[Damien Blenkinsopp]: I just want to thank you so much for joining us today.
[Josh Fessel]: Sure. Thanks for having me. This is really fun for me. This is a new thing for me, but I’m really looking forward to it.
[Damien Blenkinsopp]: Excellent, Dr. Fessel. I really enjoy these too, so we’re both coming at it with enthusiasm.
[Josh Fessel]: Absolutely.
[Damien Blenkinsopp]: First of all, I always like to hear people’s stories a little bit about how they started working with what they’re working with. How did you get interested in the subject of oxidative stress and start working on that?
[Josh Fessel]: Oh, that’s a great question. I’ve been thinking about oxidative stress for the last almost 16 years and it really started when I was in graduate school or looking to start graduate school. I started a training program to train both as an MD – so it was clinical – a clinically trained physician – but also to get a PhD to do a research degree in some area. I was casting about, looking for what I thought would be an interesting area of study for my PhD research and I ended up talking to a guy named Jack Roberts, goes by Jack. His full name is L. Jackson Roberts, II. If you looked for him in the literature, that’s how you’d find him.
I sat down to talk to Jack and found out that he and I – the important part of the conversation was that he and I were very much of a like mind when it came to thinking about science. That the idea was that you could take the fundamental principles of chemistry and physiology and apply those to living systems in a way that you could learn meaningful stuff. It turned out that what Jack studied and still studies actually – he still has a very active lab – is oxidative stress and free radical injury in biological systems. I was really drawn to the approach that the lab took, basing things in organic chemistry and biochemistry and then going all the way to studies in living people. So that’s how I first got interested in it and what was going on in the lab. It was one of those things that I thought it would be fun when I started and it turned out to be even more fun than I thought it would be.
[Damien Blenkinsopp]: That’s great to hear.
[Josh Fessel]: Yeah. So that’s really how I got started and things really took off. We did some work to discover a new class of biomarker for oxidative injury and that led to an interest in mitochondrial function and how oxygen is regulated dynamically in a living system. That kind of led to what I do now, which is more focused on a broader perspective, looking at mitochondrial function and molecular metabolism, carbon source utilization in living systems. What are the fuels, how do they get used, and how do those decisions get made.
[Damien Blenkinsopp]: Great. So does that still involve oxidative stress that you’re looking at?
[Josh Fessel]: Absolutely, yeah. The two are very closely linked. I think about it like a car engine and if a car engine runs perfectly with perfect efficiency, every drop of fuel is converted to motion to useful energy. But we all know that that doesn’t really happen and that you get leaks in the system. Some of that from a car engine leaks out as heat – sometimes it leaks out as an actual sort of fuel or other things and the human body is really no different. And so if the cellular engine runs perfectly, every molecule of fuel is converted to carbon dioxide and water and useful energy, but that doesn’t happen perfectly and the byproduct – the leak – is free radicals and that gets you right into oxidative stress.
[Damien Blenkinsopp]: Right. Why do you feel this is an important subject? Oxidative stress. Are these leaks? And maybe we could talk about the broad strokes of where the leaks are bigger and smaller. But, in terms of oxidative stress, why do you think that’s something worth looking at? And would it be worth tracking, for instance, in people as they age or as they through different health conditions or even, perhaps, when they’re looking at performance.[Josh Fessel]: So, I definitely think it’s something worth looking at. I’ll tell you, I have a personal sort of one-man crusade to actually get rid of the term oxidative stress because I think it’s too nonspecific. It sort of carries with it the idea that every free radical that’s produced in a living system is bad and we know that’s not right. Some of them are quite useful and serve signaling roles, bacterial killing roles. Some of them, under particular circumstances, are harmful and I think that’s what we really worry about. So, I talk a lot of times and I’m trying to be more rigorous in my scientific writing talking about oxidant injury versus oxidant signaling and teasing those two apart. But I definitely think it’s something worth studying, quantifying, tracking in detail because fundamentally, I think, we still don’t really understand all of the concepts that tease apart useful oxidant production from harmful. And so one of the ways I think that we can start to get at that is collect data and be careful about how we define the conditions that we’re studying and then from there you can begin to kind of back calculate and figure out okay in this situation a little bit of stress to the system maybe was actually useful; whereas in this other situation, it was clearly harmful. So I think in spite of the fact that people have been studying free radical biology and oxidative stress for decades now, there’s still a lot we need to learn before we really can translate those findings into something actionable.
[Damien Blenkinsopp]: Alright. Yeah, there’s still many different theories. I guess you’re juggling and trying to prove and disprove different ones. Let’s take a step back. It’s always interesting to see how someone, especially someone working in this area and doing the studies and everything, it’s interesting what they do themselves. Have you tracked your own oxidative stress or you follow that? Do you ever look at that in yourself and have you compared it over maybe a few years or anything like that?
[Josh Fessel]: That’s a great question. So, I have measured my own levels of – I probably shouldn’t admit this. We aren’t really supposed to do this, but we all do in science where you need a so called normal sample and so a lot of times that ends up being you. So in some small studies, yeah, I have actually done that. On a routine basis, there’s nothing that I track as far as oxidative stress or products of redox reactions. This question always comes up as to what would a person track. I think in a research setting there are a lot of things that are useful to look at and I’ve certainly participated as I say in research studies of, for example, looking at products of lipid peroxidation and looking at oxidized lipids that float around in the plasma. And I think that’s really useful, but when it comes to what I would recommend to a person or what I do myself, I tend to be a little more conservative because I really – hang up isn’t exactly right – but I focus on that word actionable because I might be able to tell you that on any given day [unclear 10:47: oh [ axles of] isoprostanes] are this, and my levels of guanosine are this and my levels of malondialdehyde or whatever the product is. But I don’t really know what to do with that and so when it comes to a person in the real world – whether it’s you or me or a patient of mine or whoever – I tend to focus on pretty low level stuff and this is true in my own life. I tend to focus on pretty low level stuff that we know has a pretty clear impact on health and wellbeing.
[Damien Blenkinsopp]: By that you mean that you like to focus on biomarkers which are being used consistently for a longtime of 20 years of research behind them, a link to specific disease conditions or aging?
[Josh Fessel]: That’s exactly right. You got it.
[Damien Blenkinsopp]: My understanding is that – I’ll maybe start calling it oxidant injury. Maybe that would be the correct term. But as I understand it, like F2 isoprostanes and Ado DG guanosine – I always have a problem with pronouncing that one – but these are linked to aging as one byproduct, just as we get olderthese tend to correlate where they’re kind of sloping and steadily get higher. Is that true?
[Josh Fessel]: In general, that is true. In a broad sense, most products of oxidant injury will tend to increase with age and this gets at the whole free radical theory of aging. The idea that at the molecular level, one of the things that drives the aging process is that slow leak of free radicals that’s just part of the normal process of being alive and having an active metabolism in an environment that is or an atmosphere that’s 21% oxygen. And I think there’s some core validity to that idea. In general, I think its right. In the specifics, I think there’s still a lot more learning. I was just reading a paper this morning, for example – it was just published – that where in a given cell or organism free radicals are produced can have a pretty profound impact on lifespan. Now this was in a very simple model organism and how this actually maybe applies to you or me – that’s anyone’s guess. But I think that’s what makes it fun that in general I think the theory has validity and that’s evidenced by the fact that somebody that’s 80 years old, by and large, is going to have a higher circulating level of F2 isoprostanes than somebody who’s 20. But there are a lot of variables that come into play and we’re just teasing all those out and I think it’s really fun to do that.
[Damien Blenkinsopp]: Yeah, I guess there’s like two things we’re often trying to do. Sometimes we’re trying to diagnose or basically zero in on something we can act on. [Inaudible] is actionable. Here at The Quantified Body we’re all about action. Exactly the same like idea. If we’re measuring it and it’s not actionable, we’ll there’s not much point especially as a lot of these tests of devices or things out there are relatively expensive and we talked about that on shows before. So you have to really be careful about which measures you’re wanting to invest your time in because it also takes times, conveniences, all sorts of pay offs in our equation in terms of your lifestyle and the benefits you’re getting out of it. So, in terms of the payoff for these, would it be interesting, for instance, to relate that to age? If you’re interested in longevity, would it be interesting to track? You’ve focused a lot of your work on F2 isoprostane and the benefits of that marker. So, based on your knowledge, would it be something useful? If I started tracking it right now and continued for the next 10 years, would it be possible to compare myself to benchmark people of the same age? And then also maybe get concerned if it tended to go into an upward trend that I felt was sharper than I’d want at this stage of life?
[Josh Fessel]: That’s a really interesting question and I’m trying to think if I know of a study where anybody’s done that where they’ve actually looked over time of a cohort of people to see what happens. I can’t call one to mind, which is not the same thing as saying it hasn’t been done. It might be very interesting. You’re exactly right when you say that the way that you’d want to think about that, the first thing you’d want to know is fairly large group of essentially normal people or more or less normal people of varying levels of fitness and varied diets and all that kind of thing. What does the population look like with respect to any biomarker be it F2 isoprostanes or whatever? And then that gives you a basis for comparison. And then it might be very interesting to see what one’s individual trend over time was with regard to that some markers would be easier to do that with than others. There are lots of ways to measure these things and some of those – some of the methods are more robust than others and that kind of thing. And so, for example, we’ve talked a little bit about F2 isoprostanes and related lipid peroxidation products that I’ve studied over time. Those are really, really robust markers. They’re chemically stable. They’re detectable in every biological sample type you can think of. They’re detectable at pretty small levels, so you don’t need a huge signal to confidentially say okay the level of F2 isoprostanes in the blood or the urine or whatever was this. The problem is that they are expensive to quantify and for a really robust measurement it requires a pretty sophisticated setup. It’s mass spectrometry and blah, blah, blah. So, it sort of fails that aspect or it fails on that criteria and for an ideal test which should be easy, cheap, reliable, robust, [and] applicable to a wide range of situations. So I think we’re still – in terms of what a person would do on a day to day basis, I think we still don’t have the perfect thing to look at and I’ve had people ask me, “Well should I send in a sample for this array of tests for oxidative stress or whatever?” And my general answer is if you want to know and you’ve got the disposable income to do it, yeah that’s probably okay. But it shouldn’t be the top thing on your budget because there are lots of simple things to do that we know are going to have a positive impact on oxidative stress and on every other aspect of health. You know dietary things to think about, regular exercise, [and] all that kind of stuff. So in that regard – the other thing is that as far as the normal aging process goes, I don’t yet have an intervention that I can tell you to try that will reliably slow down or modify the aging process. There are few things that look promising, but I couldn’t say oh you seem to be aging rapidly. Why don’t you try this?
[Damien Blenkinsopp]: That’s an interesting discussion and longevity is one of the things we look at and we recently had Aubrey de Grey on the show. If you’ve heard of him or you follow some of his work, he’s very focused on longevity and promoting ending the aging equation and investing in research. He actually wrote a book about the mitochondrial theory of radicals and so on. So I’m sure you’ve connected there. So, he’s looking at a whole bunch of markers every year – 160. But I think he feels like you do, he’s really looking for something that goes perhaps an extreme, I think. I think maybe this is like an angle that could be interesting. It’s like if something goes extreme in terms of its nearly off the normal curve. It’s in the top 10% or the top 5%. Then he gives you reason to kind of look at it. But while it’s remaining within a range, which has been detectable, then I think what you’re saying is like it’s not like it’s very actionable or you already can think of something. And I guess oxidative stress – there’s still a lot of controversy around it – oxidative injury. So, when it comes to vitamins – vitamin C, vitamin E, succinate, and other interventions that people use to try to increase their antioxidant levels and lower oxidative stress, I guess in terms of the actual research supporting that and evidence that’s not really there yet. But we were just talking about it before this chat and we’ll talk about it more is the diet. And there’s obviously a lot of people doing different diets today and it’s a subject we’ve discussed before and we’ll keep coming back because there’s so much confusion over which diets work and which don’t and what they’re useful for. But I think it does come to mind that your diet could have an impact on your oxidative stress levels. So, potentially tracking F2 isoprostane once per year and changing your diet for a year and seeing what happens or perhaps a shorter amount of time, might be something relevant just to see if that has an impact in terms of how would you compare it to say inflammation such as high sensitivity CRP, which is a bit very common standard measure of inflammation. So you can often see an impact in CRP when it comes to diet – pretty substantial. It varies. I’ve been following mine, for instance, for a very, very long time and as I’ve changed my diet and optimized it, like it’s virtually zero at this point where it started at closer to 1, like around .8 – it was somewhere around. Which isn’t high, but it’s just you can see the difference over time. So, I’m wondering if you could see that kind of change over time if you feel that you might be able to see that. I know maybe in the research it might not exist, but sometimes if we’re looking to kind of go ahead of the research and just see – it’s like then it equals one experiment and maybe we can inspire someone to do some research if we go ahead.
[Josh Fessel]: Absolutely. I think that kind of thing could be very valuable and in small studies those sorts of interventions have been done where people have been transitioned to – for example, Jack Roberts – the guy I mentioned – the guy that discovered isoprostanes did a small study where he took young, relatively healthy – in other words, no chronic diseases – nonsmoking adults, but who were overweight and measured F2 isoprostane levels and they were increased and had them participate in a program of caloric restriction. So they did and it was pretty robust. It was about a 40% caloric restriction. So 60% of their typical core needs average over like a 3 day period or something like that.
[Damien Blenkinsopp]: So, could you just specify? Is that caloric restriction based on normal human needs or was it based on their original intake?
[Josh Fessel]: If I remember – I got to think about that. It may have been based on normal dietary recommendations. I’m trying to remember the specifics of that.
[Damien Blenkinsopp]: We can check that. We can link to the study or whatever.
[Josh Fessel]: Yeah.
[Damien Blenkinsopp]: It’s not essential, but I thought it was interesting. I imagine they probably did it at normal human intake.
[Josh Fessel]: I think that’s probably what they did actually. Although, as I recall, they did sort of do a food diary and the caloric intake that these people had, while they were overweight, it wasn’t wildly off what the normal recommendations were. Maybe 10% different or something like that. But the only intervention of this short period of time was a caloric restriction and there was a rapid fall in plasma F2 isoprostane levels well before there had been any substantial weight loss. I think the average weight loss at the time of the nadir of F2 isoprostanes was something like a pound or two. So it was not a significant percentage of bodyweight, but there was this really pretty impressive effect on this marker of oxidant injury and so I think what you’re describing – tracking over time within and individual and modifying diet in some way, be it increased antioxidant intake or even somebody had weight to lose and they wanted to try a more calorically conservative diet and then track markers like that, I think that could be very informative if the means exist to do it and all that kind of thing.
[Damien Blenkinsopp]: Well so let’s talk a bit more about the isoprostane because you’re work has kind of shown, as I understand, that it’s one of the better markers compared to the ones that are used more popularly, we’ll say today, still because they’re kind of the ones – I don’t know how you say it – the ones that have been in place a long time. So, what kind of markers exist today and why do you feel the F2 isoprostane has been a more useful marker?
[Josh Fessel]: That’s a great question. So there are tons of markers that you can look at and most of them are some byproduct of free radicals reacting with some large class of biological molecules. So you can look at the products of free radical reactions with sugars or lipids or proteins or DNA or – and depending on where you start from, that determines what kind of product you end up with.
[Damien Blenkinsopp]: So it’s kind of like you’re just trying to measure the volume of free radicals by what happens when they hit other thing and –
[Josh Fessel]: That’s right. That’s exactly right. Yeah because, by their nature, free radicals are fairly evanescent things. They’re reactive and they don’t last long. There are techniques to actually measure the radicals themselves and those rely on techniques like electron paramagnetic resonance measurements and that sort thing. So they’re specialized techniques and they’re really kind of research only sorts of deals. So if you really want to know about the radicals themselves that’s what you end up doing. But for most of us and again if you’re thinking about oxidant injury in particular, I actually find it more useful to look at the byproducts of reactions that we know to be fairly uncontrolled reactions because, in my mind, that conceptually gets you back to a process that’s injury as opposed to a deliberate signal. So you can look at anything from – we mentioned 8-oxo guanosine. That’s a product of free radical interaction with DNA. You can look at malondialdehyde, which comes from lipids and can come from some protein oxidation. There are protein carbonyl assays you can look at and they all tell you some information. The reason that we’ve settled on F2 isoprostanes and related compounds is that we know a lot about the chemistry of formation. We know from the moment the inciting radical is generated, we can walk through the reactions that lead to F2 isoprostane formation. And this is through work that Jack did. When these things were first discovered in the 1990’s, we know that once they’re formed, they hang around in a more or less unchanged structure – a more or less unchanged form. And further when they do get metabolized, we know what the metabolites are. So there’s no source of spurious generation. When you look at things like malondialdehyde or like the TBARS assay, the thiobarbituric reacting substance – the problem with assays like that is that they tend to generate some signal in the process of the measurement of itself and so it’s hard to know, except in a relative sense, how much of what you’re measuring was there to start with and how much of it came about as a result of the measurement itself. By contrast, I’ve heard Jack tell this story a few times of when they discovered the isoprostanes back in the early 90’s, they did an experiment where they took a beaker of urine and sat and measured the level of isoprostanes in the urine and then sat the beaker of urine on a hotplate for about 72 hours which ought to – any spurious generation’s going to happen, that’ll do it and the levels were exactly the same as they had been 3 days before.
[Damien Blenkinsopp]: Wow.
[Josh Fessel]: Yeah, so really robust and –
[Damien Blenkinsopp]: Yeah. So that means you could ship it around the world. So you’re talking about urine samples here?
[Josh Fessel]: Yes, yes.
[Damien Blenkinsopp]: Right. So that’s also very accessible –
[Josh Fessel]: Correct.
[Damien Blenkinsopp]: Compared to blood. Yeah.
[Josh Fessel]: That’s correct, yeah. So exactly what you say has been done. We’ve analyzed urine samples from the deep jungles of Southeast Asia looking at measurements in patients with malaria and all that kind of stuff. So it really is robust in that regard. There’s also a series of studies actually that are sort of interesting reading called the Biomarkers of Oxidative Stress Study or the BOSS study. And this was published in four or five installments. It was a study sponsored by the National Institute of Environmental Health Sciences and the NIHS wanted to know exactly the question that you’re asking. What are the best markers of oxidative stress or oxidant injury in a living system and so they did head to head comparisons of a variety of different biomarkers in a bunch of different contexts starting with different oxidants, looking at different biologic samples and the isoprostanes emerged as of one of the most robust. I don’t want to overstate – it’s certainly not the only thing that’s useful to look at. But in the BOSS studies, the isoprostanes emerged as one of the most robust across a variety of context, samples, that kind of thing. But the BOSS studies are NIH sponsored. They’re publicly available. They’re kind of interesting reading actually.
[Damien Blenkinsopp]: Great. Yeah, we’ll definitely link to all of this stuff in the show notes. One of the big things I understood was there was a difference between in vivo and in vitro. Could you talk a little bit about that because sometimes people go and read studies or they go to a link for a study and it’ll be in vitro. They just assume that it’s going to be exactly the same in the body. So, first of all in vivo means inside the body and in vitro basically means in a test tube.
[Josh Fessel]: In a living system.
[Damien Blenkinsopp]: Right.
[Josh Fessel]: That’s right. So most of the time when people talk about in vitro they’re talking about something up to cells growing in a dish. So, it might pure chemicals in a test tube, it might be cells growing in a dish, something like that. In vivo is referring to in some intact living system. Sometimes as simple as a worm or a fly, but it’s an intact organism. Worm, fly, mouse, human, something like that. So the distinction is really important. You can make lots of things happen in a test tube or in cells in a dish that may never happen in a living system for a thousand different reasons. Just as one sort of easy example to grasp, if you’ve got cells growing in a dish, they have a very limited capacity to respond to any insult you throw at them and you know that’s not true of an intact human being for example. You’ve got all sorts of immune responders and chemical antioxidants and the liver and the kidneys eliminate toxins and this and that. So there’s interplay of a hundred different systems in an intact organism that may run counter to or may enhance the effect that you’re looking at and so to extrapolate from a test tube or cells in a dish to a person or even a mouse in a cage, that’s a long stretch. Now what we constantly do in our research is exactly that. We find something interesting in a very simplified system in vitro and then we say can we find any echo for this in the living system, can we see the same thing, or how was it modified between the cells and the dish and the person in the lab.
[Damien Blenkinsopp]: Great, great. And in terms of these oxidant injury markers, I’m trying to adopt your expression there, what did you find in terms of the markers? Were there some of them which were working better with in vivo? Because I mean at the end of the day we want to know what’s going on in the body of course.
[Josh Fessel]: That’s exactly right. One of other reasons we really like lipid peroxidation products in general or that I really like lipid peroxidation products in general and isoprostanes in particular and related compounds is that every cell with a membrane is fair game for study. So, for example if you wanted to measure DNA oxidation products, well there are are cells in your body that lack DNA. Red blood cells, for example, have no DNA in them. Platelets have little shreds of DNA. But every cell has a membrane, so every cell is fair game for study and it lets you really refine your question. It also means that if I can get ahold of the membrane, I can study it in vivo even down to the subcellular level. So I can take a sample of liver tissue, skeletal muscle, whatever and get the mitochondria out of it and measure the levels of isoprostanes or isofurans or whatever in the mitochondrial membrane and I can tell you something about what happened to that level of detail in a living system and so that’s how we try to bridge that gap between things that are very simplified in vitro and move into in vivo. But there are lots of things you can do in that regard. There’s a lot of literature for example on looking at oxidized DNA floating around in the plasma as a marker, not only of oxidant injury, but of cellular injury. So people are looking at the DNA contained within mitochondria, for example, and looking not only at how much is there floating around in the plasma because it’s not really supposed to be there in it’s free form, but of that how much of it is oxidized and how extensively. And you can get a really pretty granular view of what must be going on at the cellular level. Now, it doesn’t tell you things like is it in one specific spot in the body or is this a whole body thing, but you can get pretty detailed information in a living human. From a research standpoint, a living human is a really complex and sort of filthy place to do your research, right. It’s very uncontrolled. There are a million variables that you can’t do anything about and yet that’s what you have to do and the techniques are such that we, in a research setting, we can get pretty detailed.
[Damien Blenkinsopp]: Yeah because I mean the body has so many variables. If you’re just thinking about it. It has a long dynamic equation – some crazy calculous. There’s so many variable that to do science is actually really difficult because you can’t control so many different variables that are going on. So, you have to appreciate the efforts people are making to study how we work just in the incredible in-complexity. We’ve looked at hormesis quite a bit, which I think illustrates quite well the concept you’re explaining here about in vivo being different where we have things like our hormetic curcumin for example. You put it into the body and it ends up creating some kind of anti-stress kind of like an antioxidant effect. Although the mechanism as we understand it today is actually a small oxidant kind of injury as I understand it. So there you see it’s causing the opposite of what you thought. I’m sorry – It’s very illustrative of the importance of focusing on the in vivo. So, okay we understand why you like isoprostane. What kind of things have you seen our reduced high levels of isoprostane if anything? You mentioned caloric restriction as being seen. Are there any other things that have been seen that have some kind of impact on it?
[Josh Fessel]: Yep. You can supplement dietary antioxidant intake and see a measurable effect on isoprostanes and there are a number of studies that have done that using various dietary sources. Regular exercise is a pretty clear – it’s interesting and this may get to that idea of hormesis. There was a study where they took people – and this maybe isn’t surprising when you say it out loud. They took ultra-marathoners and measured their levels of isoprostanes right before and right after an ultramarathon and then maybe up to a week later. And not surprisingly, right after the run and obviously these are extremely fit people, right after the run their levels of isoprostanes were incredibly high.
[Damien Blenkinsopp]: Sky high, yeah.
[Josh Fessel]: Yeah.
[Damien Blenkinsopp]: Cancer patient levels.
[Josh Fessel]: Right, right or more. I mean if you just looked at the numbers and didn’t know what had happened, you’d say oh my God, what’s going on with these people. But as you say, it’s the biological of that which doesn’t kill you makes you stronger and so clearly these are fit and when you look at their baseline levels, their baseline levels were quite low. So regular exercise we know improves the efficiency of the machinery that tends to leak free radicals or improves the ability to respond and maybe both. So it’s a lot of the things that you might guess at anyway. The healthy diet that’s low in fat and high in fresh fruits and vegetables, that kind of thing. Oh, the other really big thing is we know from a number of studies that smokers are under a huge constant oxidant stress. It not only enhances the formation of free radicals and masking goes hand in hand with this, depletes levels of multiple different endogenous antioxidants. So, the other thing that we know is beneficial is if you smoke, please stop.
[Damien Blenkinsopp]: Alright. So, you’re talking about glutathione and –
[Josh Fessel]: Yep. Glutathione, ascorbate. I can’t remember if there was a measurable effect on vitamin E or not. Lipoic acids – many of the usual suspects and they were all depleted in the smokers.
[Damien Blenkinsopp]: Great, great. So, I guess increasing your glutathione or having low glutathione is going to have an impact on your isoprostane levels just because you’re indigenous antioxidant system is different. You brought a very important aspect of it there. They weren’t for a run for a few hours and they completely changed their isoprostane levels. So then we have to think about, okay we really have to control. If this can change that rapidly – give that that was quite an extreme circumstance. But what kind of things do we have to control for it to make sure that we’re not getting some kind of useful reading with isoprostanes.
[Josh Fessel]: Yeah, that’s a really good question. So, we know that people who are heavier – who are overweight or obese – have higher levels. So you got to control for that. As I say, we know that smokers have higher levels, so you have to control for variables like that. It ends up being a lot of the variables that you would control for in a fitness type of study anyway. It turns out that the specifics of – at least in a short time window – the specifics of dietary composition aren’t as important as you would think. So, year’s back we actually did an experiment in the lab where a bunch of us – because we wanted to know is it possible that what you’re measuring when you measure a plasma level of isoprostanes for example is coming in with the food you’re eating. A bunch of us in the lab went and got a very high fat meal from a popular fast food chain and measured our levels.
[Damien Blenkinsopp]: I wish you would say the name, but we can guess.
[Josh Fessel]: I won’t necessarily say the name.
[Damien Blenkinsopp]: Have they been in the news lately?
[Josh Fessel]: Almost certainly. So we measure our levels beforehand – blood and urine. And then ate a very fatty meal and then I think it was something like 6 to 8 hours later, measured plasma and urine levels and they really didn’t change. Which was kind of a surprise, but it was very reassuring. It suggested that what you’re measuring is more reflective – or at least, if it’s not more reflective of a steady state, it’s at least not so sensitive that you can tip with –
[Damien Blenkinsopp]: With just one meal.
[Josh Fessel]: That’s right.
[Damien Blenkinsopp]: Right, right. Okay.
[Josh Fessel]: But, overall dietary composition is something you would want to know something about if you were doing a controlled measurement.
[Damien Blenkinsopp]: Is there anything about time of day or with a lot of blood tests we do fasting. Will it make any difference if we fast say 6 or 8 hours or 12 hours and then do it in the morning? Or is it okay to do in the evening – to take your sample then if urine for example? Are those kind of influences important? How about like summer or winter? Are these good questions because if I imagine if I’m interested in tracking this just say for aging or for some other aspect, then I want to know that I’m not just going to get hectic data basically. Like one day up, one day down. One season up, one season down and basically can I be completely fooling myself that I’m tracking anything useful?
[Josh Fessel]: That’s exactly the right question to ask. So, as far as we know – at least in plasma levels – there’s no diurnal variation and that’s true actually of a lot of the different measures, not just isoprostanes. If you’re measuring anything in urine, in general, the best time to measure is the first morning urine. Not necessarily because you get diurnal variation, but what happens is you’re awake throughout the day. You tend to take in fluid and that’s going to tend to dilute your sample. But that’s true of almost literally anything you would measure in the urine.
[Damien Blenkinsopp]: Well that’s a great rule that you just gave use there.
[Josh Fessel]: Yeah. And then as far as seasonable variation – that’s a really interesting question. To the best of our ability to determine, no there isn’t any seasonal variation. I actually did a study when I was in graduate school to see if sun exposure had any impact because you’re delivering radiation to a large area of the body if you’re out in the sun and radiation is ionizing and creates free radicals and so I wanted to know was there any acute effective of sun exposure and the short answer is no there isn’t. So, for all those reasons, these tend to be pretty robust measurements and like I say, some measures are going to be a little more noisy than others, but in general these are things that – the one thing that would have an impact on the acute measurement of any index of oxidant injury would be if you had some sort of acute illness. So, if you had that flu for example. We know that people who are acutely ill have – and we’ve probably best studied oxidant injury in the setting of acute illness. We know that people who are acutely ill will have higher levels and the sicker you are the higher they’ll tend to be. So, if you were doing any kind tracking of any biomarker really over time, you’d want any individual measurement to be fairly representative of how you are on a day to day basis.
[Damien Blenkinsopp]: Absolutely. So I actually ran into this problem very early in my tracking. I was tracking high sensitivity of the C reactive protein. And the second time I ever tracked it – this is going back like 8 years or so – very early – and I actually had an injury to my coccyx by falling – I can’t remember – falling over something. Very painful, it was really horrible.
[Josh Fessel]: That sounds awful.
[Damien Blenkinsopp]: Yeah, yeah. It was because you can’t sit down. It’s very difficult. But anyway, I took my CRP and it was like much, much higher of course. I can’t remember the levels. I think it was 8 or something, which it was completely off the chart compared to what it was. I honestly had to look and it really wasn’t worth me spending my money on that CRP this time just to find that yes, you have a coccyx injury or any other injury, you kind of expect these kind of things. So very, very important point there.
So just wind of the isoprostane discussion. So we didn’t’ really talk about TBARS. The thing about TBARS and the MDA is when you look at, for instance, supplements and things like this, you often see that they talk about the TBARS as supporting evidence that it’s lowering lipid peroxidation. Do you feel like it’s reasonable to trust statements from backing supplements and stuff? Should we really be looking at the isoprostane levels? And can we trust – if we’re reading stuff on supplements and it seems that lowering lipid peroxidation, would you trust that or what issues would you see with trusting that TBARS method?
[Josh Fessel]: Yeah, that’s a great question. So, what I often tell my patients when they ask about supplements is remember the job of the person who printed that label is to sell you the supplement. So know that whether they’re making a claim about TBARS and MDA or isoprostanes or protein carbon meals – so know that. The question, I guess, is to dig in and find out what are the quality of the data that they’re sighting? And it seems like you’re speaking to a really engaged and educated audience here and so my advice would be dig into it and see do they site a study? And if so, go find the study and look at it. And if it doesn’t make sense, go talk to your physician or whoever – somebody that you know has some background to help you pick through it and say – because some of the studies that are out there that have looked at TBARS and malondialdehyde and all that – they’re fine studies. They’re well designed and you’re going to get relative quantifications that probably do tell you something. There are plenty of studies of isoprostanes out there that are not as well designed and probably not as informative as better design study of TBARS. So whether you trust the claim or not – I always go in with skepticism and my first question is okay well let me see if I can find the study they’re actually talking about. If I can, I’ll look at it and say okay this is actually pretty good or this has some problems. And then the other thing is independent of that, I’ll look for other investigations of the same thing. So maybe the study they site isn’t that good, but there are 10 other studies that have been better done and they actually seem to suggest yeah there’s something here or the conclusion is no, there’s really nothing here. So I say take each on a case by case basis, but get as much data as you can before you spend your hard earned money and educate yourself on the front end.
[Damien Blenkinsopp]: Great. Is there anything in particular which would, if you were reading a study and it had TBARS in it, is there anything in particular you would look at for that marker which you’d be like, “Ah that could be an issue.
[Josh Fessel]: Yeah. Sometimes it’s hard to pick out what can be the issues. If I’m reading a study – this happened once. I was reading a study that were analyzing samples that were 10 years old and that gave me pause because anything that sits around long enough, unless it’s stored under really rigorous conditions will show generation of malondialdehyde and isoprostanes and all the other products of oxidant injury or oxidative stress just by virtue of sitting around. So, when I saw that it was red flag to me that oh, I need to interpret this data cautiously. Are they making comparisons between groups and how comparable are those groups, really? Exactly as you eluded to? You’re controlling for the things that could influence that. Did they study? Was there intervention in a group who, on average, was 10 or 20 years younger than their control group? Well that’s a problem for reasons that we’ve already discussed. So, I look for things and these may sound goofy. Like of course they would control for that, but sometimes they don’t or can’t or won’t or didn’t or whatever and so you just look for things like that. That’s true not just for TBAR’s measurements, but for anything.
[Damien Blenkinsopp]: So there’s nothing specific that you highlight that you know is a weakness of the TBARS?
[Josh Fessel]: Not really. I’ll say that the one caveat I guess with TBARS, Is that the more complex the sample that they’re measuring, the more cautiously I’d interpret the data. So, for example, if it’s a study of TBARS in urine, urine is a biological sample. It’s pretty simple. It’s got salt and a little bit of protein and few other things and that’s about it. Plasma on the other hand, is really complex. It’s got proteins and lipids and a few cells. So if you were making measurements using the TBARS protocol in urine, I would tend to hang a little more validity on that than if you were in the plasma. I think it’s a dirtier biological matrix.
[Damien Blenkinsopp]: That’s interesting because I think most people assume that blood’s the ultimate measure. So, just of now, does an isoprostane – does urine correlate well with the blood sample levels? So, are they pretty much exactly the same?
[Josh Fessel]: They’ll tell you the same information. And the nice thing with isoprostanes is that – because we’ve had it come up before where people say, “Well how do you know they aren’t being made in the kidney and that’s really what you’re measuring?” That’s a fair question. So the one nice thing about isoprostanes is that we also have defined metabolites that are excreted in the urine. So the only way you can get that is if you formed the compound, released it in the blood, and then the enzymes that metabolize isoprostanes have a chance to work on it. So, you can measure urinary metabolites and they’re very stable compounds and say there’s no way this was generated in the kidney, this had to come from the total body pool. But in general, yes, they do correlate.
[Damien Blenkinsopp]: Great, great. Thank you very much. Okay, so I know that you’ve been starting to get involved in a project that’s going on. We have someone who wanted to change something in their life and so I brought that up and it’s very interesting case study to bring up on the program. So, it’s called Feeding Danny. Could you give us a quick background about it?
[Josh Fessel]: Sure. I’d be happy to. Thanks for asking about it. Yeah, so this is a project that started with my friend and my wife’s friend, Danny. Danny, like a lot of people has struggled with his weight over time and Danny is very overweight. In medical terms, you would say he’s morbidly obese. He carries a lot of extra weight. I’m guessing and I don’t know for sure – I’m guessing he weighs he weighs somewhere around 350-400 pounds. He’s a big dude and has health problems associated with his weight. He’s got joint problems, sleep apnea, asthma, all sorts of things. And so he has tried many different ways to get a handle on this and has had a lot of trouble and like I said, he’s clearly not alone in that. And so what came about is two friends of his approached him with the idea that they wanted to stage what you might describe as a dietary intervention. They said, “If you’ll allow us to do it, we will take over your diet for a year’s time and change everything about what you’re eating. We will make sure that the only thing going into this system are all natural, organic, pesticide-free, hormone-free foods and that by doing that we feel certain that you will, not only lose weight, but you’ll see improvements on any number of health related measures and act scenes.” And so when I heard about this I said I would love to help out if I can because I love my friend Danny and I want to help him, but beyond that I thought this was a really interesting concept on a single person as you say case study and that’s really what it is. Can you do this dramatic intervention and see a positive change. What I thought I could offer was to bring the medical perspective to things just in terms of overall fitness, but also bring the science perspective because I come from a slightly different place than the women that are doing this. Their names are Leilani and Vanessa. I tend to think about things in a very sort of pragmatic, low level kind of way. I think this will work because if you’re eating a diet like they’re describing – and it does include meat and that sort of thing as we discussed. This is not a strict vegan diet or anything like that. But I think if you’re eating a diet that’s high in fruits and vegetables and whole grains and lower in saturated fats and all that kind of stuff, you’re going to lose weight because your caloric intake is going to go down. I suspect what we’re going to learn is that as we go along they are thinking more along the lines of eliminating toxins from the diet and that sort of thing and I always halt a little at that because as I say, just as I don’t like the term oxidative stress because it’s nonspecific, I don’t like the idea of toxins because that’s nonspecific. What do you mean -What toxin, can I measure it, what are the levels, that kind of thing. And so, it doesn’t really matter who’s right as long as it works and so I’m excited to participate in this. What they’re proposing to do is to do this intervention for a year. They’ve uprooted their lives in Chicago and have moved to Nashville. They just got here about a week ago. What they want to do is do this for a year and document it on film and hopefully at the end of it have a true representation of what happens over the course of that year.
[Damien Blenkinsopp]: Alright. Those things are great – documentaries – because they can be inspiring for people, often more inspiring than this show when we’re talking about scientific data like this one for a lot of people. So, they’re really, really great, but it would also be like really cool if there were some controls in place to kind of understand a little bit like what really did happen. So, my understanding is that the intervention is basically a diet of organic foods, right. So they’re going to be buying specifically organic, certified organic produce and probably they’re going to basically eliminate all of the stuff in the middle of the supermarket. So you’ll walk around the edges and you’ll grab all the vegetables, fruits, meats and so on, but most of the stuff in packages isn’t going to be included in the diet.
[Josh Fessel]: That’s correct and ideally they’ll actually, in as many instances as possible, eliminate the supermarket and go to the farm where it’s being raised. And Nashville’s actually a good place to do that. There are a lot of certified organic farms and you can locally source just about everything. So this is kind of an ideal place to try what they’re proposing.
[Damien Blenkinsopp]: I guess somebody other kind of confounders in terms of diet because the diet world is so complex in terms of all the people have different opinions. Whether it’s grass-fed meat or its grain-fed meat, there’s a whole question of grains. In this case it seems like grains isn’t the issue. But like we were just talking before like it’s just important to define exactly what the diet intervention are in it – what limitations are and what the limitations aren’t to kind of get started. What kind of other things would you feel would be worthwhile controlling for? I understand the budget probably isn’t going to be really high, right, in terms of testing and things like that? But there’s probably some things they could track and it would probably maybe help the documentary or just be useful to kind of look at afterwards and be like yeah. So maybe we can say that toxins did play a role or – although I haven’t come across so far a kind of generic marker of toxins like you’re kind of alluding to. I’m not sure it is a generic toxin marker unless you want to say oxidant injury potentially. So what would be your thoughts on kind of if you wanted to get a baseline today before everything started and to see where things are at and then I know what kind of time scale would control certain things and at the end, in one year’s time, what would you like to control for if you could?
[Josh Fessel]: Yeah, that’s a great question and this is something that we’re in discussions about right now because, you’re exactly right, budget is going to be limiting and so there are some things that I think we’ll need to do just from a general sort of health monitoring standpoint. There are some things I’d like to do that we may or may not be able to do, but all of it is in service to trying to figure out did anything actually work. Where my thinking is, is that we’re going to need to look at some really standard, basic measures of health, particularly metabolic health, and this is real simple stuff like cholesterol, like hemoglobin A1C, blood sugar, triglyceride levels in the blood, if I had basic kidney and liver function, that kind of thing. If I had a complete wish list, I’d probably want to know about thyroid function and that kind of thing. And then to branch out from the traditional, clinical indices as far as biomarkers and thinking about what else I would want to know. I would actually be really interested to know what the circulating levels of isoprostanes were and compare that with circulating malondialdehyde or TBARS. I would love to know high sensitivity CRP. I would love to know what plasma levels of ascorbate and vitamin E and all the other small molecule antioxidants. I think that would all be fascinating and to see how those change with this fairly profound diet modification that’s going to happen. How much of that we’ll be able to do I don’t really know. Since some of those things make sense clinically, some of those things are more on the research side and this is an interesting case study, but in the strictest terms this is not a research study. So, we’re going to have to be a little judicious in how we go about these things. But nonetheless, I think what we’ll end up doing is certainly hitting all the things that we need to look at just from a basic health and safety standpoint and then I hope that there’s additional funds available to dig into some of these other things, not only to get a baseline, but hopefully to measure them periodically over time and see what did we really do.
[Damien Blenkinsopp]: Yeah. That’s great. And I think you’ve mentioned a lot of different things and I think especially for people to get the value out of the markers they’re tracking and given how most things are still pretty expensive today. Some of the things you mentioned I thought particularly kind of practical are blood sugar regulation. You mean just taking like the blood sugar reading.
Recently, had a conversation with Bob Troia on The Quantified Body. He was on the one of the recent podcasts and he tracked his blood sugar every day for a long time. It was interesting to see it went up and down all time based on what he’d been doing the night before and everything. so the problem that I realize is like sometimes when I’m having my blood panels, I’ll get my fasting blood sugar taken and I realized I’m kind of wasting my time because, unless I’ve been very careful about what I’m doing the night before, in terms of exercise and intake and everything. But on the other hand, there’s a pretty cheap method. It’s the Precision Extra pinprick blood sugar devices where you can take a couple of reading. It’s pretty cheap. Unfortunately you have to prick your finger and you have to think about okay is Danny going to want to prick his finger like once every day or maybe once a week or like whatever you’re trying to control for. Obviously, blood sugar regulation’s one thing that’s going to fit with the research that there’s definitely going to be some changes there. One of the things I was thinking of is cardiovascular risk. Is that something he’s worried about? Given the weight and everything, we worry about that a lot. There’s one other test out there that I’ve been meaning to get someone on the show for, for a while is the LDL particle number, which the research has been looking at more sharply because it correlates better. They are looking at some other things they are using CRP which is one you mentioned too. So, just kind of figuring some of the other things I thought would be interesting and of course like a weighing scale because in terms – like I think one of the great things about this project is that you could take pictures every day and obviously there’s going to be video footage, which is going to motivating for other people, but sometimes you can’t see it yourself as well when you’re measuring. But if you got a scale and you’re just jumping on it every day, that’s a very easy thing to keep you motivated to see that something is happening. We have to be aware of something that you said earlier in our conversation today. Which is that there were benefits being seen with caloric restriction before any of the pounds were coming off in your example, right. So we have to also be aware that although sometimes maybe the weight isn’t’ coming off, there are other improvements that are going on inside our bodies.
[Josh Fessel]: That’s absolutely true and that’s why I hope we’ll be able to quantify as many different parameters as possible as you say. In terms of a quantified body, a quantified life a bathroom scale is probably one of the most useful things you can have. But you’re exactly right in that let’s say that weight loss – let’s be pessimistic and say there isn’t as much weight loss as we there’s going to be, we might still have one real victory, but you’ve got to know what to look for. You got to be able to look for it. And so for exactly that reason I think the more carefully selected data we can have in this case – and this is true, not just in the case of Feeding Danny, but in a broader sense I think that’s useful. My clinical life is in part spent in the intensive care unit taking care of critically ill patients and that’s about as quantified as you can get on an acute basis and all of that information can be really helpful, not only as individual data points and not only as trends, but also as a gestalt of what’s going on with the person. And i think this maybe a similar conceptual exercise over a much longer time scale. So I’m hopeful that we’ll be financially able to look at all these things. But if nothing else, like you say, daily weights and looking at blood sugar over time and things like -one of the things that I hope we’ll be able to do – one of the sort of quantified self-measures that I haven’t personally gotten into, but that I think has a lot of potential utility for not much investment is looking at actigraphy things like the fitness trackers and whatever. But just getting a sense of over days/weeks, what is your activity level? What are you really doing? And patterns emerge that you would never observe as you say on a day to day basis.
[Damien Blenkinsopp]: That will be interesting for this project as well because like I’m sure as your weight goes down your activity naturally tends to rise.
[Josh Fessel]: That would be my hypothesis.
[Damien Blenkinsopp]: And then as a benefit that most people aren’t going to think of like straight away, but it would be great – just have a Fitbit – be wearing a Fitbit. We discussed on one of our last episodes about the whole market and basically the Fitbit tends to be one of the better trackers at the moment. Or another one as long as it’s giving you directional info, it would be really interesting just to see that. So I think these projects are great, like I said, for inspiring other people for change. So good luck with that. In terms of your own personal life, just always interested to find out what people are doing with themselves. Are there any biomarkers or personal data you track on any kind of routine basis or monitor just related to health, longevity or performance, anything about your body really?
[Josh Fessel]: Yeah. So, the bathroom scale is there. So I track my weight every day and I track that pretty closely. At times I’ve even charted it out, made graphs, that sort of thing. That’s been really informative. I’m a pretty careful calorie counter. I keep a really close count on a daily basis of the calories going in and –
[Damien Blenkinsopp]: Is that just by kind of eyeballing? Like that’s roughly 200 I’m consuming right there.
[Josh Fessel]: It’s about that. I mean I spend a lot of time reading labels and that kind of thing. I’ve had periods where I had the flexibility in my schedule to actually weigh foods and that sort of stuff and carefully measure out serving sizes and I love being able to do that. In terms of satisfying the practical demands of every day, it’s a lot of times by eye, but I’ve been doing it for a while and so actually have a pretty good database built up of “Oh okay I know that this is going to be this many calories and so on”. And I do that essentially on a daily basis.
[Damien Blenkinsopp]: Okay, great. So you kind of track roughly how much you consumed in a day of calories and you track your weight. Has anything interesting come out of that for you whether it be accountability? What kind of value have you got out of that?
[Josh Fessel]: Yeah, absolutely. Like so many people, I’ve struggled with my weight for a long time too and so at my heaviest I was probably about 230, 240 pounds.
[Damien Blenkinsopp]: Just out of interest, how are you now?
[Josh Fessel]: So now I weight between 145 – 150.
[Damien Blenkinsopp]: Okay. So like a big deal, a lot of difference.
[Josh Fessel]: Yeah. So I lost a lot of weight. Some of it was diet modification, some of it was activity, most of it was diet actually. But by being very careful about tracking calories and tracking daily weights and that sort of thing, I’ve been able to take that weight off and keep it off and that’s worked really well for me. It’s also made me very conscious about the dietary choices that I make. So, in general, I’m – lazy isn’t the right word – but I like to spend mental energy on particular things. And one of the things that I don’t love to spend a lot of time thinking about is what am I going to eat for any given meal? Or, if I’m hungry and I want a snack, I want to sort of check that box and get on with whatever it is I’m actually interested in doing. And so that coupled with being careful about calorie accounts has really had a great positive impact on my diet because the things that you can mindlessly eat without destroying your daily calorie count, tend to be pretty healthy things. So that’s worked really well for me and I’ve had some patients that that’s worked really well for. Others are much more exercise oriented and that’s the area that I’ve started more recently tracking my exercise over time with following either how many calories burned in any given workout session or I’m mostly doing treadmill and cardio aerobic kind of stuff.
[Damien Blenkinsopp]: So you’re using the machines or using your own device?
[Josh Fessel]: I use the machines typically. I haven’t yet invested in, like I say, an actigraph or a Fitbit or anything like that, which I think would be really interesting. But I’ve started tracking what kind of distance do I do and to motivate myself a little bit because I know that the piece that I am personally missing is regular physical activity. I think the data are really solid that that has health benefits beyond weight control and that sort of thing. So I’m trying to live by example as when I tell my patients to do this – and these are people – so I’m a pulmonary doctor by specialization. So the patients that I see all have lung disease. So here I am telling these people that have difficulty drawing breath to go exercise and it’s pretty hypocritical of me if I don’t make the effort myself.
[Damien Blenkinsopp]: Great, thank you for that. Okay, so last question. We’re talking about data on this show. So, do you have one recommendation? Like what’s the most important insight you have about using data in a way that’s going to be valuable to improve health, longevity, or performance? What would recommendation would it be?
[Josh Fessel]: If I were going to say anything about using data to guide performance, health status, anything, it would be to pay close attention to know what it is that the data are telling you or going to tell you before you get it and know what you’re going to do about it before you get it. This gets to the whole actionable thing. So, not all data are useful. If you don’t know what the data are really telling you, not useful. And if you know what they’re telling you, but you can’t do anything about it, not useful. And this is true in really any context I think. So before I would get a test results or order any kind of assay or whatever, I would want to know. And I do this in my research lab, I do this in my clinical practice. Before you order a test, before you run an experiment, have an idea of what it’s going to tell you and what you’re going to do with the likely or the potential outcomes. If it’s this, then I’ll do this. If it’s that then I’ll do this other thing. And if you can’t set that up on the front end, that’s not going to be a useful piece of data to you, so don’t waste your time or spend your money.
[Damien Blenkinsopp]: Great and we talk often about things being actionable, which is kind of like a jargon. It’s a bit of a jargon word, so I really liked the explanation you just gave, which was very clear and it was kind of like an exercise. It’s like before, plan what action you’re going to take once you find out the data is this, once you find out the data is that. And that’s a way of learning if it’s actionable – that it’s actually going to be valuable. But I think a lot of people don’t think about it. So I think that’s really a great piece of advice. It’s a great exercise before anything you’re going to think through that way. It will kind of force you to understand if it’s going to be of value to you in terms of taking action on it.
[Josh Fessel]: Well thank you. Yeah, that’s exactly right. That’s why I force myself to do it because if you don’t know – if you can’t make a plan, then it’s probably not actionable. And so maybe wait until you have other information or maybe discard it entirely and change the line of inquiry.
[Damien Blenkinsopp]: Well Josh, like final thing. Where can we reach you, get in contact? Are you on Twitter? Are you on a website? Where can people find you?
[Josh Fessel]: That’s a great question. No, I’m kind of a lead eye. I don’t even have a Facebook page, but I’m pretty findable. So, google search for Josh Fessel will find me. I’m on the faculty at Vanderbilt University. So, I’m that Josh Fessel. And I think there are a couple other people out there with the same name, but a google search and if you include Vanderbilt you’ll find me. That will link to my faculty page that talks about my particular background and my research interests and that sort of thing. And I think email addresses are there too. So, I can be reached any number of ways. I’ve spared the world my thoughts a 140 characters at a time. So, like I said, I’m a little behind the times there. But, yeah, I’m pretty findable online and that’s probably the best way to do it.
[Damien Blenkinsopp]: Great. Well Josh, thank you so much for your time today. I really appreciate it. It’s been a great discussion.
[Josh Fessel]: Oh, no. Damien, thank you. It’s a pleasure.