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Audio- Nutrition and Food Science: Episode II

July 12, 2019
  • 00:01You know podcast network.
  • 00:06Hello and Welcome to another episode of the Yale Journal of biology and medicine podcast? Why'd IBM is a pub. Med indexed quarterly Journal edited by Yale medical graduate and professional students and peer reviewed by experts in the fields of biology and Madison.
  • 00:22Each issue of the Journal is devoted to a focus topic and in this series. We took you through the past, present, and future of food and Nutritional Science in the previous episode and in this episode, which is the 2nd of two devoted to wijay. BMS June 2018 issue on nutrition and food scientists.
  • 00:40Will take, will interview a Yale faculty member you can find all our podcasts and the 20 June 2018 issue on YJ. BMS website or pub. Med I am near of Indra 1/4 year graduate student in the molecular biophysics and Biochemistry Department at Yale and the managing editor of YJBM and I'm your cohost, Amelia Hall worth first year graduate student in the microbiology program at Yale.
  • 01:07And with us today to talk about a really fascinating connection between many different fields, but of course related to food and diet is doctor. David Hafler Professor of at least neurology and biology, but but why don't we let you tell us who you are and what you do thank you. Thank you for having me so I kind of wonder sometimes what I am. But in essence a physician scientist and that is my career has been around trying to understand.
  • 01:40Human disease and the biology behind it, and the fundamental model that we used is to try to understand basic biology by using nature's experiments of human disease to provide insight into fundamental biologic processes in my carnal. I had spent 29 years in Boston to Harvard Medical School and was recruited here now 10 years ago to chair the Department of neurology, but being recruited. I pointed out to the Dean that though I am a clinical neurologist.
  • 02:14I'm really an immunologist and with a deep interest inflammation of the central nervous system and thus where's my clinical activities are in neurology particular and multiple sclerosis. My laboratory is very much a part of immunobiology here at Yale.
  • 02:33That's a really interesting way to describe yourself as a scientist in general, but I guess it's a people probably aren't too familiar with information in the brain and neuroimmunology specifically do you want to how would you describe that sure well traditionally noor immunology was the field of multiple sclerosis was very clear, though I began my interest in Ms as a freshman in college at Emory College back in 1970 and I.
  • 03:03New I was interested in Menology. In fact, my interest immunology. A goes back to childhood as fascinated by the blood and began to read textbooks about Hematology, but wasn't really the red cells that interest me. With the white blood cells. Think of it from the perspective of the 11 year old little PAC man running around eating up bacteria. I really found it interesting and in fact, just a little side was moving my mother about 3 weeks ago and I.
  • 03:35Was interested in doing photomicrography and actually set up a little toy microscope with a camera and I stuck myself with a pin and made a blood smear took a picture of it back in the elementary school and my mother found the picture and now habit of my blood that I took back then, so there's always a very strong interest in immunology. Then I became interested in neuroscience? How could you not be interested in the brain that how it works, so to put that together?
  • 04:05It became multiple sclerosis, so I spent my whole career attempting to understand how the adaptive immune system can lead to this disease that we see in clinic. The most common neurologic disease if young adults. A multiple sclerosis, so that is where much of newer Malji was 20 years ago, 10 years ago. The surprise of Nuro. Menology has been the involvement of the immune system another disease.
  • 04:35Process is in fact, in neuro development, beautiful work from colleague and Boston. Beth Stevens have shown that the innate immune system not adopted T cells, but microglia up a type of Maná. Sida macrophage that resident in the brain is devolved in synaptic pruning that is at the nervous system develops and as 1 gets signaled for which connection should stay and not stay. These my quickly are involved in actually pruning the.
  • 05:05Synapses so that you have the right connections. That was a big surprise another big surprise in the field of newer menology very broadly with the finding that schizophrenia may a strong genetic component. Many of the jeans relate to the immune system, including MHC and compliment and other work has shown that a lack of synaptic pruning by microglia in the complement system may lead to too many synapse associated with schizophrenia.
  • 05:37Then we have the field of Alzheimer's disease awards been now shown that the microglia are involved in removing the amyloid plaque and there are certain molecules involved in the monocyte function particular molecule study here by Jamie groups liner called trim two? Which of defective leads to a much worse form of Alzheimer's. So we know that the innate immune system plays a very central role in neuroinflammation, so this become a very important area investigation.
  • 06:07Path the obvious disease of multiple sclerosis before we go too much further would you mind giving like a quick description of? What multiple sclerosis? Is sure people like me? Who didn't know much about it, sure so we now know that that Ms is an autoimmune disease, So what do we know about the disease are a lab part of our lab in a larger consortium? Which I first developed up in Boston called the international Ms genetic consortium has identified the genic basis for the disease, we now have.
  • 06:40233 common variants 8 rare variants associated with risk of developing the disease. So no there's a strong autoimmune component. If you take those genetic variants and compare them to individuals with other autoimmune diseases. It turns out that Ms looks most like Crohn's disease and celiac disease get into our future topic of food and nutrition. So we know that MSN the jank variance involved predominantly mean system.
  • 07:11They don't appear to involve the nervous system and we now know that there are autoreactive. T cells in the blood? Which recognized mile in Witcher markedly increased in patients with Ms these mild reactive T cells are activated. They secrete inflammatory cytokines and we believe that is what drives a disease if we take a T cell from a patient with Ms take that T cell receptor put it into a mouth with the right so-called restricting element MHC.
  • 07:43The animal spontaneous develop inflammatory disease, which looks almost identical to Ms.
  • 07:51So we believe it's not immune disease initiated by autoreactive T cells. Then the question becomes what are the environmental factors which lead to the activation of those cells so we know the gene the Jake Basis of the disease. We know it's autoimmune. We know it, fits in that cluster of autoimmune diseases. We know there activate autoreactive T cells and most importantly, we know that if we turn off those activated T cells. Now, most probably by getting rid of B cells, which appeared to be the critical sells for turning on the T cells.
  • 08:24You can basically stop relapses so this major ban some disease. The paper was published by colleagues of mine large consortium, which we were not part up. But we now become very active in trying to understand why does B cell depletion work so well so we can basically shut down the disease by treating it early on with B cell depletion, which is really a major advance. So I'd summarize the diseases. It's not bad jeans, there good jeans that fight off infection bottle.
  • 08:55Cancer is not a bad environment, but the bad interaction between jeans and the environment again in the genetically susceptible host which leads to this autoimmune disease. I love you. I love your answer because it's so mechanistic and you talk your answer about Ms is the way you see it seems to be entirely molecular mechanisms, which is great, but what's it like for the patient.
  • 09:18Well, that's the other part which I also greatly enjoy when I started in the 1970s began my residency in 1978. We had really no treatments for the disease. So if you were diagnosed with Ms there is not much. We could do for you. In fact, for those of you interested in becoming interests, becoming physicians. The Fields Generala G has evolved tremendously from where I began in the 70s to where we are now going from a field with relatively few therapeutic options to a field that's
  • 09:51Very therapeutically driven and Ms being a prime example. But other diseases. Such a stroke and also there and in my Stena Gravis and other diseases. Parkinson's disease. We have amazing new therapies for the disease, so from the patient's perspective as I say to patients. My job is to make you have the happiest life. You can now, what we're doing. We put patients on these treatments very early on one of the major questions in the field of Ms for searches if you stop the disease early.
  • 10:23That is stop the exacerbate tions which convolve for example, numbness and tingling Los of vision. And I weakness of a limb difficult to a bladder function. These are common early symptoms. If we stop that do we stop the secondary ner gegend of portion of the disease and that to me is the major question, we can stop inflammation. We've gotten good at doing that.
  • 10:48But what we have not been good at doing is growing back brain. That's been damaged and we know that early on in Ms there can be damage to the nervous system.
  • 10:58So it's the matter of being a physician and caring for patients answering their questions and most importantly, getting them on treatment early. I should add a hold another branch of that's involving which is more than just Noor Immunology is the whole field of course have cancer biology.
  • 11:17The fact that there are cancers evolve and unlike in autoimmune disease will you have immune cells attacking self cancers have evolved to survive to obeid immune system and expresa decoy or molecules such as PD. One lie again and such which or CD155 diesel against which can turn off the being system. And when the big advances in the whole field of Medison have been the ability to turn off these.
  • 11:50Negative signals so called checkpoint inhibitors to allow the immune system to attack tumors that I mentioned that in the context of neurobiology because we're now doing clinical trials with these treating brain tumors trying to get the immune cells into the brain and to attack the tumors and we have not yet had success, but we have some ideas of which pathways we should be targeting so that's a whole. Notha area of Nuro Menology, which become really central.
  • 12:20Now that we figured out Ms.
  • 12:22So it seems that neurology and immunology and food science have all been studied is pretty separate fields for a long time and then recently. They've all kind of connected into like one big interdisciplinary area of study is there any particular reason for the timing of this has there been some kind of technical breakthrough that's allowed this interdisciplinary work to happen.
  • 12:42Of course some of it is the random walk, but I think most importantly is the microbiome and what. So, we've known for a long time that about 90% of the immune system is in the gut.
  • 12:56And we've known that we sort of made a pact with the devil to survive and that packed is we need relates to Enerji and taking starch and sugar and fats and processing it into Enerji. It's always a bad enerji and so the deal, we made us with bacteria that we have this canal, it go through US is tube, which starts in the mouth and becomes the esophagus stomach.
  • 13:28Intestines and such and it's really outside the body an through there. We are colonized with bacteria, which we count on to processing our food, then turning it into Enerji That's the pact. We made trouble is those bacteria if they escape. This tube, which may be inside of us, but it's really outside of us an if they escape. This tube and go into the body you will die of sepsis. He's a very toxic bacteria.
  • 13:58So there for a good part of the immune system majority of immune system is in the got to workout. This deal to keep the bacteria contained there within the gotten intestines to process food. If you get rid of them. Get rid of the lymphocytes. Neutrophils by giving high doses of chemotherapy. For example, you then began having leakage of bacteria. This is a well known phenomenon. Medison, where if the white count goes too low the bacteria will leak.
  • 14:29Right into the blood and you will die, so there's this constant equilibrium between the gut and the bacteria in terms of keeping them in check and we have another phenomenon known as oral tolerance something that we've studied extensively over the past 2030 years. So it turns out about 1% of the proteins had taken by mouth go in through this tube through the intestines into your bloodstream well.
  • 14:59Why don't you have the mean responses to those bacteria damn into those proteins in fact you do but rather than having a positive being response, you have tolerances called oral tolerance.
  • 15:10So if I were to feed either of you pick up protein of choice, you will develop tolerance to that. Protein then if I then inject the protein under your skin with a nagibin you will not respond to it because he been dollarize to that protein. We tried to take advantage of that to treat all immune disease by feeding Mylan proteins. It worked really well in animal models. The Phase 3. Clinical trial didn't work, but the concept is still an interesting one.
  • 15:40So you have this these bacteria in the gut need to be contained her proteins coming in which are altering which going into the system? Which you need to tall arise. You're mean response to and then you have again this factory a bacteria, which are making metabolites. These metabolise escape out of the intestines into your body and there's a whole literature developing an metabolomics.
  • 16:07Coming out of the bacteria that again in these factories and all the byproducts of these factors beat Eric Acid and others, which are involved in regulating the mean response.
  • 16:19Yeah, so, so oral tolerance than matters diet will influence your oral tolerance right and also kind of to what extent do you think that your diet will influence the microbiome I mean? Where is that especially with respect to my linen and other autoimmune diseases specifically in the brain well in terms of the microbiome. The question is what influences the microbiome. No part of it relates to how you're born vaginal or cesarion birth because going through the vaginal canal begins to succeed.
  • 16:52To seed the flora. It changes overtime. There's a great deal literature into their people know a lot more about this. I do, but there is a whole process of seeding. The floor in the gut, which is very well controlled and the question is what are environmental influences will certainly antibiotics change the floor about when you become an adult it begins to go back to where it was we recently number investigators and.
  • 17:24We have recently married Dayton humans that their number of food substances, which can alter the microbiome that for example, salt, which we can talk about the moment clearly has a major effect on the on the consistency of the bacteria in the gut and there also just the whole environmental environmental you that you grow up in very much dictates the microbiome and I think the related to autoimmune disease.
  • 17:54Probably the most eloquent paper on this was published last year and sell by Romney. Xaviar colleague who's at at the Broad Institute and ronic looked at populations in Finland. Estonia and Russia. An instance of type one diabetes use me also not immune disease.
  • 18:13And Iran, Nick found that well, we know that the diet that the hygiene for example, in Russia and the Stony is quite different from that in Finland and the microbiome is very different between the 2:00. The instance of type. One diabetes is about 10 times higher in Finland compared to for example, Russia and he map that to differences. The microbiome and 2 metabolites from the bacteria that were different which were influencing the immune system.
  • 18:45There's a very clear example of two populations of richly identical genetically which have very different environment in terms of clumsiness and hygiene with two very different conversations. The bacteria with different metabolites in a very different instance of autoimmune disease, so would you say that looking at the effect of diet on diseases that a field that's over studied or understudied or maybe that's just not a good question, we should be focusing on these bacteria more.
  • 19:15I don't really so.
  • 19:18You are what you eat I didn't make that up someone else, said that was hard to say what's over studied and understudied. We I think understanding the issue is?
  • 19:32So he did take a step back so figuring out the jeans that cause autoimmune disease is relatively easy to do.
  • 19:39It took many 10s of millions of dollars. It took us 18 years, but it was a very tractable problem. We looked at 48,000. Now 48,000 patients 50,000 control, so we could do that with great certainty environmental influences a much more difficult to study particularly studying human so think of the issue that are there so if we study micro if we studied the gut flora. We study stools? Well, that's the end product no pun intended but you really want to do is to study.
  • 20:14This tool in the ileum and huge enemas probably where you want to go. That's not easy to get access to in humans. You have new technology. Asked about technologies while the ability to sequence. The Microbiomes had a major impact in our understanding of what's there and particularly sequencing method. So I went to medical school in 1974. We knew there were E coli. That's about all we knew 'cause you can grow the E coli from the gut the few other things that.
  • 20:45Can get there when you was sick like salmonella and other such things well once we start sequencing? We realize that that was the tip of the iceberg that gave us a mean to me the big discovery in all of this is the ability to sequence bacteria that were very difficult or impossible to grow to give us a true look at what's there an understanding at a deep level as to? What are the constituents the microbiome? How different environments influenced the microbiome?
  • 21:15And what metabolites are being made, and probably the metabolites that much more important than what's there.
  • 21:22Is just the tools just coming aligned to do that? So is understood overstudy lot of people studying microbiome now but we have a lot to answer and understanding it.
  • 21:37Yeah, so I'm actually just since we have you here. I'm kind of curious about. I mean immunology in general is such a an exciting field right now? I think and especially the young scientist. I kind of want to know I mean, is it is not over study, but is it too hot, to some extent and sort of sort of related sort of related to that is.
  • 21:59You know, I mean? What extent do you think that there is promising basic science research left in there because a lot of the approach you've described as taking the disease and then by understanding what's going on with the disease to understand? What's going on with the basic biology in the normal condition is that like a really promising approach or is there a really big gap in kind of understanding how the immune system works.
  • 22:24In the normal state not in right well, let's yeah, let's go to the normal state.
  • 22:30So questions get answered and what for those of you who are entering science would you get the big bucks for is picking the right areas study and so I train with Henry Konkle when I finished my residency and conchal back in the 60s was able to give an example is able to recognize the fact that if you take protein from a patient with a disease called multiple myeloma, you take the serum.
  • 23:01You can isolate monoclonal populations of antibodies was it cancer where the plasma cells were making tons of antibodies and by purifying them. His laboratory, Jerry L elements laboratory was able to lose state. The structure of amino globulin so in 1950s early 60s that was a big problem and then won the Nobel Prize for that work but problems gets out and the structure of amino globulin's would not be a great thing to study now it's been well resolved there.
  • 23:33Thousands of crystal structures of antibodies always questions to answer when I was a young storing my postdoc. The big question was a T cell. Receptor has that isa recognize. Antigen was there. One receptive frantic and one for MHC. We knew this MHC protein majors to compatibility complex is very important 1980.
  • 23:588182. You read the journals. One papers say one I mean, we just didn't know.
  • 24:04Crystal structure by the late Don Wiley of class one with peptide answered the question peptides in class 1T cell. Receptor was clone, so that's been answered. Those are really big fundamental questions and immunology. Eregli how the mean system is regulated. The record the regulatory T cells first discovered by Shimon Sakaguchi.
  • 24:28In the late 80s was critical for understanding the field. Our laboratory say, though, I'm very much an implied immunologist. Our laboratory took the fundamental work by saga. Gucci were able to identify these cells in humans and healthy. Humans had to show later on. They were dysfunctional autoimmune disease.
  • 24:48So it's an interesting question about where field is and what the important questions are maybe a bit biased. But I think they fielded immunology is moving more tored. The Clinical Spear. Now we're taking all these fundamental discoveries and applying them to understand human disease, so cancer me know biology a very, very big field now.
  • 25:11Again, synaptic pruning and how they made systems involved in in development of the nervous system of very, very big, big field so I think there are clearly areas of Immunobiology that related to other biologic processes are very important, and main discoveries yet to be made. But the fields different now than it was in the 80s when the major questions of how does a T cell recognize engine that's such a fundamental question?
  • 25:44An it's been answered so is it mean I guess if if you were to ask back in the 70s. I thought immunology was ready for much discovery. An I was able to ride that wave from my career if I were starting today. I probably would do neuroscience where the fundamental discoveries are yet to be made, but of course, a lot of that may involve them penology, yeah, let's let's go ahead and get get right into what kind of the reason why all of you.
  • 26:16Food eaters out there are listening to this particular podcast and why were talking to David Hafler kind of revolves around this really, really good really cool paper that your lab publish in 2013, where you specifically looked at high salt diet and it's kind of influence. However, that might be we can talk about that or we will talk about that on Ms Multiple Sclerosis sure well. The 1st question. How do we make that connection connection discovery? So we were actually doing a project Marcus Clown would felt really gets.
  • 26:50Credit as a postdoc my lab for the initial observation and we're asking How does the microbiome influenced immune system so we did a very we took a group of healthy subjects measure the frequency of inflammatory cells cells that creating an inflammatory sadakane, which we now know is certainly involved in the process of Ms called I'll 17 and were asking well? How does the microbiome?
  • 27:21Influence production of bile 17. We did a large cohort did sequencing of the microbiome looked at the frequency of aisle 17 positive cells in the blood and it is simple dietary history and what we found is if you ate at a fast food restaurant. More than twice a week. Add more inflammatory cells, we said. Ha ha.
  • 27:44What is under the Golden Arch is well it's basically fried fat and salt at the end of the day and now we have a very active program looking at different fatty acids what they do the mean system. I put that aside down that's another interesting topic, so we did a very simple experiment. In fact, some of the based on other work by NTC and others who are renal doctors and we're looking at the effect of salt and we added salt to the culture.
  • 28:15Now, as you all of you in cell biology know that when you do experiments in cell biology. The concentration of salt that you use the concentration of salt in the blood and seawater at 150 mil equivalence of salt?
  • 28:30And that makes sense well it turns out that the concentration of salt in tissue best studied and skin is higher. But 190 hundred 80. One 9200 mill equivalents assault. So it turns out that the concentration of salt in tissue where lymphocytes go when they leave the blood is significantly higher. So when you think about it. You don't want to have inflammation your blood called septic shock, so you want the condition the blood where the mean system doesn't get activated.
  • 29:02But does get activated when the leaves the blood and lymph node goes into that issue when you have infections or other or other such events.
  • 29:11And so when we added 20 mil equipments assault, increasing it to the concentration in tissue. That was remarkable changeable emphasize they went from being very question to noninflammatory becoming extremely inflammatory about a log increase.
  • 29:29Not only that we then fed animals a high salt diet? Which of course turns out to be the normal million diet and the animals with the experimental model of Ms went from a limb tail to a quadra paresis so their disease, which much worse. Now we knew that we were not changing the concentration of salt in the blood by feeding a high salt diet because you just pee out the salt, but it turns out that this salt was directly affecting the gut tissue in the surrounding lymphocytes infiltrating the gut.
  • 30:02An subsequent studies have been done in models of Crohn's disease. Another showing that high salt really exacerbates disease quite a bit now in parallel. Dear friend and colleague of mine for over 20 years. Professor VJ Chuchu at Harvard was studying what induces the TH 17 cells.
  • 30:25And he found a particular molecule called SDK 1 certain glucocorticoid. Kanes one which is central in the production of this inflammatory side of coin. BJ recognized the fact that this was assault, sensing kinase, well. We talked all the time we have 3 grants together and so we were pursuing high salt and what it did in the animal models and what it did human T cells and he had this observation about SGK one.
  • 30:57Well, we put it together and said Gee is SGK one really work and so he worked on it, and his own. I we worked on it, and we publish A2 papers back to back the brilliant observation is really the one made by Chuchu and the work. He did to identify SGK one, but the work could came together. He did mouth as he normally does. We do human which we normally do and we we knocked at SG K1 in the human cells, he lost the effect of high salt.
  • 31:24Through able to workout the mechanism and again more as I mentioned earlier. Recent data suggests that high salt also has an effect on the microbiome so there multiple effects.
  • 31:35So, in this paper that you published you had some really striking results, especially with the effective salt on Interleukin 17, which is a protein that this really associated with autoimmune disorders like Ms, but you are also really cautious not to conclude too much about the effects of this diet on humans since you were only looking at cells in mice do you know if there have been any clinical trials that have been started as a result of this paper? Yeah, there's a more recent paper published in nature by Marcus and his colleagues them back in Germany.
  • 32:06In humans showing the effect of high salt and we have some plumber data were just looking at last week in a cohort of healthy individuals fed a high salt diet and we see remarkable changes in the microbiome leading to a picture that looks like an Ms microbiome, so the question is jumping what do you say to patients?
  • 32:29What I say the patience is that we don't know if the hisel diet really affects Ms but we know high sold diet is bad for you in terms of hypertension in terms of other regional problems. So we suggest that you should be on the healthy diet avoid the Golden Arch is avoid high fats and high salt because we know both those conditions induce inflammation at the end of the day everyone and we were selected.
  • 33:00Out of Africa out of eastern Africa and Western Africa. That is on the very low salt diet. The average salt intake in Africa was about 200 milligrams a day. The average western diet is about 3 grams a day. This probably relates to the very high incidence of hypertension is hard to find people in the 60s or warrant on the mild anti hypertensive and this probably relates to diet and the imbalance of salt from what are genetic selection was to our environment?
  • 33:31If you think about building, moving out of Africa were able to do that in part by using salt to cure food and cure meats and Adam and save them. Over the winter that was a critical technologic discovery, which allowed us to leave the more temperate climates to move into the more frigid tundra of the N so high salt is very much integrated into our culture.
  • 33:59And our ability to subi game back to a point and made early is not bad diet is not a bad environment. Not bad jeans. But the interaction of the 2:00. I think it's very important to note that a high salt diet will probably only affect a subset of patients who have the genetic predisposition and again while the genetics have been relatively easy working through genetics interacting with the environment is a much more complex.
  • 34:29Puzzle and just specifically answering your question there was a study published about 3 years ago, based on the work that we're doing looking at patients with Ms Whore Hatkar Alley and what he showed that a high salt diet with associated with increased number of exacerbations.
  • 34:49In patients with Ms terms of MRI in clinical attacks. There are flaws in the paper and there hasn't yet been replicated. So I won't have to take the paper with a grain of salt, but I think one has to be careful in terms of interpretation, however, is not a radical thing to say to a patient you should be on watch your salt consumption. Easier said then done a living in western society. The other guy point out to the patient that where is decreasing salt in your diet?
  • 35:20May have a modest effect on disease, depending upon your genetics. We don't know what those jeans are at the end of the day. We had therapy that really work well and probably far outweigh any changes in diet.
  • 35:33Yeah, so I just think it's so interesting that if you have a high salt diet. If you eat a high salt diet that it pools in your tissues and then that trigger is sort of an autoimmune response. But I mean? How far thinking about the brain now specifically how far does that interaction go. I mean, if it effects your immune system so strongly could it affect things in the nervous system. A high salt diet. I mean, like pruning for example, like synaptic pruning and not just Ms no, I think it can to the extent that there's migration there's a.
  • 36:06Equilibrium of cells going from the gut throughout the body, including the brain. The high salt diet will not affect the brain per say because your kidney will excrete the high salt, but it will affect the cells that are in the got that will then migrate to the brain and may be involved in that context again. The hard to study the other interesting way of looking at this is work done again by Jen TC, who's at Vanderbilt, who is a worked on Salton is.
  • 36:37Nafr Ologist's work on the kidney and he says to me, you in Altus have it all wrong. You look at CD4 cells of cells involved in in autoimmunity and fighting off infection cancer. Yeah, maybe they do that. But I look at them as something that sense, is salt and they go round. The body doing equilibrating salt. I mean think of you have a cell not CDH little bit CD. 4 cells are very sensitive to salt and they go around equilibrating salt, sensing it, and having sodium pumps and adjusting salt, he goes I think that's the major role.
  • 37:10Of CD4 cells.
  • 37:12An interesting other perspective we each look under own lamppost, but he is very convincing data of the critical role of CD4 cells insult equilibrium throughout the body. I mean, they had licensed to go everywhere. And they can send things and bring the information back so another way of looking at the role of the immune system and and salt.
  • 37:33So do you think that the frequency of Ms would decrease in a population then if we got everybody to magically decrease their salt intake. I have no idea I mean, maybe?
  • 37:48But again very Einstein said ask the most important question and that is a very important question. But then ask the ask the question you can answer and the big question we're trying to answer now is why is it? Does B cell depletion work so well to induce the animal model of multiple sclerosis if you just take a mile in protein and inject it into the skin and foot Padova Mouse, nothing happens. Same thing by injecting the two of you. Nothing will happen in order to get in the mean response to have to have an Adjutant.
  • 38:21In a genetically predisposed host animal so my question is, are the B cells. The adjutant are the B cells infected with the virus may be simply a ZBB infection and they become turn on they become a nagibin. They present Mylan proteins again in the host that's acceptable. That's police disease. So the most important question. I want answer right now is what are those B cells doing in the disease and what salt doing to be so I can turn you that sold also turns on those B cells.
  • 38:54Yeah, so just before we may be switched to the fatty acids topic is there. There's really anything are there. Other explanations for why there's an increase and autoimmune diseases result? I mean other than high salt diets? Well, I don't think it's just remember the high salt diets been on going on for hundreds of years. It's not new if I had to make a bet. I'd bet on the microbiome's probably even more important than salt.
  • 39:24Or made this all has an influence on it. No one always wants to think one's own work is the most important thing but.
  • 39:31At the end of the day, I have to bit more in the microbiome enthalt.
  • 39:38OK, so are there? How about some other changes to the western diet in our risk of contracting an audio means is disorders, especially like fatty acids? How to fatty acids affect well. That's the whole field of metabolic control of the immune System Z come front and center is a very important area. We know that inflammatory T cells use glycolysis, whereas a regulatory T cells use oxidative phosphorylation.
  • 40:08I have the main metabolic pathway have a graduate in my lab looking at different metabolomics in terms of T cell function? How long chain fatty acids affect T cell function and T Reg function. Some very dramatic results, which probably relate to the metabolic control of those cell types, so clearly. In an isolated setting in vitro long chain short team fatty acids have major effects on the immune cell function.
  • 40:39Are they affecting the patient in terms of diet? Almost certainly but we haven't gotten that far yet again much more difficult to study but we also know for example, we did it work did some work with my colleagues again at the Broad Institute looking at high fat diet in my San probiotics and it was really kind of neat, we found that if you feed the Swiss mice a high fat diet.
  • 41:10They became obese.
  • 41:13Well described if you look in their fat that fat is full of inflammatory T 817 cells and Lawson. They lose regulatory T cells.
  • 41:24That was interesting you put him on the high pro biotic diet it reverses.
  • 41:31So they get less fat or do they just lose that inflammatory they lose the weight?
  • 41:37And they become less inflammatory so that's of interest. Another experiment that we're just writing up now as we said well let's look at fat in Ms patients.
  • 41:50So we set up a program with a plastic surgeon where we took a group of patients with Ms than the series of healthy age match controls and we did liposuction basically we put a syringe in and we sucked out some fat tissue here in the abdomen, subcutaneous fat and we did single cell RNA sequencing of the T cells. The regulatory T cells in Ms patient versus controls but one thing we know is that when cells go into a tissue there begin to.
  • 42:24Acquire the characteristics of the tissue that there in so these T regs hide numbers of of lipid receptors compared to those in the purple Bud. That was interesting but I also found that the regulatory T cells in the fat of Ms patients made more inflammatory cytokines compared to the age matched control.
  • 42:46That's really crazy, you've kind of neat, you know, enrolling patients for couldn't controls for clinical trials, usually isn't that easy. I don't understand when we offered free liposuction. We had absolute no problem. Rolling anyone and I was the first to volunteer are there any positive aspects to the western diet like there any changes that might protect us from autoimmunity?
  • 43:11Well let let's let's flip it that may be more inflammations could fighting off cancer.
  • 43:17So one of the reasons are very careful not to say to tell people what to eat is that there are times you boosting the immune system may be good for you and in fact, in some work done by a number of different laboratories. In another animal model of automated the NOD non obese diabetes model, the diabetes. He's been a high salt diet is protective so I think we have to be cautious about this is good for you. That's bad for you, I mean, the whole problem with that field.
  • 43:50Is that go from ideas to clinical predictions and this is a problem with the field of Medison in general?
  • 44:00Don't get me wrong, I think physicians define spunk as friends of physicians. But physicians often a take extrapolate from very pure in vitro experiments and use it to make pronouncements that what the clinical effects will be and the the whole field of dietary science and its effect on human disease suffers from that type of conclusion where people get out and say, Well, Gee. I did this and this model look? What happens therefore make broad pronouncements and this is a very.
  • 44:33This is society and how we do things so, so you say you won't give a secure all healthy diet prescription. It depends upon your genetic so I look at Eskimos, who take Eskimos and who grew up, who were selected environment where they get a polar bear every X amount of time in the winter and they had to hold on to every single fat molecule or they could hold onto in order to survive that's their genetics.
  • 45:04Well, that's fine for living in that environment you take that same Eskimo move them to South Florida under the Golden arches again, where this plentiful fat and salt and the instance of diabetes. Type 2 diabetes is astronomical So what makes it really interesting is the we have to look at environmental conditions in relationship to the genetics and because the 2:00 highly integrated so in terms of finding the right cure all diet.
  • 45:36You start with what is the genetics of that individual we selected if you're in western Africa selective low salt there, but maybe you would others were selected for migration out of the bottle neck out of Africa and selected to survive better with high salt because of curing food and they didn't have extreme hypertension with selected for that. So it's the future of Medison is the integration of the environment with the underlying genetics.
  • 46:07So what would you say moving into talking about changing people's diets? What would you say are some of the largest problems that might prevent some of these patients from changing their diets and how do you approach this when you're talking to them as a doctor?
  • 46:20Well people like salt and fat and sugar, it tastes good and and you might not know their their genetics right and he's only I mean, part of it's a whole food industry and the whole issue of fast food so I mean, I think one of the fundamental issues is that fast food is cheap food. It's a cheap way of getting calories.
  • 46:46And it's not terribly nutritious if you look on the side of a cereal box and in terms amount of sugar and and fat and salt is it's very, very high and so I think educating consumers about processed food. I think it's really process for them or anything else and it's moving back to a diet, which is more what we were selected on so.
  • 47:17No, it's everything you heard growing up fresh vegetables. Getting protein with non getting right sources of that. But then the epidemiological studies of always been often difficult to replicate and I think we confuse the population or one year, we say this is good for you and then there's another epidemiological study. We said this is good for you and I don't think it's really clear to to the.
  • 47:48Public about what really is a good diet. We kind of want a bad diet is. I think it relates to common sense. I eating at home fresh vegetables, not getting a lot of eating fish, not getting a lot of calories from saturated fatty acid is probably a good idea.
  • 48:11But you know, I am not a dietitian so.
  • 48:17And yeah, so, so thank you so much for your time and we wanted to ask just one more question, which which I always really like because your physician you're a scientist you interact with so many trainees and and patients so do you have any practical advice for our listeners, especially maybe for young and aspiring researchers?
  • 48:37It's a tough one sorry no it's A wonderful question.
  • 48:44Find out what you're passionate about but also what you're good at doing so in if it. Yeah, it's so that's .1 if you got bitten by the bug of research done to it, you have to be just excited about discovery.
  • 49:07To have to be good at it, you may or may not be good at it, you have to find that if you're good at it and it often. It's the idea of jumping ideas about pudding different ideas than putting salt and T cells together with kind of a crazy idea. But it's a leaping of different ideas and being creative thinking not being constrained so that's very important, and the other point, which may not that so obvious. You've heard that let me say something it's not obvious about being a scientist.
  • 49:38It's a lot of relates to management, and what makes you good as a graduate student may not make it good as a lab chief.
  • 49:47So understand the fact that learning how to I mean to me the great irony is that we generally say 2 individuals to be a physician have to be good working with people and people. That sort of thing and scientists. The idea of someone who's isolated working on the by themselves and maybe for mathematician or type. Maybe that's true but my observation is well. I walk in to see a patient. I'm wearing a white coat. I'm the doctor there, the patient.
  • 50:18If you just care a bit and really care a bit about the patient that's all that's really important, and the skill set required may not be all that Great 'cause. There's a very well defined role against the common wisdom running a laboratory. My first mentor. Dale McFarland had a copy of the psychiatric manual D. CM3 sitting on this desk and someone to come in and complain about behavior. He flip open. The book and so let me show you this behavior over here, so the skill sets imagine people.
  • 50:49Are in fact really quite complex so much they need to imagine degree? But if you're going to work in isolation, fine, but most biologists no longer work in isolation and when you start up a laboratory. There's a real skill set with it. And remember, the fact that the the graduate students and postdocs that come with work with you and you look at this when you find mentors that your job is to help their career that you work for them, they don't work for you.
  • 51:19Understanding the fact that their success is your success an caring for the people around you at every stage. Akarere is really critical 'cause. The people who just care about themselves and don't care about anyone else have to be a lot better.
  • 51:35Then the people who care because it's really important part of it. So it's not just being good at what you do in having the creative skillset. Obviously hard work. That's an integral part of anyone's success, but caring about the people around you at every stage of career ends up being very important 'cause. We want people to work with you quickly gets out if you're caring or not.
  • 52:02Thank you so much for that advice try to think something that is not the female, yeah, no. I appreciate that so with that. It's time to wrap up. Thank you for tuning into this episode of the Old Journal of biology and medicine podcast.
  • 52:17Join us next month for an X podcast series on medical technology and thank you to the Yale School of Medicine for being a home for YJBMN for the podcast. Thank you to the Yale Broadcast Center for help with recording editing and publishing our podcast. Thank you to the entire why JBM editorial board and for more information on why JBMNR podcast. Please visitmedison.yale.edu slash wide IBM and be sure to check out our Journal by searching Yale Journal of biology and medicine at pub.com.
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