mechanism underpinning both diseases. It's because if you have cancer, you have higher mortality. You're not going to go on to live long enough to be diagnosed with Alzheimer's disease.

Interviewer: It certainly makes sense. And that's actually really important, you've said, when you're thinking about aging-related disease and the aging population. Can you talk about that a little bit more?

Dr. Hanson: Yeah, absolutely. So when we're aging, there's a lot going on. You aren't usually suffering from a single chronic disease. There are multiple thing going on at the same time. And if you think of aging in a single context or aging with a single disease and you're ignoring all of those other things that are going on, you're missing the bigger story.

Interviewer: Do you think someone could come along a few years from now and find that maybe you didn't consider something in your analysis?

Dr. Hanson: Absolutely, and that's why I like science so much. We're not coming up with the best answers all of the time. It's an iterative process. We should all be considering each other's work, and we should all be critical of each other's work and figuring out how we can really understand what's going on. And to do that, it's necessary to be critical and to try to decide, okay maybe if we look at this a different way, we will be seeing something else. So maybe there is this underlying mechanism and if we're able to look at it this way, we can get more into what's going on. And that's what should be happening.

Interviewer: Yeah, that's a really good point. I think one of the issues that you had brought up is that you're really trained to really look at the data and consider all the factors that might go into some of these correlations or some of these results. What do you think can happen to make sure that some of these people who are trained in the life sciences might consider some of these other types of analysis or other types of questions?

Dr. Hanson: Yeah, one of the biggest things that I think can really help that is working interdisciplinary. If we are working across our own disciplines, naturally we are trained to think different ways, naturally we're going to approach problems from a different direction, and naturally we want to start to question different things. Things where I've been trained to somewhat ignore them through my training, someone else may look at the same problem and say, "Wait a second. You're not thinking about this. You need to be really critical of this."

And that's what's so fascinating and fun to work with individuals from different disciplines. It's how really good science is done, in my opinion. And really good science can't be done without that difference of thought. I think it's absolutely necessary. And I'm seeing a lot more of it, which is exciting.

Interviewer: So do you think this is a common problem that people aren't considering their questions carefully enough?

Dr. Hanson: I do. I think it's a very common problem. I think that people find the results that they're looking for a lot of times, and I think that's unfortunate. And I think that publication bias leads into the kinds of problems that we are seeing where people are only reporting certain things or things are only getting published if they are of interest to the public. I think that causes problems. I also think the really big push to publish fast causes huge problems. And it's unfortunate.

People just aren't as thorough with their statistics, with their methods, with their thinking through the problem as they should be because there's such a push to get the publication out. It's this huge push. Everybody wants to move things quickly, do one analysis and send it off. And that's what you do. And I think it's unfortunate.

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

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Interviewer: All right. Here's a question. How can you reduce the use of imaging tests for patients that you are evaluating for appendicitis? That's what Dr. Eric Glissmeyer's research focused on. Thank you for coming to help answer that question. First of all, why did you want to answer that question?

Dr. Glissmeyer: Well, particularly when we're evaluating children that are being seen for abdominal pain and they may have appendicitis, we like to not do dangerous things or harmful things to children. It's not uncommon that a CT scan, a test with ionizing radiation that exposes the child to potential risk of harm, is done, especially in uncertain cases. So we wanted to try to set forth the protocol with the support of our surgeons and our radiologists that helps us one, standardize our approach and two, reduce CT use and that was our primary objective.

Interviewer: How have people tackled this problem before?

Dr. Glissmeyer: Well, there are a number of places around the country that have done great work in establishing protocols that many times have been just developed iteratively in a quality improvement kind of way, that have had the focus of reducing CT use.

I think that one unique approach that we took here is we didn't want to just know when is CT scan used in patients who are ultimately proven to have appendicitis, but when is it used in that larger demographic, that larger denominator of patients who are evaluated for suspected appendicitis? The doctor goes and feels their belly and says, "They may have appendicitis. I better rule them out for appendicitis."

What do you do next? We have a lot of tools at our disposal and there's a lot of variability in what people do. We wanted to standardize that with that objective of reducing advanced imaging tests like CT scans.

Interviewer: All right. Here's the moment of truth. What do you do?

Dr. Glissmeyer: What we believe the best thing to do is to take a standardized approach driven by physical exam and utilizing a scoring scale. We use something called the Pediatric Appendicitis Score and there are a number of other scores being used. We don't really think it matters exactly what the score is. We don't think there's any magic in one particular lab value or one particular physical exam finding.

Appendicitis is sneaky and it likes to present many different ways. What we've found though is with the support of our surgeons and our radiologists all working together to determine an algorithm, that as we go down and we do a blood count and we do an exam and we see what some of those initial results come back as, we can either put the patient into a category of low risk and, "Gosh we're done." We really don't need to have much worry about appendicitis unless things get worse, intermediate risk, where perhaps an ultrasound test and certainly you have to have an organization that does ultrasound well.

Pediatric ultrasound for appendicitis is not an easy test. Our ultrasonographers have been doing this a long time at primaries and are very good at it. We actually know based on what they see on the ultrasound there are four different grades for the ultrasound result. We know what the likelihood of appendicitis is for those different grades.

So we've got some great data to drive our decision making out of the results we get. You know what? There are some patients who don't even need an imaging test to diagnose their appendicitis. If it's a classic case, straightforward, the labs support it, you're done, call the surgeon, take the appendix out. This was done 20 to 25 years ago with no imaging tests regularly because they didn't have any. So we kind of need to go back to that in some ways.

Interviewer: And in your research, how accurate was this method?

Dr. Glissmeyer: For patients who come in and we see for having appendicitis, I want to first say how do we know when we were looking at this retrospectively that the patient was actually being evaluated for appendicitis? How did you crawl into that doctor's mind and determine, "Well, did they actually suspect appendicitis or were they just coming in for gastroenteritis?"

We developed a surrogate definition, whether they had an ultrasound done, whether they were coming in for a chief complaint or abdominal pain and the word appendicitis was used in the note and a CVC was obtained that 95% of those patients were evaluated for appendicitis.

It had a sensitivity and a specificity of 95%. We're confident that we could evaluate the patients or rather identify the patients that were being evaluated for appendicitis. So in that group, I think the real question people would want to know is what were you doing before you did this protocol and what did you achieve after in terms of the CT use?

Interviewer: Yeah, did it reduce it?

Dr. Glissmeyer: We were one of the lower utilizers in the country in CT. Our baseline data showed we were doing CT scan only 15% of the time in this cohort of patients being evaluated for appendicitis. If you look nationally, it's more around 30%. So we were already a low utilizer of CT.

But what I was so pleased to find was that as we instituted this protocol that has not just the standardization but this follow up option that we'll talk about too, we were able to drop that low rate in half again, from 13% to 6%, from 13% to 6%. So we were really pleased to see we were even able to cut that in half further.

Interviewer: Is there an ability to even cut that more, do you think?

Dr. Glissmeyer: I think potentially. But I think you achieve a certain baseline minimal rate where you get your unclear cases, you get your cases where your patient has been having pain for a week or so and you really suspect that this is a ruptured appendicitis and CT scan is really the optimal test to use. I think around 5% or so is probably about the minimum you want to achieve.

Interviewer: All right. Explain the follow up option you were talking about.

Dr. Glissmeyer: Probably somewhere around a third of patients who have abdominal pain are being evaluated for appendicitis. It's not totally clean, a third, a third, a third, but let's talk about it in those terms because it makes it easy.

If a third of patients come in and it's pretty obvious after your exam and some labs they don't have appendicitis, you're done. You don't need imaging tests. About maybe less than a third, somewhere around 15-20% and they come in and they have pretty clear evidence of appendicitis, labs support it, you call surgery, they get their appendix taken out, no imaging tests needed there.

Then there's this larger middle where the fall into an intermediate range of a Pediatric Appendicitis Score that we have called between 4 and 7. If they have that score, you do an ultrasound scan first. Boy, when it shows the appendix and it shows it's normal or it shows the appendix and it shows it's not normal, that's really helpful. Then you can make your decision based off of that, but if it doesn't see the appendix, what do you do then.

The patient still has some tenderness, you're still a little uncertain. Do you just go stick them in the CT scanner to get your answer? That's what I think historically has been done, when the ultrasound fails to give you the answer you want, we go and scan them. We work with our surgeons to say, "You know what? We've observed this patient for a couple of hours here in the ER. Their pain is not really getting worse. It's not a clear cut appendicitis. Why don't we have them come see you tomorrow morning in clinic?"

So if it's Sunday night between Sunday night or Thursday night where they could go the next morning, that being between Monday and Friday, they can show up at about 7:30, 8:00 a.m., come into surgery clinic, get their belly pushed on, be examined, get lab tests repeated if they need to, perhaps do another ultrasound if necessary and find themselves in the hands of another expert the next morning also with not a second ER charge, which is nice, but being able to come into the clinic.

We thought, "Are we going to go and be doing surgery clinic follow up now? Are people going to just be like all the time overrunning the surgery clinic the next morning?" Actually it's only about one patient every ten clinic days that utilizes this resource. But the fact that you can offer it to them in the emergency department the families love and the docs love because in the faces of uncertainty, it gives them a plan. That's been the magic of the approach.

Interviewer: What's the next iteration then of this research? Where do we go from here?

Dr. Glissmeyer: We've been pleased with what we've been able to achieve at Primary Children's Hospital. It's to take it to other hospitals within Intermountain Healthcare, University Healthcare, having the support of surgeons at those other hospitals is key and radiologists as well, we're working on that. But only half of the appendix case present to the tertiary children's hospital here, Primary Children's Hospital. We want to address that other important half and that's where we're going next.

Interviewer: Getting that feedback from the surgeon afterwards for the patients that didn't get the imaging but had the operation and you find out how successful you've been or haven't been. Have these tools proven to be pretty successful?

Dr. Glissmeyer: That's a great question. You wouldn't want to be going and admitting to the surgery service a lot of patients who you as the ER doc are convinced have appendicitis and then they go in there to take it out and then, "Uh-oh, it looks normal." That happens on a rare occasion. Nationally about 5% is the rate of negative appendectomy. You go in and, "Oh, we thought it was appendicitis and it's not."

Our rate here is about 2-3% and it's not increased since the use of the protocol. So going in and taking out patients' appendix without ultrasound test or any imaging test, it still is successful and doesn't increase that negative appendectomy rate.

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Interviewer: We'll talk about irreproducibility in science, up next on The Scope.

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Interviewer: I am talking with Dr. Tom Parks, Vice President for Research at the University of Utah.

Irreproducibility in science, these are scientific discoveries made by one group that can't be replicated by another. There has been a lot of discussion around this lately. Is this as big of a problem as people are making it out to be?

Dr. Parks: I do think it's a serious problem. There has been developing literature over the past ten years that I've been aware of, and I assume some of it is probably known earlier than that, that there are major flaws in the way research in certain fields, particularly biomedical science and social behavioral science, that cause a lot of published results to not be replicable or sufficiently reliable.

Interviewer: And what's the scale of the problem, do you think? Is it widespread?

Dr. Parks: Estimates are that as much as half or more of published research is not replicable, and a recent study estimated that $28 billion a year of federally-funded research is, you could say, wasted on research that cannot be replicated.

Interviewer: Those are big numbers.

Dr. Parks: Those are big numbers

Interviewer: And it could be undermining a trust in science by the general public, do you think?

Dr. Parks: I know it is. I mean, one of the things that has surprised me is that I've been following this for ten years and yet I find that many scientists are not aware of this issue, yet there have been pretty prominent articles in general interest magazines like The Economist, The New Yorker, The Atlantic, The Wall Street Journal and so forth that have laid out these issues quite clearly. So a lot of educated general public is aware of this, legislators are aware of it, funding agencies are aware of it, journals are aware of it, but many practicing scientists are not aware of this problem.

Interviewer: And that could be a contributing factor, I guess.

Dr. Parks: I think so, but I think part of the reason, either people are not aware or they're in denial about it because the consequences for scientists of changing, of making research more replicable will be significant.

Interviewer: And what has brought us to this point? What are some of the causes, do you think?

Dr. Parks: There are a number of them. In method sections we don't provide enough information to make a study easily replicated. We don't make available all of the data from results. We don't restrict ourselves to testing our priori hypotheses on an experiment where people often go in and look post hoc after the experiment is done and find significant effects, and the statistical power that is the sample size of many studies, a shockingly large number of studies have statistical power that is too low to reliably generate reliable results.

Interviewer: So a lot of problems, a lot of causes.

Dr. Parks: Yes, and I should also mention that we don't publish negative results. We don't register every study. I mean, we don't know how many studies have been done in a particular field because only the positive ones are ever published.

Interviewer: No, you used to run a lab. Were you ever in a position where you couldn't replicate someone else's results? Dr. Parks: I can't think of an example where we did that, but I think that is part of the problem. Individual investigators are rewarded for publishing new and original innovative findings and ideas, and there's really no reward for replicating previous studies. That is a big part of the problem with replicability.

Interviewer: So how do you think we could even overcome this problem?

Dr. Parks: In clinical trials fields or the consequences of poor replicability or reliability have consequences for human patients. They've sort of moved ahead with this. Trials have to be registered so that people know when a trial is underway, and then federally-funded trials have to report all of their results, whether positive or negative. I think journals are coming to expect more detailed methodology and eventually, I believe, federally-funded research will be required to have all of the data posted online and made available to anyone who wants to reanalyze it or replicate it.

I think journals will begin requiring larger sample sizes, more statistical power in studies. There are other more subtle issues with the specifications of reagents and the consistency of reagents and analytical methods and so forth. There's a lot of contributors to poor replicability but I've mentioned the ones that I think are the most significant.

Interviewer: So those are kind of sweeping changes. I mean, how likely do you think it is that those will happen?

Dr. Parks: We already see politicians on both left and right arguing with scientific evidence when it doesn't suit their ideological stance, and this will give them another way to argue against evidence that they don't like. I think the funding agencies, to maintain the funding, will have to insist on some of the changes that I just mentioned, and I think the journals, they're the ones who are publishing research that can't be replicated and I think they will eventually put in higher standards for getting papers published.

Interviewer: Does knowing about this issue taint how you look at new research that's coming out? If there's some new exciting discovery on the cover of Nature, do you sort of take it with a grain of salt?

Dr. Parks: Many years ago a grizzled old senior scientist said in a talk I went to, "If it's true it isn't new, and if it's new it isn't true," and at the time I thought that was a cynical old person's thing to say. But that's more or less my position now. As lots of people remark, cancer has been cured in mice thousands of times for every new therapy that gets to people. I think people should be very skeptical

Scientists by nature are very skeptical. We haven't been sufficiently skeptical about our own work until now, but I think it's coming.

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.

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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.

Interviewer: New insights into how the brain might be set up differently in certain people intellectual disabilities and autism, up next on The Scope.

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Interviewer: I'm talking with Dr. Megan Williams, assistant professor of neural biology and anatomy at the University of Utah. Dr. Williams, despite the fact that autism and intellectual disabilities are pretty prevalent, not much is known about the biological changes that take place early on that might set these people down that pathway. But you've found some new insights here.

Dr. Williams: Our new study has shown that there's a very specific defect in connections between neurons in the brains of mice that are missing in autism associated gene. And I think what's unique about our study is that autism and intellectual disability, these are disorders in which it's not going to be easy to see connectivity changes because they're going to be very subtle and probably quite small. It's not like people with autism are missing a whole part of their brain.
And so we've looked at very high resolution at two very specific neuron types and identified a very subtle but very important change in connectivity.

Interviewer: Your research focuses on a gene called Kirrel3. Why did you focus on that gene?

Dr. Williams: I become interested in that molecule almost 10 years ago. It was identified in the C. elegans, which is a round worm, as a very important molecule for synapse formation, and then there started to become a lot of human autism and intellectual disability genomic studies that implicated this gene in these disorders.

Interviewer: And just quickly, what is the synapse?

Dr. Williams: A synapse is the special cell junction between two brain cells, and that's really the essential point of communication between the cells. So your brain cells require synaptic connections really to process any kind of information to see, to hear, to think.

Interviewer: Your research was investigating what defects are caused by changes in that gene. So you approached that question by disrupting that gene or knocking out gene in mice. And what did you find there?

Dr. Williams: Kirrel is expressed in two cells and it probably helps these cells stick together, and because synaptic junctions are places where the neurons sort of stick together and send their signals to one another, it signaled that Kirrel may be important for the synapses between these two very specific cell types. So the two types of neurons that express Kirrel normally have a synaptic connection, and when you're missing Kirrel, they have about one-third fewer of these synaptic connections.
Although that seems like a fairly small change, what happens is it greatly impacts the whole network activity. So all neurons are sort of interconnected to other neurons eventually, much like roads are in a city, and when you disrupt about 30% of them, of this one kind, you end up affecting basically the traffic or the flow of information in the whole brain.

Interviewer: Okay, so that part of the brain is not as active?

Dr. Williams: Actually it's interesting because we're very interested in understanding exactly which synapses might be defective in these disorders. These mice are missing some excitatory synapses, so that means these are synapses that activate the network. But the trick is that these are excitatory synapses that form on inhibitory neurons, so we are really talking about missing excitatory synapses or activating synapses onto neurons that quiet the network.

Interviewer: Okay, interesting.

Dr. Williams: And so this is sort of a double negative and what ends up happening is that we end up exciting the network too much in these knockout mice.

Interviewer: How can we think about that is the idea may be that there's more chatter going on in the brain and it's just harder for the brain to control.

Dr. Williams: That's right. Actually in the hippocampus, this brain region we investigated, synaptic transmission is usually very sparse and that sparseness allows you to have . . . it's thought to allow you to have distinct memories, and so what could be happening is that there's much higher chatter or electrical noise in your brain and it may be sort of inhibiting that encoding of unique memories and they may blur together or not be as crisp and this of course affects learning.

Interviewer: You looked at sort of young mice, do we know whether those changes persist through aging?

Dr. Williams: So we looked at young mice first because this is where these disorders become most diagnosed, but we also looked at older mice, so what we would call adult mice. So it seems like the brains older mice missing Kirrel, though their synapses are not normal, the overall network activity seems to be back to normal.

Interviewer: They kind of compensated for that change later on.

Dr. Williams: That's right.

Interviewer: Could it also be that those early changes might be setting off another chain of events that you just haven't been able to find yet?

Dr. Williams: That's right. In the adult, the older mice, the synapses are still not normal and so especially if the system is stressed, we don't know how the brains would respond. Kirrel3 is also expressed outside the hippocampus, so all our work was in this brain region, but it is expressed in other places and we would imagine it is probably affecting synapses in other brain regions.

Interviewer: And you had mentioned that Kirrel3 had been found to be associated or mutations or variations in that gene was associated with people who have intellectual disabilities or autism. How common was that association seen?

Dr. Williams: Autism linked genes are still only a few percentage of people with autism and Kirrel is one of these and it's still going to be very low percentage of people that have autism and intellectual disability. So this is common and this is one of the reasons we know so little about the brain changes underlying these disorders, but as the buzz words of personalized medicine grow and genome sequencing becomes easier, it's possible that in the future patients with autism and intellectual disability if we can identify their mutation that caused it, if it is a genetic cause, then knowing if they have a Kirrel mutation and whether what the exact defects are in the Kirrel, patients can at least inform those patients' treatments.

Interviewer: Is there anything else you'd like to say?

Dr. Williams: I think one of the really big take-home messages of our paper is that a very small and subtle synaptic defect can have a very big impact on circuit or network function, and so this is why it's really key to identify these very seems so small and possibly insignificant, but these defects in your brain which is hyper connected can amplify to cause some major problems.

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

Announcer: Medical news and research from University Utah physicians and specialists you can use for a happier and healthier life. You're listening to The Scope.

Lisa: Hello. This is Lisa.

Interviewer: Hi, Lisa. How are you doing? This is Scott from The Scope.

Lisa: Hi, Scot.

Interviewer: So today I thought we could talk about supporting adults on the spectrum. So when it comes to supporting adults on the spectrum, what is the latest information that has you really excited right now?

Lisa: I think the increased attention on autism on adults is the most exciting thing. There's a lot of focus now at looking at transition age kids and adults as the number of kids with autism increases. They're all growing up and becoming adults. There's been a call to action to look into what's happening with adults with autism and how we can do best by them, provide services for them.

Interviewer: What's some of the latest information as far as what can we do? And how can we provide for them better? Did we have any new breakthroughs or new thoughts on that?

Lisa: Well, the area that I've been looking at is healthcare and health status. We completed the study that's just been published that really documents the very increased rates of many different medical and psychiatric conditions among adults with autism. We don't really know why many of those conditions are occurring at such a high rate compared to the non-autistic's counterparts. So we have to understand that better and then figure out ways to treat and provide health care in a better way.

Interviewer: Sounds like we're very much at the beginning of this journey.

Lisa: I think that's true. It's just been the last couple of years really that there's been a lot of talk about adults in transition-age youth and adults. So I think that's just going to increase and it's nice to see all the attention being put in that direction.

Interviewer: So a lot of talk, a lot of attention. What do we need to do to start making progress at this point? Is that going to be a hard transition to make or is it going to naturally occur? What are your thoughts on that?

Lisa: I think it's going to naturally occur because there are increasing numbers of adults with autism out there in every sector of society. The education system, all these kids who are identified with autism in K through 12 education, they're aging out and then there's a huge need for continued services for them. Yet there's not much organized for them. So in the education realm, in the employment realm, in the health care realm and the social service realm, all those areas are being increasingly tapped because, there are all these individuals looking for those services.

Interviewer: You had mentioned earlier that for adults that have autism we're starting to identify other medical issues that face them? What are some of the more common ones that we're starting to discover?

Lisa: All of the medical issues that we've seen occur more frequently in children with autism, we also see them occurring in adults with autism. These are things like GI problems, sleep problems, mental health issues like anxiety and depression. Some immune conditions. All of those things have been identified as perhaps occurring more commonly in children with autism compared to non-autistic kids.

Then we see that happening in adults as well. But, in addition to those conditions, we found almost every diagnostic increased at a higher rate in the adults with autism. So these are things that commonly you don't identify in children because they occur later in life. So things like hypertension, obesity, some heart disease, metabolic disorders. The list goes on and on.

There are only a few conditions for which the adults with autism were no different than their non-autistic counterparts. And that was cancer was one thing that stood out. They didn't have increased rates of cancer compared to the non-autistic adults.

The research I'm doing on adults is looking at the health status ad health service utilization. And, also looking at the health care providers, what they know and what researches they need with regards to caring for adults with autism.

Interviewer: What types of resources are they missing that you are finding that they do need? And what could we do about that?

Lisa: We did a survey of over 900 health care providers who provide care for adults in the Kaiser Permanente system here in northern California. They reported that their knowledge is very poor. Their knowledge about autism is very poor. And they require better training, like training on how to communicate effectively with patients with autism, resources that are available that they can direct their patients to, the need for resources, the need for better ways for providing care for them. They're really unsophisticated when it comes to dealing with patients with autism because they just haven't seen that many or they're not even aware that they have patients with autism.

Interviewer: Oh, yeah.

Lisa: So there's difficulty communicating with them and difficulty doing assessments on them because of what the autism is. So they're really sort of facing this big wave of children who are going to be entering their practices as they become adults and they have very little training, background knowledge, comfort level, resources available, strategies to communicate, all of those things they're saying they really need help.

Interviewer: That sounds like a lot. That sounds like whole sections. And maybe medical school education is going to have to change to help physicians be more up to speed on this thing. Or, do you see specialties arising where you're going to have specialty doctors that deal just exclusively with adults with autism?

Lisa: I think there really is a need for general training in medical schools so every medical student is taught about autism spectrum disorders and what it is and that they persist throughout their lifespan. It's not just a pediatric condition. These kids grow up to be adults and they still have these impairments. Or maybe there's a need for a specialty in adult medicine that's going to deal with adults with neurodevelopmental disorders. People with autism have health issues, as I've mentioned, all different kinds of health issues just like people without autism do. And they're being cared for by their primary provider. And so there's really a need for training of those primary health care providers on this segment of the population.

Interviewer: What's next? What is it that you want to look at next? What piques your curiosity?

Lisa: We're going to be starting a project very soon looking at this transition in healthcare from pediatric to adult medicine. Really trying to identify what are the health issues facing that transition-age youth population? And what are the barriers and facilitators to care for that population? We're going to be talking to patients and their caregivers and providers. And then we want to try, based on what we learn about what works and what doesn't work, try to develop and test some strategies, things that will improve that transition. So that's our next focus.

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