Search for tag: "research"

Interviewer: Systematic reviews or meta-analyses may be trickier to carry out than you think. But there's help out there. 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 Melissa Rethlefsan and Mellanye Lackey from the Eccles Health Sciences Library at the University of Utah. Melissa and Mellanye you're putting a lot of efforts into improving the quality of systematic reviews. And that's a very particular type of research. First of all, can you tell me what systematic reviews are?

Melissa: A systematic review is a pre-specified methodology that looks at the literature to answer a very focused question, usually about patient care.

Interviewer: So can you give a certain example?

Melissa: So for example, usually it's a PICOT type of question with a patient intervention, comparison and outcome that a researcher might be looking to answer. So for example, it might be looking at teenagers who are depressed and whether or not SSRIs would be better than placebo or a different drug class in preventing the onset of further depression or suicide or some other outcomes that would be of interest to a researcher.

Interviewer: So it's really important that these studies are set up correctly. How can not taking some of those steps lead to issues in research reproducibility?

Melissa: If you do not have a librarian or someone who's extremely familiar with literature searching methods involved, then what you can produce is the systematic review that may answer the question, but that because it was not well documented, it can't be replicated. So people, we can go in and they can look at the systematic review and they can think that they're getting an unbiased answer. But then, when you look at the details of the study, you realize that you have no idea how the study was actually performed.

It's very similar to in a clinical trial that's not well reported. You might have no idea if the results that they're getting are actually true because you can't tell enough detail from the methods to be able to ascertain that for yourself.

Interviewer: Really, it starts with the very question that they decide to ask in the first place. What are some of the issues that come about in that arena and how can you address those?

Mellanye: Sure. One of the things we do as librarians is help make sure that people are asking questions that can be answered by literature that aren't too big or that aren't too narrow. And once they have a question that there's adequate literature to support studying that question and so we can do initial searches into the databases to identify gaps in the literature, to see if that study has already been done, if it needs to be updated, if it hasn't been done in a while. We can find if it has been done, was it done accurately? Was it done well? And if not, what areas they could . . . if they need to change their question slightly so as to carve out a unique area of research for themselves. We can help identify just the body of literature that addresses their question.

Interviewer: And how you do those studies, of course, is important too.

Mellanye: Absolutely. And so we as librarians encourage people to register their study in a protocol registry and this helps them ensure that they're going to be doing . . . that they've thought about as a research team, do they have the capacity to do the whole study? It makes them think about every single step of what they will do in their study and outline it and submit that to an international body that is open to anyone to read. And it just helps the researchers go through the entire process, think through the entire process before they actually get started.

Interviewer: So how does it do that? Does it prompt with certain questions or . . .

Mellanye: Definitely. It's a lengthy, not too lengthy, adequately lengthy set of questions that asks them to describe previous studies in their field, that asks them to describe their search strategy and describes their approach and anything that makes their contribution unique or any limitations that their study will have. And then it puts it out into the Internet, into the field for their peers to look at and they can comment on it. It also secures their place, so this says, it lets them set a flag, "Yes. We are doing this study, " helps them find out if anyone else has already started on that study and it prevents them from being scooped.

Interviewer: What is that registry called?

Mellanye: PROSPERO. P-R-O-S-P-E-R-O.

Interviewer: And do you feel like people are using that or is this something that's kind of new?

Melissa: I think people are using it. I think it is somewhat new. People don't have to publish a protocol in PROSPERO. A lot of times, people will also publish their protocols in a journal. And there is a specific type of systematic review called the Cochrane systematic review. And in order to do a Cochrane systematic review, you have to publish your protocol in the Cochrane database of systematic reviews prior to the publication of the full systematic review.

So I think it is something that's been around for a long time. I think what we often find, though, is the lower quality systematic reviews out there aren't doing that. And we're trying to really help elevate the quality of systematic reviews much in the same way that clinical trials are trying to do by pre-registering their trial protocols, by making sure that all of the inclusion and exclusion criteria are out there from the beginning, that they know the outcomes that they're going to be looking for so that people can't go back later and switch the outcomes or make up new outcomes or decide because they're an expert that they want to include a certain study that doesn't actually meet their eligibility criteria.

So it's a quality measure, people are definitely accepting of it. And registering your protocol is actually part of the PRISMA guidelines, which is a reporting guideline for systematic reviews. It stands for Preferred Reporting Items for Systematic Reviews and meta-analyses. And it was published in 2009, I believe. And since then, the incidence of protocol registration has gone up quite a bit. It is still not great, but it has gone up significantly.

Interviewer: And you just touched on reporting guidelines. Tell me a little bit more about that and what that involves and why it's useful.

Melissa: Sure. Well, reporting guidelines, there are hundreds of them out there these days. But for systematic reviews, there are two that are out there that are really well disseminated and used. PRISMA, which I already mentioned, and the other one is MOOSE.

Interviewer: Oh. So many acronyms.

Melissa: Meta-Analysis Of Observation of Studies in Epidemiology. But reporting guidelines are really there to guide a researcher through the process of what things are really key to the reporting process. When they're actually writing that final journal article, what has to be in there so that this study can be reproduced and understood by the reader? And for systematic reviews, research time and time and time again shows that people are just not reporting their systematic reviews in such a way that is actually reproducible. And this is one of the ways that I think that librarians are really key, is because we can really help increase the reproducibility of this specific type of methodology.

Interviewer: Well, Mellanye, we've quite a bit about another common pitfall, which is how to search through data.

Mellanye: [inaudible] has 25 million citations in it. And you don't want to ask a question, you don't want to have a search strategy that's so large, you get lots of irrelevant results and you bring up a lot of static. That can be a real burden on the research team to have to go through extra thousands of results. But you don't want to ask the search strategy in such a way that it misses very relevant results. So as librarians, we can work on the search strategies to make sure we get exactly the right amount, not too many, not few, just right.

Interviewer: So give me an example of a search that might give you the wrong . . . maybe not the wrong information, but not enough, or too much. Either one.

Mellanye: Sure. One of the searches that I have worked on before, the research team did their search strategy with just the term "developing countries" and they missed a lot of highly relevant research. When they did their search they got about 17,000 results. When I added my search strategy in, including country names, including directions to the database and then form field tags and only searching for specific words in certain fields, it's kind of technical, but it really improved the results that came back. And it brought back about 3,500 results, many of which were actually relevant and would have been missed by that group.

Interviewer: You know, we're kind of going through the beginning, through to the end. What sort of an end step that you can help with?

Melissa: I think the end step, really, is the production of that final manuscript. Here in our systematic reviews core team, we do require authorship on manuscripts. And that's so that we can actually control how our literature searches are being reported. Because there's a tendency if you're not an expert in that area that you might not know what things actually need to be reported in order to make a literature search reproducible. So that really is our final step.

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

Interviewer: What's becoming loud and clear is that most scientific studies are, well, unreliable. But there's help out there for scientists. 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 Darell Schmick, research librarian at the Eccles Health Sciences Library at the University of Utah. So there are a number of reasons for what some people are calling a research reproducibility crisis, including fraud. But even scientists with the best intentions are at risk for doing sloppy work and there are a lot of reasons for that as well. One of the things that you're interested in looking at is data management. I really like this example of the Postdoc who leaves the lab.

Schmick: So it was it an age-old issue where you do a lot of work and it happens to be on your personal computer. It happens to be in a folder with poorly-named files and you produce a bunch of research on behalf of the institution, but then, once you're done, you obviously take your computer with you, right, and then head off to that next position. Now, that seemingly innocuous, however, has a lot of implications. The data that you produce on behalf the university has ownership concerns. Is it the Postdoc's? Is it the University's?

Interviewer: How can that lead to issues with research reproducibility?

Schmick: So if the Postdoc takes all that data with him or her and hasn't been saved into the department bio or anything like that, how can you ensure that you have records of all the work that Postdoc has done? They could have taken just a little bit of it, they could have taken a substantial chunk of it. And it really leaves the PI as well as the rest of the members of the lab with potentially a significant disadvantage.

Interviewer: So there's a lot of knowledge that can be lost?

Schmick: Absolutely.

Interviewer: So what are some ways to avoid that?

Schmick: We do teach a research administration training class that talks about just the basic fundamentals of just good data management, which involves things like where to properly back up your files and how often to do that. Myself and a couple of the librarians on campus have been working on a pilot for electronic lab notebook technology.

So if, say for instance, you happen to have the perennial issue of lab members recording data in their own personal computers because it's inconvenient to share it, this sort of technology allows for a lab to share in a collaborative notebook technology something that has all those questions that we're talking about answered, like how frequently will it be backed up? Is it going to be backed up in a trustworthy source?

Interviewer: Right. Well, and not to mention that most lab notebooks that I've seen are kind of a disaster.

Schmick: Are you saying that scientists don't uniformly have amazing handwriting?

Interviewer: Exactly. Right, we're all human. And even how the information is recorded is varied from person to person. So the idea is that this would become more standardized?

Schmick: You hit the nail on the head there.

Interviewer: Any other approaches to make their data more accessible or reliable?

Schmick: When we're talking about optimizing the mechanics of anything in the research process, we want to ensure that we're doing it in a way that is not only accessible by us because we can look at our notes, presumably, and be able to understand what we were saying, understand what we were recording, understand what we were encountering in that process. But to think about how the results that you're producing are going to be read by somebody else that's not in that same context. So if you're doing an experiment, you do it for you, but you also ensure that you're doing it in a way that if somebody wants to reproduce that experiment, they can do that.

Interviewer: You've talked about ways about preserving information within a lab group, for example, a research group. What about sharing information more broadly with the scientific community?

Schmick: That's a great question, Julie. And a lot of people think that all you are able to really produce is that end product, that finalized article. And we don't realize, many times, that when we're doing experiments, when we're producing all this data that we're talking about, that data could be good data. It could be good information and good intel for another scientist that's stumbling across that same issue.

If you're embarking on answering a research question and you come across a dataset that has already sought to ask that question, you find out that maybe those results weren't satisfactory enough to produce something into a finished article, that could potentially save you years in otherwise reinventing the wheel.

So another thing that we like to talk about is the idea of ensuring that researchers know that the data that they produce is of value and there are places that you can store that. So one example that comes to mind is figshare. And figshare is a repository that you can actually assign a DOI to the data sets that you're uploading on there. Figshare are all about open science so they say as long as you're making it public, I mean, you can upload it for free.

Interviewer: So how can sharing data with the scientific community help with research reproducibility?

Schmick: There's a lot of news as of late in the way of that openness toward science where folks on a peer review panel want to see the steps you were able to take in order to draw the conclusions that you were able to take or able to make. And if they're able to go ahead and see that data right there from the start, it answers all those questions.

It's when things like that data being withheld presents a larger problem not only for you as author but greater implications for science in general. When we start to withhold that data, when we start to conceal certain steps in that recipe toward what we ended up with the final product, it leads towards a slippery slope of was it not open science and that closed scholarly environment, I think, is something that is well worth fighting against.

Interviewer: Where can people go to learn more about best data management practices?

Schmick: There are a lot of places. If you're embarking on a data management plan there's a great tool called DMPTool. That's dmptool.org, and it'll take you through the steps of the processes of, "Let's take you through the steps of the data management process." By asking you in a 20 questions format, "What's this data going to be for? Which agencies are going to be seeing this data?" And it'll give you recommendations at the end from there. If you're at the University of Utah's campus, I'd encourage you to talk to me or one of our other fine staff at Eccles Health Sciences Library. I'd be delighted answer any questions regarding data management plans.

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.

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. 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.

Interviewer: Aging on a microscopic scale, 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. Adam Hughes, Assistant Professor of Biochemistry at the University of Utah. Dr. Hughes, when I think of aging, I think about getting wrinkles, going gray, slowing down, but you think of aging on a different scale. How do you think about aging?

Dr. Hughes: We think about aging, I'd say, more at an organismal level or even more specifically than that, the cell biology level. Sort of looking at not how aging affects the whole organism, but how it affects specific structures within our cells within different tissues.

Interviewer: A lot of your research focuses on one component of the cell, an organelle called the mitochondria. First of all, can you orient us to the mitochondria? What does it do?

Dr. Hughes: Sure. Mitochondria, they're known as the powerhouse of the cell. Historically, they're drawn as kidney-bean-shaped structures you see in all the textbooks, but mitochondria do a lot of different things in metabolism. They're a double-membraned structure that produces lipids, they're involved in oxidative phosphorylation, they basically make energy for cells and also participate in a large number of metabolic reactions.

Interviewer: Studying the mitochondria is actually a whole field in and of itself. What's some of the evidence that mitochondria is involved in aging?

Dr. Hughes: Mitochondria has drawn a lot of attention, not only for its role in changes in mitochondrial function affecting how long an organism lives but it's also become very clear that as mitochondria become faulty with age, which happens for a number of different reasons in a number of contexts, this is also been linked to driving the development of a large number of age-associated disorders as well.

Interviewer: And as it turns out, there's quite an elaborate system for getting rid of or repairing mitochondria that does not function well. You've just published some research about this in the journal "eLife."

Dr. Hughes: I haven't explained much of what we've been doing. We've been using yeast as a model system to understand the aging process. So it's pretty cool that the single-celled eukaryote, the simplest one, and a lot of labs have been using it for a very long time to understand lifespan regulation type processes. And so our lab actually uses this organism in it does, in fact, age. A yeast cell, we measure aging by the number of times a cell can divide before it dies. Now, it happens about 30 times before a cell dies. And so in these old cells, it started several years ago when I was a postdoc at the hutch in Dan Gotchling's lab, we found it in old cells there was damaged or dysfunctional mitochondria.

So we decided to use this system to try to see what we can learn about how cells handle this, how they respond, what can they do. And we went into it, at the time, wondering if we could model pathways that were already known in mammals, one of the most prominent being the autophagy-dependent or self-eating pathways that had already been fairly well characterized. And so when we went into this, we set out to see in an old cell, do we see pieces of mitochondria? And we're visualizing all this on the microscope, being ripped off and degraded after they're damaged/

And we saw that there was, in fact, this going on in old yeast cells and so we initially thought it was similar to what had been observed already. And that's how we got into it. We didn't go into it looking for new pathways, but eventually it sort of, as we got more into the details of what this is going on, we realized they totally new type of quality control that we discovered that was different than anything else that had been described before.

Interviewer: So what is it? What did you find and how is it different from what was there, what you knew before?

Dr. Hughes: In general, in this field, it was always thought as a mitochondria became damaged that these systems aren't very smart for a lack of a better word, that they would go to the damaged mitochondria and just degrade the entire thing. Which seems a bit wasteful and so when we came into this we thought the same thing and we were using a protein on the mitochondria. We are monitoring it by microscopy and we could see that it was being eaten. But what we did that went beyond these original studies and other systems was there are about 1000 different proteins in the mitochondria. And we just started looking at other ones too. So most of the studies in mammalian cells had only looked at one or two and made conclusions.

And so we went on and looked at all mitochondrial proteins to see how they were all being degraded. What we discovered, based on this, and this is the big crux of this study, is that the pathway we've uncovered now is the concept and idea that mitochondria actually, under these situations when they're damaged, don't just get totally degraded as a whole. They can actually be broken down piece by piece. And what I mean by that is certain proteins can be basically selectively sorted out and removed from the mitochondria and degraded and the rest of it can be left intact.

Interviewer: Do you have any ideas yet of whether this pathway relates to aging or how it relates to aging?

Dr. Hughes: We got into it looking at aging, but we think it's actually going to have many applications in other systems, especially sort of metabolic-related disorders. We've been working from the standpoint of seeing the structure and it forms, it's sort of very descriptive. It forms, it gets released, it gets degraded and certain proteins go into it and certain ones don't. But understanding what the importance of it is and why it happens has been a much more difficult question. And we are starting to get at that.

We didn't get into a lot of it in this currently published paper, but some of our certain experiments are directed in the range of one thing that we did include here. And one big clue to us is the identity of the proteins that are actually degraded by the system. So again, the mitochondria has about 1000 proteins in yeast and when we looked at the proteins that are degraded by the system that we discovered, it's only about 10% of those proteins. And it turns out it's very selective for one particular group, which is a group of proteins called the mitochondrial nutrient carrier protein.

So the role of this group of proteins, there are about 30 of them, in the in the mitochondria, they basically facilitate the transport of all nutrients into and out of the mitochondria. So we're working from the fact that these are the main targets of this pathway and we think that giving us a big clue as to what might be its role. And so clearly, they're metabolite transporters. They're very heavily involved in all aspects of metabolism. And so we're testing the idea now, a hypothesis that this pathway may be very important for actually protecting mitochondria in times of changes in cellular metabolic state.

Interviewer: It's also kind of amazing to me that, especially in something as simple as a yeast, that there are still entire processes that we're still discovering.

Dr. Hughes: Yeah, I think that's definitely a really cool point. Sometimes, yeast in this day and age will get a bad rap. You hear all kinds of things that yeast research is done and things that we used to only be able to do in yeast, now we can do them in humans and other organisms. But what's sort of the big arena right now, I'd say, in the yeast field is cell biology. And it's been very limiting for a long time, the ability to look at all different proteins and all different things within the cell.

And what's really cool in the yeast field is that many, many years ago now, probably 10 years ago, a lab developed a collection of all yeast proteins tagged with a fluorescent protein, GFP. So it's about 6000 proteins in yeast. And so we have strains that contain every single one of them. And so there are a number of labs across the country, including ours, that are essentially using this collection to look at how the entire protium changes not in terms of levels, but in terms of localizations in cells.

And people are discovering a lot of new things that no one had ever noticed simply because we have the tools to do it now. And this is what's really nice in yeast. And we still don't have the ability to do this in mammalian systems yet. So I think the future will get there and we'll be able to start looking at these. But there's a lot of new, I'd say, cellular structures, cellular compartments that form under very particular conditions that people just hadn't seen before.

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

Interviewer: Older adults are at a higher risk for death if they have low levels of bicarbonate in their blood. Bicarbonate, it's the main ingredient in baking soda. 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. Kalani Raphael, a nephrologist and Associate Professor of Internal Medicine at the University of Utah and at the Salt Lake City VA. Dr. Raphael, tell me about the main finding of your study. It's pretty interesting.

Dr. Raphael: In this study, we were looking at the association between serum bicarbonate levels and mortality in a generally healthy older population. The basic finding from our study was that in people with low bicarbonate levels, they had a higher risk of death and their risk of death was about 24%, 25% higher over a mean follow-up period of about 10 years or so.

Interviewer: So that's pretty significant. What is bicarbonate?

Dr. Raphael: Bicarbonate is very important in the body for maintaining your pH levels in a normal range. In order for our cells and our organs to work normally, the pH needs to be kept at a range of about 7.40.

Interviewer: So people with low bicarbonate would have blood that's more acidic. Why might that be unhealthy?

Dr. Raphael: The bicarbonate levels could be low for two main reasons. One is it could be because the kidneys are holding on to too much acid and your bicarbonate levels fall. That's something we call metabolic acidosis. Or the reason the bicarbonate level could be low is because the lungs are breathing off too much carbon dioxide and your bicarbonate levels fall as a compensatory response is what we call that.

So we're not exactly sure why the bicarbonate levels were low in these people. If I had to guess, I would say that the most likely reason the bicarbonate levels are low is because of an impaired ability of the kidney to get rid of the acid that we need to on a daily basis. The main reason why I say that is because our diets are really high in acid content in these western diets that we have now. We don't consume enough fruits and vegetables in relation to the amount of acid that we intake.

So if I had to guess, I would say that the most likely reason that the bicarbonate levels were low is because of an impaired ability to get rid of acid by the kidneys.

Interviewer: So what caused you to even take a look at that in the first place?

Dr. Raphael: Well, in people with kidney disease, we know that low bicarbonate levels occur quite commonly. It occurs in about 15% of people with kidney disease who aren't yet on dialysis. What we know is that in people with kidney disease who have low bicarbonate levels, they have a higher risk of death and they have a higher risk of progression of their kidney disease to end-stage renal disease or needing dialysis or a transplant in order to survive.

But much less was really known about generally healthy people and so I was interested in whether or not low bicarbonate levels have any association with poor outcomes in people who are otherwise healthy. So that was really the driving force behind this research study.

Interviewer: So do you think measuring bicarbonate levels could be some sort of test or indicator that someone could do to evaluate the healthiness of somebody?

Dr. Raphael: Absolutely. I mean, bicarbonate levels are very commonly measured in clinical practice these days. Bicarbonate levels are measured usually when a physician wants to check on somebody's kidney function. They'll order a chemistry panel or a renal panel. In primary care, I'm not exactly sure how well people look at these levels and I think that one of the things that maybe doesn't attract their attention is they don't really know what it means for that person.

So if you had a healthy person sitting in your clinic who had a bicarbonate value that was low, I think most physicians would say, "Okay. It's low. I'm not sure what to do with that." But I think what this research is showing is that it's probably something we should be paying attention to. But I don't really know quite yet what we should do about that.

Interviewer: Right. Maybe it would be a signal that it's worth taking a second look at this patient to see . . .

Dr. Raphael: Absolutely.

Interviewer: . . . if something else is going on.

Dr. Raphael: Right. So, I think you said it correctly that it's a signal for potentially bad things. That might trigger the physician to look into their kidney function a little bit more or maybe consider underlying lung disease or heart problems in that person.

Interviewer: So do you think more research needs to be done to figure out exactly what this could mean?

Dr. Raphael: Absolutely. The key thing about this research is that these were really healthy people. I mean, they were older folks. They could have had diabetes. They could have had some cardiovascular disease. But they were independently living. They could take care of themselves. They could walk a quarter-mile. They could climb up stairs. These were pretty healthy, older folks.

Interviewer: Right. So not necessarily any other indication that something was wrong, right?

Dr. Raphael: Exactly.

Interviewer: Interesting.

Dr. Raphael: Yep. So I think the next steps are to kind of look into why this cohort had low bicarbonate levels in the first place. Is it an undiagnosed or yet to be determined type of kidney disease or some other underlying lung disease, potentially? Then, I think the next thing also to consider is can we raise the bicarbonate levels in these people with various types of interventions and perhaps improve their outcomes, make them live longer, those sorts of things?

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

Dr. Raphael: The takeaway from this type of research is that we can say that there are associations between bicarbonate levels and outcomes. We can't really say quite yet whether or not people should be changing their diets or taking baking soda. I think that's something that needs to be cautioned against at this point, pending further clinical trials.

But I think if somebody is interested in keeping their bicarbonate levels at a normal range, I think that the safest way to do that is to look at how much fruits and vegetables they eat because fruits and vegetables are a source of bicarbonate, that bicarbonate largely comes from citric acid in fruits and vegetables, which gets converted by the liver into bicarbonate. We all know that fruits and vegetables have great health benefits for lots of other reasons.

One of the cautions about increasing fruits and vegetables in your diet is in people with kidney disease because those have high levels of potassium and that could cause potassium buildup in people with kidney disease. So I think if somebody is thinking about increasing their fruits and vegetables in their diet to keep their bicarbonate levels in a normal range that they should probably check with their doctor to make sure that it's safe.

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Interviewer: Fish that can repair their own brain 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. Adam Douglass, Assistant Professor of Neurobiology and Anatomy at the University of Utah. Dr. Douglass, you have this cool result where fish basically repair their own brain. Tell me what you saw?

Dr. Douglass: In particular, we're interested in populations of neurons in the fish brain that release dopamine. So its cells that make the neurotransmitter dopamine release it into the brain and in figuring out what those cells do to behavior. Within our department, I collaborate closely with a group led by Rich Dorsky, whose lab is also interested in fish brains, but in different aspects of it, in particular, regenerative aspects of it.

The experiment that we did with Richard's lab was to ablate those neurons initially using a chemical technique that caused all of the cells, give or take a few, to disappear. What we found is that over the course of almost immediately, really, starting within a day or two of the ablation, the cells start to grow back such that by a couple of weeks after the initial insult in which we've destroyed the cell population, we have a number of neurons in the structure making dopamine that's almost identical to the number that we started with.

Interviewer: You also saw that the fish were able to regain their behavior too.

Dr. Douglass: Right. What we found is that immediately following the ablation and coincident with the loss of these dopamine neurons, the fish swim a whole lot less. If you put a group of young zebrafish, baby zebrafish into a dish, they normally swim around out pretty ruddily. They keep moving continuously and in contrast, after the ablation, the fish more or less just laid there. They could still move and, in particular, it was encouraging to see that if you startle the animals by tapping the dish or leaning over it; things that they normally don't like and try to get away from, they still swim around quite a bit. So it wasn't just a gross defect in the animal's ability to move. It seemed to be something related to its motivation to do so that was missing.

Interviewer: The fish have motivation?

Dr. Douglass: Yeah, they normally like to swim.

Interviewer: And that was able to come back over time after you . . .

Dr. Douglass: Yeah, and it came back in a way that more or less directly paralleled the regeneration of the neurons that we had killed. So while we think that there're probably other regenerative events or neurogenesis events that are ongoing in hypothalamus, some of which may have been upregulated following the ablation of these cells, the fact that the behavior comes back in a more or less proportional way relative to the number of these cells that are present makes us think that these probably are the neurons that are responsible for setting these weights, these tendencies to move or not move. And we are able to support that using other experimental techniques.

Interviewer: So you think a specific cell type regenerates and mediates this recovery. What cell type are you looking at and why is it interesting?

Dr. Douglass: The cells that we study make dopamine, this neurotransmitter which most people have heard about in the context of reward and things like addiction. It's certainly interesting in those contexts, but it turns out that dopamine does a lot of different things in human behavior as well as in fish behavior. For instance, as anybody who's learned about Parkinson's disease knows, dopamine neurons have a very important connection to locomotor behaviors, movement behaviors in every system where dopamine neurons exist.

There's also a variety of other stuff, literally dozens of different behavioral functions for this one neural transmitter. And one of the things I find interesting about this is that we have a poor ability to explain exactly how one molecule does so many different things in behavior. The answer at some level is almost certainly in the fact that there are multiple different brain regions that contain different populations of dopamine neurons. What my lab is trying to do is the relatively straightforward task of seeing what happens to behavior when you manipulate activity in these cells.

Interviewer: Do you think other cells in the brain might be able to regenerate this way as well?

Dr. Douglass: Historically, there's been this notion that brains don't grow back. Certainly the human brain . . . that its regenerative capacity that's capacity for new cell growth falls to zero following very early development. What we've come to realize over the past decades is that that's not true. It's a reasonable approximation for how the system works in the sense that neurogenesis does really fall off as you enter into adulthood and, unfortunately, cell death does increase.

But as people have looked more closely, they've realized that there are several brain areas where there's a significant amount of neurogenesis going on all the time through adulthood. That includes the area of the brain that we're studying, the hypothalamus, both in mammals and in fish exhibits lots of new cell growth.

Interviewer: Are there any implications for what this could mean for us?

Dr. Douglass: Our work is really unique in that it demonstrates not only that there's a cell population that comes back but it's a dopaminergic cell population and it's a dopaminergic cell population with a direct function in locomotor behavior. If you look at mammalian systems, unfortunately, the substantia nigra, the brain area containing dopamine neurons that are affected in Parkinson's disease, is not regenerative. That's one of the reasons that cell loss and Parkinson's ultimately leads to massive defects in locomotion and ultimately the inability to move.

Our brain area, the hypothalamus, which contains the dopamine neurons that we're studying is not functionally equivalent to the substantia nigra in a strict sense, but the fact that these neurons in fish are both connected to locomotion and have the ability to regenerate probably hold some clues as to how regeneration might be made to work in the human brain areas that are affected by neurodegenerative disease.

It's not to say that we're on the brink of having some therapeutic insight to this. That's far from the case, but I do think that it's reasonable to think that we'll learn something about how these systems work and potentially what's missing in the case of the substantia nigra dopamine neurons that makes them not able to regenerate. If you can identify those things, then that gives you potential sites for therapeutic and intervention down the line.

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

I think the regulatory agencies can use their platform to help inspire science and development of new tools that will provide better, safer, more effective, higher quality products, which is really what we're trying to do in terms of getting good therapies to patients.

The major barrier to entry in the market is the cost and the time that it takes to bring a discovery that's made in the laboratory actually to the clinic.

On average, right now, to bring a new drug to the market, it's probably somewhere between one and two billion dollars. If you've made a $2 billion investment in a new product, what do you have to price it at in order to get your return on investment?

If we were to try to support cures for all the orphaned diseases, it would consume the entire U.S. GDP. Clearly, we need to do a better job in driving down development costs so that we can drive down what these products are listed at in order to not completely break the healthcare system.

All of these different trends that are happening in the industry, the kind of merger and acquisition, the loss of capital, the direction that science is driving toward smaller markets, all of this is really converging to a point where this industry is under significant stress.

I think one of the things we need to do is think about establishing a national infrastructure for clinical trials. The other thing we need to think about is how we design smarter, I'll call them leaner, less expensive clinical trials that allow us to get just as much information about a therapy out of a much smaller trial.

We spend little to no effort on actually taking what knowledge we have, in terms of real world performance and things that we know about in prior studies, and integrating it back, or reverse engineering into the discovery or to the next generation product development.

Probably, most importantly, we don't include the patient and the consumer perspective. What are their opinions? What are their experiences, which are going to be critically important.

I think the academic medical centers are the drivers, or the engines of discovery and innovation, in terms of bringing basic fundamental mechanisms of knowledge of disease forward.

I think what academic medical centers could do, that might improve the situation, is take those findings a little bit further down that path of product development.

One of the problems, of course, is that they're not funded to do so. So the NIH isn't really funding product development, and that's something that I think, that the FDA is trying to change through its Regulatory Science Initiative, but it may necessitate other types of partnerships between academic institutions and private industries.