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Ever heard of immunoglobulins? While colostrum is experiencing a renaissance, you should seriously weigh the immunoglobulin supplement versus colostrum benefits.Partly because colostrum is a LOWER potency option, that sometimes isn't even standardized (depending on the brand) to guarantee how helpful it will be.That said, immunoglobulins (aka. IgGs) can be incredibly helpful for things like leaky gut (gut permeability), histamine intolerance, recovering from a stomach bug or food poisoning, and supporting your immune system during cold + flu season.Plus, I'm going to share why I prefer immunoglobulin supplements over colostrum, what the difference is between the two, and how to use them.Also, I want to how you how to avoid the fake, over-hyped colostrum + immunoglobulin supplements found online (even on Amazon)!Let's dive in!In This Episode:How I learned about the amazing benefits of immunoglobulin supplementWhy you should use immunoglobulinsDifference between immunoglobulins and colostrum benefitsHow do immunoglobulins work?Benefits of immunoglobulinsHow to take an immunoglobulin supplementBest immunoglobulin supplement + where to get itQuotes“[Immunoglobulins] were traditionally used and still are actually for more diarrhea-dominant problems. So if you've got a lot of loose soft stools, diarrhea, or even something like inflammatory bowel disease.”“IgGs can be found in the serum of your blood, and they also can be found in the serum of the blood of cows. And so historically, when people supplement with colostrum, that's derived from dairy, and it contains IgGs. So they are similar in that colostrum has IgGs and it's one of the major components that makes it so helpful, but it's not as potent.”LinksGET REAL, VERIFIED IMMUNOGLOBULINS HEREHealthy Skin Show ep. 188: Histamine Intolerance + Skin Rashes (PART 1)Healthy Skin Show ep. 192: Histamine Intolerance + Skin Rashes, PART 2

A video snippet of our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Shane Crotty: A Landmark Study on Upper Airway Mucosal ImmunityTranscriptThis is the first time a Ground Truths podcast is being posted simultaneous with a new publication, this one in Nature, by Professor Shane Crotty and his colleagues at La Jolla Institute for Immunology. Shane is one of the leading immunologists and virologists in the country; he and his group published in 2020 the first detailed analysis for how our immune system responds to SARS-CoV-2. Shane also, among many other notable contributions during COVID, illuminated the role of hybrid immunity vs COVID, the differences between and additivity of vaccination and infection.Today's paper in Nature is indeed a landmark contribution doing something that hasn't been done before—to understand the underpinnings of mucosal immunity of the upper airway. 100 participants had monthly nasal and nasopharyngeal swabs throughout the pandemic. With a median of >100,000 cells per swab recovered, they undertook single-cell sequencing and full characterization of the cells (tissue-resident memory B cells, CD4+ and CD8+ T cells, germinal center follicular helper T cells and B cells, etc.) to determine optimal immune protection of the upper airway, the effect of infections by different variants, breakthrough infections, vaccination, and age.Here is the transcript of our conversation about the new report with links to the audio:Eric Topol (00:06):Hello, it's Eric Topol with Ground Truths, and with me today is Professor Shane Crotty from the La Jolla Institute of Immunology (LJI), not too far away from where I work at Scripps. And Shane has been a go-to immunologist colleague here in the Mesa, and he and his colleagues were the ones that really first published the response to SARS-CoV-2 as far as the immunologic response. And today we're doing something very unique. We're going to go over for the first time in the two year plus history of Ground Truths, going to have a publication with at least simultaneous or near simultaneous podcast. Shane, welcome and congratulations on this really important paper in Nature.Shane Crotty (00:57):Thanks, Eric. Thanks for having me. Yeah, somebody asked if I was going to go over to Scripps for the podcast and I was like, yeah, we could.Eric Topol (01:06):You could. You could. But no, it's good. And it's nice having the logo of this great institute you work at right in the right corner. And you've done so many contributions with your colleagues at La Jolla Institute. It's really a privilege to have a chance to learn from you and particularly about what we're going to talk about today, which is mucosal immunity to upper airway infections, which is especially germane to COVID. And we're actually in the middle of a significant wave of COVID right now. And I guess it would maybe be fair to say, Shane, that we've never truly understood the underpinnings, the real details of upper airway mucosal immunity. Is that a fair statement?Shane Crotty (01:53):Yeah, it is a fair statement.Eric Topol (01:56):Okay. So today we're going to crack the case. This paper from you and your colleagues, of course, you're the senior author and first author, Sydney Ramirez did a remarkable study. I mean, just extraordinary. This is why we're doing a special podcast about it. Maybe you could just kind of give us the overview of the design because you were doing things that haven't been done before.Shane Crotty (02:24):Sure. And, I would say the genesis even of it goes back to what you were introducing. I mean, during the pandemic, we like a lot of scientists spent a lot of time and energy trying to help understanding immune responses to this virus, and immune memory to this virus, and what was involved in protective immunity. And we're certainly proud of the work that we did. And it was hard work. And after a while we were exhausted and we stopped.Shane Crotty (02:59):And then we came back to it after a while and said, well, the virus is still here. And so many people have contributed so much to better understanding the virus and creating vaccines. But there are clearly still things we don't understand. What are those biggest knowledge gaps and where might we be able to contribute? And really to me the biggest one was location, location, location. This is a virus that infects your nose, infects your upper airway—your nose, and throat, and oral cavity. And then obviously if you get severe disease, the severe disease and death are from the lungs. And it's just been a big knowledge gap in terms of understanding what actually occurs in those tissues immunologically and what is associated with protective immunity or what could be associated with protective immunity. And sort of looking forward what might be helpful for mucosal vaccine development from things that we could learn.Shane Crotty (04:12):So we started from what we would call the basics, and what does immune memory look like in the upper airways in normal people? And that hasn't been available really even in, and we started this two years ago, even in the biggest atlases published of the human body. There was no upper airway tissue representation at all. And that's because technically it's just tough to access and difficult to reproducibly get at. And so, we recruited people to a group of 20 to 30 people to come to LJI once a month, and just started testing out, published and unpublished sampling techniques to see were there ways where we could reproducibly sample immune cells in the upper airways from people. And once we got things, so the keys for us were you got to have enough cells that you can collect to learn something from. And luckily with modern techniques of flow cytometry and single cell sequencing, you don't need that many cells. And so, we could get a hundred thousand cells on a swab and that's enough to do a lot with. And second, how reproducible was it? So we showed, we had people come in every month for a year and we could reproducibly find the same things in their swab; same cell types in their swabs. And the third thing was that people would come back.Shane Crotty (06:05):We found that if you have good nurses doing the techniques, we could find ways that this would be a sampling approach that was tolerable and people would come back for repeat measures, which is really valuable to see what's happening in people over time. So that was what we started from in the study and built from.Eric Topol (06:27):And if I am correct, you sampled two places with the swabs, one in the nose and one of the throat. Or, I think one which you have in the paper as the MT for something about the median nasal turbinate and the other adenoid in the back of the throat. Is that right?Shane Crotty (06:50):So all the sampling is a swab into your nose. And when we were doing that, we were really excited to see the diversity of immune cells, particularly T cells and B cells, memory T cells and B cells that we isolated. They're like, wow, there's actually a lot of interesting immune memory up in there. And the lab said, oh, by the way, we're seeing T follicular helper cells (TFH). Now that happens to be my favorite cell type.Eric Topol (07:22):Why is that, Shane? Of all the cells, why do you say that's your favorite? I know you publish a lot on it.Shane Crotty (07:31):Because those are the T cells that are required for basically all neutralizing antibody responses. All high-quality antibody responses depend on—almost all high-quality antibody responses depend on—T cell help. That T cell help comes from T follicular helper cells. Antibody evolution is certainly one of the coolest processes of the immune system. And all of that depends on T follicular helper cells. So the fact that for example, you could get Omicron neutralizing antibodies even after only being vaccinated with ancestral vaccine, that's the immune system making guesses of what variants would look like. And those guesses come about through this antibody evolution that's driven by T follicular helper cells. So, it's really one of the most brilliant things the immune system does, and that's a cell type that's really key, but those processes happen in lymphoid tissue. That's what happens in lymph nodes and spleen. And here we were sampling epithelium, your nasal epithelium, so the cells didn't really belong there.Shane Crotty (08:37):And so, that's what turned the study in another direction. And we said, okay, let's figure out why is it that these cells are present in these swabs? And we had a couple of possibilities. One possibility was that the swab was going all the way back to the posterior wall of your nasopharynx, your top of your throat and sampling adenoid tissue. So adenoid tonsils and adenoids are a true lymphoid tissue and they're a mucosal lymphoid tissue. And so, we came up with multiple ways to validate that that's what we were testing. And in fact, it was the Sydney Ramirez, a clinician, and the ENTs involved who said, well, let's just look. And so, they actually did endoscopies with the swab to actually see where the swab went. We've got videos of the swabs going into the adenoid crypt in the back, and then we've got measurements of here are the cells that you find on those swabs.Shane Crotty (09:58):And what's cool about it is that, yes, so we did studies with two sets. We then shifted to doing studies with two sets of swabs. One where we essentially went “halfway back” where we were detecting that epithelium of your nasal passages and then one where it was all the way back and detecting the adenoid lymphoid tissue. So here we've got two different sites in your upper airways that are about an inch apart, and we're detecting essentially completely different cells of the immune system at those two places. And we tend to think of the cells present in that epithelial tissue as probably the sentinels, the cells that are sitting there that can potentially immediately react and try and protect you against a viral or bacterial infection. Whereas the lymphoid tissue, the adenoids, is really about generating the immune responses in the first place and priming immune responses. And that's where these germinal centers can occur, which are where the TFH are where you can get antibody evolution. And so, we found in the course of the study that with this non-invasive technique that we can.Eric Topol (11:14):By the way, I don't want to be signing up for the one way up there because I mean just a mid-nose enough for me. So wow, I got to give credit to your study participants for coming back every month for a year to have that. Some people call it a brain biopsy.Video of swab of nasopharyngeal tissueShane Crotty (11:33):Right. So I will tell you, it is a different experience than the COVID nasopharyngeal swab might've gotten through your car window. If you're actually sitting down in a comfortable space and there's a nurse doing it with these particular goals. We really found, we had a hundred people in the study and a total of 300 swabs, and the vast majority of people came back if we asked them to.Eric Topol (12:06):That's great.Shane Crotty (12:07):And we're certainly very thankful for the volunteers. Obviously they were volunteering in the first place to participate. So I'm a little hesitant about the video because I've told people to not show it to potential volunteers because it definitely doesn't encourage you to volunteer. You're like, wait, that's what's happening? But actually, I've had it done on me.Video of the swab to the nasopharynx for adenoid (lymphoid tissue) access.Eric Topol (12:37):Not that bad.Shane Crotty (12:39):It's really pretty compelling. And by doing these repeated samples, we actually now have the capacity to look at ongoing immune responses like after an infection or vaccination in people and see how that results in the immune system changing and what might be the source of the protective immunity that comes up. So we've actually got data in the paper looking at this antibody evolution in real time. So we've got affinity maturation of B cells occurring in just normal healthy adults of mucosal B cells against COVID. And so, that's really helping us learn what's possible, basically to figure out, okay, if you're going to try and make a vaccine, what types of immune cells are even possible to generate in this tissue? And where might you try and generate them? Or if you're trying to study some disease state, what are types of cells that might be problematic?Eric Topol (13:45):Yeah, I mean, I think the idea that so many of us have been pushing for a nasal vaccine to induce mucosal immunity because, as you know very well, the current shots are not very good at any durable or substantial protection from upper airway infections of COVID or SARS-CoV-2 and other infections. So I think one of the most important parts of this report is that it lends itself well to helping towards artificially, if you will, make a vaccine to get the protective features that you were able to identify. Maybe you could just [speculate], if you had the ideal nasal airway, what would the cellular profile look like?Shane Crotty (14:44):Ah, I see. Yeah, great question. So, first of all, antibodies are great. So most of my career has been dedicated to most licensed vaccines. The correlate of protection is antibodies. Antibodies clearly can be protective, and if you can get them that's excellent, so certainly I would want, in terms of the non-cellular component, I would want antibodies present, neutralizing antibodies present in it.Eric Topol (15:26):Are these IgA or IgG?Shane Crotty (15:31):Yeah, in an ideal situation, what would I want? I'd want a mix of both, basically. The IgAs look like they have a little more protective efficacy, but the IgGs, just at a molecular level have a longer half-life, stick around a little. So yeah, I'd want both. And then really the premise for most of what we do is saying, in situations where antibody isn't enough or the antibodies don't stay around long enough, or you've got a variant that now obviates the protective efficacy of that particular antibody, are there other types of protective immunity you can have? And the immune system has other stuff besides antibodies for a reason. Of the lymphocytes in your blood, most of them aren't antibody producing cells. Most of them are other things. And so, well sticking with adjacent to antibodies, those antibodies in the mucosa, I'd want them to be made by cells that were literally right there. So plasma cells living in that site so that you've got basically the highest concentration of antibodies you can get because they're not having to diffuse through the whole body. They're just already at their highest concentration right there. Now antibodies come from B cells, that's what encodes the antibodies.Shane Crotty (17:03):And so, the B cells can make neutralizing antibodies if it turns out that you haven't made enough neutralizing antibodies, or if there's a variant that escapes those, maybe there are other B cells that could make, once you get infected, more B cells that could make more antibody rapidly infection, or B cells that recognize this variant that is mismatched to the current antibodies you have. But memory B cells are basically a library of different antibody specificities representing different guesses about what viral variants or structures might look like. And so, I would want memory B cells in that upper airway tissue that could reactivate quickly. There are memory B cells in your blood and we don't know how long it takes. And that's one of the reasons we're hoping we and others build upon this study. But it might take, let's say five days for memory B cells to go from your blood into your upper airway.Eric Topol (18:06):Oh, right.Shane Crotty (18:08):That's right, you were already quite sick by that point. Instead, if memory B cells are right there, as soon as virus showed up, they got activated. Now maybe after (we're not sure yet), but maybe after 48 hours those cells are now activated and doing something useful. That would be optimal. So then we can pivot to the T cell side. So there's a fantastic recognition that T cells being physically present in tissues, tissue resident memory cells, as they're most often called, can really have fantastic protective capacities. From a lot of mouse model systems where you can see T cells are in the skin or the liver, or whatever [tissue] are already there, they're more protective than if the cells are in the blood. So if you could also have T cells essentially permanently parked in the epithelium of your nasal passages and in the adenoid, hopefully those could essentially be sentinels for protective immunity, and as soon as you get infected, those T cells would reactivate and start killing off infected cells. 'That's the mix that I would want to see. And I think there's at least some reasonable evidence in the context of COVID that people who have T cells in their upper airways maybe manage to control the virus so quickly that it's a subclinical infection; they never notice when they get infected. And so, building on those types of observations, that's what I would want.Eric Topol (19:56):That sounds good. I like that. I'd like to have that in my nasal airway. Now, just to make sure I've got this, what you found, of course, the memory B cells, the T cell memory, CD8+, that is the cell-killing T cells that you mentioned, the resident T cells. One clarification on that, they are not really going to do much until there's been some cells that have been infected with the virus, right? Then they come alive and kill those cells. So they're not immediate, but they can work pretty quickly still though, right? If they're resident T cells?Shane Crotty (20:45):Yeah, in theory it might take as little as 12 hours for a virus to infect a cell, and then you get some antigen presentation on that cell that could activate the T cell.Eric Topol (20:58):And that's all happening perhaps within the incubation phase of the virus, right?Shane Crotty (21:07):Correct. That's a tough thing to study, but conceptually that's the way people tend to sketch it out.Eric Topol (21:13):Right. Now the other part of the story is, and you alluded to it earlier, is the lymphoid tissue up there, higher up where there are these germinal centers; is there anything different you want in these germinal centers? Do they contribute to mucosal immunity that you haven't already mentioned?Shane Crotty (21:36):So they really contribute in this forward looking sense or really in the classroom kind of sense. The germinal centers are where you're basically teaching the B cells in advance of seeing the infection either with your vaccine or with your previous infection, evolving better B cells and better antibodies and hopefully instructing them where to go reside to then be ready for the next infection. If you get really great protection that next time, hopefully then you don't need to start.Eric Topol (22:14):Right. So it's like the training grounds for this coordinated response, I guess. Now you also noted this, I mean this is a rich paper, which is we're illuminating something that's never been done before in human beings. I mean it's pretty damn important and impressive. But you also found that you had an age relationship. Can you tell us about that?Shane Crotty (22:39):Sure. This is one of our favorite parts of the study. I'd say in particular for several of the clinicians who were involved, because the general conversations people have about upper airway lymphoid tissue, like your tonsils and including your adenoids, is that adults don't really have functional lymphoid tissue in the upper airway that your tonsils atrophy by the time maybe you're 20 or something. So, immunologically, functionally, what that means is if you have let's say an intranasal vaccine or you get infected with a new [virus] like SARS-CoV-2, if those would normally be the sites that start your immune response, where does it now happen? And instead what we saw was, we had such a diverse group of people in our studies—we realized we had people from age 18 to 68—and so we could directly ask, in normal healthy individuals across a large age span of adulthood is there functional mucosal lymphoid tissue? And the answer was yes, it was there. But it definitely declines over time, and it's declining on a log scale. Our simplest statement was that 75% of everybody we sampled still had functional tissue, but the younger the people were, the more functional it was, and the more germinal centers actually we saw; again these training grounds.Eric Topol (24:35):So this is really important because we know for COVID and obviously for influenza and other respiratory infections that people of advanced age are much more susceptible. And here you are finding something that supports that ,and it's almost like, the thymus, it involutes. After that, what age 20, and our lymphoid tissue [involutes]. We're just set up to fail. Old codgers, like me we're defenseless, I guess, right?Shane Crotty (25:12):So what I've liked about that in a positive sense is that it's not that all of these things go to zero. Like for example, naive T cells are definitely less abundant in people over the age of 60 than under, but they're not zero. And the mucosal lymphoid tissue is definitely less abundant in people over the age of 60, but in most people it still wasn't zero. And I always think about these things from a vaccine immunology perspective, and fundamentally the difference between getting vaccinated and infected frequently is that the whole point of the vaccine is you get to generate the immune response on your own time. And so, even if you're starting with five times fewer T cells or five times fewer germinal centers, if you're getting to do all that training ground in advance, you can end up with just as many bispecific T cells as a 20-year-old or just as many memory B cells as a 20-year-old because these things occur on an exponential scale because of the cell divisions. And so, it might take you three extra days, for example, to get to the same level, which again, if you're racing a virus, can be the difference between life and death. But if it's not a race and if you're doing it in the context of a vaccine, it's a much smaller factor. And that's some of what we've been trying to learn.Eric Topol (26:42):Now we only have started to scratch the surface of your findings. One of the things that drives me nutty in reading papers, especially from great immunologists like you, is that in each figure there's like 20 different panels. We get to one of the figures, figure three is all the way to panel W. I mean that starts with A. That gives you a little impression of the data. It's rich, another one goes to N or R. I mean we're talking about a lot of data. So I've only started to really deconvolute what you've done here, which is just an amazing study. But what are some other things that we should touch on before wrapping up?Shane Crotty (27:35):A lot of the goal in this study was to establish baselines of what is normal in humans in the upper airways. And that's one reason why in this case there actually are a lot of figure panels because we could work out a bunch of individual parts of the immune system that really hadn't been characterized in this way before. And something we really cared about was durability of immune memory. It's often talked about, well, mucosal responses are inherently short-lived. And we're like, well, what does that mean? Does that mean there's just no memory? Is it different kinds of memory? And so, this is the first measurement of memory B cells in this tissue in an antigen specific way. And we were doing it in people who had had recent COVID breakthrough infections. And we saw really the mucosal memory was stable for six months. And so, to me that's quite encouraging that it's not one month and it's gone, at least with an infection, it's at least six months and it looks like it'll project out for substantially longer.Shane Crotty (28:53):Amongst those cells, many of them are IgA. IgA is this antibody isotype that's particularly mucosal associated. And only 5% of the memory B cells circulating in blood were IgA. Whereas many of the memory B cells in the local tissue were IgA, which we think is also telling us that there's a lot of immune memory and the immune system in this tissue that we're probably not sampling in the blood. And so, sampling blood's great, right? It's accessible and we can learn a lot from it, but it does look like there is some tissue compartmentalization.Eric Topol (29:37):Oh, not a question. And the findings you had of the resident T cell is so indicative of that. And what's really striking, of course Shane, is that as we assess the immune system in people at large, we look at a lymphocyte neutrophil ratio [in the blood], we get almost nothing. And then in the course of the pandemic, you and your colleagues there provided such granular data on B and T cells, CD4 and CD8 T cells, and that you illuminated things that are not done ever clinically. These are research, high tier research labs like yours. The only question I have on before I just wrap up with the nasal vaccine story, interferon wasn't really part of this. As we know SARS-CoV-2 can shut down the interferon response, it's considered a frontline part of the defense. Where does that fit into the mucosal immunity of the upper airway?Shane Crotty (30:46):Yeah, it's really important. And that's in this basic divide we do in the immune system, the innate immune system and the adaptive immune system. So everything I was talking about is the B cells, the T cells, and antibodies. That's all the adaptive immune system. That's all virus specific. And then the innate immune system is the generalists, and really sort of the fire alarm, just sensing some danger. And definitely in COVID interferon is very important. I'm quite intrigued to see if using these techniques. I'm curious to see if some of these other aspects of the immune system can compensate somewhat for the fact that this virus. To me, if this virus has one superpower, it's its incredible ability to evade triggering interferon for as long as it does. And that has this massive cascading effect to almost everything about the pandemic essentially. And so, I'm intrigued by whether in people who have immunity are there ways that these other cells of the immune system or even antibodies can do things when a viral infection occurs, that helps trigger the overall immune system to recognize that something's there, even in the absence of type 1 interferons. That's where I think for now it fits in.Eric Topol (32:14):Well. I think you've so aptly described, not surprisingly, the superpower of SARS-CoV-2, which I think a lot of people haven't realized that it's so good at shutting down that defense system. Now on the basis of you having really gotten this understanding of the mucosal immunity in the upper airway, does this make you think that the nasal vaccine that we aspire to have is more of a reality? Do you kind of know what the ideal profile might look like to keep people healthy and resist infections? Do you think this is achievable in any durable sense at high level success with a nasal spray vaccine?Shane Crotty (33:04):I'm optimistic for several reasons. One is we really saw a lot of different immune memory cell types that were present, that was encouraging and seeing the B cell memory durability for at least six months—pretty flat line for that six months—was encouraging. It looks like the immune system knows how to keep these cells around if it wants to for a significant period of time. We'll have to do more in follow up. But again, it was encouraging. Third, we had some people who were vaccinated only and some people who had breakthrough infections. And really in the vaccinated only, we didn't see T cell memory in the upper airways. And I actually consider that encouraging because it suggests local exposure does give you the memory and exposure in your arm really doesn't. So I think there is something to improve upon. It can be improved upon. And lastly, I get asked all the time, I'm sure you get asked all the time: Why aren't there more intranasal vaccines or inhaled vaccines, more mucosal vaccines in some way?Shane Crotty (34:25):And I think there's more than one reason, but I tend to be very practical, and I think one practical reason is there's very little to measure, to guide you in your vaccine development. If you have six ideas or six constructs that you think might work in humans as a nasal vaccine, you basically just have to pick one, try something, and hoping there's not much you can measure it clinical trials for what might be the type of response even. So for example, the FluMist vaccine, it's the only licensed inhaled vaccine, intranasal vaccine. In adults it doesn't have a clear correlate of protection. If you get vaccinated with that, your circulating antibody responses don't increase, but also increases in nasal antibody didn't correlate with protection well. So, what does that mean? That probably means there's other things going on up there that could be indicative of protection but weren't being measured before. So I'm hopeful with these types of approaches. Now, if you're an intranasal vaccine developer, you maybe have 4, 5, 6, 7, 8 ideas or constructs. If you can try those in a few people and make these different measurements and you've got your favorite immune profile that you might, now you have something to, it's more of an engineering problem. It's not a throwing a dart problem. You're like, yeah, this has given me the type of response that I like and I'm going to try and push this into clinical trials. So those are the things that I'm optimistic about moving forward.Eric Topol (36:04):Well, I love it because we really need it. And if anybody's optimistic that means a lot; it's yours. What you've done here has been quite extraordinary because you defined for the first time really the underpinnings of the mucosal immune response, the upper airway, you did it by age, you did it by variant, you did it by vaccine and infection. And most importantly, perhaps for longer term is you established what are the desirable features to have, which didn't exist before. It seemed like whatever I read for nasal vaccines, they were measuring some IgA or IgG, and they didn't get down to the memory B cells and the tissue resident T cells, memory cells, and all these other things that you found. You did all this single cell sequencing and flow cytometry. The work is just really fantastic. So Shane, just in closing, I just want to congratulate you.Eric Topol (37:05):You made seminal findings along the pandemic. You were the one that really illuminated hybrid immunity, the advantage of if you don't want to have an infection of COVID, but if you did have that and a vaccine, you kind of had some extra synergy, if you will. But here you've done something, you and your team. Unique. Congratulations on that. No surprise that it's in Nature this week. I'm sure a lot of people will share your optimism that we will have something beyond just shots in the future because COVID isn't going away. There's other respiratory pathogens. And finally, somebody did the right study, who knows immunology inside and out. So Shane, thanks very much.Shane Crotty (37:52):Thanks Eric. Very much appreciated particularly coming from you.*****************************************Thanks for listening, reading or watching!The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informativeVoluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff for audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

Jackson's comments about the Miracle on Ice from yesterday on 101 ESPN. Blues win 4-0 last night. The Nonling's text to Tim this morning was full of good info. All love to the Nonling. First days in radio. Ken's cooking show. Picture talk. Recovering Alcholic joins the show to present a news story about Doug. It's quickly debunked. Martin Kilcoyne calls in to contribute to these allegations. Martin proceeds to roast us all. Cigs 4 Iggs. Thugs from Doug. Gimme Timmy. Shrewsbury Seminary Student joins the show. Press conference Friday. Where are they now? Learn more about your ad choices. Visit podcastchoices.com/adchoicesSee Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

Jackson's comments about the Miracle on Ice from yesterday on 101 ESPN. Blues win 4-0 last night. The Nonling's text to Tim this morning was full of good info. All love to the Nonling. First days in radio. Ken's cooking show. Picture talk. Recovering Alcholic joins the show to present a news story about Doug. It's quickly debunked. Martin Kilcoyne calls in to contribute to these allegations. Martin proceeds to roast us all. Cigs 4 Iggs. Thugs from Doug. Gimme Timmy. Shrewsbury Seminary Student joins the show. Press conference Friday. Where are they now? Learn more about your ad choices. Visit megaphone.fm/adchoices

Goyo Saavedra conversa con las abogadas María Isabel Carrascosa y Sara Larios, expertas en derecho comparado y derecho constitucional respectivamente, quienes junto con la abogada Lucky Aguilar presentaron ante la CC una inconstitucionalidad en contra del acuerdo no. 1124 del IGGS, en el que se establece que una mujer viuda podrá gozar podrá gozar de la pensión de su esposo luego de su fallecimiento, más no se establece la misma condición cuando es el esposo el que enviuda a menos que se haya demostrado incapacidad para ejercer el trabajo, lo cuál supone un requisito adicional que incurre en una violación al principio constitucional de igualdad ante la ley.

Christian conservatives are signing up in big numbers to support Premier Blaine Higgs in an internal battle within the PC party. ​CBC's Jacques Poitras took a look at who is doing the recruiting work on his behalf​.

Christian conservatives are signing up in big numbers to support Premier Blaine Higgs in an internal battle within the PC party. ​CBC's Jacques Poitras took a look at who is doing the recruiting work on his behalf​.

Christian conservatives are signing up in big numbers to support Premier Blaine Higgs in an internal battle within the PC party. ​CBC's Jacques Poitras took a look at who is doing the recruiting work on his behalf​.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.19.512755v1?rss=1 Authors: Sarkar, A., Khandelwal, S., Kim, H., Gruel, Y., Rollin, J., Wool, G. D., Arepally, G. M., Cines, D. B., Rauova, L., Poncz, M. Abstract: Heparin-induced thrombocytopenia (HIT) is characterized by mild thrombocytopenia associated with a highly prothrombotic state due to the development of pathogenic antibodies that recognize human (h) platelet factor 4 (PF4) complexed with various polyanions. While non-heparin anticoagulants and intravenous immunoglobulin (IVIG) are the mainstay of care, bleeding may develop, and risk of new thromboembolic events remain. We had described a mouse IgG{kappa}2b antibody KKO that mimics the sentinel features of pathogenic HIT antibodies, including binding to the same neoepitope on hPF4:polyanion complexes. KKO, like HIT IgGs, activate platelets through Fc{gamma}RIIA and induces complement activation. We now asked whether Fc-modified KKO can be used as a novel therapeutic to prevent or treat HIT. Using the endoglycosidase EndoS, we created deglycosylated KKO (DGKKO). DGKKO bound to PF4-polyanion complexes, and blocked Fc{gamma}RIIA-dependent activation of PF4 treated platelets by KKO, 5B9 (another HIT-like monoclonal antibody), and isolated IgGs from HIT patients. DGKKO also decreased complement activation and deposition of C3c on platelets. Injection of DGKKO into ''HIT mice'' lacking mouse PF4, but transgenic for hPF4 and Fc{gamma}RIIA, prevented and reversed thrombocytopenia when injected before or after KKO, 5B9 or HIT IgG, respectively, in a microfluidic system. DGKKO reversed antibody-induced thrombus growth in HIT mice. In contrast, DGKKO was ineffective in preventing thrombosis by IgG from a patient with the HIT-related disorder, vaccine-induced immune thrombotic thrombocytopenia. Thus, DGKKO may represent a new class of therapeutics for targeted treatment of patients with HIT. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Essas operações ficarão a cargo de instituições gestoras de garantias (IGGs), que são pessoas jurídicas de direito privado cujo funcionamento dependerá de autorização do Banco Central a partir de critérios definidos pelo Comitê Monetário Nacional.

When I interview Dr. Sherri Tenpenny last year, it was the first time I'd ever heard an in-depth description of Covid vaccine "shedding." That was back in May when the big push to get every man, woman, and child on earth jabbed was just getting ramped up. We were censored heavily at the time; the powers-that-be DEFINITELY did not want people concerned that those who have been jabbed might be spreading their manufactured spike proteins to the people around them.Here's an excerpt from the transcript of my interview that is eye-opening:"Well with these shots, we are not injecting a live virus, a whole virus. We're not even injecting a part of a virus. We are injecting laboratory generated messenger RNA in the the Pfizer and in the Moderna shot, and in the J&J and the AstraZeneca shot, we're injecting an adenovirus, a common cold adenovirus that's had its core shelled out, I mean, its genetic material taken out, and a piece of DNA, double stranded DNA, they call it trans gene, that has been put inside of that shell."That whole conglomerate is then injected into your body and released. The DNA is released into the cytoplasm. It makes a messenger RNA, which then makes a spike protein and that double stranded DNA, your body can make antibodies against it, which are associated with a long list of autoimmune diseases, or that double strand of DNA can get incorporated into your own genetic material."There's nothing in my language I just said in the last minute there about a virus. So it's not really shedding. But we do know something is being transmitted because we have well, the last time I looked there are over 11000 reports of women, this last time meaning a couple of days ago, there were over 11000 reports of women who had not received one of these shots or injections, but had been around people who had that weren't even necessarily close personal contacts like a spouse or an adult child or something like that."This might be just people they work with in their place of business. Like we've had reports from hairdressers that were not injected, that were around their customers that had been injected. And these women are having horrific bleeding diatheses. Some women who are postmenopausal start to bleed. They haven't bled… they're in their 70s, they've never bled before. Some women in their 30s and 40s, that their periods every month have been like clockwork, absolutely rhythmical."They're starting to bleed and they've bled so much, they've lost two thirds of their blood volume. There are younger women who are getting clots inside of their uterus that they're clotting so hard and becoming calcified that as they passed this clot, it's like passing like a miscarriage and it tears off the uterine lining on the inside."We've had reports of 22 month old girls passing clots the size of eggs. This one report that we had was a little girl, was twenty two months old, who had spent the weekend with her grandparents, both of whom had been injected. Now, I know that there is more of a bleeding diathesis problem that's been associated with the J&J shot in the AstraZeneca shot."I mean, AstraZeneca was pulled off the market in, I think, 18 or 19 countries. And how did they rerelease it to those countries? It wasn't because they did any more research or scientists came forward and said there's nothing to be concerned about. AstraZeneca issued a press release and said this is a rare condition and it's more important to get the shot so that you don't get Covid. And all the countries went OK, and they started using it again, and so… but we  also know that those bleeding tendencies of whatever is being transmitted, we don't really know."I personally, this is my own personal opinion, believe it's the spike protein. I believe that there's billions of spike proteins and it's a protein that then can last longer. And some people have said they think it's the messenger RNA. Messenger RNA is pretty unstable. And so I don't think it would last very long. But if you were having close personal contact with people like a spouse and you were hugging or kissing or having sex with with someone or or like with the grandchild and probably sitting in Grandma or Grandpa's lap, something is being transmitted that is causing horrible problems and not just bleeding problems."As I noted, we were called crazy conspiracy theorists for insinuating that these experimental drugs might be shedding onto those who had no taken them. Now a news study all but confirms that we were right all along. The sad part is that they're positioning this as a positive thing because now parents can, in part, help to "vaccinate" their children just by being around them. You can't make this stuff up.I discussed this on the latest episode of End Medical Tyranny. In it, I read parts of an article (below) by Igor Chudov who talks about the study and its implications.Before I get into Igor's article, I want to note that Dr. Vladimir Zelenko has a new nutraceutical protocol called Z-DTox. While he cannot explicitly say that he designed it to help those who have either been jabbed or who may be experiencing shedding from those around them, that's exactly what the intention of these pills really are. I'm no doctor. I can only go by what I'm told by actual medical experts.Here's the article by Igor...Vaccine Shedding Finally Proven!Statistically Significant Vaccine Shedding from Parents to ChildrenDo vaccinated people shed their vaccine byproducts to us? We definitely, for sure, knew that vaccine shedding was not a thing, because "health experts and fact checkers" told us so. And we "believe science" and our "health experts". Right?Except that it is WRONG and vaccine shedding has just been proven by science!Even I believed that there was no plausible mechanism for vaccine shedding. I thought that it was a baseless conspiracy theory. Stupid me. It turned out that I WAS WRONG and vaccine shedding is real and can be measured.A study "Evidence for Aerosol Transfer of SARS-CoV2-specific Humoral Immunity" was just released.Evaluation of samples in this fashion revealed that high intranasal IgG in vaccinated parents was significantly associated (p-value = 0.01) with a 0.38 increase in the log transformed intranasal IgG gMFIs within a child from the same household (Fig 1F).Let me try to explain it. First, these scientists from the University of Colorado looked at face masks, worn by vaccinated health care workers. They found that those workers shed antibodies generated by vaccination, and some antibodies got trapped in the masks and could be detected. This means that vaccinated people are literally "shedding" vaccine-caused antibodies.Interested in that, scientists looked further: they compared unvaccinated children living with unvaccinated parents, to similarly unvaccinated children, but living with vaccinated parents.It turned out that vaxxed parents actively shed vaccine-produced particles onto their children so that the kids acquired "humoral immunity" following shedding from their parents! Not only was this finding evident in the data, it actually was STRONGLY statistically significant with p-value of 0.01! This means that this was not a chance finding.It remains to be explained WHY children have intranasal IgG. The authors seem to think that it is because of antibody shedding via droplets. In other words, they seem to propose that what is transferred is IgG itself in saliva droplets. They may be right. That said, there is a possibility that children DEVELOP intranasal IgG because other vaccine byproducts or exosomes are being shed.It could even be due to lipid mRNA nanoparticles themselves shed and being transferred via saliva, like a virus. In fact, considering two replies to this article that I quoted at the bottom, mRNA lipid nanoparticle shedding is most likely. Why? Because the responders report experiencing STRONG IMMUNE REACTIONS.Such byproducts would be CAUSING intranasal IgG in children as an immune reaction in children, rather than those IgGs being essentially mechanically spat from parents onto their children.The article, while very interesting, is only the first step in researching vaccine shedding and I hope that further light will be shed (pun intended) on this phenomenon!The authors, possibly in hopes of getting their article approved by science censors, call it a good thing:Our results suggest that aerosol transmission of antibodies may also contribute to host protection and represent an entirely unrecognized mechanism by which passive immune protection may be communicated. Whether antibody transfer mediates host protection will be a function of exposure, but it seems reasonable to suggest, all things being equal, that any amount of antibody transfer would prove useful to the recipient host.I am not sure if I can call it a good thing myself. Antibodies or mRNA nanoparticles from vaccines NOT approved by the FDA for children are being shed from parents to children, without consent or knowledge of either parents, or children. All of this is followed by denials by authorities.Do you think that it is a good thing?Please share this article widely!(Get your Don't Shed on Me shirts from my buddy, Jeff Dornik) This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit endmedicaltyranny.substack.com

Cardinals lose, but let's get to the important stuff. Pepper & Geenie debuted yesterday to rave reviews. Gold star to both Iggs and the PlowKing. The open is world class. Iggy's story with Chase Richards makes an appearance on the show. Gay thoughts. Bots on Facebook. Elon. Plowsy proposes his OnlyFans account to management yesterday. It was approved. What is going to be the content? Food porn. This is going to be hot. FPCC preview. Cletus and Callahan. Wines. Lensmen. Larry Nickel joins us for the WWE Recap.

Pepper & Geenie coming Monday! Let's go!! YouTube recaps of games. Cardinal game on Apple TV tonight. DraftKings Cal calls in to complain about the audio and Iggy's disdain for the Grint. Doug boots Cal off the station. Steve in Wildwood buys a SoundStory for Iggy with Lern. Iggy's canned good gambit. Lern will be at Dotem. Bon Jovi last night. Iggy is going to Samantha Fish tonight. StrodeCast for today and for the weekend. Iggy gives an early StrodeCast look for next Sunday's FPCC. Huey Lewis and the News. Grint. YouTube chat doesn't enjoy Iggs. Masturbatory stats. Iggy's clubs. Streaming sports and the issues involved with that.

Iggy warbles Samantha Fish. Mark Hannah joins the presentation. Is Mark going to go with Iggs to Samantha Fish concert? Iggy doesn't even have tickets. Shaq was late to NBA on TNT, and his cohorts gave him trouble. Larry Nickel interviewing Hulk Hogan and keeps badgering him about the George Forman grill. Clean Up on Aisle 4 Tour. Tervis Parish is banty about Grint and a number of topics. FPCC. Is Iggy lying about the Ritz-Carlton. EMOTD.

Iggy is not present at the beginning at the seggy. Winner of EMOTM gets Cardinals tickets. Riggs vs. Iggs. Iggy tweeted at Min Woo Lee. Coach Drink at speaker's circle. Lakers coaching vacancy. KayRod broadcast. Who would be good on a ‘ManningCast' style baseball broadcast? Yankees legacy. Golf shirt update.

Hrabe in, hey Chris! Was Iggy wrong on the StrodeCast? Hrabe grills the Kenster. Where will the pin be at Normandie #5. Hrabe and Plowsy's first show together. Cardinal home opener. Iggs has a take. Plowsy is already muting Cardinals clichés. How many standing o's did the Cardinals? Iggy saying Albert didn't acknowledge the fans. The texters go after him. Cameo. Masters update. Hijack alert. Undershirts.

Iggy's smoking. Should we all get a hotel room tonight? TMA Hall of Fame. Iggy's fonzie shirt. Is Misty a first ballot guy? Big victory for the StrodeCast Mungenast DFS Showdown. Jackson does it on a random name generator. Hrabe calls in to give his lineup. Hrabe gives it to Iggs.

When is Cinco de Mayo. Iggy's commute. Mungenast DFS Showdown (checkout the lineups on twitter @TMASTL). Iggy defends his squad. G Mo in Orlando goes after Iggy for driving distance. G Mo calls in to go after Iggs. Will Tim qualify for the US Open? Chicken meat suit. Everglades. Iggy is about to go on a blocking spree. The breathing. NPR.

Men and women universally experience a decrease in sex hormones with age. Given this knowledge, researchers previously conducted a study to assess the correlation between aging, estrogen levels and the release of glycans (carbohydrate-based polymers) among all proteins in the body. Glycans are also important components of immunoglobulin G (IgG). IgGs are serum antibodies which provide immune protection against bodily infections and mediate systemic inflammation. Each IgG molecule usually includes about 3% glycans. However, changes in the composition of glycans attached to IgGs can significantly influence antibody activity. A decrease in galactosylation has been correlated with the onset of disease and aging. “The decrease in IgG galactosylation was first reported over 35 years ago in patients with rheumatoid arthritis and osteoarthritis [4].” The researchers found that estrogen regulates glycosylation. However, the data they analyzed did not differentiate IgG glycosylation from the other proteins. The Glycan Age Index (a combination of three IgG glycans that appear to be both biomarkers and effectors of aging) can be used to calculate glycan age. Glycan age is associated with lifestyle and disease-risk biomarkers, and could potentially be used to monitor healthy or unhealthy aging. “Here arises probably the most exciting aspect of the relationship between aging and IgG glycosylation: the potential of IgG glycans to distinguish between healthy and unhealthy aging, and to monitor the effect of introduced life-style changes on biological age.” To identify changes in IgG glycans, researchers—from Genos Glycoscience Research Laboratory, University of Colorado Anschutz Medical Campus, Eastern Colorado VA Geriatric Research, University of Zagreb, Brigham and Women's Hospital, and Boston Children's Hospital—reanalyzed samples from the previous intervention study using state-of-the-art glycoprofiling technology. The focus of this study was to evaluate the effects of estrogen suppression, followed by estradiol supplementation, on biological age measured by the glycan age. Their paper was published in Aging (Aging-US) Volume 12, Issue 19, in 2020, and entitled, “Effects of estradiol on biological age measured using the glycan age index”. Full blog - https://www.impactjournals.com/journals/blog/aging/can-hormone-therapy-improve-aging/ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.104060 DOI - https://doi.org/10.18632/aging.104060 Full text - https://www.aging-us.com/article/104060/text Correspondence to: Gordan Lauc email: glauc@pharma.hr Keywords: biological age, glycan age, estrogen, aging biomarkers, glycosylation About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at http://www.Aging-US.com​​ or connect with us on: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/agingus​ LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Aging-US is published by Impact Journals, LLC please visit http://www.ImpactJournals.com​​ or connect with @ImpactJrnls Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Certamente você conhece alguém que não quer se vacinar contra o coronavírus. Aqui seguem apenas alguns argumentos destas pessoas: As vacinas são experimentais; existem efeitos colaterais; a fase 3 da vacina se encerra em 2023 e somos os cobaias; vacinas são feitas de vírus ativos ou contem chips; a vacina foi desenvolvida muito rapidamente, por isso não é segura; as vacinas aumentam o número de mortos; a imunidade natural é melhor que a vacina; vacinados transmitem o vírus igual os não vacinados, etc. Neste penúltimo episódio da segunda temporada, nós esclarecemos cientificamente cada um destes pontos (e mais alguns). As vacinas são uma das maiores invenções da humanidade. Se você está escutando este episódio hoje, é devido a efetividade delas. Então, vacine-se e ciencie conosco! Algumas referências bibliográficas citadas no episódio: Mapping global trends in vaccine confidence and investigating barriers to vaccine uptake: a large-scale retrospective temporal modelling study https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31558-0/fulltext Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00648-4/fulltext Third doses of COVID-19 vaccines reduce infection and transmission of SARS-CoV-2 and could prevent future surges in some populations https://www.medrxiv.org/content/10.1101/2021.10.25.21265500v1 Viral dynamics of SARS-CoV-2 variants in vaccinated and unvaccinated individuals https://www.medrxiv.org/content/10.1101/2021.02.16.21251535v3 Lower probability and shorter duration of infections after Covid-19 vaccine correlate with anti-SARS-CoV-2 circulating IgGs https://www.medrxiv.org/content/10.1101/2021.09.24.21263978v2 https://agenciabrasil.ebc.com.br/saude/noticia/2021-09/anvisa-vacinas-em-uso-no-brasil-nao-sao-experimentais https://butantan.gov.br/covid/butantan-tira-duvida/tira-duvida-fato-fake http://www.iff.fiocruz.br/index.php/8-noticias/756-mitoseverdadescovid19 https://iqm.unicamp.br/movimento-antivacinas-uma-s%C3%A9ria-amea%C3%A7a-%C3%A0-sa%C3%BAde-global

DJ R DUB L & K Niggz – Intro K Niggz - Adrenochrome Skizza Feat. K Niggz, Pimpton & Infa-Red – Travolta (Prod by AK Productions) K Niggz – Mamma I Made It K Niggz & Mr Foxxx – Nightmares Youneak & K Niggz – One For Sask Savage feat. V.I.P & K Niggz – Day & Night Cain Iggs - Incircle Medusa & K Niggz – Money Circle K Niggz – Pancakes (Prod by AK Productions) Ace Feat. Dekoy & K Niggz – Opportunities K Niggz – Lord Knows Remix (Prod by SampsonOnDabeat) K Niggz – Sheep Clothez K Niggz & V.I.P – Music Is Everything DJ XL Feat. K Niggz, Gucci Brady & V.I.P – Pot Of Gold Freemo & K Niggz – Pictures K Niggz & Sask Savage – Money K Niggz, Creation, Gucci Brady & Sask Savage – Fucking Faded AMF Feat. Gucci brady & K niggz – Losing My Mind K Niggz – Product K Niggz – Spirts (R DUB L Remix) Produced by FilthyRich K Niggz – Bust It Down Desmond Ali & K Niggz – Blood Money K Niggz – Broke Gucci brady & K Niggz – New World Amaz3n & K Niggz - #6 Murda More K Niggz – Who Do You Know K Niggz – Family First K Niggz – Go Away K Niggz – Afterschool (Prod by AK Productions) K Niggz – The Re-Up K Niggz & creation – Everybody K Niggz – On My Mind K Niggz – drive (Prod by AK Productions) Lil Coke Feat. K Niggz & Creation – In My Pocket K Niggz & Filth The Enabler – My People AMF – Wet Suit

This episode is also available as a blog post: https://garycgibson.wordpress.com/2021/02/13/bouncing-about-that-iggs-field-scale-poem/ --- Support this podcast: https://anchor.fm/garrison-clifford-gibson/support

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.18.302950v1?rss=1 Authors: Hentrich, C., Kellmann, S.-J., Putyrski, M., Cavada, M., Hanuschka, H., Knappik, A., Ylera, F. Abstract: Antibodies are essential tools in research and diagnostics. While antibody fragments can be rapidly produced in Escherichia coli, full-length antibodies with an Fc region or antibodies modified with probes are time and labor intensive in production. SpyTag/SpyCatcher protein ligation technology could covalently attach such functionalities to antibody fragments equipped with a SpyTag. However, we found that the necessarily periplasmic expression of such antibody fragments in E. coli led to rapid cleavage of the SpyTag by proteases. Here we show how this cleavage can be prevented, making the SpyTag technology accessible for E. coli produced antibodies. We demonstrate a modular toolbox for rapid creation of synthetic IgGs, oligomerized antibodies, and antibodies with different tags or enzymatic functionalities and measure their performance in a variety of immunoassays. Furthermore, we demonstrate surface immobilization, high-throughput screening of antibody libraries, and rapid prototyping of antibodies based on modular antibody assembly. Copy rights belong to original authors. Visit the link for more info

Brad Miller is the best player of all time. Heine Meine. Tim will be in the Hampton's the rest of the week. Big upgrade following a weekend in Marlborough. Tim is playing with listeners at The Lemmings Open. Apple picking. Back to school. Unboxing today at noon. Breakfast cuck. Kris Cheddar met up with Iggs at Mulligans. Pearl Sinn. Hottest Fan Pin member? Somebody is knocking on the door. Clayton calls in with some numbers regarding Cards uniforms. Mizzou gets a 6PM kick for Alabama.

Iggy warbles to Kenny Loggins. Iggs doesn't pay for golf balls. Drew calls in to hype Nomad. Mount Rushmore of burgers. Mount Rushmore of sandy shops. Doug hates Labor Day. LOTO hoosiers. Springer radio. Graham Bensinger. Biff has a cuckholding story. Biff calls in. EMOTD.  

Brad Miller is the best player of all time. Heine Meine. Tim will be in the Hampton's the rest of the week. Big upgrade following a weekend in Marlborough. Tim is playing with listeners at The Lemmings Open. Apple picking. Back to school. Unboxing today at noon. Breakfast cuck. Kris Cheddar met up with Iggs at Mulligans. Pearl Sinn. Hottest Fan Pin member? Somebody is knocking on the door. Clayton calls in with some numbers regarding Cards uniforms. Mizzou gets a 6PM kick for Alabama.

Iggy warbles to Kenny Loggins. Iggs doesn't pay for golf balls. Drew calls in to hype Nomad. Mount Rushmore of burgers. Mount Rushmore of sandy shops. Doug hates Labor Day. LOTO hoosiers. Springer radio. Graham Bensinger. Biff has a cuckholding story. Biff calls in. EMOTD.  

Iggy's putt on 18 Satty. Iggy and Tim played golf with that fraud Chris Hrabe. Berube's post game comments. Tank and Steener were "unfit to play." If we can just get hot, we can win this baby. Biff's gentlemen's club update on Biff & Show. Gabbie and LaSerina69 had a new scene drop. Iggy drops an s-bomb in regards to Prod Joe. Gabbie's cans. Shelby Gash's feet. Tim talks Blake Lively. Top ladies from Boomerang. Tough hour for Iggs. Has Gaga had work done? 

Iggy's putt on 18 Satty. Iggy and Tim played golf with that fraud Chris Hrabe. Berube's post game comments. Tank and Steener were "unfit to play." If we can just get hot, we can win this baby. Biff's gentlemen's club update on Biff & Show. Gabbie and LaSerina69 had a new scene drop. Iggy drops an s-bomb in regards to Prod Joe. Gabbie's cans. Shelby Gash's feet. Tim talks Blake Lively. Top ladies from Boomerang. Tough hour for Iggs. Has Gaga had work done? 

Draft Kings. FPCC preview. Iggy is the odds on favorite to take it down. Gateway Natty is pure af. That's enough! Anna pulled in a couple hundy to caddy for Iggs. Cletus will be on the bag today. Iggy's new chair. People are more bummed out than ever. Caller Adam quotes 2Pac. 

Draft Kings. FPCC preview. Iggy is the odds on favorite to take it down. Gateway Natty is pure af. That's enough! Anna pulled in a couple hundy to caddy for Iggs. Cletus will be on the bag today. Iggy's new chair. People are more bummed out than ever. Caller Adam quotes 2Pac. 

EP213 - Deloitte's Kasey Lobaugh Recessions and the Future of Retail Episode 213 is an interview with Kasey Lobaugh, Principal and Chief Retail Innovation Officer for Deloitte. This time we discuss a report Deloitte published last year "Boom, gloom, or doom? What the next recession might mean for consumer companies" which is suddenly very relevant to retailers facing the Covid-19 epidemic. Kasey also gives a sneak preview of new report exploring the history of predictions around "The Future of Retail". Look for announcement about that research on Kasey's twitter feed @klobaugh http://jasonandscot.com Join your hosts Jason "Retailgeek" Goldberg, Chief Commerce Strategy Officer at Publicis, and Scot Wingo, CEO of GetSpiffy and Co-Founder of ChannelAdvisor as they discuss the latest news and trends in the world of e-commerce and digital shopper marketing. Transcript Jason: [0:24] Welcome to the Jason and Scot show this is episode 213 being recorded on Thursday March 19th 2020 I’m your host Jason retailgeek Goldberg and as usual I’m here with your co-host Scot Wingo. Scot: [0:38] Hey Jason and welcome back Jason Scott show listeners Jason one of our most popular annual Traditions now second only to our annual predictions is when we have our friend Casey lobaugh on from Deloitte and he is systemically been able to share with us some really cool insights what’s going on with retail and consumer Behavior. Personal favorite and I talk about this all the time in my pitches is the bifurcation difference between the convenience working to consumer in the valuing consumer so that’s all Chestnut for me so I’m really excited to have Casey back on the show. Tonight’s an extra special Casey appearance first of all he canceled his fancy Australian vacation to be on the show so we appreciate them doing that and then second of all he was set to reveal some pretty interesting to research around the shop talk conference but that was moved due to this pandemic thing that we’re dealing with so we twisted his arm and got Casey to to agree to reveal This research on our show tonight so we’re really excited welcome back Casey. Kasey: [1:44] Thank you I’m thrilled to be here. Scot: [1:46] Yep and you you have a very interesting title so let me get to see if I can nail this Casey is Chief retail Innovation officer and a principal for the retail and consumer products practice at Deloitte and you know that’s pretty worthy title and it makes soup Jason super jealous because he’s tried to jam as many words in there and I think he’s only got a quarter of what you have. Kasey: [2:08] That’s that’s the correct title this week who knows what it’ll be next week. Jason: [2:13] Yeah and for the record of all the things I’m jealous of about you Casey that your title isn’t even in the top 10. Kasey: [2:20] Well thank you I’m plenty plenty jealous of you for all the things that you do as well. Jason: [2:28] That I don’t know what those could be but I’m I’m I appreciate the praise know and accept the praise nonetheless. Scot: [2:35] I’m starting to feel like the awkward third wheel over here I’ll I’ll go on mute while you guys do whatever it is you do. Jason: [2:42] No but. Kasey: [2:44] Jason Jason III really really think highly of you and Scott you’re here as well. Jason: [2:53] Kasey I share Scott’s enthusiasm about having you on the show because I desperately need Scott to get a new Chestnut so I feel like. He’s reading your last Chestnut for like several years and we got to get him some new material I was hoping he wouldn’t bring up our annual prediction show though because spoiler alert later in the show you’re going to totally debunked. Kasey: [3:17] Right right we’re going to talk about some of the research we’ve done. Jason: [3:20] Yeah but that being said I know you’ve been on the show a number of time so our most loyal listeners are pretty familiar with your background by now but as you may know we have a massive new audience that’s growing all the time so can you kind of give us the highlights of your career and. What all those words in your title mean at Deloitte. Kasey: [3:43] Oh I’m happy to do that so and I I think I’m losing count now but I’ve been with Deloitte in our retail practice now I think it’s going on 20 23 or 24 years and in that capacity really during that time I’ve I’ve served the vast majority of the world’s largest retailers. Mostly you know helping those retailers sort of grapple with with whatever was on the horizon so you know early on in my career I was helping retailers with you know moving online so I did a lot of work with just the the.com portion of retailers you know early on when I did a lot of work around you know omni-channel and how the channels come together how we need to think about inventory differently and and these days are really thinking a lot about where retail goes next how do we pay attention to the signs and how do we read those signs and how do we help our clients sort of navigate through that so that’s really the quick flyby of my career with Deloitte. Scot: [4:46] Cool so we covered the pandemic last week so don’t want to go back into that and frankly it with a good our job is to distract people from from all this stuff going on but you know one thing I think we all agree is that this kind of crisis has created dramatically increased the recession that will fasts will face the recession here part of the research you guys have out there one segment is this is kind of I guess pretty good prediction you had said that there’s probably a recession on the horizon and then you guys were talking about what that could mean for Consumer Behavior retailers consumer product goods let’s dive into that give us give us some highlights of that research. Kasey: [5:28] Yeah sure thing now first of all this this research at this point is probably about 8 months old and about 8 months 9 months ago you know of course if you’re around the industry long enough you’ve seen you know the economic cycle is about eight or nine months ago there were signs that started to say that the economy was starting to weaken and so we had gotten organized around that and done a piece that we call are you ready for the next Consumer recession. And the signs that we were seeing at the time where you know several first of all you know we know that the US has faced a recession every on average about 6.1 years and it has been nearly 10 years since the last recession so that in and of itself led us to believe that you know at some point we would be facing a downturn in the economy. But more importantly and probably more ominously the the yield curve actually not only flattened but then inverted. [6:23] And for you know those those of us that sort of follow economics and. You know think about those things the yield curve is really where you know short-term interest rates you know are inverted with with long-term interest rates and it’s it’s known as sort of the number one predictor a recession no it’s not it’s not completely foolproof I think they say it predicted nine of the last seven inversion of the yield curve predicted nine of the last seven economic downturns so we saw that occur you know roughly a year ago we also saw tightening monetary policy we saw Rising asset prices and really ultra low unemployment you know which which. [7:05] Can and did and was starting to result in in Rising wages and inflationary pressure though the inflationary pressure really hadn’t appeared to the extent that we thought it was going to but those are just the ominous clouds and and of course you know. One of the things I say about this is that this is like to use an analogy it’s like. California comes out and says look we don’t want you burning bonfires because. [7:31] It’s really windy and it’s really dry and conditions are ripe for for economic downturn and so really that the clouds that I’m talking about these ominous clouds were really those signs that said we’re not sure what the spark will be but we do know that the conditions really are starting to set themselves up for for this downturn and by the way you know any any spark that you’ve ever seen whether it was 9/11 or any other you know economic event that’s occurred you know often times you can look at that and say boy that was. You know how would you have predicted that that would have been the spark that really pushed us into you know into whatever economic position we get pushed into so you know we weren’t trying to predict what the spark was we were just saying the conditions were starting to get ripe and there’s a there’s a quote that are I work closely with Danny Bachmann who’s our delete US economic forecaster. [8:26] And he’s got a quote that I like he says I can predict with a hundred percent accuracy that the US economy will face another recession. And then in small print he would say I just can’t predict when so we kind of knew you know something was coming we knew that the potential is out there but of course we’re we weren’t even attempting to predict what that was so then we said okay if you know knowing that that’s the case let’s look at previous recessions specific to retail and consumer products and ask ourselves you know what can we learn from those. So we looked at the last two recessions the.com burst and then of course the Great Recession in 2008 and when you look at those recessions and you look at the, the the market impact the impact. And the recession themselves were different right the cause of.com burst was over Valley tech stocks and then the Great Recession was the housing market crash. If you looked at corporate profits you saw two very different recessions as well.com burst corporate profits dropped only by 0.2% and meanwhile during the Great Recession they drop by 13.5%. And the same on wages and salaries the impacts were very different as well the differences were in the labor market. So we don’t know exactly how the next recession will play itself out but when it happens. [9:49] It’ll likely have a significant impact on the consumer and the consumer companies that that’s what we we sort of highlighted so then we said okay well if those things are different. You know where there are things that were. Common where the things that we can actually pull away from those and and he’s actually become really important as we think about our situation today but we came up with three things that became very clear. Happened the first was the growth in digitally and e-commerce. Now of course we knew that e-commerce was growing but when you look at the numbers you look at it comparatively to brick-and-mortar we actually saw in both cases and acceleration. Of e-commerce During the period of economic downturn now overall like retail you know showed weakness but when you pulled it apart what you actually saw was acceleration of e-commerce. [10:42] In addition to that what we saw was. The rise of new competitive entrance now this is really interesting because you know something was happening at the same time you know barriers to entry were coming down because technology was changing but also Capital was becoming increasingly, cheap right as as the FED move to increase liquidity interest rates came down what we actually found was there as. It’s this combination of barriers to entry falling and and available cash was actually allowing new competitors to enter the market at increasing rates during and right after the economic downturn this included not only you know new small digital native startups but we also saw European retailers you know aggressively accelerating their growth in the u.s. marketplace we also saw consumer products accelerating their direct-to-consumer efforts so all those things together where this this new competitive entrance that that really, were fueled during the downturns. [11:43] And then finally and this is sort of relates to the bifurcation that you talked about Scott Lee saw the rise of discount players consumers really materially shifted to the discount players and they were experiencing average growth rates of about 6%, while the rest of the retail industry was declining about 5% in particular during the Great Recession and after the Great Recession discount maintain that growth rate. That they had you know obtained during the downturn so the consumer learned of a new Behavior consumer found a new channel of course that channel ended up with a flood of. You know of quality because the traditional retailers were really trying to liquidate product so it really sort of added to the to the mix so if you think about those things as we said here today you have to ask yourselves. You know how will those play themselves out you know we believe that we’ll see an acceleration of digital and e-commerce will we see. Discount and an off price you know accelerate as well. [12:48] In addition to this we see something happen with the consumer the consumer based fundamentally changed. Due to the uneven economic recovery it happened after the first downturn of the.com. Bubble bursting and also happened after the toothache 2008 recession if you looked at discretionary income changes during the.com cycle. And the Great Recession cycle they were very uneven so for example if talk about the Great Recession from 2007 2017 if you were in the low-income bracket you actually ended up, decreasing your discretionary income by three thousand dollars at the same time if you’re in the high income bracket up. $18,000 so it was real uneven recovery and a largely that came from that came from. [13:39] Well many facets but one facet was availability of capital so. Liquidity slated to the market if you had good credit ratings you could Access Capital at very low interest rates. The problem is at the same time that liquidity became available because the housing bubble you know led to the downturn we actually raised. The regulations and raised the criteria by which we would give people loans so if you were in the high enough income bracket you could easily secure a very low interest rate loan, the lowary off you were the less accessible that Capital was to you. [14:18] So coming out of all of that then what was interesting this is a this is something we highlighted this year ago was this idea that if you looked at the industry of retail there was something going on you know even a year ago that was really a little interesting and maybe a little disturbing and I was a substantial decrease in the return on assets. That the industry was was showing and if you go back over the last 20 years 30 years what you’d find is during times of, I’ve strength the industry would have growing increasing return on assets and only during economic downturns with the return on assets start to slip and go you know move in the opposite direction. The problem is for retailers starting in 2012 even though we were in strong Economic Times and we were coming out of a downturn we were in the recovery starting in 2012 we actually started to see a negative. Yeah yeah impact on returning that on assets we started seeing return on assets moving down all the way through 2017 as if the economy was actually not doing well in fact it was, and that sort of leads to the question of what happens to an industry that is operating in in a relatively healthy economy but they’re showing signs of weakness when it actually gets weak so I know that’s a lot of information about the research it was pretty fascinating and go through it and of course it’s more interesting to me now to look back on the research given where we’re at today. Does that make sense. Jason: [15:44] It totally makes sense and just to augment that one point you made like you talked about the acceleration of digital through these. These recessions that you track. That that’s even more surprising because you kind of looked at a couple specific recessions and one of them was the.com bubble right and so there you go, you know man did it people overvalue dot-coms did they also sort of overvalue the utility of dot-coms and so you might have expected. Digital shopping to decelerate when a.com bubble threw us into a recession and even there you saw digital grow. Kasey: [16:26] Yeah interesting that the way we looked at it was and on a relative basis because of course you saw you like right in 2008 we actually saw you know retail softens sort of overall but when you looked at it relatively speaking and said okay when someone is shopping retail you know which way are they shopping, so you have to look at it that way to understand the acceleration because the acceleration actually occurred during a period where it looks soft and it looked like the market was softening but when you looked at it relative to brick-and-mortar that’s where you really see the acceleration. Jason: [17:01] Yeah no that makes perfect sense so I read I got thank you for reminding me about that research I read it when you published it but then it was. Prescient to kind of re read it right now in my big takeaway is like that there’s demonstrable evidence that these recession events exacerbate bifurcation right both of businesses. It seems like there’s a chunk of businesses. The do better in the recession than other businesses that there’s a gap that opens up and also as you would have to recently. It exacerbates bifurcation of consumers and you talked about the Gap in real earnings but you’re in your report you also talked like. Literally life expectancy there’s a big gap between affluent consumers and non-employment consumers. Kasey: [17:52] Yeah the idea of economic bifurcation is so prevalent when you really start to use that as a lens and you’ll hear me talk about this on every one of our research reports because it just. Constantly comes back up is the whole Market wants to be fixated on age. You know as a driver of behaviors but over and over again what we find is it’s this it’s the economics and this economic bifurcation that dramatically is more important. To how consumers are behaving than ages so po what I say is people behave like their income. Not like their age and I’ve got so many data points so many different lenses that we’ve used to prove that time and time again. Jason: [18:36] Yeah Amen on that I feel like the age was actually never that, never correlated that well but it just that was the attribute we knew about our audiences right and so like that was the attribute that everyone used but so when I will get your research and I say hey, what can I business leader that’s contemplating like you know all the. Current events you know there’s there’s a very real chance that throws us into a recession or at least recession like economy what are some takeaways for how best to. Sort of be one of the winners in that bifurcation and I there a couple things that jumped out at me but like do you have sort of a top level 4. Wait what’s the general advice you give to someone about thinking about the kind of Investments they should make and the. The kind of financial moves they should be making like when they find themselves in a. Kasey: [19:35] Yeah well actually the advice is better about how to think about it before the recession think about it before you find yourself in in really difficult times. What we’re finding increasing as you can’t fall back on the old Playbook you know compressing vendors cutting sg&a reducing headcount feeling Back Store labor and just going promotional if you look back at who the winners and losers were coming out of both of the previous recessions what’d you find out was those are not the playbooks that that led to healthy successful outcome what we found was, for those retailers that increasingly really focused on why they matter and I know that’s an easy thing to say but but what you find is is that. I must say it’s like being. [20:23] Knowing what it is that your consumers really value about you and then being Unapologetic about investing into that so if you’re an off-price retailer you know know that and then invest into that, if you’re you know if your product is supreme the know that in invest into that and what we found is that during these times and you falling back on the old Playbook we. You know our retailers in the marketplace consumer products companies you know often times focus on the Playbook and they lose sight of that we also said build a war chest to invest in the growth cuz it’s during these times that those companies that found themselves you know investing into the structural change that’s happening during the downturn are the ones that are best positioned for what’s about to occur coming out now, if you find yourself in the recession and you haven’t invested into the war chest that allows you to invest into that growth you really find yourself in difficult position because you can begin to see the market. You know come back together get healthy and start to thrive again but you haven’t you you know you don’t have the resources that allow you to you know aggressively invest into that we also know that embracing technology automation to increase your leverage during the times of growth. [21:39] And then looking outside your four walls to embrace new Partnerships those are the things that really came out when we looked at who won and who approached you know the growth coming out of downturns. Differently as opposed to the old old Playbook I I love this quote that Benjamin Franklin. [21:57] Had we said by failing to prepare you are preparing to fail. And that’s why we wrote that’s why we did the research because you know eight months ago was the time when we were you know trying to get our clients that sort of recognize that the risk was increasing and that they really needed to you know begin to take it seriously and begin to prepare. Jason: [22:18] Yeah it is I think that’s fascinating in that I had an early Mentor who was a very very successful retailer Wayne huizenga and he used to constantly heart on this philosophy that. In economically good times that’s exactly when you should most be focusing on cost reduction and cost controls and in economic down times that’s exactly when you should be investing because your your. Capital actually works harder and gives you a higher return in those economically distressed times than it does when everybody is pretty flush. Kasey: [22:56] Yeah I think that’s that’s that’s easy to say it’s really hard yeah I always like to put my practical like as insulting it’s easy for me to say here’s what you need to do but I was trying to put my practical hat on and recognize how difficult that really is to do that said when you look at who the winners and losers were coming out of the previous recessions that’s exactly what they did. Jason: [23:17] Yeah I briefly tried to learn how to ride a jet ski once and counter-intuitively when you’re about to fall off the jet ski and it’s unstable the correct thing to do is give it more gas and go faster because that’s what makes you stable but it’s not what your brain wants to do. Kasey: [23:34] That’s a great analogy. Jason: [23:38] Well that is awesome one last question on sort of learnings from recessions do you have any point of view like. So you’ve got a consumer that go through a recession you know consumer confidence goes down you know eventually those recessions in. Do we tend to see consumers behaviors rebound and do they act exactly like they did before the rebound or do these recessions tend to have sort of a hangover effect on consumer Behavior even when the economy turns around. Kasey: [24:11] Yeah. Without a doubt our research research tells us that the consumer adopts new behaviors during the down times that they maintain coming up. So I I would expect a lot of the behaviors a lot of the things we see going on even today with people adopting new behaviors that that those are going. Accelerate those are going to become prominent and I don’t expect those to fully bounce back I I would expect some behaviors to you know to bounce back somewhat, however I think predominantly I’d say the people are learning new behaviors as they do they stick with those new behaviors. Scot: [24:51] Michael hopefully on-demand car washes one of those papers, all right well now that we have all that kind of Downer recession pandemic talk behind us let’s dig into the new research Casey what’s the high level of how you guys came up with this and what you’re revealing on the show tonight. Kasey: [25:10] Yeah sure thing you know here we are its 2020 and we are the number one request for getting from our clients is it tell us about the future. Of the industry tell us about the future of retail or we get you know the future of the store and of course that seems to be a topic that that that is hot with our clients but it’s also you know very well published out there so we looked at it and just said, okay you know how would we think about it how would we approach that topic and how do we do it in a different way than maybe you know has already been done and that’s really what what got us to dig into this this research that, you know that we call retail and consumer products 2020. Scot: [25:54] Cut it and you were kind enough to give us a little bit of a sneak preview of the research and I have to say I really enjoyed it and looking forward to when you publish the final version in there you kind of talk about seven Trends you know of what this retail 20/20 looks like I thought they were all really good so maybe give us a high level overview and then Jason and I want to tease apart a couple of. Kasey: [26:17] Yeah before I do that let me give you a little of the Segway that gets us to the seven trends. In in the research one of the things we did before we started our own research as went back and said, you know how good is the industry at this idea of predicting the future so we went back and spend time over the last 20 years of research is trying to assess. How good are we as an industry and there’s great you know Publications a lot of great you know commentary that’s out there but what you find when you summarize it all together is, we’re really not that good as an industry. Professing the future and then the question is well okay well if we’re not that good as an industry we haven’t been that good at it for 20 years what makes us think that you know that we had Deloitte and the way we’re going to research this is any different. [27:09] And it’s really the findings that relate to his kind of that backwards view that gets us to how to think about this problem differently and the way I like to call it is let’s move away from prophecy. And let’s actually get practical okay because what you’ll discover is most of the future of pieces are just. Prophetic there’s just people sort of imagining pie-in-the-sky with the future will be like and and the Saving Grace by the way generally is they never tell us when the future will be here so it’s potential that all those predictions they make will you know will be true at some point however the vast majority of the predictions that have been made over the last 20 years actually as we sit here today are not true. [27:50] Okay so if prophesizing doesn’t work then if I look back in history how would I have known, we’re we would have ended up as an industry and the interesting part is it’s actually there it’s actually there in the data if we’re actually paying attention to what’s going on in the data we can actually play out trends that lead us to where we’re at today so that’s the Segway and that’s sort of the the approach that we said okay so if we’re not going to prophesize about the future let’s go look at the data. And so we looked at our we’ve got a group with that we call our Center for Consumer insights that has phenomenal data, a lot of different sources of traffic and sales and consumer behaviors Etc and we said well what’s the data tell us about the future and that’s where through working with the center for Consumer insights we came up with the seven trends that we see that are broadly shaping the future of retail and consumer products, no by the way you got to recognize it retail and consumer products is a really broad industry said everything from apparel fashion luxury goods to grocery you know consumer products tables Etc so these are really Broad you know in their application but I’ll go through what those seven are that the data tell us the first one is commoditization and premium ization a [29:15] And I’ll talk a little bit more about what’s going on there but we also have digital success is growing even more elusive that’s the second Trend the third Trend pertains to physical retail. And the third trend is smaller and closer I’ll talk about the data that we’ve got there as well the next train is new models become material. And the interesting part here is not when I see new models things like rental things like resale you know in the apparel world or or, yo ghost kitchens in the restaurant industry those sorts of things are all new models, and in and of themselves are not that interesting in terms of size or scale but when you put all the new models together they actually start to become material in terms of how they’re eating into share. [30:07] The next train we identified was convenience. As the new Battleground so again I talked earlier about the idea in the industry that says everything’s experiential and we’d actually say convenience as an element of The Human Experience in particular is what’s driving the new Battleground the next train is health and sustainability for some. And we talked about that Jason the bifurcation is that when you dig into health and sustainability it actually is not a broadly applicable trend is actually really applicable the higher income you go the lower income you go you actually find reverse Trends in play. [30:46] And then the last point is it builds upon research we had done previously and it’s fragmentation and consolidation of market share we actually see some really interesting Divergence happening in terms of how market share is is consolidating where it once was fragmenting or fragmenting where it once was consolidating, so those are those are the big seven forces that we go deep on and use data to support how those are shaping the future. Jason: [31:13] That’s awesome and I let’s jump into a couple of those I do want to say I suspect you’re being slightly kind because you talked about this this ocean of retail prophecies and how you know most of them are just kind of. Prophecies are opinions and I suspect there is a huge chunk of those in fact I just did a Google search on future of retail and there’s. Seven million two hundred thousand results. Kasey: [31:41] And and I had a team that actually had. Through those 7 million two hundred results and we’ve got them all categorized and we’ve gone through them so we really stared at him and said you know what are they telling us and in our research paper we really go deep into it so that you can sort of see what the flaw is that that’s behind a lot of the approach to sort of thinking about the future. Jason: [32:03] Yeah and so to your team and they’re listening I’d like to apologize for the 500 of them that were me but I think there’s another big chunk of prophecies in there which are the self-serving ones right which is like the the. Computer speech vendor predicting the future of retail is computer speech. Kasey: [32:22] That’s right that’s right there there’s plenty of those in some of those are commissioned so they’re they’re commissioned by you know vendor you know I something that does research but when you dig into them you can go okay this makes sense you’ve commissioned this study. Jason: [32:38] Yeah so moving on from the the. The grand setting to the sort of seven trends that you guys notice that we’re sort of grounded in your, your consumer data set what the first one that jumped out to me is actually the first one on your list because it’s a topic I talk a lot about but that’s the commoditization and premium ization which I feel like I’ve said that before but I never thought it was an official word until I saw the what use. Kasey: [33:07] That’s right now you can use it officially yeah you know when you look at products in particular and you look at what’s going on you know you certainly see this again and you’ll hear me talk a lot about reduction in barriers to entry, that that consumers have access to technology that gives them visibility in a way you know that they didn’t previously have and then it also gives you know anybody selling a product they’ve got Avenues to you so you know if you’re buying a particular brand of something like mac and cheese you’ve literally got thousands of options to buy that very same product. And what happens when that occurs when you know we’ve got you know slowly you’ve got margins that are being eaten into as one after another tries to out price you know the other so we’ve got a lot of great research about how you know margins on products are being eaten away, and that’s the commoditization at the same time you have this explosion of choice, so you if you looked at a traditional grocery store and you looked at 1990 they’d have you know roughly 7,000 items would be available in a grocery store in 2018 it’s 35,000 items so just an explosion you know of options that the consumer has available to them. [34:24] At the same time we’ve seen this growth of private label in fact from 2015 to 2019 there’s been a considerable you know, growth with you know with retailers who are coming out with their own private label product growing from about a hundred and thirty billion to about a hundred and forty three billion over a period of about four years. [34:46] And at the same time that we’ve got private-label happening we’ve got a premium ization of private label so in 2016, of that private label product about 15% of those products or the dollar amount would have you know been categorized as a premium, private label product and go to 2019 and it’s grown to about eighteen percent so not only do we have private label which was once really a value play we’ve now got private label that’s now more of a premium play so really this opportunity for differentiation really becomes you know. The the critical component to think about in a world that’s both commoditizing and premium I guess I can’t say premium icing. Unless I just made up yet a new. Jason: [35:34] You can say it. Scot: [35:35] You did sure weird. Kasey: [35:37] Thank you Jason said Jason says I could. Scot: [35:39] #premium izing well well I kind of out of those seven I wanted to dig in on convenience as the new Battleground so tell us more about what you guys saw there as you looked at the data. Kasey: [35:55] Well first of all when we when we talk to Consumers and you find out why they shop where they shop what we find is the convenience is the number one reason a consumer selects a particular retailer so you have to start there and by the way there’s nothing you know I knew about that that’s not a new age consumer sort of thing in fact we as we studied this what matters most idea you know over the last 10 years we found that convenience, continually comes in first as the most important thing so you start their second of all then we said okay well let’s go look at where the growth is in the industry. And what we did is we took you know a look at categories where convenience or particular retailers where convenience is a major or a primary element of the value proposition and when you categorize that way we find about 67 percent of retail growth from 2016 to 2019 comes from retailers that that prioritize convenience as part of their value proposition in addition that you can certainly see a lot of the growth that’s happening let’s say with mass retailers their initiatives that they’re undertaking like curbside or delivery things like that but also relate to convenience. [37:08] And of course grocery in particular is the most desired area for convenience but we also see things like this like what’s so fascinating about the future of predictions is there things occurring in the industry that nobody was predicting so for example we see you know solid Healthy Growth in convenience stores. And nobody’s nobody in you know in any of the predictions did we see someone talking about the rise of convenience stores as an important you know, attribute are– element in the marketplace. So across the board we see a lot of different ways you can look at it and what we see is convenience you know is really becoming this new competitive Battleground you know much more so than say, experience like entertainment sort of elements that you might bring into the store. Jason: [37:56] Yeah that was super fascinating it’s funny to me because I sometimes wonder like. If convenience is even an unfortunate word to describe a category of store these days because they’re often are so many more convenient ways to. To get a product then then those convenience stores and yet they continue to thrive and grow. Kasey: [38:19] This idea of convenience shows up in in in like when we looked at what’s really going on with physical retail it shows up very prominent there as well. Jason: [38:29] Yeah another one of the trends that got me excited because, embedded in this trend you talk about one of my favorite sawhorse is what I call the mobile Gap as this like shift to mobile devices but aov and conversion rate or not. Equivalent of mobile devices to what they were on desktop so but your macro Trend was digital success grows elusive, and explain a little bit what you mean to our to our listeners about that. Kasey: [39:01] Yeah yeah first of all certainly we know that digital continues to drive a significant amount of the of growth in the marketplace it’s roughly driving 50% of of the growth just last year. You know in retail and it’s growing at about 14.9% sort of depending on what you know what source you look at when we look at it. You know the u.s. figures that come from the government and we’re seeing about 14.9 percent growth rate however, we’re seeing this dramatic shift. To Mobile so now mobile represents about 45 percent of online sales and that’s growing fast you know Mobile sales grew at about 36 percent kegger since 2014 versus only six percent for other digital channels so you seeing this shift occur but there’s a problem when that shift occurs and you mention it and it’s that the conversion rate on mobile is actually dramatically lower than the conversion rate on desktop dropping from about four percent on average down to about 1.7 percent on average at the same time the average order value is dropping from about a hundred and twenty seven down to 86 percent so as your as many retailers and many consumer products companies are paying for traffic to show up at digital that that conversion is converting to dollars at a slower rate and the amount of dollars that is converting or actually lower. [40:24] So that’s problem number one that makes digital success more more elusive however when you then add to it this idea about ad spending because we’re certainly seeing you know an increase spending that shift is happening towards digital advertising and we look at the increase on digital advertising or advertising overall Because by the way as you shift to digital advertising we actually not seeing a commensurate decrease in traditional advertising which means overall advertising is actually increasing at a fairly good clip when retail sales themselves are not you know increasing at the same rate. [41:01] At the same time the cost for digital spend or the digital advertising is increasing and digital ad spending per person is going up again meanwhile TV is staying. Roughly the same if not increasing slightly so that sets up a world where we have to pay for traffic right we’re buying traffic effectively you know as we’re investing in different you know traffic programs that traffic is showing up and is converting at a lower rate driving that traffic through advertising is more expensive than ever and then on top of that shipping rate you know I have an increase from 2010 to 2020 ground shipping is increased 76% and are 80% so, not only not only is it like advertising but its fulfillment as well and of course wages for warehouse workers have also gone up you know considerably all those things put together those Trends lead us to believe that going forward of course digital is an important. You know aspect of growth but that growth is becoming either less and less profitable or in some cases it’s got a deteriorating effect on margins for four major retailers so that’s only going to become more of a problem as we move forward. Jason: [42:16] Yeah I liked all that except the part where you dissed on Advertising because I think that pays my salary. Kasey: [42:22] I take back anything that pays Jason salad. Jason: [42:26] No no no but like just I mean to kind of highlight how real it is like in your in your data set you show in like 2011 Brands were spinning considerably more on television than digital and in 2017 the television spending was about the same but now the spend on digital was much higher than the televisions been so it’s. That that inflection point has really been passed. And yet all the digital advertising and I say this as a digital Advertiser still kind of sucks like I’m super disappointed. With all the events this week that we like you haven’t seen more more advertisers like curtail their advertising for what is at the moment in a relevant product or service. But I digress. Kasey: [43:13] Yeah no no it’s a good point I mean advertising is becoming you know less effective more expensive. Jason: [43:20] Yeah so that was that’s just going to depress me so I don’t want to spend too much time on that I do want to try to squeeze one more in because this was fascinating to me VII Tran fragmentation and consolidation and Tower westerners with that man. Kasey: [43:35] Yeah if you follow the research that we do out of the the industry sector you’ll you’ll know this term because several years back we were trying to assess. [43:46] What the heck disruption meant everybody was saying it but we don’t know how to measure it we didn’t know, you know there’s got to be if it’s occurring there’s got to be a way to understand what it is and to quantify it and then measure is it decreasing or increasing or you know what’s going on with it we came up with a way to think about it you can argue that this is the right way but this is how we came up with a way to think about it when an industry is being disrupted you know new entrants are coming in and in doing so they’re disrupting the market share most likely they’re stealing market share where you’ve got the losers or those that you know you got you got the companies that are donating market share and you’ve got new entrance that have shown up with a new better mousetrap better offering and they’re stealing market share so we would assume that in a market that’s being disrupted you would have increased you know turn over, of market share so we’d be able to we’d be able to understand that by studying what was going on with market share you know and in that came the first term II called it turnover but it’s volatility you know how volatile the market share is for an industry is a measurement that we came up with on how to study disruption and then once you study whether or not it’s volatile. [45:05] The next question is is it volatile because it’s fragmenting or is it volatile because it’s consolidated. [45:13] And you know as we’ve studied that what we saw you know it was roughly 2016 when we study the first time for retail in particular what we found was the volatility was increasing as new smaller players came into the market and not only that but fragmentation what is what was driving that volatility so now you fast forward and we looked at it again to say what’s going on now in retail what we found was the opposite and this is really sort of interesting to think about is that volatility of market share in retail is actually going down, over from 2016 to 2019 and meanwhile what we saw was it was concentration. That was driving that volatility so in other words the big players were getting bigger as opposed to the small players were stealing enough market share to you know stealing it from the big players which we saw occurring roughly in 2016 so it’s interesting just to think about how the Dynamics of competition have changed and therefore how the nature of whatever disruption we see is starting to change. Now if you jump over cuz we studied it also as it pertains to packaged goods and we actually saw the exact opposite. [46:21] Occurring what we really saw for packaged food companies is the fragment by the way with packaged Foods you have to look at it by brand not by aggregate company because of course a big you know. Branded company will have many many brands that they’ll hold so we actually have to break it down and say let’s look at this by Brand level and when you look at it by Brand level what you find is the smaller brands are really weather driving the volatility and you see dramatic fragmentation happening in the packaged food area so just ways for us to think about disruption and to understand the Dynamics of competition and how that’s changing and therefore you know what do we think maybe you know shaping the future. Jason: [47:04] Yeah and like to sort of sum that up like super briefly. So retailer power is concentrating into a few big players and cpg power is getting fragmented into more entrance and so like obviously there’s a, shift in leverage in the whole retailer brand. Dynamic there when that happens so that’s an interesting thing to think about when when you know both tons of companies are plotting their future. Kasey: [47:36] And when you begin to put that together with we talked earlier about premium ization you know a product and and and private label all of that plays together to think about how the consumer is shaping their view of. What they want to buy and where they want to buy it. Scot: [47:54] Very cool so in the paper you go into quite a bit of depth on these Trends and there’s some really good data in there and then you kind of then springboard forward and you say well let’s let’s kind of look forward and see if you you know what you should be doing maybe give us some highlights of that for looking kind of. Kasey: [48:14] Yeah sure thing yeah I know it’s it’s sort of difficult. To lay out I mean one of the things that comes out of this it’s difficult to say the future of. The industry is X because what history would tell us is that the future you know plays itself out differently for different companies and different segments for different customers selling different products so there is no no singular future and in fact as much as one companies is Iggs and has success that actually creates opportunity for another company to zag and have success so you know as one company finds that online retail works and other company finds that physical discount retail works and they’re they’re not at all the same future however they do certainly coexist, and that’s really important to sort of think about you know how you think about. [49:09] You know your company how you think about setting strategy what we say is like think about opportunity through the lens of data, you know for every data point that tells us something is occurring you got to look at the converse and say is opportunity being created on the back sides of this you know for like we talked about Health and Wellness you know we can say oh man the market is being driven by health and wellness you go it is for certain consumers but there’s opportunity for for other consumers who maybe are an economic constraints and maybe don’t have the luxury of. You know buying the high-end health and wellness product maybe they still care but maybe they’re under different constraints so what we try and do is we help our clients sort of think about how do you scenario plan around this how do we use our you know Center for Consumer insights to really think deeply about your consumer and identify where there’s pockets of opportunity you know and generally I’d say look you can read the predictions about the future that are that are prophecies and you know read them as. As input but I certainly wouldn’t be you know in certain would be encouraging my clients to make big Broad bats you know based on Prophecy what I be saying is let’s make that you know based on a deep understanding of our consumer a deep understanding of what opportunities will exist given the the changing competitive landscape. Jason: [50:29] But if you are going to make future bets based on Prophecy they should be mine. Kasey: [50:33] They should be Jason’s that’s for sure. Jason: [50:37] Well I feel like that’s the perfect place to leave it because we have once again used up all our a lot of time but Casey this is super fascinating thanks so much for sharing the research and I know you’re going to figure out in the weeks to come where this gets published and we’ll make sure westerners know how to find it but thank you very much for your time tonight. Kasey: [50:57] No it’s always thank you guys for allowing me to share what we’ve been up to. Scot: [51:02] Kasey if folks want to find you online what are you a are you Snapchatting with a client’s or what’s your. To get in touch with her buddy. Kasey: [51:11] So of course that you can find me Casey lobaugh I’m on LinkedIn I also M @k lob aaugh on Twitter where we publish a lot of our research and our findings we do a lot of speaks at what we’re up to there as well. Scot: [51:26] Thanks for joining us and until next time happy commercing. Kasey: [51:31] All right thanks guys.

Dr. Mohammed is the Founder and President of ManaGene considered one of the most innovative leaders in the emerging personalized medicine and lifestyle genomics space.   In August 2018, ManaGene merged with Youtrients (www.youtrients.me) to form a new company known as The DNA Company. The DNA Company represents the evolution of functional genomics and is focused solely on the optimization of human health and performance.   Dr. Mohammed is widely regarded as a pioneer in medical genomics and has been the recipient of multiple academic and industry awards. He is the holder of several patents in the general fields of molecular diagnostics and genomics research and is one of the most sought-after national and international conference speakers in the genre of personalized medical genomics. In this interview, Lisa and Dr. Mansoor dive deep into the power that lies in understanding your unique genes to change the outcome of your health.   Some take the fatalistic view that if you have a bad gene or combination of genes you are powerless against them so it's best not to know but nothing could be further from the truth. Understanding your genes through DNA testing is like getting the user manual to your body and learning how best to care and treat it. The granularity with which you can start to understand processes and how these affect you and how you impact these is astounding.   This s actionable knowledge that will help you make informed decisions regarding your health in such areas as your hormones, your cardiovascular risk factors, your methylation, your detoxification processes and even your mood and behavior, why for example some have a tendency to more problems around depression or PTSD than others.    Never before in the history of the human species have we had such deep insides into the way our intricate and complex bodies work.    This episode is set to blow your mind and the work of Dr. Mohammed and his team is set to change the future of the world's health. We have the opportunity for the first time to take control of our own destinies rather than falling victim to our genes through a lack of knowledge.   Once you start to see and understand the power of functional genomics you won't be able to go back to the way you understood yourself and your body before. Your level of self-acceptance and the ability to help yourself heal and be healthy and whole will be taken to a whole new level.   If you would like to get your hormones or your whole genomic profile tested you can find out more at www.thednacompany.com    We would like to thank our sponsors for this show:   www.vielight.com   Makers of Photobiomodulation devices that stimulate the brains mitocondria, the power houses of your brains energy, through infrared light to optimise your brain function.  To get 10% off your order use the code: TAMATI at www.vielight.com   For Lisa's New Book Relentless visit the website below to order https://shop.lisatamati.com/products/relentless   When extreme endurance athlete, Lisa Tamati, was confronted with the hardest challenge of her life, she fought with everything she had. Her beloved mother, Isobel, had suffered a huge aneurysm and stroke and was left with massive brain damage; she was like a baby in a woman's body. The prognosis was dire. There was very little hope that she would ever have any quality of life again. But Lisa is a fighter and stubborn. She absolutely refused to accept the words of the medical fraternity and instead decided that she was going to get her mother back or die trying.   For more information on Lisa Tamati's programs, books and documentaries please visit www.lisatamati.com    For Lisa's online run training coaching go to https://www.lisatamati.com/page/runningpage/ Join hundreds of athletes from all over the world and all levels smashing their running goals while staying healthy in mind and body.   Lisa's Epigenetics Testing Program https://www.lisatamati.com/page/epigenetics/ Get The User Manual For Your Specific Genes Which foods should you eat, and which ones should you avoid? When, and how often should you be eating? What type of exercise does your body respond best to, and when is it best to exercise? Discover the social interactions that will energize you and uncover your natural gifts and talents. These are just some of the questions you'll uncover the answers to in the Lisa Tamati Epigenetics Testing Program along with many others. There's a good reason why epigenetics is being hailed as the "future of personalized health", as it unlocks the user manual you'll wish you'd been born with!  No more guesswork. The program, developed by an international team of independent doctors, researchers, and technology programmers for over 15 years, uses a powerful epigenetics analysis platform informed by 100% evidenced-based medical research. The platform uses over 500 algorithms and 10,000 data points per user, to analyze body measurement and lifestyle stress data, that can all be captured from the comfort of your own home   For Lisa's Mental Toughness online course visit:  https://www.lisatamati.com/page/mindsetuniversity/ Developmental strength, emotional resilience, leadership skills and a never quit mentality - Helping you to reach your full potential and break free of those limiting beliefs.    For Lisa's free weekly Podcast "Pushing the Limits" subscribe on iTunes or your favorite podcast app or visit the website  https://www.lisatamati.com/page/podcast/     Transcript of the Podcast   Speaker 1: (00:01) Welcome to pushing the limits, the show that helps you reach your full potential with your host, Lisa Tamati, brought to you by Lisatamati.com Speaker 2: (00:13) Hey team. We're this week I have an absolutely superstar, the world's number one leading functional genomic specialists, Dr. Mohammed from Toronto and Canada. Dr Mansoor, Mohammed has two guests now. He is a scientist and entrepreneur in the field of genomics and is regarded as one of the most innovative leaders in the emerging personalized medicine and lifestyle genomic space. Dr Mohammed is a PhD and president and scientific officer at the DNA company and is really considered to be a pioneer medical genomics. He's a classically trained molecular immunologist who has received academic and industry awards, published numerous papers and holds patients in the general fields of molecular diagnostics in genomics. Now functional genomics is about understanding the DNA and how it behaves in every definition and this Dr. Mentor was very different than many of the other DNA companies that I've looked at recently and that he doesn't just look at the single litters, if you like, of the DNA, but it looks in combinations of genes. Speaker 2: (01:22) And how they're playing out. And this makes him very, very different. This, he sees DNA like a language rather than a vocabulary and language that has grammar, sentence structure, Syntex and nuances. And you've got to be able to read genetic structure at the holistic level. Now I'm super excited about document's all his work and I'm studying functional genomics at the moment and it is the next level in personalized health. I'm really, really excited to bring this interview to you. It's taken me months to get documents or on this podcast and I'm hoping later on the year to get Dr. Mansoor Down to New Zealand for a lecture tour to speak to functional medicine practitioners down here as well as the public. So if you'd like to know more about that, please reach out to me and let me know. I'm just like to remind you before I hand over to Dr. Mansoor that my book launch is happening just next week over the time of this recording is the 6th of March and on the 11th of March. Speaker 2: (02:26) So by the time this recording actually comes out, my book will be live. It's called relentless and it tells the story of bringing my mum back after a major aneurism myth. You're fighting for a life and lift her in and basically not much over a vegetative state. Massive brain damage at the age of 64 and what I did to beat all the odds and bringing my mum back to health, all of the CRPS I used, the protocols, the attitude, the mindset, the obstacles that we had to overcome, the problems that I've discovered in our medical system in on it goes. So this book is really, I'm, I'm so pleased to be able to bring it out. It's taken me two years to get this together and to bring it to the public, but I really want to pay it forward and I want to help thousands and thousands of other people facing difficult challenges to take them are hit on with the right mindset to overcome great obstacles. Speaker 2: (03:18) So if you'd like to check that out, we can head over to my website. I have Lisatamati.com Hit the shop button and you'll see all of my books there and my jewelry collections. But make sure you check out the neatness. It's really going to be worth a read for anyone who has major medical problems at the moment. Or of course anyone who has a stroke aneurysm Alzheimer's dementia, and wants to know about brain rehabilitation or optimizing your brain function and who isn't interested in that as well as the whole mental attitude and mindset that it takes to do all this. So without further ado, over to Dr. Mansoor Mohammed. Well, hi everybody. Lisa Tamati here at pushing the limits. It's fantastic to have you back again. Now I am just grinning from ear to ear. I can't stop smiling because I've been waiting for this interview for weeks. I have a very, very special guest, Dr. Mansoor Mohammed, all the way from Toronto in Canada. Dr. Mansoor How are you going? Speaker 3: (04:17) I am great, Lisa. And likewise, it's been something that I've been looking forward to, to the audience. Please forgive me. I'm a little bit sleepy from Jeff blog from last night, but Lisa has been pumping me up and so we're going to have some fun of this Speaker 2: (04:31) Now. I know what it's like when you're a little bit jetlagged and you have a main very much in demand. So I'm just so excited to have a little bit of time with you now. Dr Mansoor, I do the whole introduction on a separate recording, but dr Mansoor, can you give us a little bit of background about your what you did your PhD in your, your, a little bit of a brief history of your back. Speaker 3: (04:55) Sure. genes. Genetics has always have always been my love. The study of how this operating manual, just just thinking, just, just dialing it back and thinking that the human being, we've got this operating manual that by every definition of the word it behaves like an operating manual. And to think that it's there and to think that one date might be accessible and that we could read this and we could read it intelligently and just simply understand myself much less, much less. Anyone else has always been my love. And so I started, my PhD is in applied molecular genetics and immunology. So I was looking at the genetics of the immune system. I was very, very fortunate to have an awesome mentor. She was then the chair of molecular biology at UCLA invited me to UCLA. So I had an awesome couple of postdocs there where I got deeper and deeper involved in eugenics. Speaker 3: (05:47) But a real pivotal point happened when I was done, invited to come to Baylor college of medicine and Houston, Texas. And it was that heavy time just about the human genome project, its, you know, sort of pinnacle. And I was asked because of the work that I had been doing with UCLA to come over to Baylor and start a company, the goal of this company was to begin looking at multiplex genomics. In other words, to really do the, you know, the barrage searches into the human genome. Not one gene at a time, but looking at the entire genome in pathway type manners. Now initially we applied this knowledge to cancers. We apply this knowledge to developmental disorders syndromes, Prader, Willi syndrome, autistic spectrum disorders and so on and so forth. And about 15 years ago, after many years of doing what I call disease genomics, looking at the operating manual, looking at when the operating money was broken out of what happens from a disease perspective. Speaker 3: (06:45) Then I sort of thought, okay, well that was fun. That was good. That was, but why should I not look at the operating manual? But nothing is purportedly broken, but just the operating manual. So then still we can tell presumptively healthy individuals how to stay healthy or how to get over the type of chronic illnesses. So this is what I've been doing for the last 15 years, studying, researching and applying the knowledge of the human genomic operating manual. So we've been, we can just simply understand it. How does the body work, which clearly there's an individuality to that, obviously. I mean, we are human beings. We all, our cells, our organs, our bodies, all have to accomplish the same jobs that we do. These jobs with nuance differences, some of us less optimal, more optimal, more efficient, less efficient. And when we can zone into that, when we can read this operating manual from that perspective, really Lisa miracles happened with the sort of insights that you get, the nuances that you can tease out. It really has transformed the clinicians. We train the patients, we work with the transforms, it empowers the individual to understand how their body works and what they might do to obtain that optimal health. Speaker 2: (07:59) This is, and this is a super exciting and I can feel your passion coming through despite the jet lag for this area and it's now mind you, passion is of the last maybe two months or six weeks or however long it is now that I've been diving into this world and just going, Oh my gosh. Oh my gosh, this is just, this is just the next level and the information that I've been searching for to try to understand because everything seems so generic. And this a personalized house and yeah, doctor man saw you the president and founder of the DNA company, which is offering direct to public and in conjunction with conditions. A couple of reports. So our full genomic report in a hormone report and I want to tease apart a little bit today, why should people even consider having a look at these, the sort of testing what benefits they can get out of it. Speaker 2: (08:58) And I'd like to also tease a little bit about looking at other, like I've, I've looked at a lot of gene companies and that do gene DNA testing. And you had an analogy on a Bulletproof radio that I heard you on the same show who's amazing Dave and his work that was about the most people are looking at it DNA as a vocabulary and not a language. And that just seems them light bulb up in my head where I realized, okay, so it's not the siloed genes looking at them individually, but looking at cascades and pathways and combinations of genes as we are then interpretation has been missing today. Speaker 3: (09:43) Oh, 100%. So I always say, you know, Lisa, anyone that is in the data business, regardless of whatever data you're collecting, data is really quite dumb. Data in and of itself doesn't mean anything unless you know what to ask of the data unless you know how to triage, how to approach the data. So when we use the analogy as DNA, the operating manual, the genome, it really meets all the classifications and descriptions of a language. Thus far we've been looking at DNA and genetics from a language perspective purely as a vocabulary exercise. The more words we know, the better we presume to think we know the language. And as much as that is important as per the analogy that I drew with on Dave, show a person simply knowing more vocabulary by no means mean they understand the language. And so when it comes to DNA, when it comes to genetics, when it comes to how this awesome operating manual, the architecture of it, it's not just about vocabulary, it's not just about the individual genes. Speaker 3: (10:51) So here are the two layers implicit in your question that we do a bit differently and why we need to do that differently and why it's important that it's done this way. The first is this. When you're looking at the DNA, if the person are either genetic makeup, the vast, vast majority of companies right now, they're looking at things called snips, single nucleotide polymorphisms. In other words, they're looking at places which is absolutely important. They're looking at spelling variations in this operating manual. And of course these spelling variations, these single nucleotide polymorphisms will impart to you mean Jane, Paul, Peter, the same cellular job that we all want to do. These spelling differences can impact the efficiency with which we do that job and that is important to know, but while we're at that point of spelling, you see per any language, if I wrote a paragraph, I might have spelling errors in that paragraph, but there are examples where I may have inadvertently deleted a sentence or deleted a couple of sentences in that paragraph. Speaker 3: (12:00) Now, if the analogy here is that the gene is the paragraph, so your operating manual are these 23 volumes. Think of it. Think of a 23 volume and psychopathic set these awesome, huge volumes. Now we're going to inherit two of these 23 volumes. One from mom, one from dad, and these volumes are properly arranged and when we open up any page, let's say we go to volume three from mum volume three from dad, we open up page four on each of those volumes and we look at paragraph five page four, volume three we, I see the same paragraph. We're going to see the same information from dad's gene paragraphs of genes and mom's gene. We're going to see the same information, but when we look really carefully, when we look at those paragraphs, really collect carefully, we might find that there's some spelling differences. Those are the snips. Speaker 3: (12:57) We may also find that on either dad or mom's paragraph, a sentence was missing and I just taught this over the weekend. So I was in the auditorium and I said, okay, here's an instruction that was waiting for me coming to this auditorium to give this lecture, Dr Mansoor, go to auditorium B and to the left door approach to podium from the right side, press the enter button, begin your lecture. That's an instruction. That's a paragraph. That's an instruction and that's the equivalent of a gene. Now in that paragraph they make has been a few spelling errors or changes that may have confused me a little as to what the instructions are. But when I look at it carefully, I could sort of still figure it out. Okay. But if in that paragraph, the sentence that says go to auditorium B was missing at, of course there are multiple auditoriums, all of the other parts of the instructions are there. Speaker 3: (14:03) But I can really be confused as to what is the ultimate thing that I'm supposed to do. It's called an indel. So in our genes, not only do our genes have slips, many important genes actually have places within them that I'm missing. So until we test for those type of changes, we're by no means getting the full picture of what is happening. The third thing is this, not only do we have slips, not only do we have in Dells, there are occasions where the entire gene is missing is show I'm supposed to show up. I got to the hotel where the conferences are and the instruction just telling me what it's just not even there. So here I'm in the lobby going, I don't know what I'm supposed to do. This example is a genetic phenomenon keeping the analogy, this is called this C and V copy number variation. Speaker 3: (15:03) We see because we were supposed to have two copies of that. Paragraph five page four, volume three. Sometimes believe it or not, when we go to page four we've opened up mum's volume three dad's volume three. There they are. We're going to read both of the instructions cause that's what yourself has to do at any given moment. When there's a job to be done, your cell goes and pulls the volume that has that instruction, takes down a mum's copy, takes down, dad's copy, opens up and reads the instruction. Now in the case of a CMV copying of the variation, we can open up mum's volume three page four there is paragraph one, paragraph two, paragraph three paragraph four paragraph six. Oops, wait a minute. Where's part of our five? It's gone. There's part of four. There's part of six. I look over a dad. He's got all of the paragraphs or vice versa. Speaker 3: (16:02) Sometimes Lisa, both paragraph fives are gone. Okay. So the point of the first answer to your question, why we do things a bit differently is we're not just in the business of collecting data for data's sake. We're collecting data. Are you were doing gene testing to understand a process. When we designed genetic tests, we don't begin with genes. We begin in a whiteboard saying, what is the thing in the human body that we want to study? What is the thing that we want to study? Genetics, just good old fashioned medical textbook, human physiology. Do we want to study the way the newer chemicals are produced and bonding and response? Do we want to study how the human body makes sex hormones? Something we should talk about when it comes to human performance. So how does the male and female body makes progesterones androgens Astros? And then we mapped that out. Speaker 3: (16:56) Forget genetics, which is not about how does the human body do that? No, of course, if the human body's having to do something, then it means there are genetic instructions for that film. So only when we map out the cellular, the cellular biology, the cascade, only when we met that out, then we come in and we pencil it. This gene is responsible for here. This gene is responsible for there such that at the end of the exercise, we've got a genetic test that already tells a story. The result from that genetic test is telling you the entire cascade. Step one, step two. We look at each of those genes that are telling us the story and we ask are these snips that are important? Are there entails that are important? Are the CNVs that are important because all three make a wow. And so the first part to the answer to your question is if you've been looking at genetic tests that are only reporting snips, you are dramatically limiting the variations that you and I and every other person have within our genome. So you're missing the nuances that are in your language to clarify the job to be done. Does that make sense? Speaker 2: (18:16) Absolutely. So that actually puts them together in my head because I've been starting this, I don't know, like for example, the GSTT one gene and the detox and antioxidant pathway, one of those types of genes that can be completely done. Speaker 3: (18:31) Completely. Totally said, absolutely. And of course it belongs to super family. So there are multiple G S T genes, but two minutes on that. If you're going to design the human body and you're going to say, listen, one day we're going to make this thing called human being and we're going to put him or her in this wonderful world, but mind you, he or she is going to have to deal with some toxic insults, both from without and from within. Where would you, and you know that, where would you put your detox defenses? Well, they're about four places. If you're an intelligent designer, you would put your detox, different defenses at least in four places. You would say, how and where do things get into the human body, dermal skin, the nose, nasal Bronxville lung, the GI track. Okay. So those are how things get it. Speaker 3: (19:23) And unsurprisingly you would want to make sure your detox genes and the things that you'd want to make sure there's super active in those places. And then you, you'd also say, well look, at the end of the day, things are always going to get past borders inside of the body, their waste products. So then I'm also going to put a detox organ. The liver, when we go to the human body, this is where we find these detox genes expressing themselves. And each of the GST is have sub specialties. Some of them are more important in the nasal bronchial track, some of them more important in the GI track and so on and so forth. So when you know the story that you want to read about the body, you know how to read the manual and interpret, is the GST T one gene deleted or not? This is a massive implication to the human body. Speaker 3: (20:16) Can you imagine the GSTT one gene is one of, if not the most important bio transforming antioxidizing enzymes in the body per its name and its gene and its enzyme. And if a person doesn't have it, literally it's not in mere manual. The GSTT one gene is on volume 22 and if that paragraph you have not inherited it from either mum or dad, you are missing an enzyme in your body. That is one of the most important detox. Now doesn't mean that you're not compatible with life, but it most certainly means you could not be the person who says, well you know what do you have a metals mean after all they're not that bad. Oh you know what, my uncle smoked until he was 80 years old. I'm going to smoke as well. Well you can't compare yourself to that person cause you don't have one of the most awesome detox genes. Speaker 2: (21:13) You don't have a good defense mechanism. And so like the detox is actually the first port of call before the immune system even does this job. So I'm, I'm excited to get my tests back cause I haven't gotten gotten through the reports yet. I'm, I'm suspecting that I have a problem in my GC jeans because I'm a very young age. For example, I've been the next medic as a, as a severe asthmatic, as a child, and I'm very hypersensitive to smells and anything. So I'm like a Canary one C one, which is theta. Yes, Speaker 3: (21:54) Very important in the liver. Key one PI GSTP one is the one that's really important in your nasal bronchiolar lung cavity. Individuals with a suboptimal P one are at extreme risk of early ectopic asthmas. They're the ones that if they go into the shopping mall, you know, the perfume resection, they've got to avoid the perfume resection. Right? Those are the GSTP ones. Speaker 2: (22:21) Wow. I'm obey. Fascinating to see if that's what comes back. And so if you want it deleted into them, we'll get onto hormones next because I really want to dive into there, but just to, to to look at the GST genes. If you don't have, you either have only one inherited GST, one gene, your mother or your father and you're missing the other ones or you're missing both altogether, are you more likely to have you're more likely to have toxins coming in that you can't deal with as well. And then your immune system is this way or auto-immune or part of the Speaker 3: (22:57) Brilliant, brilliant question. Just before we answer that, I had mentioned there were two layers to differentiate yourself, so just so that we close the chapter on what we do differently. So I'm going to come back and, and so now we will take it forward. We just mentioned that there you have to be mindful of the three different layers of variations, snips in Dalles with pieces of the genome missing and CNVs where the whole gene may be missing. The other quick differentiator, bringing back the analogy of a language, bringing back the story of the human body, it's this, and I told the audience this, there was an audience of clinicians in Phoenix this weekend. I said, have you ever read a really good, you know, suspense novel and not suspense novel, the novel that the author's painting the character and you're thinking he's the bad guy, you know, and he's falling around the heroin and he knows he looks a bit shady. Speaker 3: (23:51) And then until or unless you've read the entire book, you only find out that he was a protector or he was something. He was a guardian and words. He wasn't about that guy. Now what the heck does this have to do with genes? The second player, when we mentioned that we do things differently, we said that DNA is really a language by all of its definitions, with its nuances is this, there are many genes, Lisa, where if you were to look at that gene as a standalone and if you was to look at the genotype of that gene, in other words, what version do you have? You think you have either the best version or the worst version depending, and you may think you have the best version for example, but it is not until you look at a completely independent gene that has nothing to do with this gene, that the version of that independent gene wow colors, whether your actual optimal version of gene a will stay optimal or not. Speaker 3: (24:52) Or conversely, whether you thought you had the suboptimal version of a bad guy, you read the full story, something else tells you what you fought was the bad guy was not the bad guy. Wow. And this is what it's called at peace basis. You see we're all concerned about epigenetics, which is important. FP genetics. How are we reading? Are we actually going to read that paragraph on the page or are we not going to read? That's at the genetics, but nobody's talking about epi. Stacy, this is Stacy. This is often, we've read the page after we've read the paragraph. We cannot yet make a conclusion until we read 10 pages later, 15 pages later, something there. We'll bring it to life. We'll color what we read on page three. Speaker 2: (25:48) Yeah, so, so for example, if you're, if you're looking at a specific gene and it has an, that is say the faster for the sip, 79A1 gene and the hormone a kiss guide. If it's a fast one that's not in and of itself a good or a bad thing. It depends on the other things. It depends on the, so that's what you're meaning. So one of Speaker 3: (26:14) The best examples of that is this, the BDNF gene, the BDNF gene, brain derived neurotrophic factor. What are the most important genes in the brain? Well, in the whole human genome that tells the brain how to secrete this awesome thing that heals the brain. You and I were having a conversation about a loved one, so that loved ones B, D and F was going to be hugely important. And how that loved one recuperated from the challenge that she had met BDNF. Now the beating of gene has an important variation. A snip this time, which is either a G version or a version. Okay. TheG version, Jews and George as in guanine is the optimal version of BDNF, the optimal version. So if you're a GG blessed, that's good. You are naturally predisposed. You have the in Harrods, the innate ability to make more BDNF. Speaker 3: (27:13) And let me tell you that's a good thing. Any which way you slice it. Wow. An independent gene, the TPH to gene the trip to five hydroxylase gene to TPH, two gene, which is involved in how the body deals with serotonin. K two has a sip. It comes in a G version and a T version G as in George T as in Thomas. The G version is considered optimal but hold on. If you happen to be GG fatigue, pH two and GG for BDNF ostensively both those genotypes for each affair genes are optimal, but if you were GG for both, it creates a haplotype. It creates a combination that is an act risk combination and it is, it is the negative combination. It is the, it is the deleterious combination when it comes to certain aspects of human behavior. These individuals, when you're GGGG, they exhibit poor inhibition of negative emotional stimuli. Speaker 3: (28:28) In other words, when something negatively emotionally affects them, their ability to kinship, the ability to say, you know what, I'm not going to focus. I'm not going to hamster wheel constantly play that over and over over again. They haven't, they have a hard time giving up that when something gets under their skin. So to speak emotionally, they have a really hard time getting over it so they have a strong imprint. The memory imprint, very strong EMI, emotional memory imprint and of course the stronger you EMI emotionally memory imprints, the easier you emotional memory recall EMR is because the deeper something is imprinted then the smallest cue. You have a love, you have a partner and you know you love each other to bits, but like human beings, you're going to have your ups and downs. I mean it's where human beings after all, and on one particular evening you were both getting on each other's nerves and she was wearing that beautiful red dress and that was the evening that you both said things you shouldn't have said and it hurts the person who has this phenomena. Speaker 3: (29:36) Whenever he sees his wife, would that red dress down the road, everything's perfect. You, you're going up for a birthday party, you're both happy, it rises back up. He remembers that evening more than he should. It brings back to the surface and vice versa. This is that Paul, inhibition of negative emotional stimuli that lead to profound memory imprinting and therefore profound memory. Recall. The point of all of this and the reason I mentioned this is, and we're going to come back to the GSTT one, was to clarify, you see Lisa, it's not just about even the type of things you're looking for. What matters is the interpretation we sell the combination, we are reading the manual, not just flipping, picking words out. Speaker 2: (30:24) This is we have a calmer is well we are the, the apostrophes are this is someone that is what they would be more prone to PTSD Speaker 3: (30:36) 100 that's the point actually and that is further exacerbated based on the no adrenergic pathway which dramatically increases the risk of PTSD. It is exacerbated based on how quickly they are removing their dopamine and noradrenaline via content. So what happens is you begin to pixelate a picture and you've got a low resolution picture and then the more intelligence information you put in, you start to increase the resolution of that picture. You start to get a clearer picture of the person that you're looking at. But to do so, you've got to know where to pick slate. If I'm trying to get a better look at what Lisa's face look like, I don't really be pixelating your toes. I need to pick slick your face and this, this ability to read intelligently. Lisa, I stress intelligently. Riyadh, human genome. Yeah, that's what we do. We do Speaker 2: (31:35) That is absolutely insane. And they've vacations because yeah, I would have seen, Oh, you've got a G G G is good, but I've just understood that nuance, that combination of things. And now I can't wait to get my reports and my family reports so I could because this helps us also understand like the speed in which you are dopamine is processed and gotten rid off or the speed of which we're saratonin tone and all of these things have a fixed on your personality and that we're not 100% to blame for some of our differences. Speaker 3: (32:12) Oh gosh, no. Gosh, no. In fact, what this needs to do on the one hand, it creates the empathy of appreciating, look, this is how some of this is their predisposition. Now, on the other hand, it is not to create a sense of fatalism. While that's the way I am, I know I have found and I have done. The only thing that I've done, probably somewhat unique and special Lisa, is I have reviewed thousands upon thousands of profiles. In terms of my in the world, most of my peers that work at the level I do would say Dr. Mansoor Probably reviewed the most genomic profiles in the world. I don't know if that's true or not, but I certainly have reviewed several thousand meaning meeting the patient, speaking with their doctor, looking at their health profiles and looking at underlining genetic phenomena to see if we can understand what's going on. Speaker 3: (33:00) You know what I found, at least as a fellow, when you empower a person to understand a predisposition, you, you might think that leads to fatalism, but when you explain the functional reality, it actually does the opposite. It gives the person a sense of ownership and then they can finally say, you know, I have dumped with my entire life, I've been this way and I just, I didn't even know why it was that way. Now that I can even understand what's going on, it gives me some closure. Yes, but it now gives me something to appreciate. I can, I can envision how this is working, how my emotions are working. I can now go, you know what? As soon as I see that stimulus that would have got me on that slippery slope, I'm going to stop. I'm not going to go down that slippery slope because I know if I do, there's no coming back for the next two weeks. Speaker 3: (33:52) So what we've found is that this crew all around it just creates empowerment. Which brings me now to the question that you asked about GSTT one and you are, your connections are on point, Lisa, the connection between the detox mechanism of the body. Here's the threefold, and of course it's a bit more complicated, but it's also remarkable. You can take complex systems, break them down to building blocks and keep the acuity. So there are three building blocks we need to look at when we connect detoxification pathways in the body and the immune system. And the, the only thing missing is the inflammatory system. So the triangulation between toxins and immune responses goes like this. The human body's insulted with whatever. It's insulted with the intentional, the unintentional of our daily lives, those toxins enter the body or they try to enter the body. Step number one, how individually efficient is that person at negating bio transforming, neutralizing those toxins either before they can enter the body, such as in the mucosa of the lung, the alveoli lumen, the the lining of the lung, such as the GI mucosa and so on. Speaker 3: (35:16) And so what can we, can we neutralize it so the toxin doesn't even get into the bloodstream? And of course to the degree that it gets into the bloodstream, can we live a hepatic re detoxified so that at least it does not by you accumulate in the body so that at least it does not reach levels that are unsafe. First step number one now too, there are genes, there are whole gene families, their whole cellular processes, GSTs, glutathione, ionization, UGI, Ts, glucuronidation, methylation, self, phonation and acetylation. These are the major enzymatic steps linked to genetic genes that are responsible for bio transforming neutralizing things in our body, okay? So what we need to do is we say, what is the lifestyle environmental context of the person? What are they getting exposed to? I'll be living in a home that has written with mold, are they living and so on and so forth. Speaker 3: (36:17) Okay, step number one, step number two, how good are they at individually neutralizing those toxins so as to not bio accumulate them to the degree that those, whatever. The answer to that question is we're going to have an individualization and with some individuals are better at getting rid of toxins and others are not. If a person is not genetically, innately efficient, optimal at getting rid of their toxins, then what happens? Well, what do toxins do? Toxins cause cellular inflammation, okay? And they cause inflammation via any number of methodologies. They can inflame cell surface receptors, they can get into the cell and create overproduction of oxidants as they can hamper the energy modules, the mitochondria. That's one of the places you'd never want toxins getting to. And of course they can get into the nuclear eye. They can get into the libraries of the operating manual and they can start to change gene expression. Speaker 3: (37:23) So toxins do all of these things. Ultimately, you see Lisa 15 not even 15 years ago, 10 years ago, if you told that a medical conference, there's this concept of inflammation. You'd have a lot of professionals. Well, come on, you gotta be more specific than that. We actually now know that there is a phenomena called chronic inflammation, and regardless of what stimulated that inflammation, bat bacterial toxin B, it's an inorganic chemical. It be it a physical inflammation. It does not matter the way the sun looks, the way the cell begins to behave when it has been insulted with toxins, with exposures, remarkably is the same regardless of the stimulus. Because chronic inflammation has hallmarks that are similar regardless of the stimulus. Now at that juncture, when the cell is inflamed, when the machinery in the cell isn't doing the job that it's meant to do properly, that cell now starts to be like this pulsing red thing just by analogy. Speaker 3: (38:35) In other words, the body is looking at it going, something's happening in there. It's not behaving the way it should. Okay, so now we're going to have two steps. The body now has an anti inflammatory set of steps to quiet us, to bring the cell back into line cause they Whoa, Whoa, hold on. You're starting to misbehave. There's too much inflammation. This is where it's selling the process known as methylation comes in. Cellular methylation can be viewed. It's a detox reaction by the way, but it is a cellular cascade that is radically responsible for bringing your soul from that humming, inflamed, you know, ticking bomb type of modality back down to acquire essence behavior. That's cellular methylation. Now, to the degree that you're able to do that, because suddenly methylation is a multigene cascade, multiple places where things could be not as optimal as we would like. Speaker 3: (39:36) So to the degree that we then triage, we stratify the patients based on their detox potential. We then stratify them based on their anti inflammatory potential. Now, to the degree that we are not quite yessing that chronic inflammation, this is where the immune system can be activated. Immune system was meant to be activated in acute episodes, not chronic episodes. The more you ask the cell to produce antibodies, IgG, IGA is IGMs, particularly IgGs. The more you keep telling that the body pump out IgG, something's not working right, something is there, which is why chronic infections are now very well understood to be linked to autoimmune diseases. The infection did, did not go away, constantly demanded of the body to produce antibodies. And somewhere along the line those antibodies begin to forget what was the bacteria or what and what was the self. And now we just start shooting friend and foe alike. Wow. This is the triangulation that has become now a focal point of so many diseases. Some diseases being more relevant to the whole, you know, things like lying disease. Do you guys have lung disease down in New Zealand? Speaker 2: (41:05) I think, yes, we do. And I think you know we have a massive problem with like thyroid, Hashimoto's sort of autoimmune diseases, crones, IVs. So this is, this is where the body is actually going in overdrive. So the, the original detox genes haven't been able to do their job because combination. Speaker 3: (41:26) There's that one. Exactly. There's inflammation. Yup. Speaker 2: (41:33) Yes. Speaker 3: (41:33) Methylation didn't do the job that was supposed to do and now we're triggering. So there are meta-analyses meta-analyses that show the deletion of the GSTT one gene or overall poor Ghouta finalization has been strongly linked with ulcerative colitis, Crohn's disease, IBD, strongly linked with ectopic asthma, particularly GSTP one in early childhood asthma. Then of course, if you, if you double down on poor math on poor detoxification with poor methylation, you really start seeing Speaker 2: (42:10) Clinical outcome. Yes. Yeah. So, so if we then we, we, we find out all this about ourselves. We find out we've got either the good or the bad and the ugly. And these combinations are not ideal. Then how, you know, we've got this information now, now we want to know what the heck do I do about this? I can't change my DNA. Of course, all things that these reports that your company does, for example, where it can actually lead to some successful outcomes. Obviously avoiding cigarette smoke or exhaust folk tunes and things your GPS deleted. But, but beyond that, nutraceuticals, new nutrients what can be done to help people. Speaker 3: (42:52) So it starts with, so the first thing I would have to say is we take our reports only so far. So the actual report, we take it to the point of explanation of what's happening. And there are certain recommendations, but the real magic must still come from a trained population, you know? So what, so what we do is through also training a certain class of healthcare providers. We might call them the, the new modern day biohackers. The healthcare providers who are really sniff, they're no longer just, you know, pill pushers. They're looking. So I just wanted to clarify. We take the reports, we explain the systems, we explain what's happening, but we also have to be careful so that people aren't jumping to conclusions and self-treating based. So you still want to have someone who understands the bigger picture. And by the way, that's the second part of what our company does. Speaker 3: (43:47) As per my travel schedule, I'm constantly traveling, teaching people, teaching auditoriums full of doctors who are now saying, listen, if I keep practicing medicine the way that I'm practicing, I'm just dealing with a disease population. I'm not healing people. Okay, so with that minor clarification, now we come to, let me paint a picture, paints a thousand words not to be, you know, blahzay here's what I like people to picture and here's what you would want to picture for yourself. Lisa. Picture slide. Okay, so there's a slide your screen, okay, and a circle. And then picture a circle on that screen somewhere on your screen. There's a circle. Now because you're a human being, your circle is going be on the screen. In other words, this is the screen of all human beings and your circle, you, your circle is somewhere on the screen or what does the circle represents? It represents your genetic makeup, which represents a part of your genetic makeup for whatever biochemical process we were studying. So this circle is Lisa's genomic pathway. Okay. Speaker 3: (44:56) I want you to then think of an equilateral triangle that equal three sided triangle that just perfectly encompasses your circle just perfectly. Your circle is perfectly encompassed just right in that triangle. And the emphases of this triangle are labeled environment, lifestyle and nutrition. Yes. What we're learning and what we're recognizing more and more is other than extreme cases, other than extreme cases, and there are mind you extreme cases where a particular genetic combination was really just a real doozy. And in other words, we're going to see some, you know, with the best of efforts, we're going to see some probably deleterious outcomes. Fair enough. But other than those extreme cases, for the vast majority of us, the spite, any inefficiencies we might have if we find the right triangulation of lifestyle, nutrition and lifestyle, nutrition and environment. If we could figure that out and it perfectly matches, I would circle. Speaker 3: (46:08) This is optimal health. So image, the image of optimal health is when you can find your genomic makeup, your circle for whatever you're studying and contextualize it perfectly within the right for you. For Lisa Laughlin, sir, not for Joanne Felisa. What is leases? Optimal lifestyle, nutrition and environment. Now the problem is, Lisa, when we begin working with a patient, obviously and clinicians with their patients, the vast majority of individuals, they do not know their circle. They don't know what's the economic influence. So they don't, and if you don't know your circle, your triangulation, choices of lifestyle choices, nutrition choices, and environmental choices offers skewed and they are not synergistic with your circle. So first objective of this, did you get that picture? Do you know when people say, well, it depends on your genes, your genes. It depends on how you're using your body. If you are, if you took, if you took five identical individuals, they were, you know, quintuplets identical, contemplative. Speaker 3: (47:27) If such a thing exists in today, the same genes and you give those five people at 35 years old, the exact diet. But if those five, one of them was an ultra marathon runner and extreme sports enthusiasts, the other was a couch potato, I don't know, doing whatever the other was a, you know, an accountant who had a nine to five job. We can exercise worrier, but from Monday through Friday really just goes to work, comes home, eats, goes to that and so on and so forth. Even with the same jeans, you can put the nutrition and an obviously not expect the same outcome because they got to know the genomic legacy. You've got to know what is the lifestyle context, what is the nutritional context, what is the environment or context? If one of the things quintuplets moved from your gorgeous country and move to massive metropolis with, you know, air quality, that breathing for one day is the equivalent of smoking a pack of cigarettes in your beautiful country. Speaker 3: (48:36) He or she may have gotten away with a GSTT one or GSTP, one suboptimal ability. He's living in those, you know, that wonderful country views. He's practicing otherwise good, not eating foods with pesticides and herbicides and so on and so forth. And he was going about life actually, not really realizing there was any suboptimal ability until one day his job took him to a big metropolis somewhere. He lost track of the quality of his foods. He's just so busy. He's day in, day out breathing the equivalent of a pack of cigarettes and then six months into this, all things ELLs as equal, his jeans are equal, but he now starts to show symptomologies that he would never have had any different environment and a nice clean environment. Right? So this triangulation is so important. Now coming back to the specifics, once we understand the pathways, we begin first with the dose. Speaker 3: (49:31) It may seem simple, but it actually enters Lisa into, it's not just about the obvious things that you might imagine. I give the example, Lisa, and by the way, it's relevant to the GSTT one gene. Now, juice, TT. Let's focus on the T one. It's the big sister in the glue, the fine fabric. So GSTT one no, it's what's called a phase two detox pathway. Phase two detox. Because when it talks and enters the human body, we typically go through two steps. We take toxin a, we converted into an intermediate B. Yup. We take B further, convert that to C. C is what leaves the body, the B to C part of the transformation. That's where the GSTs come in. The a to B. This is where your cytochrome P four 50s come in. That's the phase one. Bio transforming enzymes. Now if I were to ask you something, when you say fiber to say, would it be a good practice for person to start drinking a nice cup of green juice? Speaker 3: (50:38) You know, like some juice, juice, broccoli and some maybe put a little bit of a baby spinach in there. A bit of ginger, maybe some cute, cute curcumin at the end of it. Would that be a really healthy drink? Yes. Something I do every day. Beautiful, beautiful. And it is healthy generally speaking. So now someone puts a blog together giving this recipe of something that's ostensibly so healthy and there's this mechanic who works in a shop all day with fuse and so on and so forth. He read this blog, she read this blog and she decides that before she goes to work, she's going to have this beautiful juice. This green juice that they read was so healthy and it was a detox juice and they feel good about themselves. Hold on, hold on. Many of the ingredients and not green juice. Many of the ingredients in that green shoes turn on certain phase one sip four 50 enzymes so as to accelerate the conversion of a to B. Speaker 3: (51:54) Now some of the toxins a that this mechanic was facing in her shop, in the, in the, in the mechanic shop that she was working at, when she converts a to B, we know that the B, the intermediate is truly more toxic than wow. And by the way, she did not know she was a GST one deleted individual. Oh, so what did we do to this young woman? We encourage the things that is that we're getting into her body. When she drove that beautiful healthy green juice, she more rapidly converted her A's into B and then ups B's and to CS very well. Wow. Even something that would ostensibly be really healthy by normal standards. Do you see that's a healthy nutrition on the triangle, but we did not ask what was the environment on the triangle and so now we have skewed her triangle away because her genetics circle, she does not have the GSTT one. Do you get that picture? This is a little bit frightening for people who are listening to this or who might be going well, what's the point being? Speaker 3: (53:16) This is weird. The reports have the super value, isn't it? That's the point. It's, it's actually not discouraging. It's, it's finally, and this is all gold. It's finally meant to unravel those nuances that there is such a thing. Have you been? How many of us, you know, we do something that 20 or the coworkers swore was the best thing since sliced bread and then we tried it and not only did it not work, we actually felt like crap or less healthy, and we, we're all aware of this until it's what is it led? It's led for most of us to become numb. We're just kind of get to that point where we're like, well, I don't know what's right for me or run for me. Plus today it says one thing tomorrow it says another thing. So creating some sanity from this confusion is what this goal is about and it can be done. Speaker 3: (54:11) Lisa, when you take your time to read things, intelligent meals, explain things. That's why we've got these epiphany moments that constantly, I like my consults with patients because I feed off of the energy. When a patient just, you see that epiphany admission and they light up and they go, Oh, that's why this hasn't been working with. That's why that was better for me. That's why I took methyl B12 because everyone's telling me methyl B12 is the best version. But every time I take methyl B is it just in my head. I get a headache every time I take micro B12 I get a, and then I go, no, actually I got one too. I can't take methyl before. That's an actual thing. I can't take methyl B12 because my methylation cascade is inconsistent with me taking methyl Beto when I take a dental Sobe 12. Oh, completely different. Speaker 2: (55:07) Wow. So this is getting really granular for each individual. And this is what makes me so excited. And, but before we go on, we have to go and cover off the hormone report. This is something that I and, and this is, you know, for me and any woman, but I wanted to focus a little bit more in on the woman. We've got very complicated hormones, households, but this was the cascade for men and women is very, very similar, isn't it? Yes Speaker 3: (55:33) It is. It's just remarkably, this is what we taught at the cost on the weekend after introducing genomics, it was the first open to eyes that the cascade, the circadian rhythm with which the human body converts progesterones into androgens, androgens to estrogens, men, we do not have a monopoly over androgens. Women, you do not have a monopoly over estrogens. In fact, your estrogens come from androgens. Men, we have estrogens. It's just a matter of the circadian rhythm. When is it happening? How quickly is it happening? And of course, ultimately how much of any of these hormones are produced. And then the final component is how responsive are you, the the woman's body, all things equal. She's designed with the estrogen receptors to be more responsive to estrogen. She responds to androgens as well. Conversely, for men. Now keep in mind something as simple as, I can't believe how many clinicians do not realize how an androgen or estrogen receptors. Speaker 3: (56:32) Now let's stop there for this cascade. We can talk about all of the things about how hormones are produced and how they're metabolized and so on and so forth. But ultimately, how is estrogen affecting your body? Lisa, you're a young woman. You're making estrogen as if you're menstruating or if you want hormone replacement, there's likely some estrogens in your body, one way or the other when estrogen binds to your estrogen receptor. And to the degree that that can happen, mind you, because there are variations to that fidelity, this complex estrogen. So the estrogen receptor androgen to Stastrom, DHT to the androgen receptor. These complexes are some of the most potent DNA transcribing complex. They go into the nucleus and the churn on genes. This is how estrogen and testosterone impacts the human body. They live. They're not just, I don't know, causing breast development or, or, or, or Andrew demise in the book. Speaker 3: (57:39) They do that by churning on the genes that cause the cells to behave in a more underutilized manner or more estrogen. So the first thing I want, our audience needs, our clinicians, we need to re re climatize reacquaint ourselves with that. These hormones potently DNA transcribing, they go into the nucleus and they turn on and off genes. That is why they are not to be dealt with trivially. Number one. Number two, in a menstruating woman. Now I just told you when estrogen enters a cell, I did binds its receptor. It's not just staying in the, in the Maloo of the South, it's going in to the volts, the nuclear volts and churning on and turning off genes. Wow. When you look at the ministerial cycle of, of a, of a relatively normal, repeatable menstrual cycle, you will notice something radically important over the course of 28 days. Speaker 3: (58:43) The human female body isn't exposed to estrogen at the same amount every day, not at all. The human female body in 20 days only has about a six day or so window in which your estrogens that are really elevated and then it comes down. In other words, what is this telling us from a human biology perspective? It's saying that the type of gene expression changes the epigenetic phenomena that estrogens cause on your operating manual. You don't want that to be consistent and constant across the month, and this is very frightening when you look at contraceptive pill or hormone replacement therapy. So it's most certainly very frightening. That is not, let me be clear. That is not to say that there isn't a place or a time for these things. You know they are absolutely a young woman has to have the right to how she treats her body and what she does. Speaker 3: (59:47) But there is a place in time you at least be equipped, at least be empowered before you make this decision as to a knowing what it's doing for you. Say, okay, look for these few months of my life, for these couple of years of my life, this is going to be a bit more important that I take these precautions, for example, but you should know that to do so indefinitely, month after month, year after year. Now they've got clinicians encouraging young woman not to even have a bleed through. There's no point for even the bleed. So just stay on the, you know, constant level, 24 seven three 65 15 years. How is this compatible with normal human physiology? When you understood what I just said? Yep. Now let's go a step further than that. You see estrogens do what we just said. They bind their receptors, they go into the cell so they go into the nucleus. Speaker 3: (01:00:47) They change gene expression as they're meant to for brief periods during the month. Fair enough. Now, once those estrogens have done what they've done for those days, then the point of it is there's a circadian rhythm. The body breaks down those estrogens metabolizes them by a transforms them so that they're no longer active. They've been neutralized, and then we hit repeat, rinse and repeat, and we start a new cycle. But here's the point. Every a woman, Lisa, every a woman, a man for that matter, but let's focus on the ladies when she made her estrogens or she took her estrogens, because even whether you take it or whether you make it innately or you take it, it doesn't matter. You've got to metabolize the estrogen. Now, every young woman can metabolize estrogens into three byproducts. I estrogen 400 Z estrogen, 16 hours for hydroxy estrogen. Every human being does this, and this is a crucial point. Speaker 3: (01:01:49) Absolutely. But these three metabolites do not impact yourselves in the same way you say. If you thought of it, you've made the estrogen small window. Now you want to neutralize it so that the body isn't under its constant influence. So you want this metabolite, this estrogen, this hub light to have lost bind to the receptor. You want it to last. It's estrogen Ising properties. Lo and behold, four estrogen, one of those three metabolites retains the ability to bind the estrogen receptor. In fact, some studies show it might be an even more potent comm when it, when it binds and it creates this, this common, a tutorial, Leiden and receptor, it's DNA. Transcribing effects are even more potent, much like the analogy between DHT and the androgen receptor versus testosterone. DHT dihydrotestosterone, which is a metabolite of testosterone, has a higher potency binding affinity to the androgen receptor. Speaker 3: (01:03:00) Four hydroxy estrogen is to the estrogen receptor as DHT is to the androgen receptor. Wow. The ability innate tendency of a young woman when she's faced with estrogens to make either the two hydroxy which is considered protective because has lost or the four hydroxy that inmate differentiation is radically genetically determinable. Now, if something as simple as that, Lisa, when you stitch these things together, when you understand, look, estrogen should be my body needs security and rhythm. I do not want estrogen is constant. When I break down those estrogens, I want my body to have had a break from them. And you did not know whether you were four hydroxy dominant or not. If you had a tendency to make more of the four hydroxy than the two and why is four hydroxy so naughty? Three reasons. A, it binds the estrogen receptor, not giving your body a break from the estrogen ization one to four hydroxy estrogen if you are not flushing it out of the body and how do you flush out for drugs, the estrogen through methylation, the comp gene, which is catechal methyl transfers an oops. Speaker 3: (01:04:29) Can you imagine if you were innately genetic info, hydroxy dominant and have the slow comps because now you're making too much four hydroxyestrone you have a tendency to do so. You do not have the enzymatic ability to get rid of it. Now you buy your stagnate, your four hydroxy Astrid. Do you know what full hydroxy estrogen does other than binding the estrogen receptor and Quinones? Quinones? Listen, my God, you're speaking more than some of the best medical biologists that I've spoken to. So the, the decompose into Quinones and do you know what Quinones do? They get into your DNA. They stick to, they are mutagens. They stick to your DNA, causing the DNA to not be able to unravel and repair itself and by the Quinones then cause accidents. So here's what you don't want to be. You don't want to be the young woman who is genetically predisposed to overly produce four hydroxy estrogen simultaneously, have a poor comp, simultaneously, have a low GSTT one GSTP one, which was the thing, Quinones, and then have a poor mitochondrial superoxide dismutase or antioxidation to get rid of the oxidants Speaker 2: (01:05:52) And add to that. You're in your forties or your 50s and you're making more EstroZen, Speaker 3: (01:05:57) Which is a breast tissue because it's not in the liver anymore. The liver organ, at least it was designed for that type of metabolism. You're doing this in the breasts, you know, God forbid. Okay, Speaker 2: (01:06:10) This is where the cancers can come in Speaker 3: (01:06:13) This is weird and just why we have the the epidemiologic rise during that shift where the woman's body shifts from doing that grunt work in her liver, which was designed for it to doing that grunt work in such as breast tissue, cervical tissue, an ovarian tissue and so on and so forth. Which of course the human body, the female body does not express estrogen receptors, the same level for every cell type. You know, when you were, we lobby at nine years old and you could have gone outside, you know, flat chested like any other boy and you know, and then when, when men awe kits and the body changed your elbows and forms didn't change, it was suitable zone. Those are the zones that have more estrogen receptors. Speaker 2: (01:07:03) And this is so this is how we can see like when you're looking at the phenotype, if we can go look like the the the hormone cascade just for people that are listening, it's going from producer owns and pregnenolone's into testosterone's which can sometimes go into DHT and which then go into the estrogen. Is thrown in your estradiol if you're pregnant when you're older you have more strokes coming in which are, that's coming from the the other top of testosterone isn't it? One on one and then it's means a lighter than these three path rates into the two hydroxy four h

Eden Snower talks about IGGS, New Trier Dance Team, her tattoo, and herpes infected monkeys.

Chris Duncan passed away over the weekend. The Cat and Doug have nothing but good things to say about Chris. Plowhawk is having some board issues. Weekend people leave the studio in disarray. Biff calls in from Hannibal. Pizza Hut and Hedo. Biff will wing man Iggs in Jamaica. Biff gets loaded outside the gates of Kirkwood football games. EMOTD.

Chris Duncan passed away over the weekend. The Cat and Doug have nothing but good things to say about Chris. Plowhawk is having some board issues. Weekend people leave the studio in disarray. Biff calls in from Hannibal. Pizza Hut and Hedo. Biff will wing man Iggs in Jamaica. Biff gets loaded outside the gates of Kirkwood football games. EMOTD.

[intro music]   Host – Dan Keller Hello, and welcome to Episode Thirty-Nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features the second part of our interview with Joseph Berger of the University of Pennsylvania. But to begin, a couple of updates.   Last week we told you about our Drug-Development Pipeline, which includes continually updated information on 44 investigational agents for MS. Since last week’s podcast we added two new trials, we updated information on 10 other trials, and we added 10 other pieces of information. The drugs with important additions and changes are dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, and phenytoin. To find information on all 44 compounds, visit msdicovery.org and click first on Research Resources and then on Drug-Development Pipeline   Two weeks ago we described how we curate a weekly list of all newly published scientific papers on MS and related disorders. Last Friday’s list included 53 papers. We selected two of them as Editor’s Picks: One is a Cochrane meta-analysis of dimethyl fumarate – trade name Tecfidera – for treating MS. The other is a study from Paul Tesar’s group at Case Western Reserve University. That study, which appeared in Nature, is entitled “Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo.” To find the full weekly list and the Editor’s Picks, click on the Papers tab at msdiscovery.org.   [transition music]   Now to the interview. Dr. Joseph Berger is a professor of neurology at the Hospital of the University of Pennsylvania. In part one of his interview we talked about risk of progressive multifocal leukoencephalopathy. This week, Dr. Berger discusses diagnostic dilemmas in MS.   Interviewer – Dan Keller Dr. Berger, how do these present, and what are some of them?   Interviewee – Joseph Berger They’re legion, actually. There are a lot of different diseases that can look very much like multiple sclerosis both in terms of the history and physical examination as well as in terms of the radiographic findings. And the question is, do you want to avoid treatment that is not very helpful and expensive? You know, once you’ve made a diagnosis of multiple sclerosis you tend to put the patient on a disease-modifying therapy that they would remain on for the rest of their lives. And there’s an expense and some risk depending on what you put them on, associated with that. Secondly, there are diseases that, if you miss the diagnosis, these are diseases that can be aggressive in and of their own right, and if you’ve misdiagnosed it there’s a concern that disease may go on and create its own problems for the patient. So there are a variety of reasons why you want to ensure that what you’re dealing with is truly MS and not one of the MS mimics.   Among the common MS mimics, one that we’ve had increasing experience with in the recent past, is neuromyelitis optica. So, neuromyelitis optica was a disease that we lumped together with multiple sclerosis, but we’ve realized recently that not only is the pathogenesis different than multiple sclerosis, it being a humoral immune disorder, but that the therapies that we employ for multiple sclerosis may actually aggravate neuromyelitis optica. So that’s a common concern and one of the reasons why we frequently obtain neuromyelitis optica antibodies in patients, particularly when they present with optic neuritis or transverse myelitis, and certainly when they present with both of them.   MSDF That would be aquaporin-4 antibodies?   Dr. Berger That’s correct. It’s an aquaporin-4 antibody, but not everybody with neuromyelitis optica has the aquaporin-4 antibody that’s demonstrable. A certain percentage of them have what appears to be an anti-MAG antibody, and others we simply don’t know what the antigen is. And that’s being worked out. So there’s this whole spectrum of neuromyelitis optica that you certainly want to sort out from multiple sclerosis. But there are also a wide variety of other illnesses that can look like multiple sclerosis. In fact, if you take any broad classification of diseases – infection, vascular, neoplastic, toxic, metabolic, genetic, etc. – if you do that and say, are there diseases in these categories that can appear like multiple sclerosis and be mistaken for multiple sclerosis, there are. So every single one of these broad categories can have within it a disease that can be mistaken for multiple sclerosis.   MSDF Would they be mistaken for multiple sclerosis on many measures or mainly signs and symptoms or is it radiologic on imaging? How do you sort out this kind of gamish of different diseases and how they present, and really nailing down an MS diagnosis, not even considering a diagnosis of what else it could be?   Dr. Berger So it can be enormously difficult to do so. And I’ll give you some examples from my own practice. I have, for instance, seen individuals with a disorder called hereditary spastic paraparesis where you were unaware of their hereditary nature of their disease. And the patient has come in with a progressive myelopathy. And you say, well, could this be primary progressive multiple sclerosis? And could be extraordinarily difficult to sort out, particularly if they don’t have common mutations, and they don’t have a family history. And you say, well, which is it? The spinal fluid can be very helpful in that regard.   The MRIs can be very helpful in that regard, but not always. I’ve seen individuals who’ve had vascular disease where the MRI abnormalities have looked very much like multiple sclerosis. They’ve had recurrent episodes of neurologic symptoms be it numbness or weakness or visual problems, and it be mistake for MS. I’ve seen individuals with intravascular lymphoma, a rare disease, but one where they’ve presented with both clinical picture and MRI that looks very much like multiple sclerosis.   Although we have good diagnostic criteria, there is no single test that tells you that this is MS. But there are times when all of us, even the very best clinicians, scratch our heads when a patient’s reappeared in the office; nothing new has happened to him. Ten years have elapsed, and you say to yourself, did they really have multiple sclerosis? So, again, it’s a matter of comprehensive history and physical; the appropriate radiographic studies; looking at the spinal fluid when that’s indicated; and doing the appropriate laboratory studies to rule out things that may mimic multiple sclerosis.   MSDF Is that why there is a diagnosis of CIS? If it never returns, then it was CIS?   Dr. Berger I guess one could say that, but I use the term CIS to mean the very first episode of multiple sclerosis. So when I label somebody with CIS, I already believe that they have multiple sclerosis. I think that if they have CIS in the absence of any radiographic findings, I’d be unlikely to label them CIS. CIS to me is in the continuum of MS, so you have CIS, relapsing/remitting multiple sclerosis, secondary progressive multiple sclerosis. So that’s how I use the term.   MSDF Can you definitely rule in or rule out multiple sclerosis?   Dr. Berger I think that there are probably rare instances where people fulfill all the criteria for multiple sclerosis. And at the time of autopsy you say, how about that? That wasn’t multiple sclerosis. There’s an old expression in medicine that you can never be a 100% certain. You can never have a 100% certainty. So I think that you do the best you can. And I think that probably the rate’s 99% or better, but in these people fulfilling the criteria that have been established. However, you can never be entirely certain.   And it is not that uncommon in my practice, and I’ve been practicing medicine nearly 40 years, where an individual has presented the office after a long hiatus. And the chart is unavailable to me, and they come in with a diagnosis of multiple sclerosis, and I say, who made the diagnosis of multiple sclerosis in you? And they go, you did, Dr. Berger. So I think go down to the cave where they keep the charts that are over seven years old only to find out that they had all the criteria for multiple sclerosis; that they had oligoclonal bands, and they had hyperintense signal abnormalities on their MRI, and they had relapsing symptoms, but, you know, over the course of the last 10 years they’ve had little. And you scratch your head and say, geeze I wonder if this is truly MS?   There are probably people who carry this diagnosis, and there’s literature on it, that carry it incorrectly.   MSDF Those criteria, even though it never turned out to be MS, satisfied a diagnosis of MS. When you see something like radiologically isolated syndrome, do you work it up for MS, or only once it presents later does it become MS?   Dr. Berger This is a very difficult question, and we see this with some regularity, that is, the individual that has hit his head in a car accident or developed a headache that somebody’s decided to do an MRI on. And they come in with an MRI that looks all the world like a patient with multiple sclerosis, yet they have no symptoms and no signs on physical examination that is suggestive of multiple sclerosis. And the question then becomes, what do you do with them?   There’s currently a study in which that question is being addressed. However, I will tell you what I do, currently. I do look for multiple sclerosis. I look for lesions in their spinal cords because I think that if they have that, the prognosis can’t be good, and I would likely start somebody with lesions in their spinal cord, who I’m convinced has MS, on a disease-modifying drug.   I look their spinal fluid. And I look at their spinal fluid for oligoclonal bands, and, if I see that, I’m increasingly convinced that that’s what we’re dealing with. And I would be inclined to treat those people as well. Now whether I’m doing the right thing or not, I don’t know, but for others in whom there are no spinal cord lesions, there are no signs or symptoms, and the spinal fluid is pristine, I’ve elected to wait. That is not necessarily the consensus among the MS community. That’s simply how I practice, currently.   MSDF People don’t need oligoclonal bands to have MS, though, do they?   Dr. Berger No, not at all. So, we certainly see a fair number of people – and it depends on the study – who have pristine spinal fluids. That means no oligoclonal bands, no cells, no increased protein, no elevated myelin basic protein or IgGs who still have multiple sclerosis.   MSDF What about fatigue as an initial symptom of multiple sclerosis? A lot of people have fatigue – tiredness. Is there a way to differentiate the fatigue of multiple sclerosis from just being tired or a sleep apnea or an insomnia or they just don’t feel good?   Dr. Berger Well, I think your history is very helpful because the sleep deprivation and excessive daytime sleepiness is not the same as the fatigue that people with MS report. The fatigue that people with MS report is akin to the fatigue that one experiences when they have a viral illness. So when you have the flu you go, oh man, I just can’t get out of bed. I feel terrible. And that’s precisely what the people with multiple sclerosis have. And what’s so interesting is how common it is. So it’s been said to be the greatest cause of disability in the MS population. It’s an acceptable cause of disability; not blindness, not incoordination, not weakness, but fatigue.   And it’s curious, when I practiced in Kentucky, I had a number of patients who were wheelchair-bound, had very poor vision or had double vision because of paralysis ocular palsies, who went to work every single day. And then I had patients that looked as healthy as you and I, and they were on disability. And I said, well, why is it that you can’t work? They said, I’m just too fatigued. I can’t do anything. It’s affected everything.   So the fatigue is different, and getting back to the frequency of it, so in individuals who have been diagnosed with multiple sclerosis, and I was part of this study, if you look at large numbers of individuals diagnosed with MS or who are on disease-modifying drugs for MS and go back and look at their medical records prior to the time of the diagnosis, you will see that about a third of them had been labeled by their family physician or their internist as having one of two diagnoses: chronic fatigue syndrome or fatigue and malaise. They’re the only two diagnoses with fatigue in them that you could put into the ICD-9 classification.   So, this is striking that so many individuals have fatigue recognized, yet it’s an advance of their having any neurologic symptoms that were believed to be the consequence of multiple sclerosis. It’s not to say that they didn’t have them. You know, it might have been some transient numbness or transient tingling or slight weakness that went away that nobody ever thought was due to multiple sclerosis. So that we don’t know about. But what I can tell you is that prior to an established diagnosis of multiple sclerosis, roughly a third of individuals have been labeled by their family physicians with fatigue.   MSDF It’s interesting that you make the analogy between this sort of fatigue and that with a viral illness like the flu. Could this be a prodrome telling there’s an inflammatory process going on? I mean, is there interferon release or are there other mediators that seem to be unique to this kind of fatigue?   Dr. Berger I would like to think that that’s the case. I would like to think that this is due to the very same cytokines that cause the fatigue that’s associated with viral illness. That’s not been convincingly demonstrated, although it’s been proposed. I think it makes a lot of sense. Coming full circle, eventually, although most of my colleagues classify multiple sclerosis as an autoimmune disease, there must be a trigger for the autoimmune disease. And my own belief, coming to this from virological angles as opposed to coming at it from an immune angle, is that there’s probably some infectious origin.   One of the things that’s so striking is the association between Epstein-Barr virus and multiple sclerosis where virtually every adult patient with multiple sclerosis has evidence serologically of having been exposed to Epstein-Barr virus. Now I’m not saying that that’s necessarily the cause, but in some way it must contribute to the development of the disease perhaps in a way that low vitamin D levels contribute to the genesis of the disease.   MSDF Is there anything you’d like to add about diagnostic dilemmas or any kind of a mental framework for approaching this sort of thing, in nutshell?   Dr. Berger Yes. The one thing that I would say is never be too confident. Never be too confident. I found that my highest confidence levels were right before I took boards in neurology, which was a long time ago. And I thought I knew everything. And the more I practice neurology, the more humble I’ve become in terms of establishing diagnoses and selecting right therapies for patients. So I always have a healthy skepticism. I have a healthy skepticism of things that I feel certain about. And when patients represent to office I always question myself, particularly if there’s something that doesn’t fit with the diagnosis. And I think that that’s good advice to anybody practicing medicine.   MSDF Very good! Thank you.   Dr. Berger My pleasure.   [transition music]   Thank you for listening to Episode Thirty-Nine of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.   [outro music]

Cortisol is a stress hormone, which is produced under stressful conditions, one of them being heavy training. A CrossFit viewer asked how they could nutritionally support their hormones under heavy training loads. The first hormone that comes into mind is modulating the hormone Cortisol.   Cortisol is a stress hormone that is produced in the adrenal glands and is designed to be released in short bursts. Cortisol is an anti-inflammatory hormone and it also helps us mobilize energy. This is used in times of fight or flight when these short energy bursts are necessary to run or fight.   In modern times, we disrupt our Cortisol production by poor sleep, overworking, heavy training and poor nutrition. Cortisol production has been directly correlated with training load. It is important to pay attention to your body and note that if you are overstressing your body and producing large amounts of cortisol, your body will start to break down. It will break down your muscle because it is a catabolic hormone.   Your body makes cortisol preferentially over other hormones.  When there is a large amount of cortisol being made, you will see other hormones decline like testosterone and DHEA. These hormones are responsible for building your body up. This is why it is important to take a rest after heavy training.   Make sure you get 20-25 grams of protein within ten minutes after heavy training. This will blunt the rise in cortisol. Triton Nutrition makes Vital Vegan Protein and ProFit Whey and these can be used in combination with Vital Greens or Vital Reds. Please check out our site where delicious recipes are listed using these proteins.   Another great product is Triton Nutrition's Immuno Growth Factor with PRP, which is a pure, cold-pressed colostrum product made from grass-fed, organically grown cows. This cold-pressed technique maintains Immunoglobulins (IgGs) and proline-rich polypeptides (PRPs). PRPs help balance inflammation and IgGs are needed because the immune system can be weakened during heavy workouts. This is a very efficient form of protein and can be combined with the other powdered forms of protein.   There are two products by Triton Nutrition that also help with Cortisol regulation: Relora-plex and Adrenal Shield. Adrenal Shield contains extract from three herbs: Chordyceps sinensis, Ginseng root and Rhodiola rosea root, which helps balance the cortisol and the other hormones responsible for balancing energy, like DHEA. This will help with afternoon fatigue.   Relora-plex is a specific blend of herbs designed to reduce cortisol. Relora-plex is specifically helpful when someone would like to start on hormone replacement therapy but his or her cortisol is elevated. You don't want to start therapy before getting the elevated cortisol under control first because the other hormones supplied during therapy won't function properly. Relora-plex allows the person to feel less anxiety and more smooth energy throughout the day. At nighttime they fall asleep faster and they stay asleep. It is important to sleep well because that is when 80% of growth hormone is produced.   by Robert Seik, PharmD

Präklinische Tests zur Beurteilung der Pharmakokinetik humanisierter therapeutischer Antikörper werden üblicherweise an Mäusen durchgeführt. Konventionelle Nagetiermodelle spiegeln aber nicht die Pharmakokinetik im Menschen wider, da der neonatale Fc-Rezeptor (FcRn), der eine wichtige Rolle bei der Regulation der Homöostase von Immunglobulin Gamma (IgG) spielt, speziesspezifische Unterschiede in der IgG-Bindung zeigt. Aus diesem Grund stellen Mäuse mit modifiziertem FcRn ein wichtiges pharmakologisches Modell bei der Erforschung therapeutischer Antikörper dar. Es wird propagiert, dass Mäuse, denen murines FcRn fehlt und die transgenes humanes FcRn exprimieren, ein vielversprechendes murines Modell sind, um Pharmakokinetiken von therapeutischen humanen IgGs in Primaten vorherzusagen. Um zu klären, ob human FcRn-transgene Mäuse ein geeignetes Nagetiermodell zur Beurteilung des pharmakokinetischen Verhaltens von therapeutischen IgGs darstellen, wurde das pharmakokinetische Verhalten von strukturell und funktionell sehr unterschiedlichen humanisierten Antikörpern in drei unterschiedlichen FcRn-modifizierten Mauslinien untersucht und verglichen. Zusätzlich sollten die Ergebnisse mit Daten von Primaten verglichen werden, um der Hypothese nachzugehen, dass human FcRn-transgene Mäuse geeignet sind, Pharmakokinetiken in Primaten vorherzusagen, und so der Einsatz von Primaten in der pharmazeutischen Forschung verringert werden kann. Antikörper, die in vitro eine erhöhte Affinität zu humanem FcRn besitzen, zeigen in human FcRn-transgenen Mäusen häufig ein verändertes pharmakokinetisches Verhalten. Die Oberflächenplasmonresonanzspektroskopie ist eine in vitro Methode, die eine Echtzeitmessung der Wechselwirkung eines gelösten Antikörpers mit immobilisiertem FcRn erlaubt. Deshalb wurde mit einer Korrelationsanalyse geprüft, ob ein statistischer Zusammenhang zwischen pharmakokinetischen Daten von Mäusen und Oberflächenplasmonresonanzspektroskopie-Messungen besteht. Trotz ihres häufigen Einsatzes in der medizinischen Forschung finden sich in der Literatur nur vereinzelt phänotypische Daten dieser FcRn-modifizierten Mäuse, die zudem aufgrund unterschiedlicher Messmethoden oft, nicht als Vergleichswerte herangezogen werden können. Um genetischbedingte Unterschiede der Mauslinien von versuchsbedingten unterscheiden zu können, wurden die Tiere hinsichtlich Hämatologie, klinischer Chemie und Körperwachstum phänotypisiert. Da die eingesetzten Mäuse optisch nicht zu unterscheiden sind, bedurfte es einer sicheren Methode, mit der es möglich ist, die Mauslinien zu differenzieren. Zu diesem Zwecke wurde eine Genotypisierung mittels PCR und anschließender Gelelektrophorese etabliert.